Obviously, it is the only answer that encompasses all the causes of sudden loss of consciousness and that allows us to somehow filter the diagnosis.

Obviously, [HIDDEN] and that allows us to somehow filter the diagnosis.

A 47-year-old male patient who consults the emergency department for sudden loss of consciousness Which of the following has a higher diagnostic yield?

[Syncope: many studies and few diagnoses?].

Syncope is a frequent disorder shows diagnostic difficulties, so that an important percentage of patients remain without diagnosis after the implementation of diagnostic tests that sometimes are unnecessary. A retrospective analysis of the patients admitted during a period of two years because of syncope in an Internal Medicine Service was carried out. Of a total of 2,878 patients hospitalized during the years 1999 and 2000, 79 were admitted because of syncope (2.74%). Forty-five (57%) were men and 34 (43%) were women, with a median age of 68.8 years. Twenty-seven patients (34%) had history of syncope. After a median hospitalization of 9.5 days, the etiological diagnosis was established in 53 (67%) patients: in 25 patients (31.6%) the syncope was mediated by neurological mechanisms, in 16 (20.25%) it was of cardiology origin, in 4 (5.06%) it was of neurological origin and in 8 (10.1%) the syncope was secondary to other causes. In 54 patient (68.8%) at least one cardiology test was carried out (41 Holter, 32 echocardiograms, 6 tilt board tests, 3 maneuvers of massage of the carotid sinus, 3 ergometry studies, 3 electrophysiological studies, 2 coronary angiographies and 3 ventilation perfusion lung gammagraphies). In 51 patient (64%) at least one neurological test was carried out (31 EEG, 42 CT, 2 MNR, 1 Doppler cranial ultrasound and 3 electroneuromyogram). Only 4 of the Holter carried out were diagnostic, as well as 3 of the echocardiograms and only 2 of the CT carried out. No EEG was useful for the etiological diagnosis of the syncope. There is an excessive utilization of some diagnostic tests (EEG, Holter, cerebral CT), in spite of which in an important percentage of patients with syncope the etiological diagnosis is no done (33%). The use of diagnostic algorithms based on detailed clinical history, physical exploration and assessment of the ECG is proposed, that they would make it possible to issue a diagnostic hypothesis from which there could be begun the diagnostic study with a use as rational as possible of the complementary examinations.

Diagnostic yield of syncope investigation (initiated) in the emergency department: a pilot study.

To determine the diagnostic yield of investigations in patients presenting to the emergency department (ED) with syncope. To determine the cause of the syncope. We retrospectively identified consecutive patients presenting to the ED who underwent investigations for syncope at a 1900 bed university teaching hospital during 4 months. From the medical records we abstracted clinical information, results of testing and the cause of syncope. A total of 117 patients participated in the study. The mean age was 57 year (range 6-93 year), and 45% were male. Diagnostic procedures most often performed were blood analysis, ECG, chest X-ray and Holter monitoring (respectively in 94.1%, 88.8%, 74.4% and 36,8% of the patients). The corresponding diagnostic yield for these test was 4.5%, 6.7%, 0% and 16.3%. Other procedures were (% of patients; diagnostic yield): Ct scan of the head (35.1%; 0%), transthoracic echocardiogram (24.8%; 6.9%), ECG monitoring (24.8%; 27.6%), EEG (19.7%; 0%), neurovascular imaging (19.7%; 0%), abdominal ultrasound (11.1%; 0%), Ct scan of the chest (11.1%; 23.1%), head up tilt test (7.7%; 11.1%), carotid sinus massage (3.4%; 0%), pulmonary ventilation perfusion scintigraphy (2.6%; 33%) and exercise test (1.7%; 0%). The most common cause of syncope was neurocardiogenic (58,5% of patients), followed by orthostatic (11.1%), cardiac (11.1%), unknown (9.3%), hyperventilation (3.4%), pulmonary embolism (2.5%), drug related (2.5%) and others (1.7%). Patients admitted in the ED for syncope undergo various investigations. However, the diagnostic yield is poor.The most common cause of syncope is neurocardiogenic, followed by orthostatic and cardiac.

Evaluation and outcome of emergency room patients with transient loss of consciousness.

