Among the options presented, the only measure not included in the Surviving Sepsis Campaign guidelines on the management of sepsis and septic shock (like the patient we are dealing with) is the administration of IV dobutamine. The appropriate procedure would consist of fluid administration, blood culture extraction, serum lactate measurement and early administration of broad-spectrum antibiotic therapy directed to the suspected septic focus. If we do not obtain mean arterial pressure for adequate perfusion of the organs, we would initiate noradrenaline perfusion, as discussed in question 51.

Among the options presented, the only measure not included in the Surviving Sepsis Campaign guidelines on the management of sepsis and septic shock (like the patient we are dealing with) is [HIDDEN]. The appropriate procedure would consist of fluid administration, blood culture extraction, serum lactate measurement and early administration of broad-spectrum antibiotic therapy directed to the suspected septic focus. If we do not obtain mean arterial pressure for adequate perfusion of the organs, we would initiate noradrenaline perfusion, as discussed in question 51.

A 67-year-old woman with a history of dyslipidemia, who comes to the ED with dysuria and pollakiuria followed by fever, chills, and deterioration of general condition. On arrival she appears severe and is tachycardic, tachypneic, with blood pressure 60/40 mmHg and temperature of 39°C. Which of the following measures would NOT be included in the INITIAL management?

Sepsis, severe sepsis, and septic shock: current evidence for emergency department management.

In the middle of a busy shift, a patient arrives by ambulance from a local long-term care facility with a report of altered mental status. You enter the room to find a chronically ill-appearing 85-year-old man with fever, tachycardia, and hypotension, and it is instantly apparent that this patient is septic. What is not clear is what the source is, what modifications in treatment might be necessary based on preexisting microbial resistance, and which of the array of invasive resuscitation techniques are appropriate when meaningful recovery is questionable and efforts may not be desired by the patient and family. You order IV fluids and broad-spectrum antibiotics; send lab tests, including lactate and cultures of blood, urine, and sputum; and begin to review his extensive history to discuss goals of care with his family and primary doctor. While reviewing these issues, a 54-year-old woman with a history of asthma is brought straight back from triage with respiratory distress. You listen to her lungs, expecting wheezes, but hear decreased lung sounds at the right base, preserved air movement elsewhere, and her skin radiates heat. Now, on the monitor, she has a heart rate of 135 beats per minute, blood pressure of 90/60 mm Hg, O2 saturation of 86%, and a temperature of 39.4 degrees C (103 degrees F). You again identify sepsis and instruct your team that you will be using your department's severe sepsis protocol. Equipment for monitoring and procedures is assembled, your staff provides preprinted order and monitoring flow sheets, and the ICU is alerted. Within an hour, the patient is intubated, has a central line placed, and has received IV fluids, broad-spectrum antibiotics and norepinephrine, and you are pleased to see a MAP of 67 mm Hg, a lactate decreasing from an initial value of 7.0, CVP of 10, and ScvO2 of 78%.

InternalMed_Harrison

Bacteremia Presence of bacteria in blood, as evidenced by positive blood cultures Signs of possibly harmful systemic Two or more of the following condi response tions: (1) fever (oral temperature >38°C [>100.4°F]) or hypothermia (<36°C [<96.8°F]); (2) tachypnea (>24 breaths/min); (3) tachycardia (heart rate >90 beats/min); (4) leukocytosis (>12,000/μL), leukopenia (<4000/μL), or >10% bands Sepsis (or severe sepsis) The harmful host response to infection; systemic response to proven or suspected infection plus some degree of organ hypofunction, i.e.: 1. Cardiovascular: Arterial systolic blood pressure ≤90 mmHg or mean arterial pressure ≤70 mmHg that responds to administration of IV fluid 2. Renal: Urine output <0.5 mL/kg per hour for 1 h despite adequate fluid resuscitation 3. Respiratory: PaO2/FIO2 ≤250 or, if the lung is the only dysfunctional organ, ≤200 4.

Obstentrics_Williams

One scheme for management of acute pyelonephritis is shown in Table 53-2. Urine cultures are taken, but prospective trials show that blood cultures are of limited clinical utility (Gomi, 2015; Wing, 2000). We obtain blood cultures if the temperature is >39°C. Intravenous hydration to ensure adequate urinay ouput is the cornerstone of treatment. Antimicrobials are also begun promptly with the caveat that they may initially worsen endotoxemia from bacterial lysis. Surveillance for worsening sepsis syndrome includes serial monitoring of urinary output, blood pressure, pulse, temperature, and oxygen saturation. High fevers are lowered with a cooling blanket and acetaminophen. his is especially important in early pregnancy because of possible teratogenic efects from hyperthermia.

Surgery_Schwartz

tachycardic, but they do not exhibit a reduction in blood pressure until over 1500 mL of blood loss, or class III shock. Physical findings should be used as an aid in the evaluation of the patient’s response to treatment. The goal of fluid resuscitation is to re-establish tissue perfusion. Fluid resuscitation usually begins with isotonic crystalloid, typically Ringer’s lactate. However, for patients arriving in shock (persistent SBP <90 mmHg in an adult), instead of crystalloid the current practice is to activate a massive trans-fusion protocol (MTP) in which red blood cells (RBC) and fresh frozen plasma (FFP) are administered. The details of a MTP are discussed later. Patients who have a good response to Brunicardi_Ch07_p0183-p0250.indd 19110/12/18 6:17 PM 192BASIC CONSIDERATIONSPART Ifluid infusion (i.e., normalization of vital signs, clearing of the sensorium) and evidence of good peripheral perfusion (warm extremities with normal capillary refill) are presumed to have adequate

First_Aid_Step2

■Signs and symptoms are similar to those of cystitis but show evidence of upper urinary tract disease. ■ Symptoms include f ank pain, fever/chills, and nausea/vomiting. Dysuria, frequency, and urgency are also possible. ■UA and culture: Results are similar to those of cystitis, but with WBC casts. Send blood cultures to rule out urosepsis. Pyelonephritis is the most common serious medical complication of pregnancy. Twenty to thirty percent of patients with untreated bacteriuria will develop pyelonephritis. When in doubt, admit a patient with pyelonephritis and administer IV antibiotics. Urosepsis must be considered in any elderly patient with altered mental status. SIRS = two or more of the following: 1. Temperature: Either < 36°C or > 38°C (i.e., hypothermia or fever). 2. Tachypnea: > 20 breaths per minute or PaCO2 < 32 mmHg on ABG. 3. Tachycardia: HR > 90 bpm. 4. Leukocytosis/leukopenia: WBC < 4000 cells/mm3 or > 12,000 cells/mm3. CBC: Reveals leukocytosis.

Rapidly progressive fatal pneumococcal sepsis in adults: a report of two cases.

We report two cases of a rapidly progressive fatal overwhelming pneumococcal infection. Patient 1 was a 67-year-old man with a 24-h history of fever and malaise and was transferred to our department. He was severely ill, tachypneic, and felt a chill. A purpuric discoloration with ecchymosis of the skin was noted over the body. The chest X-ray findings demonstrated thickening of the bronchovascular bundle in the right lower lung field, which later revealed the presence of bronchopneumonia. Laboratory studies revealed the presence of metabolic acidosis and disseminated intravascular coagulation. After presentation, rapid deterioration occurred followed by cardiopulmonary arrest. Despite cardiopulmonary resuscitation, the patient died only 3 h after presentation. The isolates from the patient's blood revealed penicillin-susceptible Streptococcus pneumoniae, serotype 4. Patient 2 was a 30-year-old woman with a prior history of uneventful pregnancies was transferred to our department with a 2-day history of fever, nausea, headache, and malaise. Although she was in the 19th week of pregnancy at the time, she suffered a miscarriage just prior to admission. Upon presentation to our department, she demonstrated unstable vital signs, diminished consciousness, anuria, and icterus. Purpuric discoloration with ecchymosis of the skin was noted in over most of her body, including the distal extremities. The chest X-ray findings were close to normal. Initial laboratory studies revealed the presence of severe metabolic acidosis and disseminated intravascular coagulation with multiple organ failure. Despite aggressive cardiopulmonary support, normal neurological responses disappeared on the 2nd day following admission and the patient died on the 16th day after admission. The patient's isolates from blood and vaginal swabs both later revealed penicillin-susceptible Streptococcus pneumoniae, serotype 12F. The presentation of rapidly progressive septic shock should raise the treating physician's suspicion of overwhelming pneumococcal infection, which has limited management options.

Who needs a blood culture? A prospectively derived and validated prediction rule.

The study objective was to derive and validate a clinical decision rule for obtaining blood cultures in Emergency Department (ED) patients with suspected infection. This was a prospective, observational cohort study of consecutive adult ED patients with blood cultures obtained. The study ran from February 1, 2000 through February 1, 2001. Patients were randomly assigned to derivation (2/3) or validation (1/3) sets. The outcome was "true bacteremia." Features of the history, co-morbid illness, physical examination, and laboratory testing were used to create a clinical decision rule. Among 3901 patients, 3730 (96%) were enrolled with 305 (8.2%) episodes of true bacteremia. A decision rule was created with "major criteria" defined as: temperature > 39.5 degrees C (103.0 degrees F), indwelling vascular catheter, or clinical suspicion of endocarditis. "Minor criteria" were: temperature 38.3-39.4 degrees C (101-102.9 degrees F), age > 65 years, chills, vomiting, hypotension (systolic blood pressure < 90 mm Hg), neutrophil% > 80, white blood cell count > 18 k, bands > 5%, platelets < 150 k, and creatinine > 2.0. A blood culture is indicated by the rule if at least one major criterion or two minor criteria are present. Otherwise, patients are classified as "low risk" and cultures may be omitted. Only 4 (0.6%) low-risk patients in the derivation set and 3 (0.9%) low-risk patients in the validation set had positive cultures. The sensitivity was 98% (95% confidence interval [CI] 96-100%) (derivation) and 97% (95% CI 94-100%) (validation). We developed and validated a promising clinical decision rule for predicting bacteremia in patients with suspected infection.