We identified 198 patients who presented to our emergency room with transient loss of consciousness. Seizures (29 percent of patients) and vasovagal/psychogenic episodes (40 percent of patients) were the most common presumptive causes of loss of consciousness, but the cause of loss of consciousness remained uncertain even at follow-up in 11 +/- 6 months in 13 percent of the patients. The history and physical examinations were sufficient for diagnosis in 85 percent of the patients in whom a diagnosis could be established. These data guided inpatient and outpatient with potentially dangerous causes of loss of consciousness except for one patient who had pulmonary embolism. In selected patient, diagnostic tests such as blood chemistries (three patients), electrocardiograms (four patients) electroencephalograms (three patients), and Holter monitoring (four patients) provided crucial information, and CT scans identified new brain tumors in four patients with focal neurologic presentations. At the time of follow-up, 7.5 percent of patients had suffered either major morbidity or death related to the cause of the index episode of loss of consciousness. Patients with cardiac causes represented a high risk (33 percent) group for such poor outcome, whereas patients who were under age 30, or who were under age 70 and had loss of consciousness on a vasovagal/psychogenic or unknown basis, constituted a low risk (1 percent) subgroup.

[Short loss of consciousness: etiology and diagnostic approach. Results of a prospective study].

Transient loss of consciousness is a frequent reason for hospitalization, but very few prospective studies have been devoted to this topic. Our study involved 150 patients who were admitted for sudden and total loss of consciousness (syncope) with spontaneous return to normality. All patients underwent thorough physical examination, standard laboratory tests, electrocardiography (ECG) and radiography of the chest. Depending on the results of this first evaluation, the patients were investigated for postural hypotension and had carotid sinus massage, electroencephalography (EEG), computerized tomography of the brain, cardiac Holter recording, electrophysiological exploration and, if necessary, other special examinations. The cause of the syncope was found in 93 cases (62 per cent); it was cardiac in 39 cases (bradycardia 25, tachycardia 14), vascular in 20 cases (vagal 14, postural hypotension 6), epileptic "grand mal" type in 32 cases and "miscellaneous" in 2 cases. The syncope occurred in a state of acute drunkenness in 14 cases and was unquestionably due to the absorption of medicines in 6 cases. Clinical findings and ECG or EEG provided the aetiological diagnosis in 82.7 per cent of the patients and the other, sophisticated examinations in 17.3 per cent. These results are similar to those of other prospective studies found in the literature. It may be concluded that the causes of the syncope are only found in about 2 out of 3 cases, that clinical data are all-important in the diagnostic approach and that complementary examinations are either unnecessary or yield little that is not already suggested by clinical examination.

[Head injuries in the pediatric emergency department: a 5-year experience at the Pediatric Clinic of Modena].

We re-evaluated the cases of 436 children with minor head injury admitted in the paediatric department of Modena University Hospital in the years 1991-1995 in order to revise diagnostic and therapeutic protocols. The external lesions, the presence of loss consciousness, vomiting, vegetative reactions, late complications, skull X ray, TC scan and EEG were considered. Signs and symptoms at admission have been faced with instrumental findings and eventual late complications to evaluate the prognostic significance. External lesions and vomiting did not correspond to TC scan and EEG positivity or significant sequelae. A more close connection to these parameters was found when an history of immediate loss of consciousness after trauma, or presence of vegetative reactions. Skull X ray appeared useless both to judge the seriousness of the lesion and to formulate a prognosis. EEG appeared a sensible tool to evaluate the gravity of the trauma and its late consequences. TC has confirmed to be the unique instrument able to solve any diagnostic or prognostic doubt. When symptoms suggest a bad prognosis, diagnostic procedures should be limited to TC and EEG. By our point of view, patients that at admission have a normal neurological examination at the Glasgow Coma Scale, no significant symptoms and signs, an history of a minor impact dynamic and no signs of child abuse, can be discharged from the emergency department; in this case parents should be instructed how to do an observation at home in order to evaluate eventual complications.

Diagnostic yield of neuroimaging in syncope patients without high-risk symptoms indicating neurological syncope.

Diagnostic tests are widely used for patients with syncope in the emergency department (ED). This study aimed to determine the diagnostic yield of neuroimaging in patients with syncope without high-risk symptoms. Adult patients who presented to the ED with syncope in 2016 were screened retrospectively. Patients who suffered from mild head trauma due to syncope were also included. Patients with neurological examination findings (confusion, amnesia, focal neurological deficit, severe headache, dizziness, nausea and vomiting), patients on anticoagulants, patients with known intracranial malignancies and those whose loss of consciousness was attributed to reasons other than syncope were excluded from the study. A total of 1114 patients were included in the study. The median age was 48 years (IQR = 34-66 years) and 576 (51.7%) of the patients were male. The neuroimaging tests performed were cranial computerized tomography (CT) in 694 (62.3%) cases and magnetic resonance imaging (MRI) in 114 (10.2%) cases. Mild head trauma due to syncope was observed in 116 (10.4%) patients. None of the neuroimaging studies revealed any clinically significant findings. Neuroimaging is not beneficial in patients whose medical history and physical examination do not indicate neurogenic syncope, even if the patient has mild head trauma.

Urgent computed tomography brain scan for elderly patients:  can we improve its diagnostic yield?

We conducted a retrospective study of 291 patients aged 75 years or older who were admitted to the emergency department and who underwent a computed tomography (CT) brain scan. Our aims were to assess the reasons for requesting an urgent CT brain scan, to record the diagnostic yield of cerebral imaging, and to seek out predictive factors of an intracranial pathology. The three main reasons for requesting an urgent CT brain scan were the presence of localizing signs (60%), delirium (21%), and disorders of consciousness with a Glasgow Coma Score of less than 14 (14.5%). In our elderly population, we found no typical patient profile when concerned with the risk of having an intracranial pathology. The multivariate logistic regression found that predictive factors for intracranial bleeding were localizing signs, disorders of consciousness with a Glasgow Coma Score of less than 14, head trauma, sudden-onset headache, or headache associated with at least two episodes of vomiting.

The role of EEG in patients with syncope.

EEG is a popular, low-cost examination used in neurologic and nonneurologic evaluations. Nevertheless, the diagnostic usefulness of EEG has some limitations, and it may increase medical costs. The manifestations of syncope may lead to misdiagnoses, and frequently, it is mislabeled as epilepsy. An EEG is usually obtained, yet some studies have suggested that EEGs have little value in diagnosing this condition. We aimed to determine the diagnostic usefulness of EEG in patients with syncope. We retrospectively examined EEG recordings of 10,408 patients. EEG findings were evaluated for all patients with a diagnosis of syncope (syncope, convulsive syncope, loss of consciousness, or sudden unexplained falls), including requests from neurologists and nonneurologists. EEGs were classified into (1) normal, (2) epileptiform discharges (spike/sharp waves), and (3) slow waves. The EEGs were separated according to gender and age. From 1,003 patients with the diagnosis of syncope, 899 (89.53%) were normal, 62 (6.18%) showed bilateral slow waves, 19 (1.89%) right slow waves, 18 (1.79%) epileptiform discharges, and 6 (0.6%) left slow waves. Epileptiform discharges only occurred among females. Left focal sharp waves were disclosed in 18 (50%), generalized discharges in 8 (44.4%), and right focal discharges in 1 (5.6%). Bilateral slow waves were more prevalent among adults. We conclude that EEG is not useful for evaluating the diagnosis of syncope because of its very low diagnostic yield. Patients with syncope must have a correct history and physical examination plus cardiovascular tests.

[Head injuries in children. Considerations on 3,715 consecutive cases].

The authors present their personal experience of 3715 cases of head injury in pediatric patients, occurring during the last three years (1997-1999), admitted to the Emergency ward at the "Anna Meyer" children's hospital in Florence. A prospective study was made, starting from the evaluation made by the paediatric surgeon and following the subsequent diagnostic and clinical course. Depending on the severity of injury, this took the form of immediate discharge with a written sheet of instructions, "short observation" (up to 12 hours) in an Emergency ward and/or admission to neurosurgery or general medicine or to intensive care. The authors also analyse the diagnostic and instrumental tests carried out at the various stages (cranial X-ray, direct cranial CT, EEG) and the specialist consultations required (neurosurgery, neurology, paediatrics, resuscitation). Data for injured children transferred from other hospitals for neurosurgery were excluded from the study which only included patients examined primarily at our hospital. If admitted for more than 48 hours, a neurosurgical outpatient check-up was programmed one week later. In more severe cases, patients were admitted to day hospital between six months and one year later. Injuries were minor in 91% of cases and the age of patients ranged between 5 days and 14 years; moreover, 60% of the patients observed were male. Only 1.5% of cases seen in Emergency were admitted to hospital and 8.4% of all head injuries, with a total stay of between 1 and 6 days. There were 4 deaths in severely polytraumatised patients. There was only one case of firearm injury which was not fatal. Head X-rays were performed in 13.4% of patients showing evidence of fracture in 19.1% of cases. Direct cranial CT was performed in 10.2% of cases with pathological findings in 23.9% of cases. Neurosurgery was performed in one of the 5.9% patients admitted to hospital. The late sequelae to head injury included one case of epilepsy that occurred 7 months after injury. Anamnesis showed that the most frequent reason leading to head injury was lack of adult supervision and that the majority of severe injuries were caused by road accidents, both as pedestrians and as passengers. Lastly, the authors emphasise the importance of recognising and correctly treating so-called secondary cerebral damage, which has a non-immediate onset but is potentially severe, and identifying the risk factors for head injury in order to reduce the incidence and severity.