Sepsis

Early recognition and focused management may improve the outcomes in sepsis. Current professional recommendations include a number of actions ("bundles") to be followed as soon as possible after diagnosis. Within the first three hours, someone with sepsis should have received antibiotics and, intravenous fluids if there is evidence of either low blood pressure or other evidence for inadequate blood supply to organs (as evidenced by a raised level of lactate); blood cultures also should be obtained within this time period. After six hours the blood pressure should be adequate, close monitoring of blood pressure and blood supply to organs should be in place, and the lactate should be measured again if initially it was raised. A related bundle, the "Sepsis Six", is in widespread use in the United Kingdom; this requires the administration of antibiotics within an hour of recognition, blood cultures, lactate, and hemoglobin determination, urine output monitoring, high-flow oxygen, and

InternalMed_Harrison

The disposition of younger, previously healthy heat-exhaustion patients who have no major laboratory abnormalities may include hospital observation and discharge after IV rehydration. Older patients with comorbidities (including cardiovascular disease) or predisposing factors often require inpatient fluid and electrolyte replacement, monitoring, and reassessment. The clinical manifestations of heatstroke reflect a total loss of thermo-regulatory function. Typical vital-sign abnormalities include tachypnea, various tachycardias, hypotension, and a widened pulse pressure. Although there is no single specific diagnostic test, the historical and physical triad of exposure to a heat stress, CNS dysfunction, and a core temperature >40.5°C helps establish the preliminary diagnosis.

Near-infrared Spectroscopy in Transport With a Patient in Multi-factorial Shock.

A 14-year-old male with a history of repaired truncus arteriosus presented to an outside hospital emergency room in respiratory distress. The triage report to the transport referral center included the following vital signs: temperature of 36.6°C, respiratory rate (RR) of 26 breaths/min, heart rate (HR) of 144 beats/min, and blood pressure (BP) of 113/52 mm Hg with peripheral capillary oxygen saturation (SpO<sub2</sub) of 95% on 4 L via an OxyMask (SouthMedic, Barrie, Ontario, Canada). Additional information indicated severe right ventricle to pulmonary artery conduit stenosis; anuria for 2 days; and cool, mottled extremities. The transport team was dispatched via helicopter. The vital signs upon arrival were as follows: temperature of 36.5°C, HR of 153 beats/min, RR of 48 breaths/min, BP of 81/52, mean arterial pressure of 62, and SpO<sub2</sub of 96% on 8 L via an OxyMask. Physical assessment revealed the patient was alert and oriented, tachypneic, tachycardic, and displaying poor perfusion. An epinephrine drip was initiated while the patient was being prepared for transport. Near-infrared spectroscopy (NIRS) was initiated with cerebral NIRS of 71% and renal NIRS of 39%. The epinephrine drip was escalated, and norepinephrine was initiated and titrated up for continued poor perfusion and low renal NIRS. Vitals at the transfer of care at the receiving facility were HR of 142 beats/min, BP of 91/51 mm Hg, RR of 56 breaths/min, SpO<sub2</sub of 99%, and cerebral NIRS of 75% and renal NIRS of 53%. The patient required mechanical circulatory support shortly after admission. NIRS monitoring was used to help measure perfusion and reassess interventions made during transport.

Risk factors for heat related death during the August 2003 heat wave in Paris, France, in patients evaluated at the emergency department of the Hôpital Européen Georges Pompidou.

This study sought to determine the risk factors for short term mortality in the victims of the heat wave of August 2003 in France from among patients evaluated in our emergency department (ED). It was hypothesised that age, temperature, and some long term therapies and pre-existing pathologies were factors associated with short term mortality. A retrospective analysis of a seven day period. Four experts decided blindly, in pairs, whether a patient had presented with a heat related problem. Inclusion criteria were: core temperature > or =38 degrees C and/or clinical signs of dehydration. Comparisons were made between the survivors and one month non-survivors for 57 different items. Short term mortality was defined as death in the ED or within the first month of the ED visit. Of 841 patients attending the ED in the study period, 165 were included in the study, of which most were elderly women. Thirty one (18.8%) died within one month. Factors associated with short term mortality were: a greater degree of dependent living; more severe clinical condition on admission (higher temperature and heart rate, lower blood pressure, hypoxia, and altered mental status); higher values of blood glucose, troponin, and white blood cell count; lower values of serum protein and prothrombin levels; pre-existing ischaemic cardiomyopathy; pneumonia as associated infection; and previous psychotropic treatment. The total number of survivors at one year was 91. Although this study is limited because of the small sample size, the results have helped determine factors useful for future identification of patients at greatest risk of death in order to implement a more efficient patient care protocol.

[Status epilepticus induced by prolonged immersion in hot herb bath: report of one case].

A 6-year-old girl with cerebral palsy developed conscious disturbance and generalized convulsion after one-hour hot herb drug bath. Physical examination on admission revealed rectal temperature 41 degrees C, hot skin, respiration 46/min, regular heart beat 98/min, BP 130/60 mmHg, Glascow coma scale 4 (E2M1V1), soft and flat abdomen, no hepatosplenomegaly, no skin rash, no focal neurological sign, increased generalized muscle ton. Laboratory data showed CBC: WBC 20400 cumm (Neutrophils 31%, Lymphocytes 69%), Hb 11.6gm%, ESR 11 mm/hr, arterial blood gas: PH 7.077, PO2 43mmHg, PCO2 57.1mmHg, HCO3- 16 mEq/L, BE-11.5mEq/L, serum sodium 143 mEq./L, potassium 5.2 mEq/L, chloride 101 mEq/L, free calcium ion 3.8mg%, GOT 63IU/L, GPT 263 IU/L, amylase 193 IU/L, alkaline phosphatase 388 IU/L, LDH 1245 IU/L, CPK 677 IU/L, total bilirubin 0.8 mg/dl, direct type 0.1 mg/dl, BUN 18 mg/dl, Glucose 35 mg/dl. Urinalysis revealed proteinuria( ) trace hematuria and pyuria, but no cast. Lumbar puncture is within normal limits. Bacteriology including blood and CSF are normal. Multiple organ failure was noted at that time. Intensive cooling methods were performed including central and peripheral cooling. We used luminal and valium to control the seizure. Condition didn't improve. Afterwards cardiopulmonary arrest developed. Patient expired 8 hours after admission despite of resuscitation. Heat stroke in infancy and childhood is different from that in adulthood. The predisposing factors are high ambient temperature, dehydration, very young baby, sweat gland dysfunction, or ectodermal dysplasia. Definition of heat stroke includes 1) rectal temperature above 41 degrees C, 2) behavioral change, 3) warm skin, wet or dry.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypotension

Volume resuscitation (usually with crystalloid or blood products) Blood pressure support with a vasopressor (all seem equivalent with respect to risk of death, with norepinephrine possibly better than dopamine). Trying to achieve a mean arterial pressure (MAP) of greater than 70 mmHg does not appear to result in better outcomes than trying to achieve a MAP of greater than 65 mm Hg in adults. Ensure adequate tissue perfusion (maintain SvO2 >70 with use of blood or dobutamine) Address the underlying problem (i.e., antibiotic for infection, stent or CABG (coronary artery bypass graft surgery) for infarction, steroids for adrenal insufficiency, etc...) The best way to determine if a person will benefit from fluids is by doing a passive leg raise followed by measuring the output from the heart.

[Electrocardiographic and hemodynamic changes during systemic hyperthermia (42 degrees C)].

During systemic hyperthermia (42 degrees C), depression of ST segments or T wave changes in the left precordial leads were noticed in 56% of patients, and 29% of cases showed right bundle branch block. Supraventricular tachycardia was found in 26% and temporary deviation of mean frontal vector to the left axis was observed in 15%. These changes disappeared following recovery to normal temperature. The ECG findings for any particular patient were similar even during a second period of hyperthermia. Pulse rate became elevated by 1.7 times, and cardiac output became up to 2.4 times higher at 42 degrees C.

A Middle-Aged Woman With Hematochezia, Hypotension, and Leg Cramps.

A 57-year-old woman with a history of mantle cell lymphoma presented to the ED with complaints of vomiting, bleeding per rectum, and leg cramps, that started 6 h prior to her arrival. She had received chemotherapy a week prior. Her leg cramps were not associated with pain or swelling of the legs; she also denied any trauma to the legs. She did complain of mild lower abdominal pain at presentation. Review of systems was negative for fever, chills, diarrhea, chest pain, and dizziness. She denied using alcohol or nonsteroidal anti-inflammatory drugs. The patient was tachycardic with a systolic BP (SBP) of 85 mm Hg and was administered 1-L normal saline, with improvement in her SBP to 90 mm Hg. The hematocrit level was 24%, the WBC count was 0.3 × 10<sup9</sup/L, and the platelet count was 6 × 10<sup9</sup/L in the ED. On arrival in the ICU, she was noted to have an SBP of 70 mm Hg. Resuscitation with IV fluids was initiated, followed by transfusion of packed RBCs and platelets, based on the blood counts. Despite aggressive fluid resuscitation and improvement in her hemoglobin, the patient remained persistently hypotensive. The diagnosis of underlying septic shock because of neutropenia was considered; the patient was started on vasopressors and empirical broad-spectrum antibiotics, with improvement in her BP. After this, the patient was sent to radiology for a CT scan of the abdomen and pelvis with contrast to evaluate for mesenteric infarction, enteric or colonic bleeding, and the need for arterial embolization.