Cranial computed tomography in the resuscitated patient with cardiac arrest.

The incidence of out-of-hospital and in-hospital cardiorespiratory arrest from all causes in the United States occurs not infrequently. Postresuscitation care should include the identification of the inciting arrest event as well as therapy tailored to support the patient and treat the primary cause of the decompensation. The application of one particular testing modality, cranial computed tomography (CT) of the head, has not yet been determined. We undertook an evaluation of the use of head CT in patients who were resuscitated from cardiac arrest. Prehospital (emergency medical services), ED, and hospital records were reviewed for patients of all ages with cardiorespiratory arrest over a 4-year period (July 1996-June 2000). Information regarding diagnosis, management, and outcome was recorded. The results of cranial CT, if performed, and any apparent resulting therapeutic changes were recorded. Patients with a known traumatic mechanism for the cardiorespiratory arrest were excluded. A total of 454 patients (mean age 58.3 years with 60% male) with cardiorespiratory arrest were entered in the study with 98 (22%) individuals (mean age 58.5 years with 53% male) undergoing cranial CT. Arrest location was as follows: emergency medical services, 41 (42%); ED, 11 (11%); and hospital, 46 (47%). Seventy-eight (79%) patients demonstrated 111 CT abnormalities: edema, 35 (32%); atrophy, 24 (22%); extra-axial hemorrhage, 14 (13%); old infarct, 12 (11%); new infarct, 11 (10%); intraparenchymal hemorrhage, 6 (5%); skull fracture, 5 (4%); mass, 3 (2%); and foreign body, 1 (1%). Therapeutic and diagnostic alterations in care were made in 38 (39%) patients-35 abnormal and 3 normal CTs. The following alterations occurred: medication administration, 26; withdrawal of life support, 7; additional diagnostic study, 6; neurologic consultation, 6; and intracranial pressure monitoring. 4. No patient survived to discharge. In this subset of resuscitated patients with cardiac arrest, abnormalities on the head CT were not uncommon. Alterations in management did occur in those patients with abnormalities. The indications and impact of head CT in the population of resuscitated patients with cardiac arrest remain unknown, warranting further investigation.

Paired receiver operating characteristic curves and the effect of history on radiographic interpretation. CT of the head as a case study.

The use of a statistical technique for paired comparisons using receiver operating characteristic (ROC) curves is illustrated by studying the extent to which clinical history altered the interpretation of computed tomographic (CT) examinations of the head. Eighty-nine CT examinations of the head were presented in random order to four readers, first with minimum history (age and sex) and then several weeks later with complete neurological history as of the time the CT examination had been obtained. Using a paired ROC analysis, a small but significant (p less than .05) improvement was detected for the interpretations in the presence of complete history; for readings without history the average area was 94.4% and for readings with history it was 97.7%.

Healthcare in Belgium

In a general hospital any of the following departments may be at the disposal of patients, but not all general hospitals offer all these facilities and departments: Emergencies and trauma center usually backed up by an intensive care unit. Operating theatres. Polyclinic consultations, ambulance or out-patient care: patients can come during office hours to see a specialist either in the diagnostic phase, therapeutic phase or post-therapy follow-up consultations. Technical diagnostics such as collection of blood or bodily fluid-samples, and lab testing; medical imaging; X-rays, CT-scan, MRI or ultrasound); EEG, ECG and extended monitoring outside acute illness situations; Nursing units: standard hospital ward type of sections where patients get 24/7 care, post-op recovery Specialized units may be sections in a general hospital, independent units within a general hospital or independent specialized clinics: Neo-natal and Pediatric clinics Re-hab and recovery clinics

Syncope-related trauma: rationale and yield of diagnostic studies.

Syncope occasionally occurs in trauma patients. The most appropriate and cost-effective evaluation for such patients is unknown. Trauma patients admitted to a Level I trauma center with a diagnosis of syncope or possible syncope between 1988 and 1994 were reviewed. History, physical examination, and past medical history were noted, as were the results of tests done as part of the syncope evaluation. Eighty-eight patients were reviewed; 45% had been injured in falls. Thirteen patients who remembered their entire injury and denied syncope as a cause had negative evaluations. History, physical examination, and admission laboratory values were helpful in diagnosis 59% of the time. Subsequent evaluation provided useful diagnostic information 30% of the time. No patients with normal admission electrocardiograms (EKGs) had cardiac causes for their syncope. (1) Patients with possible syncope without loss of consciousness require no further evaluation. (2) A cerebrovascular evaluation should be the initial diagnostic approach in patients with signs and symptoms suggestive of stroke or transient ischemic attack. (3) Possible syncope patients with normal admission EKGs should undergo computed tomography of the head and electroencephalography. Those with abnormal EKGs should undergo echocardiography.

Syncope of unknown origin. The need for a more cost-effective approach to its diagnosis evaluation.

The records of 121 patients hospitalized in Presbyterian-University Hospital, Pittsburgh, during 1976 to 1980 for syncope of unknown origin were reviewed. The were 58 men and 63 women, whose mean age was 63.1 years. Cardiac monitoring in 67 patients showed abnormalities in seven patients, considered diagnostic of the cause of syncope. In 13 patients with electrophysiologic studies, four patients had abnormal results, suggesting a probable cause for the syncope. Cardiac catheterization in 14 patients showed significant findings that demonstrated the cause of syncope in three patients. Glucose tolerance tests in 37 patients, head computed tomographic scans in 39 patients, radionuclide brain scans in 15 patients, lumbar punctures in 22 patients, and skull roentgenograms in 46 patients did not aid in the diagnosis of the cause of syncope in any patient. In 67 patients, EEGs produced abnormal results in 26, but the role of EEGs in the diagnostic workup of syncope could not be completely defined. The definitive cause for syncope was diagnosed in only 13 of 121 patients, with an average hospitalization of nine days and an average cost of $2,463 per patient. These findings suggest that an extensive evaluation of syncope is cost--ineffective and that prospective goal-directed approaches need to be developed.

Clinical history in management of suspected syncope: A powerful diagnostic tool.

In this paper, the role of history taking as a diagnostic tool in patients with transient loss of consciousness (TLOC) is addressed. From a literature review it can be demonstrated that, if properly performed, the history is a powerful diagnostic tool, which in the majority of cases proves to be the only 'test' necessary to establish a diagnosis other than physical examination and electrocardiogram in patients with TLOC. In order to substantiate this conclusion, we examine the different levels of history taking according to the skills and training of the physician involved, the diagnostic yield of each level, the methodology, and the influence of the venue and urgency of the case.

The Yield of Computed Tomography of the Head Among Patients Presenting With Syncope: A Systematic Review.

Overuse of head computed tomography (CT) for syncope has been reported. However, there is no literature synthesis on this overuse. We undertook a systematic review to determine the use and yield of head CT and risk factors for serious intracranial conditions among syncope patients. We searched Embase, Medline, and Cochrane databases from inception until June 2017. Studies including adult syncope patients with part or all of patients undergoing CT head were included. We excluded case reports, reviews, letters, and pediatric studies. Two independent reviewers screened the articles and collected data on CT head use, diagnostic yield (proportion with acute hemorrhage, tumors or infarct), and risk of bias. We report pooled percentages, I<sup2</sup , and Cochran's Q-test. Seventeen articles with 3,361 syncope patients were included. In eight ED studies (n = 1,669), 54.4% (95% confidence interval [CI] = 34.9%-73.2%) received head CT with a 3.8% (95% CI = 2.6%-5.1%) diagnostic yield and considerable heterogeneity. In six in-hospital studies (n = 1,289), 44.8% (95% CI = 26.4%-64.1%) received head CT with a 1.2% (95% CI = 0.5%-2.2%) yield and no heterogeneity. In two articles, all patients had CT (yield 2.3%) and the third enrolled patients ≥ 65 years old (yield 7.7%). Abnormal neurologic findings, age ≥ 65 years, trauma, warfarin use, and seizure/stroke history were identified as risk factors. The quality of all articles referenced was strong. More than half of patients with syncope underwent CT head with a diagnostic yield of 1.1% to 3.8%. A future large prospective study is needed to develop a robust risk tool.

A Clinical Challenge in the Emergency Department: A Case of Klebsiella Infective Endocarditis Presenting With Splenic Abscess.