Cases from the Osler Medical Service at Johns Hopkins University.

PRESENTING FEATURES: A 70-year-old African American man was admitted with a history of fever, chills, and malaise of several days' duration. His past medical history was notable for end-stage renal disease requiring hemodialysis, coronary artery disease, and aortic stenosis requiring a bioprosthetic aortic valve replacement. On the day of admission, the patient was noted to have a shaking chill while undergoing dialysis through his catheter and was admitted to the hospital. He complained of pain at the catheter insertion site, shortness of breath, and dyspnea on exertion, but denied chest pain. On physical examination, the patient had a temperature of 100.4 degrees F, with a heart rate of 64 beats per minute, blood pressure of 127/72 mm Hg, and an oxygen saturation of 97% on room air. He was a mildly obese man in no apparent distress. He had shotty cervical lymphadenopathy and a right subclavian dialysis catheter in place, with erythema and pus at the entry site. His jugular venous pressure was 10 cm H(2)O. Lung examination showed bibasilar rales. Heart sounds were normal, with no rub or gallop. He had a 2/6 systolic ejection murmur best heart at the left sternal border as well as a 3/6 holosystolic murmur at the apex that radiated to his left axilla. Examination of the abdomen and extremities was unremarkable. The patient's neurological examination was unremarkable, and he was alert and oriented to person, place, and time. Laboratory studies showed an elevated white blood cell count of 16,700 cells/microL. His blood urea nitrogen level was 43 mg/dL and his serum creatinine level was 4.9 mg/dL. Multiple blood cultures grew methicillin-resistant Staphylococcus aureus. An admission, chest radiograph showed no infiltrate. An admission electrocardiogram showed normal sinus rhythm with first degree atrioventricular block, left anterior fascicular block, and left ventricular hypertrophy. shows rhythm strips from lead II electrocardiograms 5 months before admission (top), on admission (middle) and 5 days after admission (bottom). What is the diagnosis?

A middle-aged female with recurrent sinopulmonary infections: a case report.

Common variable immunodeficiency (CVID) is a form of severe antibody deficiency with an estimated prevalence of 1 in 25,000 to 1 in 100,000. The disorder apparently results from currently undefined immune deregulations resulting in failed B-cell differentiation with impaired secretion of immunoglobulins. It has a broad range of clinical symptoms including recurrent infections of the respiratory tract, chronic lung disease, autoimmune diseases, liver and gastrointestinal disorders, granulomatous infiltrations, lymphoma and solid tumors. A 42-year-old Caucasian female presented with a one-day history of high-grade fever and productive cough associated with retrosternal chest pain. The patient had been discharged one week prior after a prolonged stay in an intensive care unit with multiorgan failure requiring temporary hemodialysis for two weeks secondary to sepsis. Past medical history was significant for chronic obstructive pulmonary disease, recurrent pneumonias and recurrent sinus infections since adolescence. She had a temperature of 99.8 degrees F, was tachycardic (137/min), tachypneic (26/min) with a blood pressure of 109/59 mmHg and oxygen saturation of 88% on 2 l/min nasal oxygen. Physical examination was significant for bibasilar rhonchi. Laboratory data were significant for leukocytosis of 15,700/mm3. Chest X-ray demonstrated bibasilar infiltrates. The patient was started on intravenous levofloxacin and vancomycin, and sputum gram stain and cultures were performed. Given the patient's recurrent respiratory infections, an underlying immunologic disorder was considered. Work-up revealed immunoglobulin A (IgA) 11 mg/dl (normal 70-400 mg/dl), immunoglobulin M (IgM) 2 mg/dl (normal 40-230 mg/dl) and IgG 53 mg/dl (normal 700-1,600 mg/dl). The patient was diagnosed with CVID and started on intravenous immunoglobulin. She was initially started on a four-week regimen of intravenous immunoglobulin, which was later switched to a three-week regimen as the patient had respiratory infections on the four-week regimen. She remained asymptomatic on a three times/week intravenous immunoglobulin regimen. This case emphasizes the need for a high index of clinical suspicion for CVID in patients presenting with recurrent sinopulmonary infections. Although intravenous immunoglobulin provides improvement in these patients, early diagnosis is the key to preventing significant morbidity and mortality and improving prognosis.

[Factor analysis fever in the early postoperative period following cardiopulmonary bypass surgery in adults. Correlation with bacteriological data. Statistical study of 518 case histories by computer].

The results of a continuous series of 518 adults undergoing cardiopulmonary bypass surgery, operated on by the same surgeon, comprising valvular replacement and aorto-coronary bypass surgery with a peroperative protocol of asepsis and a short prophylactic course of Penicillin and Streptomycin, a preoperative and postoperative bacteriological study, were treated by computer. The postoperative temperature chart showed a progressively decreasing pyrexia in the first 8 days after cardiopulmonary bypass. The nature of the operation, the bypass time, the quantity of blood used during operation and the blood loss were statistically significant factors. Patients with a clinical infection had significantly higher temperatures from the first on. 8,9% of patients had a febrile reaction which continued after the 10th day after cardiopulmonary bypass. The cause was not always apparent but the appearance of their temperature graphs was distinguishable after the first week. Analysis of the systematic bacterial specimens showed bacterial contamination of nearly 10% of drains, 10% of blood cultures, over 15% of intravenous infusion catheters and 70% of urinary catheters. The significance of these results is discussed. The normal appearance of the temperature chart after cardiopulmonary bypass surgery in the absence of clinical complications and bacterial contamination has been established.

[Autoimmune hepatitis complicated by intolerable pain of lower extremities and shock due to azathioprine].

A 24-year-old woman was followed for about ten months with oral administration of prednisolone (22.5-35 mg/d) for autoimmune hepatitis. In June 1995, she noticed fatigue and appetite loss and blood chemistry revealed markedly deteriorated liver function. She was admitted to our hospital. The daily dose of prednisolone was increased to 60 mg. Her elevated levels of transaminases decreased gradually. Administration of azathioprine (100 mg/d) was started with tapering of prednisolone on August 18th. Ten days later, tender cervical lymphadenopathy and high fever occurred. Azathioprine administration was stopped immediately and intravenous antibiotics were given. On September 5th, 50 mg of azathioprine was administered again. Two hours later, the patient complained of intolerable pain from the lumbar region to the knee joints, which subsided following two injections of analgesics within a few hours. However, chills, high fever and hypotension (86/30 mmHg) subsequently developed. No bacterial growth was detected in blood culture. She was discharged on September 12th. On October 4th, she visited our out-patient clinic. The next day, she took one tablet (50 mg) of azathioprine at 10 o'clock. She noted intense pain from the thighs to the knees and calves around noon again. Her home doctor found that she exhibited shock (BP 67/?). She was immediately taken to our department. The same symptoms and signs as the above-mentioned occurred. Azathioprine was considered responsible for these two adverse reactions (shock) as an allergen. Later, systemic lupus eythematosus was diagnosed in 1996. And she died to pulmonary hypertension in May 1999. Physicians should be aware of the potential adverse effect of azathioprine administered in order to manage the patients with autoimmune disorders.

[Influence of axillary temperature on blood culture yield in the emergency department].

To determine the clinical and epidemiological characteristics of patients undergoing blood culture in the emergency department and to identify the relation between the results of blood culture and axillary temperature at blood extraction. We performed a prospective, observational study. All patients who underwent blood extraction by 2 emergency department nurses, as indicated by physicians, between January 2004 and December 2005 were included. The patients were stratified into subgroups according to their temperature on extraction and final diagnosis. Bivariate analysis was performed to compare the clinical and epidemiological characteristics of the patients in relation to the presence of bacteremia and the distinct subgroups established. Isolates of common contaminating microorganisms were discarded. A total of 603 patients were included. The highest percentages of bacteremia were found in patients with high fever or hypothermia. Among the overall group of patients, a significant correlation was found between axillary temperature and bacteremia. However, when patients with a final diagnosis of a disease with a low probability of bacteremia were excluded, this correlation disappeared and no association was found between temperature and the risk of bacteremia in specific infectious processes (pneumonia, pyelonephritis, etc). The main factor associated with bacteremia was the disease prompting blood culture rather than patient temperature.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) and bromoxynil herbicide ingestion.

Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. Case 1: A 50-year-old female presented 18 h post-ingestion of 200  mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO<sub2</sub 25 mmHg). At 8h post-ingestion he became hyperthermic, hypercapnic and acidotic (pH 7.15), and was intubated, paralysed, cooled and received CVVHDF for 36 h. He was extubated after 42 h and made a full recovery. Bromoxynil and MCPA serum and effluent concentrations were measured. Peak MCPA serum concentrations were 161 µg/ml and 259 µg/ml and peak bromoxynil concentrations were 119 µg/ml and 155 µg/ml in case 1 and 2, respectively. The estimated clearance of both herbicides by CVVHDF was low (<10 mL/min). CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support.