Infective endocarditis (IE) is a serious bacterial infection of the endocardium and/or heart valves that carries considerable morbidity and mortality. Often presenting with very non-specific symptoms, this disease presents many challenges to the emergency medicine practitioner. A 47-year-old male with no pertinent medical history presented to the emergency department complaining of shortness of breath. He stated that his symptoms had been persistent for the last three weeks and were associated with malaise and fatigue. CT of the abdomen/pelvis with IV contrast revealed a 7-cm hypodensity of the spleen concerning for abscess versus infarct. He denied any trauma or IV drug use. Follow-up ultrasound was ordered, which characterized the hypodensity as a splenic abscess. An echocardiogram was recommended for possible IE, and cardiology was consulted. The transthoracic echocardiogram was performed on hospital day 2, which showed minimal mitral valve thickening with mild mitral regurgitation. The interventional radiology (IR) service was consulted for the splenic abscess in order to perform CT-guided drainage. An IR drain was successfully placed on hospital day 3. On the same day, blood cultures grew Klebsiella pneumoniae. On hospital day 5, that patient was transferred to the ICU for possible empyema formation with signs of respiratory distress. The patient underwent CT of the chest that showed the development of a left-sided effusion. The patient had also been persistently tachycardic and febrile, with high leukocytosis since admission and worsening respiratory status. Transesophageal echocardiogram (TEE) was scheduled but put on hold due to worsening respiratory status. Repeat TEE was scheduled five days later, which showed mitral regurgitation and increased size of the vegetation despite antibiotic therapy. Two days later, he was scheduled for mitral valve repair. When reviewing our case, the patient had both common and uncommon aspects of splenic abscess or IE. First, despite having respiratory symptoms for two weeks, the primary reason he came to the hospital was due to the new onset of fevers. He was febrile, tachycardic, and with significant leukocytosis. He continued to have fevers despite antibiotic therapy and IR drainage of the abscess. With no history of IV drug use history, negative transthoracic echocardiography, lack of immunocompromising condition, and blood cultures with gram-negative rods, IE became less likely of a diagnosis.  Establishing the diagnosis of IE proved to be exceptionally complicated, especially in the setting of a COVID-19 pandemic. The most notable challenge was having a high index of suspicion despite any risk factors. The patient was a previously healthy 47-year-old male with no medical problems. IE continues to be a clinical challenge for physicians, especially in the emergency department, due to the lack of diagnostic criteria such as positive blood cultures or vegetations visualized on echocardiographic studies. IE has a wide gamut of presentations with different levels of acuity. Diagnosis is more straightforward when patients present with obvious risk factors, but, in many cases, such as this one, those risk factors may be absent. A high index of suspicion is required, especially in patients with additional findings such as splenic abscess, embolic phenomenon, focal neurologic deficit, mycotic aneurysm, decompensated heart failure, new murmurs, or pleural effusions.

Reliability of the early syndromic diagnosis in adults with new-onset epileptic seizures: A retrospective study of 116 patients attended in the emergency room.

New-onset seizures (NOS) are a common reason for emergency department (ED) consultations. Decisions regarding treatment and further examinations are made based on the initial evaluation. We aimed to evaluate the reliability of the early syndromic diagnosis in NOS and find predictive factors to establish a consistent early diagnosis based on the semiology and prompt supplementary examinations. We recruited patients attended in our ED for NOS over 2 years (2014-2015), excluding patients with a loss of consciousness of suspected non-epileptic origin. All patients were assessed by a neurologist. A baseline diagnosis was established according to clinical findings and neuroimaging/EEG data. Over 1 year of follow-up in our Epilepsy Unit, a definite diagnosis was made based on clinical progress and further examinations. 116 patients were recruited (mean age 56.5 ± 22.1 years; 50% women). 47% were seizures of unknown cause. The concordance index between the baseline and definite diagnosis was κ = 0.662 (the diagnosis changed during follow-up in 25% of patients). Focal epilepsy of unknown cause was the baseline diagnosis that most often changed at follow-up (diagnostic change, 41.2%; p < 0.001). Lesions detected on CT-scanning and EEG abnormalities predicted the final diagnosis with the greatest accuracy (p = 0.009 and p = 0.026, respectively). Pathological findings in the MRI studies performed and seizure recurrence were not key factors for diagnostic changes. Despite prompt examinations, the baseline epilepsy diagnosis changes within a short time period in 25% of patients. The presence of neuroimaging lesions and EEG abnormalities was associated with the greatest diagnostic accuracy in these cases.

Clinical predictors of abnormal head computed tomography scan in patients who are conscious after head injury.