[Blood cultures when fever?].

A 78-year-old man was referred from his residency where he lives to the emergency division due to general deterioration and frequent falls in the last week. His personal history is remarkable for arterial hypertension and diabetes. Two weeks before he needed a vesical catheterism that was traumatic and profilactic ciprofloxacin was prescribed. On physical exploration he appears disoriented, blood pressure is 9/40 mm Hg, cardiac rythm 120 beats per minute, temperature 37,3 °C and 24 respirations per minute. He appears to have pain on his upper left abdomen cuadrant. When the nurse gets a peripheral vein she asks, ¿should I obtain hemocultures?

Major trauma

A FAST exam may help assess for internal bleeding. In certain traumas, such as maxillofacial trauma, it may be beneficial to have a highly trained health care provider available to maintain airway, breathing, and circulation. Intravenous fluids Traditionally, high-volume intravenous fluids were given to people who had poor perfusion due to trauma. This is still appropriate in cases with isolated extremity trauma, thermal trauma, or head injuries. In general, however, giving lots of fluids appears to increase the risk of death. Current evidence supports limiting the use of fluids for penetrating thorax and abdominal injuries, allowing mild hypotension to persist. Targets include a mean arterial pressure of 60 mmHg, a systolic blood pressure of 70–90 mmHg, or the re-establishment of peripheral pulses and adequate ability to think. Hypertonic saline has been studied and found to be of little difference from normal saline.

The Absence of Fever Is Associated With Higher Mortality and Decreased Antibiotic and IV Fluid Administration in Emergency Department Patients With Suspected Septic Shock.

This study evaluates whether emergency department septic shock patients without a fever (reported or measured) receive less IV fluids, have decreased antibiotic administration, and suffer increased in-hospital mortality. This was a secondary analysis of a prospective, observational study of patients with shock. The study was conducted in an urban, academic emergency department. The original study enrolled consecutive adult (aged 18 yr or older) emergency department patients from November 11, 2012, to September 23, 2013, who met one of the following shock criteria: 1) systolic blood pressure less than 90 mm Hg after at least 1L IV fluids, 2) new vasopressor requirement, or 3) systolic blood pressure less than 90 mm Hg and IV fluids held for concern of fluid overload. The current study is limited to patients with septic shock. Patients were grouped as febrile if they had a subjective fever or a measured temperature >100.4°F documented in the emergency department; afebrile patients lacked both. Among 378 patients with septic shock, 207 of 378 (55%; 50-60%) were febrile by history or measurement. Afebrile patients had lower rates of antibiotic administration in the emergency department (81% vs 94%; p < 0.01), lower mean volumes of IV fluids (2,607 vs 3,013 mL; p < 0.01), and higher in-hospital mortality rates (33% vs 11%; p < 0.01). After adjusting for bicarbonate less than 20 mEq/L, lactate concentration, respiratory rate greater than or equal to 24 breaths/min, emergency department antibiotics, and emergency department IV fluids volume, being afebrile remained a significant predictor of in-hospital mortality (odds ratio, 4.3; 95% CI, 2.2-8.2; area under the curve = 0.83). In emergency department patients with septic shock, afebrile patients received lower rates of emergency department antibiotic administration, lower mean IV fluids volume, and suffered higher in-hospital mortality.

A successful management after preterm delivery in a patient with severe sepsis during third-trimester pregnancy.

A 33-year-old woman visited the emergency department presenting with fever and dyspnea. She was pregnant with gestational age of 31 weeks and 6 days. She had dysuria for 7 days, and fever and dyspnea for 1 day. The vital signs were as follows: blood pressure 110/70 mmHg, heart rate 118 beats/minute, respiratory rate 28/minute, body temperature 38.7℃, and oxygen saturation by pulse oximetry 84% during inhalation of 5 liters of oxygen by nasal prongs. Crackles were heard over both lung fields. There were no signs of uterine contractions. Chest X-ray and chest computed tomography scan showed multiple consolidations and air bronchograms in both lungs. According to urinalysis, there was pyuria and microscopic hematuria. She was diagnosed with community-acquired pneumonia and urinary tract infection (UTI) that progressed to severe sepsis and acute respiratory failure. We found extended-spectrum beta-lactamase producing <iEscherichia coli</i in the blood culture and methicillin-resistant Staphylococcus aureus in the sputum culture. The patient was transferred to the intensive care unit with administration of antibiotics and supplementation of high-flow oxygen. On hospital day 2, hypoxemia was aggravated. She underwent endotracheal intubation and mechanical ventilation. After 3 hours, fetal distress was suspected. Under 100% fraction of inspired oxygen, her oxygen partial pressure was 87 mmHg in the arterial blood. She developed acute kidney injury and thrombocytopenia. We diagnosed her with multi-organ failure due to severe sepsis. After an emergent cesarean section, pneumonia, UTI, and other organ failures gradually recovered. The patient and baby were discharged soon thereafter.

EMS Clinical Diagnosis Without The Use Of A Thermometer -- Issues of Concern

The subjective assessment of fever, as well as the assessment of other signs and symptoms that occur with infectious disease, is important in EMS. Pulse can be high due to fever, or with possible associated dehydration or shock. Palpating a pulse not only gives an accurate rate, but it also gives information about the effectiveness of blood pressure and flow. This can be of significant concern with a severe infectious disease, especially sepsis. Shock can develop quickly and differentiating infectious cause for shock will be important for definitive treatment. Unfortunately, people taking medications affecting the heart rate (such as beta blockers or calcium channel blockers) may not mount a tachycardic response, so a normal heart rate does not rule out fever or infection. Additionally, sepsis, especially in the elderly, can actually cause bradycardia (associated with end-organ failure.)

Septic shock

Treatment Treatment primarily consists of the following: Giving intravenous fluids Early antibiotic administration Early goal directed therapy Rapid source identification and control Support of major organ dysfunction Fluids Because lowered blood pressure in septic shock contributes to poor perfusion, fluid resuscitation is an initial treatment to increase blood volume. Patients demonstrating sepsis-induced hypoperfusion should be initially resuscitated with at least 30 ml/kg of intravenous crystalloid within the first three hours. Crystalloids such as normal saline and lactated Ringer's solution are recommended as the initial fluid of choice, while the use of colloid solutions such as hydroxyethyl starch have not shown any advantage or decrease in mortality. When large quantities of fluids are given, administering albumin has shown some benefit.

[Accidental deep hypothermia and circulatory arrest. Treatment with extracorporeal circulation].

A 27-year old female was discovered at 4 a.m. lying in a wet field, the ambient temperature being of 4 degrees C. Her rectal temperature had fallen to 19 degrees C. She was comatose and failed to respond to noxious stimuli. Her pupils were dilated and fixed. Her respiratory rate was reduced to three to four breaths per min. Her blood pressure was not measurable and neither femoral or carotid pulse could be detected. The heart was in sinus rhythm with a rate of 40 b X min-1. During her transfer to hospital, she was ventilated with oxygen, a tidal volume of 300 ml and a rate of 10 b X min-1. On arrival in the emergency room, a short period of ventricular fibrillation preceded cardiac arrest. Cardiac massage and sodium bicarbonate infusion were continued during the transfer of the patient to the operating theatre. A femoro-femoral cardiopulmonary bypass was started with a bloodless priming, 3 mg X kg-1 heparin and a flow of 3,000 to 3,500 ml X min-1. Mean arterial pressure was maintained between 65 and 85 mmHg; cardiac massage was discontinued during the bypass. Within 50 min, ventricular fibrillation appeared, rectal temperature had increased to 33 degrees C. Electrical defibrillation (300 J) was successful. Cardiopulmonary bypass was stopped after 63 min. The postoperative course was uneventful, apart from transient pulmonary oedema. At the time of discharge, a week later, no loss of intellect or change in behaviour could be perceived.(ABSTRACT TRUNCATED AT 250 WORDS)

Shock (circulatory)

of 40 mmHg from baseline) despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may have a normalized blood pressure at the time that perfusion abnormalities are identified. The pathophysiology behind septic shock is as follows: 1) Systemic leukocyte adhesion to endothelial cells 2) Reduced contractility of the heart 3) Activation of the coagulation pathways, resulting in disseminated intravascular coagulation 4). Increased levels of neutrophils

Mycotic pseudoaneurysm of the brachiocephalic artery.

A 73-year-old woman with a history of hypertension and hyperlipidemia presented with a sharp pain ranging from the right shoulder to the upper limb. She had suffered a sharp pain at rest accompanied by general fatigue and nausea for about ten months prior to admission. Her white blood cell count was 12,800/microl, and her serum C-reactive protein was 17.5 mg/dl. A chest computed tomography scan revealed an aneurysmal change of the origin of the brachiocephalic artery. Pseudoaneurysm due to infection and aortic dissection was considered as a preoperative diagnosis. A total arch replacement was performed under cardiopulmonary bypass, deep hypothermia, and selective cerebral perfusion. Postoperatively, a bacteriologic culture of the contents of the aneurysm revealed Staphylococcus aureus. Perioperative administration of antibiotics was effective and the postoperative course was uneventful.