Indication of a head computed tomography (CT) scan in a patient who remains conscious after head injury is controversial. We aimed to determine the clinical features that are most likely to be associated with abnormal CT scan in patients with a history of head injury, and who are conscious at the time of presentation to casualty. This is a prospective observation study of patients presented to casualty with history of head injury, and who were conscious, i.e., Glasgow Coma Scale (GCS) 15 at the time of evaluation. All patients underwent head CT scan. The CT scan was reported as abnormal if it showed any pathology ascribed to trauma. The following variables were used: age, gender, mode of injury (road traffic accident, fall, assault, and others), duration since injury, and history of transient loss of consciousness, headache, vomiting, ear/nose bleeding, and seizures. Logistic regression analysis was used to identify the clinical features that predicted an abnormal CT scan. During the observation period, a total of 1629 patients with head injury were evaluated, out of which 453 were in GCS 15. Abnormal CT scan was present in 195 (43%) patients. Among all the variables, the following were found significantly associated with abnormal CT scan: duration since injury (>12 h) <iP</i < 0.001; vomiting odds, ratio (OR) 1.89 (1.23, 2.80), <iP</i < 0.001; and presence of any symptom, OR 2.36 (1.52, 3.71), <iP</i < 0.001. A patient with GCS 15 presenting after 12 hours of injury with vomiting or combination of symptoms has a significant risk of abnormal head CT scan.

Journal Club: Head CT scans in the emergency department for syncope and dizziness.

The purpose of this study was to determine the yield of acutely abnormal findings on head CT scans in patients presenting to the emergency department with dizziness, near-syncope, or syncope and to determine the clinical factors that potentially predicted acutely abnormal head CT findings and hospital admission. We retrospectively reviewed the electronic medical records of all patients presenting to an HMO emergency department between July 1, 2012, and December 31, 2012, who underwent head CT for a primary complaint of dizziness, syncope, or near-syncope. The primary outcomes were head CT scans with acutely abnormal findings and hospital admission. Binary logistic regression was used to assess the association between clinical variables and acute head CT findings and between clinical variables and hospital admission. Of the 253 patients who presented with dizziness, 7.1% had head CT scans with acutely abnormal findings, and 18.6% were admitted. Of the 236 patients who presented with syncope or near-syncope, 6.4% had head CT scans with acutely abnormal findings, and 39.8% were admitted. The following three clinical factors were found to be significantly correlated with acutely abnormal head CT findings: a focal neurologic deficit (p = 0.003), age greater than 60 years (p = 0.011), and acute head trauma (p = 0.026). Our results suggest that most patients presenting with syncope or dizziness to the emergency department may not benefit from head CT unless they are older, have a focal neurologic deficit, or have a history of recent head trauma.

Diagnostic accuracy and yield of multidetector CT angiography in the evaluation of spontaneous intraparenchymal cerebral hemorrhage.

Multidetector CT angiography (MDCTA) is emerging as the favored initial diagnostic examination in the evaluation of patients presenting with spontaneous intraparenchymal hemorrhage (IPH). This study aims to evaluate the diagnostic accuracy and yield of MDCTA for the detection of vascular etiologies in adult patients presenting to the emergency department with IPH. We conducted a retrospective study of 623 consecutive adult patients presenting to the emergency department with IPH, who were evaluated with MDCTA during a 9-year period. CT angiograms were reviewed by 2 neuroradiologists to determine the IPH site and the presence of a vascular etiology. Patients with associated subarachnoid hemorrhage in the basal cisterns were excluded from the study. Medical records were reviewed for risk factors and correlation with final diagnosis. The diagnostic accuracy of MDCTA compared with conventional angiography, intraoperative evaluation, and pathologic findings was determined, when available. Multiple-variable logistic regression analysis was performed to determine clinical and radiologic factors that predict a higher yield of MDCTA. MDCTA demonstrated a vascular etiology in 91 patients (14.6%), with a sensitivity of 96%, specificity of 99%, and diagnostic accuracy of 98%. We found independent, statistically significant higher yields of MDCTA in patients with the following characteristics: 1) age younger than 46 years (47%); 2) lobar (20%) or infratentorial (16%) IPH, especially lobar IPH with associated intraventricular hemorrhage (25%); 3) female sex (18%); or 4) neither known hypertension nor impaired coagulation at presentation (33%). MDCTA is an accurate diagnostic examination in the evaluation of adult patients presenting with spontaneous IPH and should be performed in all patients with the aforementioned clinical and radiologic characteristics.

High yield criteria and emergency department skull radiography: two community hospitals' experience.

A retrospective analysis of 75 patients admitted with the diagnosis of skull fracture to two community hospitals revealed that 48% of these patients would not have been diagnosed if the high yield criteria recently proposed by the Food and Drug Administration had been adhered to in selecting patients for skull radiography. This included four patients with depressed skull fractures and 32 with linear fractures. The remaining 39 patients had at least one high yielded criterion, the most common being loss of consciousness (21.3%).

Neurocardiogenic syncope and epilepsy in pediatric age: the diagnostic value of electroencephalogram-electrocardiogram holter.