Sepsis

Sepsis is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is followed by suppression of the immune system. Common signs and symptoms include fever, increased heart rate, increased breathing rate, and confusion. There may also be symptoms related to a specific infection, such as a cough with pneumonia, or painful urination with a kidney infection. The very young, old, and people with a weakened immune system may have no symptoms of a specific infection, and the body temperature may be low or normal instead of having a fever. Severe sepsis causes poor organ function or blood flow. The presence of low blood pressure, high blood lactate, or low urine output may suggest poor blood flow. Septic shock is low blood pressure due to sepsis that does not improve after fluid replacement.

[An elder case of accidental hypothermia].

A 87-year-old woman with accidental hypothermia was admitted to our hospital. On admission, she showed consciousness disturbance (JSC III-200) the decorticate rigidity and shock. Her body temperature was too low to been measured and her ECG revealed a J wave. She received the external rewarming and warm fluid replacement. Her consciousness level recovered to JSC II-20 after 2.5 hours of treatment, to JCSI-1 after 7.5 hours. Her body temperature reached 34.5 degrees C 9.5 hours later, and the J wave on ECG disappeared. She was discharged without complications on the 6th hospital day. it was suggested that early diagnosis and the proper therapy improves the mortality of accidental hypothermia.


SCA3 is Spinocerebellar Ataxia type 3 also called Machado-Joseph disease. It is caused by mutations in the ATXN3 gene by the CAG triplet repeat expansion mechanism. Affected individuals have between 52 and 86 CAG triplet repeats in heterozygosis with complete penetrance. The heterozygous mutation carrier has the disease as its inheritance pattern is autosomal dominant. In this clinical case, the one who has the disease and has the mutated gene in heterozygosis is the brother (26 years old) of the pregnant woman. I think that before doing the chorion biopsy, the pregnant woman should be tested to know her ATXN3 gene status. She has a 50% chance of carrying the mutation and having the disease, but since she is 31 years old, I think she should have already had symptoms. Nevertheless, I would do the genetic test on the pregnant woman to be on the safe side. If she came out without the mutation, there would be nothing more to do because the disease would no longer be transmitted. If she came out with the mutation, then I would do a chorionic villus biopsy. Answers 1 and 2 are both true, but I think answer 1 is more true than answer 2.

SCA3 is Spinocerebellar Ataxia type 3 also called Machado-Joseph disease. It is caused by mutations in the ATXN3 gene by the CAG triplet repeat expansion mechanism. Affected individuals have between 52 and 86 CAG triplet repeats in heterozygosis with complete penetrance. The heterozygous mutation carrier has the disease as its inheritance pattern is autosomal dominant. In this clinical case, the one who has the disease and has the mutated gene in heterozygosis is the brother (26 years old) of the pregnant woman. I think that before doing the chorion biopsy, the pregnant woman should be tested to know her ATXN3 gene status. She has a 50% chance of carrying the mutation and having the disease, but since she is 31 years old, I think she should have already had symptoms. Nevertheless, I would do the genetic test on the pregnant woman to be on the safe side. If she came out without the mutation, there would be nothing more to do because the disease would no longer be transmitted. If she came out with the mutation, then I would do a chorionic villus biopsy. [HIDDEN]

An asymptomatic 31-year-old woman (Consultant) is asymptomatic and has a 10-week gestation according to ultrasound study (primiparous). Her younger brother (index case) aged 26 years is affected by ataxia and genetically diagnosed as a heterozygous carrier of an expansive mutation of 70 CAG repeats in the SCA3 gene (chromosome 14). The patient is referred to the genetic counseling office where a possible chorionic villus biopsy to study the fetal genotype is evaluated. Is this invasive procedure indicated as a pre-natal diagnosis (PND) in this case?

It is indicated after studying the Consultant's genotype and only if it is heterozygous.

This is not indicated, since SCA3 ataxia is full penetrance and the Consultant is asymptomatic and therefore has not inherited the mutation.

It may be indicated in the next pregnancy, after studying the genotype of the first child and detecting the mutation in it.

SCA3 ataxia is recessively inherited, so there is no appreciable risk of disease transmission and PND is not indicated.

This is indicated regardless of the Consultant's genotype, since SCA3 ataxia is maternally inherited (transmitted by women).

Preimplantation genetic diagnosis of spinocerebellar ataxia 3 by (CAG)(n) repeat detection.

Spinocerebellar ataxia 3 (SCA3) is an autosomal dominant neurodegenerative disorder characterized by variable expression and a variable age of onset. SCA3/MJD (Machado-Joseph disease) is caused by an expansion of a (CAG)(n) repeat in the MJD1 gene on chromosome 14q32.1. A single cell PCR protocol has been developed for preimplantation genetic diagnosis (PGD) of SCA3 to select unaffected embryos on the basis of the CAG genotype. Single leukocytes and blastomeres served as a single cell amplification test system to determine the percentage of allelic drop-out (ADO) and PCR efficiency. Out of 105 tested heterozygous single leukocytes, 103 (98.1%) showed a positive amplification signal, while five cells (4.9%) showed ADO. Amplification in single blastomeres was obtained in 13 out of a total of 14, and ADO was observed in two out of the 13 single blastomeres. PGD of SCA3 was performed in a couple with paternal transmission of the SCA3 allele. Seven embryos were available for biopsy, all biopsied blastomeres showed amplification and no ADO occurred. One embryo was diagnosed as affected whereas six embryos were diagnosed as unaffected. Two unaffected embryos were transferred and resulted in a singleton pregnancy and the birth of a healthy girl.

Prenatal diagnosis of Machado-Joseph disease by direct mutation analysis.

MJD is the most frequent dominant ataxia and an incapacitating disorder. Onset is most frequently during the reproductive years, and genetic counseling is its only means of prevention. The causative mutation--an expansion of a (CAG)n on chromosome 14q32.1--can now be directly detected. We now report the first two cases of prenatal diagnosis (PND). The first presented as a simultaneous request for predictive testing and PND at 14 weeks of pregnancy. Owing to time constraints, we performed a full protocol of counseling with shorter inter between sessions, while psycho-social evaluation of the other parent obstetric consults were also begun. We ensured that the couple wished termination if the fetus was a carrier, to avoid a presymptomatic test for the unborn child. We were thus able to deliver test results two weeks before PND. As the fetus carried an expanded allele (77 CAGs) inherited from his father, termination was performed and the couple received counselling, psychological and social support. The second case was the fetus of a carrier-mother that was diagnosed as non-carrier, also after amniocentesis.

Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases. The Ataxia Study Group.

Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansions encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated familial and 60 sporadic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2, 15% SCA3, 6% SCA1, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belong to the same geographical area and share a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 35 to 46 [corrected] for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being of +67 units in one paternal transmission and giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1-2 CAT trinucleotides in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1-3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was identified as a recessive form due to GAA-repeat expansions in the Friedreich's ataxia gene.

[Clinico-genetic study of type I spinocerebelllar ataxia].

Inherited, autosomal-dominant cerebellar ataxia (ADCA) comprises a genetically and clinically heterogenous group of neurodegenerative disorders. Clinical classification of these disorders was an important step [2] in differentiation among several types, the most common one being ADCA-I, accompanied with supranuclear ophthalmoplegia, optic nerve atrophy, symptoms of the basal ganglia lesions, dementia and amyotrophia. Molecular-genetic studies indicated genetic heterogeneity of ADCA-I with mutations of genetic loci on chromosome 6p (spinocerebellar ataxia type 1; SCA1), 12q (SCA2), 14q (SCA3), 19p (SCA6) and 16q (SCA4) [3]. Spinocerebellar ataxia type 1 (SCA1) is characterized by cerebellar ataxia, ophthalmoplegia and pyramidal signs [4], but also with other neurological findings that tend to prevent clinical differentiation among patients with SCA1, SCA2 and SCA3. The mutation inducing SCA1 is an instable expansion of trinucleotide (CAG) repeats in the coding region on chromosome 6 [5]. Herein, we report clinical features in patients from two families with SCA1: family I with 15 and family II with 8 affected members in 4 consecutive generations. The acceptable data (history, examination and/or insight into medical records) were obtained for 9 patients in family I and 7 patients in family II. The age at the onset of the disease was 37.8 +/- 11.3 years (mean value +/- SD) (range: 27-60) for all the patients, or 31.8 +/- 10.7 years (range: 7-60) for family I and 45.0 +/- 8.4 years (range: 35-55) for family II. Duration of the disease was 8.9 +/- 4.6 years (range: 3-15); 10.8 +/- 4.1 (range 5-15) and 5.7 +/- 3.8 years (range: 3-10) for families I and II, respectively. The mean number of CAG repeats in the mutated allele for SCA1 of the affected individuals was 50.5 +/- 6.2 (range 45-64). A significant inverse correlation (p < 0.05) was noted between the number of CAG repeats and the age at the onset of the disease (Figure 3). Similarity of initial symptoms in SCA1 was noted. They include simultaneous gait-related problems and dysarthria (usually slurred speech). Occurrence of other neurological signs (Table 3) was also predictable in most cases and depended on the phase of SCA1 at the time of examination. Generally, it is believed that intra- and interfamilial phenotypic heterogeneity in SCA1 is lower than in SCA2 and SCA3 [12]). In conclusion, typical clinical manifestations of SCA1, at least in early phases of the disease, according to our study, include gait ataxia, dysarthria, brisk muscle reflexes and marked hand ataxia; the age at the onset of the disease was inverse, and clinical progression was directly related to the number of CAG repeats in the mutated allele on chromosome 6. Nevertheless, significant differences in clinical properties of this inherited disease are possible among different affected families.

[Autosomal dominant cerebellar ataxias in the Netherlands: a national inventory].

To provide a comprehensive estimate of the number of Dutch autosomal dominant cerebellar ataxias (ADCA) families and patients and thus estimate the minimal prevalence of ADCA in the Netherlands. Furthermore, to observe the relative frequency of SCA mutations and to study genotype-phenotype correlations. Descriptive study and prevalence computation. Genotyping was based on cytosine-adenine-guanine (CAG)-repeat expansion detection in the SCA1, SCA2, SCA3, SCA6 and SCA7 genes. We analysed the results of SCA mutation analysis with respect to the number of genotyped families, gene carriers, and clinically affected individuals per SCA locus, as well as individual repeat length and age of onset. Parent-offspring couples were studied for anticipation. The minimal prevalence was extrapolated, based on the observation that at least 36% of ADCA families cannot be genotyped. Per May 1st 2000, 137 Dutch ADCA families were genotyped (SCA1: 15 families; SCA2: 14; SCA3: 64; SCA6: 28; SCA7: 16) and 382 affected individuals had been identified within these families. The extrapolated minimal prevalence was 2.8 per 100,000. All lengths of expanded trinucleotide repeats identified confirmed earlier results regarding pathogenic sizes. Anticipation with an associated increase of repeat length was observed in SCA2 and SCA3 families. The length of the trinucleotide repeat accounted for 65% of the variance in age of onset in SCA3.

Clinical features and genetic diagnosis of hereditary spinocerebellar ataxia 3.

Spinocerebellar ataxia type 3 (SCA3) is a rare inherited autosomal dominant progressive neurological disorder, which results from a CAG‑repeat expansion in the gene encoding the deubiquitinating enzyme, ataxin‑3. At present, no effective treatment is available for this fatal disorder; however, certain studies have suggested that reducing the levels of mutant ataxin‑3 protein may reverse or halt the progression of disease in patients with SCA3. In the present study, clinical examinations were performed on a patient with SCA3 who exhibited disease features including coughing, expectoration and was bedridden with mobility limitation. CAG repetitions at SCA‑associated genes were detected in the patient's family by performing standard polymerase chain reaction (PCR) and triple‑repeat primed PCR. The numbers of CAG‑repeats within the two alleles of the gene of interest in the patient were 15 and 78. Notably, the patient's brother, who harbored 76 CAG‑repeats in one allele of the gene of interest, did not exhibit severe disease symptoms. These results suggest that the number of CAG‑repeats is a critical for determination of SCA3 disease severity and time of onset. In addition, the deﬁned phenotypic characteristics of the patient in the present study provide useful insight for more accurate clinical diagnosis and genotyping of future patients.

[Analysis and application of SCA1 and SCA3/MJD gene CAG repeats in Han population in Northeastern China].

To investigate the normal range of (CAG)n in spinocerebellar ataxia type 1 (SCA1) gene and spinocerebellar ataxia type 3 (SCA3/MJD) gene in 110 normal subjects of Han population in Northeastern China, to assess the genotypes for clinically diagnosed spinocerebellar ataxia(SCA) individuals including 25 patients from 8 families and 6 sporadic patients, and to make presymptomatic and prenatal diagnosis. DNA fragments from the normal subjects and the patients were detected by fluorescence-PCR. Homozygosities were selected for DNA sequencing. The normal   ranges of (CAG)n of SCA1 and SCA3/MJD were 20-39 and 14-38 repeats respectively, SCA1 was found mostly to be 26 and 27 repeats, allele frequency 34.09% and 20.91%; heterozygosity was 84.55%, SCA3/MJD was found mostly to be 14 repeats, allele frequency 39.55%, heterozygosity was 78.18%.(CAG)(68) of SCA3/MJD gene of one affected individual had been found in a family but no CAG mutative expansion in related members was observed. The normal ranges of CAG repeats vary with areas and races. SCAs genotyping is the first choice in presymptomatic and prenatal diagnosis.

[Analysis of SCA3/MJD3 gene mutation and genetic polymorphism in a guangxi family with spinocerebellar ataxia 3].

Autosomal dominant cerebellar ataxias (ADCAs) comprise a group of genetically heterogeneous neurodegenerative disorders among which spinocerebellar ataxia type 3 (SCA3) represents the most common form of SCAs worldwide. The fragments of SCA3/MJD gene,which is the member of family GXPL1,were amplified by polymerase chain reaction (PCR). The PCR products of SCA3/MJD gene were detected with capillary electrophoresis (CE) and sequencing to evaluate the size of CAG repeats, feature in the transmission and the mutation in the family with SCA3 in Guangxi province. The results showed that the exon 10 of the SCA3/MJD gene contains 64-71 CAG repeats in all of the affected individuals and three asymptomatic carriers of the family. The number of the CAG repeats during transmission in the normal individuals carrying CGG allele remains consistent, suggesting that CGG allele could have no effect on intergenerational stability of CAG repeats in normal individuals. In addition, two novel point mutations were identified: IVS9-113 T > C in the intronic region and a missense mutation 220 G > A (Glu > Gly) in the encoding region. These two novel point mutations have not been reported and the effect of the mutations on the phenotype of SCA3 is not clear.

Autosomal dominant cerebellar ataxias in ethnic Bengalees in West Bengal - an Eastern Indian state.

Phenotypic and genotypic patterns of a hereditary disease in a large multiethnic country like India need to be studied in relation to geographical location and ethnicity of the population. The few reported studies from India on dominant ataxias (ADCA) have mostly been conducted on multiethnic populations and hence may not reflect the patterns observed in specific ethnic groups or geographical locations. The present study attempted to look into the patterns of ADCA amongst ethnic Bengalee patients hailing from the eastern Indian state of West Bengal. Between mid-1996 and mid-2000, in a clinic based study, 37 cases (from 14 families) with ADCA were studied. This included 33 affected and four asymptomatic members with abnormal physical signs. Genotypic analyses were performed on more than one affected member from each family. Clinical, neuroradiological and electrophysiological aspects were studied. Genotype analysis revealed: two families with SCA-1,4 families with SCA2,5 families with SCA3 and three families with undetermined genotype. Of the latter, phenotypically 2 were of ADCA 1 and one of ADCA 2 type. No clear preponderance of one particular genotype over another was observed. We noted significant intra- and interfamily variations in phenotype within the same genotype form as well as overlapping of clinical signs between different genotypes. Slow saccadic eye movements and peripheral neuropathy were not seen consistently in our ethnic Bengalee subjects with SCA2 genotypes. Similarly, extrapyramidal features, ophthalmoplegias and distal amyotrophy were seen in some but not in all families with SCA3 mutation. A peculiar form of abduction lag during slow pursuit movement of eyes was observed in an asymptomatic girl in an SCA3 family. Although SCA2 has been claimed to be the commonest form of ADCA in India, this does not appear to be so in our ethnic Bengalee subjects. Phenotypic expression of the genotype also appears to be variable amongst families and individuals. Hence, phenotypic expression appears to be an inconsistent marker of the SCA genotype in our patients.

Homozygous spinocerebellar ataxia type 3 in China: a case report.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a heterozygous CAG repeat expansion in the ataxin 3 gene (<iATXN3</i). However, patients with homozygous SCA3 carrying expanded CAG repeats in both alleles of <iATXN3</i are extremely rare. Herein, we present a case of a 50-year-old female who had homozygous SCA3 with expansion of 62/62 repeats. Segregation analysis of the patient's family showed both a contraction pattern of CAG repeat length and stable transmission. The present case demonstrated an earlier onset and more severe clinical phenotype than that seen in heterozygous individuals, suggesting that the gene dosage enhances disease severity.

SCA2 trinucleotide expansion in German SCA patients.

Autosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders which lead to progressive cerebellar ataxia. A gene responsible for SCA type 2 has been mapped to human chromosome 12 and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. We investigated the (CAG)n repeat length of the SCA2 gene in 842 patients with sporadic ataxia and in 96 German families with dominantly inherited SCA which do not harbor the SCA1 or MJD1/SCA3 mutation, respectively. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with the age of onset in 41 patients revealed an inverse correlation. Two hundred and forty-one apparently healthy octogenerians carried alleles between 16 and 31 repeats. One 50-year old, healthy individual had 34 repeats; she had transmitted an expanded allele to her child. The small difference between 'normal' and disease alleles makes it necessary to define the extreme values of their ranges. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany.

Detection of the Machado-Joseph disease/spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth.

Affected members of 63 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCA), and 29 patients with similar phenotypes but no affected relatives, were investigated for the trinucleotide (CAG) repeat expansion described in Japanese families with Machado-Joseph disease (MJD). This disorder had previously been shown to map to the region of chromosome 14 which also contains a locus causing ADCA in French families, spinocerebellar ataxia 3 (SCA3). The MJD/SCA3 mutation was identified in nine families with ADCA type I, and a further family in which affected members had parkinsonism, peripheral neuropathy, dystonia, and spasticity, but little evidence of cerebellar disease. Only one of the 10 families was British (the Drew family of Walworth); the others originated from India, Jamaica, Ghana, Brazil and France. There was no single clinical feature which distinguished patients with the MJD/SCA3 mutation from those with the CAG expansion on chromosome 6 (SCA1) or ADCA type I families with no known mutation. The CAG repeat length ranged from 13-41 copies on normal chromosomes and 62-80 copies on affected chromosomes. There was a significant inverse correlation between age of onset of symptoms and repeat length, but no significant effect of parental sex on repeat length or age of onset in offspring. DNA analysis for the MJD/SCA3 mutation is useful for diagnosis in patients with familial ataxic or extrapyramidal syndromes, and will aid genetic counselling in these disorders.

Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3.

Due to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited. During the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed. A quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r<sup2</sup = 0.634, p < 0.001). The expCAG and AAO in Asian populations and western populations were compared with the Chinese population. SCA3 individuals had shorter normal CAG repeats (norCAGs) than healthy controls (Mann-Whitney, p < 0.0001). Most (92.1%) SCA3 patients had gait-ataxia onset. Their AAO and expCAGs were not significantly different from SCA3 patients with non-gait-ataxia onset. Limb ataxia and pyramidal impairment occurred less in patients with disease duration >10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals. We demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.

Spinocerebellar ataxias: microsatellite and allele frequency in unaffected and affected individuals.

The diagnosis and incidence of spinocerebelar ataxias (SCA) is sometimes difficult to analyze due the overlap of phenotypes subtypes and are disorders of mutations caused by CAG trinucleotide repeat expansion. To investigate the incidence of the SCA in Southern Brazil, we analyzed the trinucleotide repeats (CAG)n at the SCA1, SCA2, SCA3, SCA6 and SCA7 loci to identify allele size ranges and frequencies. We examined blood sample from 154 asymptomatic blood donors and 115 individuals with progressive ataxias. PCR products were submitted to capillary electrophoresis. In the blood donors, the ranges of the five loci were: SCA1, 19 to 36 (CAG)n; SCA2, 6 to 28 (CAG)n; SCA3, 12 to 34 (CAG)n; SCA6, 2 to 13 (CAG)n; and SCA7, 2 to 10 (CAG)n. No deviations from Hardy-Weinberg equilibrium were detected. In the ataxia group, we found (CAG)n above the range of the asymptomatic blood donors in SCA3 (21.74%) followed by SCA2 (5.22%), SCA7 (2.61%), SCA6 (0.87%), and no cases of SCA1. The remaining 80 cases (69.56%) have different diagnoses from the type here studied. These data defined the alleles and their frequencies, as well as demonstrated their stability in the population not affected. The molecular diagnosis test confirmed the clinical diagnosis in 28/45 cases and classified another 7/70 from the clinical unclassified ataxias group.

Hereditary spastic paraplegia and hereditary ataxia, Part 2: A family demonstrating various phenotypic manifestations with the SCA3 genotype.

Clinical descriptions of the dominantly inherited ataxic motor syndromes in a 7-generation family of German origin were first reported in 1951. To provide follow-up clinical, pathological, and genetic data for 9 patients in this family. Clinical histories and neurologic findings, gross and microscopic pathological features, and DNA analysis. Clinical presentations in this closely followed up portion of the family include fairly uniform ataxic and upper motor neuron symptoms. Nystagmus was a conspicuous and early sign, but generational anticipation was not evident. Although often present, amyotrophy was not a major source of disability. Major pathological degeneration was noted in the pons, spinal cord, and upper brainstem, where ubiquitin-immunoreactive intranuclear inclusion bodies were demonstrated. The diagnosis of Machado-Joseph disease (SCA3 [spinocerebellar ataxia type 3] genotype) was established from autopsy tissue in 1 patient and from blood specimens in 6 others. Clinical variation within this family and between this family and families with the SCA1 and SCA3 genotypes is so broad as to make the genetic diagnosis from clinical criteria alone practically impossible. The pathological definition of Machado-Joseph disease is more reliable, but some findings do overlap those of other genotypes. To our knowledge, the basis for the phenotypic variations in Machado-Joseph disease, genetic or otherwise, has not been established.

Genetic background of apparently idiopathic sporadic cerebellar ataxia.

Disease-causing mutations have been identified in various entities of autosomal dominant ataxia and in Friedreich's ataxia. However, no molecular pathogenic factor is known to cause idiopathic cerebellar ataxias. We investigated the CAG/CTG trinucleotide repeats causing spinocerebellar ataxia types 1, 2, 3, 6, 7, 8 and 12, and the GAA repeat of the frataxin gene in 124 patients apparently suffering from idiopathic sporadic ataxia, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, a typical Friedreich phenotype, or symptomatic ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age at onset between 13 and 36 years. The SCA6 mutation was present in nine patients with disease onset between 47 and 68 years of age. The CTG repeat associated with SCA8 was expanded in three patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. We did not identify the SCA1, SCA3, SCA7 or SCA12 mutation in idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the MSA subgroup. This study has revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 is the most frequent mutation in late onset cerebellar ataxia. The frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreich's ataxia.

Machado–Joseph disease

Machado–Joseph disease (MJD), also known as Machado–Joseph Azorean disease, Machado's disease, Joseph's disease or spinocerebellar ataxia type 3 (SCA3), is a rare autosomal dominantly inherited neurodegenerative disease that causes progressive cerebellar ataxia, which results in a lack of muscle control and coordination of the upper and lower extremities. The symptoms are caused by a genetic mutation that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene that results in an abnormal form of the protein ataxin which causes degeneration of cells in the hindbrain. Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness or Parkinson's disease. Machado–Joseph disease is a type of spinocerebellar ataxia and is the most common cause of autosomal-dominant ataxia. MJD causes ophthalmoplegia and mixed sensory and cerebellar ataxia.

Autosomal dominant cerebellar ataxia

Subtype 1 -subtypes in the first subclass are caused by CAG nucleotide repeats in the DNA, which code for the amino acid glutamine. This glutamine is toxic to the cell on the level of proteins and has degenerative effects. Within the first subclass of Type 1 are SCA1, SCA2, SCA3, SCA17, and DRPLA. This first subclass is the most common of Type 1 ADCAs with SCA3 being the most common subtype of all of Type 1. SCA3, Machado-Joseph disease, is the most common because the mutation repeats more than 56 times while the regular length is around 13 to 31. Subtype 2 -the second subclass of Type 1 ADCA is also caused by the same nucleotide repeats but instead in RNA and in a region that does not code for proteins. Gene expression is affected instead of proteins in subtype two SCAs because of this. Subtype 2 contains SCA8, SCA10, and SCA12.

Spinocerebellar ataxia

Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein (i.e., ataxin-1, ataxin-3, etc.) contains a large number of repeats of glutamine residues, termed a polyQ sequence or a "CAG trinucleotide repeat" disease for either the one-letter designation or codon for glutamine respectively. The threshold for symptoms in most forms of SCA is around 35, though for SCA3 it extends beyond 50. Most polyglutamine diseases are dominant due to the interactions of resulting polyQ tail. The first ataxia gene was identified in 1993 and called "Spinocerebellar ataxia type 1" (SCA1); later genes were called SCA2, SCA3, etc. Usually, the "type" number of "SCA" refers to the order in which the gene was found. At this time, there are at least 29 different gene mutations that have been found. The following is a list of some of the many types of Spinocerebellar ataxia. Others include SCA18, SCA20, SCA21, SCA23, SCA26, SCA28, and SCA29.

Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.

To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.

Spinocerebellar ataxia type 2. Genotype and phenotype in German kindreds.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant cerebellar ataxia (ADCA) for which the disease-causing mutation has recently been characterized as an expanded CAG trinucleotide repeat. We investigated 64 families of German ancestry with ADCA and 55 patients with sporadic ataxia for the SCA2 mutation. Expanded alleles were found in 6 of the 64 families and in 1 patient with sporadic ataxia. This patient had a de novo mutation from an intermediate paternal allele. Length of repeats in 21 patients with SCA2 ranged from 36 to 52 CAG motifs and was inversely correlated with age at onset and progression of the disease. Expanded alleles were unstable during meiosis; paternal transmission especially caused significant anticipation of onset up to 26 years earlier. The SCA2 phenotype differed from those of SCA1 and SCA3 with higher frequencies of slowed ocular movements, postural and action tremor, myoclonus, and hyporeflexia. However, no single feature was sufficient to permit a specific clinical diagnosis. Spinocerebellar ataxia type 2 accounts for about 10% of German families with ADCA but may also be present in sporadic ataxia due to de novo mutations. Clinical features are highly variable among and even within families. However, the size of the expanded repeat influences the phenotype and is relevant for course and prognosis of the disease.

Homozygote of spinocerebellar Ataxia type 3 correlating with severe phenotype based on analyses of clinical features.

Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCAs worldwide. SCA3 homozygote is defined as expanded CAG repeats in both alleles that might exhibit severe phenotype due to gene dosage effect. However, a study on the systematic comparison of clinical phenotypes between homozygotes and heterozygotes to indicate these verity of phenotypes of homozygotes is still lacking. A total of 14 SCA3 homozygotes (3 Chinese participants and 11 participants from various ethnicity in different published studies) and 143 Chinese heterozygotes of SCA3 were recruited for this study. The 95% confidence intervals (CIs) of age at onset and disease severity expected from heterozygous patients were analyzed to detect the phenotypic differences between homozygotes and heterozygotes. Almost all the homozygotes (13 of 14) were found to present a significant earlier age at onset compared with heterozygotes, because age at onset of most homozygotes was lower than the 95% CIs of age at onset of heterozygotes. Also, the clinical severity in most of the homozygotes (3 of 4) with identified clinical phenotypes was higher than the 95% CIs of severity in heterozygotes, indicating more severe clinical phenotypes in SCA3 homozygotes. The homozygosity for SCA3 could lead to an earlier age of onset and putative severe clinical features. The findings of the present study suggested an influence of gene dosage on SCA3 phenotypes.

InternalMed_Harrison

Classification of the Spinocerebellar Ataxias Roger N. Rosenberg Ataxias with autosomal dominant, autosomal recessive, X-linked, or mitochondrial forms of inheritance are present on a worldwide 451e basis. Machado-Joseph disease (SCA3) (autosomal dominant) and Friedreich’s ataxia (autosomal recessive) are the most common types in most populations. Mutation markers are now commercially available to identify carriers at risk in their families, which allows for precise identification of the genetic mutation for correct diagnosis and also for family planning. Identification of positive mutation carriers with family planning has allowed for early detection of asymptomatic preclinical disease to reduce or eliminate the inherited form of ataxia in specific families on a global, worldwide basis.

[Molecular and prenatal diagnosis of a pedigree with spinocerebellar ataxia].

To identify the type of a pedigree with spinocerebellar ataxia, and carry out asymptomatic carrier detection and prenatal diagnosis. The blood samples of two patients in the spinocerebellar ataxia pedigree were collected. Based on the clinical characteristics of the pedigree and the disease incidence in China, the regions containing the CAG repeat of the SCA1, SCA2 and SCA3/MJD genes were amplified by polymerase chain reaction (PCR). The numbers of CAG repeats in the normal and abnormal allele fragments were identified by using agarose gel electrophoresis and DNA sequencing. We further carried out tests on the children of the patients and fetus to identify the presence of the abnormal allele. The numbers of CAG repeat in the SCA1 and SCA2 genes were in the normal range. The CAG repeat number in one allele of SCA3/MJD gene was in the normal range, while that in the other allele was in the abnormal range. One of the children of the patients and the fetus carried the abnormal allele. It was confirmed that the pedigree was SCA3/MJD by gene diagnosis. One of the children of the patients was asymptomatic carrier and the fetus also carried the abnormal allele.

InternalMed_Harrison

1. Baylor College of Medicine; Houston, Texas, 1-713-798-6522 http://www.bcm.edu/genetics/index.cfm?pmid=21387 2. GeneDx http://www.genedx.com 3. Transgenomic, 1-877-274-9432 http://www.transgenomic.com/labs/neurology Ataxias with autosomal dominant, autosomal recessive, X-linked, or mitochondrial forms of inheritance are present on a worldwide basis. Machado-Joseph disease (SCA3) (auto somal dominant) and Friedreich’s ataxia (autosomal recessive) are the most common types in most populations. Genetic markers are now commercially available to precisely identify the genetic mutation for correct diagnosis and also for family planning. Early detection of asymptomatic preclinical disease can reduce or eliminate the inherited form of ataxia in some families on a global, worldwide basis.

Huntington's disease

Prenatal testing Obtaining a prenatal diagnosis for an embryo or fetus in the womb is also possible, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation. This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the HTTgene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy, and on the difficulties of a child with the identified gene.

Machado–Joseph disease

Spinocerebellar ataxia type 3 (SCA3) on the Azores are believed to have come from Portugal's northeast where Sephardic Jews lived. Belgium, French-Guiana and Algeria have their own MJD mutation origins. Portuguese have two mutations, while Brazil and France have one mutation, and Germans make up the majority of MJD patients in the United States. Azorean MJD sufferers have their locus on the 14q24.3-32 chromosome, the same as some Japanese with MJD. It was an Azorean, William Machado, whose offspring in New England were the first to be diagnosed with MJD. The Azorean Joseph family, living in California, were also diagnosed with MJD. The same origin for MJD is found in the Azores and in America's north-west coast. Not only Portuguese have it since African Americans, Indians, Italians and Japanese also developed MJD. In China, the mutation causing SCA type 3 has been estimated to have occurred 8,000 to 17,000 years ago.

[Type 2 spinocerebellar ataxia: acceptance of prenatal diagnosis in descendents at risk].

Type 2 spinocerebellar ataxia is a hereditary degenerative disorder of the nervous system. Advances in molecular genetics have made it possible to carry out presymptomatic and prenatal studies. A programme to define the strategies and principles for doing this has been devised. To find the level of acceptance of prenatal diagnosis in couples at risk, and to determine the effect of different variables on this acceptance. We made a descriptive type study of a series of cases. The study group included 226 persons. Forty of these were couples of descendents and the remainder were asymptomatic descendents. We applied a questionnaire, after prior information as to the aims of the study and obtaining the consent of the participants. Regarding acceptance of prenatal diagnosis by couples of descendents, we found that most (77.5%) accepted this and only 2.5% did not. Prenatal diagnosis was accepted by 67.74% of the descendents themselves. In general there was a high level of acceptance. 159 of the 226 questioned claimed that they would like to have more children and 98.7% of these accepted the test, whilst only 0.01% refused it. The main reasons given were the hope of having healthy children and that the disease would not occur in future generations.

[Clinical features and gene mutation analysis in Machado-Joseph disease of spinocerebellar ataxia type 3 in littoral of Zhejiang].

To study the clinical features and gene mutation analysis in Machado-Joseph disease of spinocerebellar ataxia type 3 in littoral of Zhejiang. Clinical manifestation and brain MRI data 18 patients with SCA in family were analyzed. The gene mutations of 18 patients and 10 family numbers without abnormal presentation, and 12 healthy persons of controls. The gene mutations of 18 patients is SCA3/MJD, and 2 asymptomatic SCA3/MJD had been detected in SCA family. Normal alleles of SCA3/MJD have CAG repeats ranging from 14 to 27, patients from 67 to 82, asymptomatic and carrier SCA3/MJD from 28 to 45. The main features of 18 patients included gait ataxia, ambiguity in speech and action clumsiness. Brain MRI showed remarkable atrophy on cerebellum and brain stem. CAG expansions were related to SCA3/MJD. The clinical manifestations are ataxia and dysarthria. The detection of repeated times CAG can provide an effective way for the genetic and asymptomatic diagnosis.

Large normal and intermediate alleles in the context of SCA2 prenatal diagnosis.

In 2001 a program for predictive testing of Spinocerebellar Ataxia type 2 was developed in Cuba, based on the detection of an abnormal CAG trinucleotide repeat expansion in the ATXN2 gene. A descriptive study was designed to assess the implications of ATXN2 large normal and intermediate alleles in the context of the SCA2 Prenatal Diagnosis Program. Four clinical scenarios were selected based upon the behaviour of large normal and intermediate alleles when passing from one generation to the next, showing expansions, contractions, or stability in the CAG repeat size. In some populations, traditional Mendelian risk figures of 0 % or 50 % may not be applicable due to the high frequency of unstable large normal alleles. Couples with no family history of SCA2 may have a >0 % risk of having an affected offspring. Similarly, couples in which there is both an expanded and a large normal allele may have a recurrence risk >50 %. It is imperative that these issues be addressed with these couples during genetic counseling. These recurrence risks have to be carefully estimated in the presence of such alleles (particularly alleles ≥27 CAG repeats), carriers need to be aware of the potential risk for their descendants, and programs for prenatal diagnosis must be available for them.

Imerslund–Gräsbeck syndrome

The disease is autosomal recessive, and can therefore skip generations. Mutations in either amnionless (AMN) or cubilin can be the culprit. Due to its autosomal recessive pattern of inheritance, affected individuals (persons possessing a homozygous recessive genotype) need to undergo genetic counseling to identify the risk of family members who might be heterozygous genetic carriers. Certain mutations on the CUBN or AMN (genes that encode cubilin and amnionless respectively) have been identified through genetic analysis, and ethnic susceptibility of some of the mutations was indicated from the current research. It has been further suggested that mutations on CUBN were restricted to exon 1-28 which encoded amnionless binding domains (EGF) and IF-Cbl binding region of cubilin, while AMN mutations primarily clustered in intron 8-11 and transmembrane domain in exon 10. Some interesting aspects of particular mutations were also elucidated by the researchers, for example, CUBN mutation

Birth after pre-implantation genetic diagnosis (PGD) of spinocerebellar ataxia 2 (Sca2).

Spinocerebellar ataxia 2 (SCA2) is an autosomal-dominant neurodegenerative disease caused by an extended polyglutamine sequence in the ATXN2 protein. We describe the development of a new single-cell multiplex PCR protocol for pre-implantation genetic diagnosis (PGD) of SCA2 and its successful clinical application. Three duplex tests have been developed, one, which combines the detection of the CAG repeats in addition to the D12S821 microsatellite, another, the amplification of the CAG repeats and the D12S1333 microsatellite and the last, the combination of both microsatellites D12S821 and D12S1333. PCR conditions were established using 226 single lymphoblasts or patient lymphocysts. Amplification was obtained in an average of 99.6%, a complete genotype in 86%, a conclusive result in 96% and an allelic drop-out (ADO) rate of 10.7% was observed. PGD for SCA2 was performed for a couple with a paternal risk of transmitting the pathology. Two cycles were done from which 18 embryos were biopsied, 8 were diagnosed as unaffected, 9 as affected and 1 gave no results. In both cycles 2 embryos were transferred, with no pregnancy at the first attempt, and a twin pregnancy at the second attempt. The patient delivered one girl and one boy at 36 weeks and 3 days.