Neurocardiogenic syncope is induced by a hyperrecruitment of parasympathetic nerve tone elicited by emotional stress or pain. The presence of a transient loss of consciousness associated with involuntary motor activity or with urinary incontinence and the misinterpretation of anamnestic data or of electroencephalogram (EEG) abnormalities often leads to wrong diagnosis of epilepsy in children with this disorder.Careful and systematic history taking, pressure measurement, electrocardiogram (ECG), and, in selected cases, head-up tilt table testing are generally enough to rule out a cardiogenic or a neurocardiogenic syncope. Simultaneous EEG-ECG Holter represents a useful instrument for differential diagnosis between neurocardiogenic syncope and epilepsy.We report 3 case reports to demonstrate how simultaneous EEG-ECG Holter can contribute to characterize functional heart-brain interactions and the exact sequence of the physiopathologic events leading to the loss of consciousness in cases in which the clinical borders with epileptic disorders are particularly subtle.

[The value of conventional skull x-rays after head injuries].

A retrospective study was used in an attempt to clarify whether skull fractures or clinical findings can be used for diagnosing intracranial injuries and which clinical features indicate that skull X-rays are unnecessary. 78 patients (1.5%) had a skull fracture and 41 patients (0.8%) had suffered intracranial injuries. Of 57 patients with skull fractures, 40% (23) showed evidence of intracranial injury and 60% (34) did not. Amongst 41 patients with intracranial injuries, 44% (18) failed to show a skull fracture. Patients with a skull fracture (without intracranial injury) showed just as many symptoms as patients without skull fracture. Patients with intracranial injuries most commonly showed neurological deficits, unconsciousness, or required intubation. Any one of these criteria or a combination of these indicated the presence of intracranial injury with a high degree of probability. These criteria permit economy with skull X-rays and indicate when to use other diagnostic means (CT). For this the patient should be mentally quite normal. There should be a definite history and a reliable observation period of 24 hours.

Prospective evaluation of patients with syncope: a population-based study.

To determine the diagnostic yield of a standardized sequential evaluation of patients with syncope in a primary care teaching hospital. All consecutive patients who presented to the emergency department with syncope as a chief complaint were enrolled. Their evaluation included initial and routine clinical examination, including carotid sinus massage, as well as electrocardiography and basic laboratory testing. Targeted tests, such as echocardiography, were used when a specific entity was suspected clinically. Other cardiovascular tests (24-hour Holter monitoring, ambulatory loop recorder ECG, upright tilt test, and signal-averaged electrocardiography) were performed in patients with unexplained syncope after the initial steps. Electrophysiologic studies were performed in selected patients only as clinically appropriate. Follow-up information on recurrence and mortality were obtained every 6 months for as long as 18 months for 94% (n = 611) of the patients. After the initial clinical evaluation, a suspected cause of syncope was found in 69% (n = 446) of the 650 patients, including neurocardiogenic syncope (n = 234, 36%), orthostatic hypotension (n = 156, 24%), arrhythmia (n = 24, 4%), and other diseases (n = 32, 5%). Of the 67 patients who underwent targeted tests, suspected diagnoses were confirmed in 49 (73%) patients: aortic stenosis (n = 8, 1%), pulmonary embolism (n = 8, 1%), seizures/stroke (n = 30, 5%), and other diseases (n = 3). Extensive cardiovascular workups, which were performed in 122 of the 155 patients in whom syncope remained unexplained after clinical assessment, provided a suspected cause of syncope in only 30 (25%) patients, including arrhythmias in 18 (60%), all of whom had abnormal baseline ECGs. The 18-month mortality was 9% (n = 55, including 8 patients with sudden death); syncope recurred in 15% (n = 95) of the patients. The diagnostic yield of a standardized clinical evaluation of syncope was 76%, greater than reported previously in unselected patients. Electrocardiogram-based risk stratification was useful in guiding the use of specialized cardiovascular tests.

Diagnostic patterns and temporal trends in the evaluation of adult patients hospitalized with syncope.

Syncope is a common clinical problem that is often difficult and expensive to diagnose. We examined diagnostic patterns and trends and use of specialty consultations in the evaluation of syncope. We retrospectively reviewed the medical records of consecutive adult patients hospitalized with the principal diagnosis of syncope (International Classification of Diseases, Ninth Revision, code 780.2) during 1994 and 1998 at 2 community teaching hospitals. A total of 649 patients (57% female) with a mean (+/-SD) age of 68 +/- 15 years were identified in 1994 (n = 451) and 1998 (n = 198). Three hundred forty-one patients (53%) underwent at least 1 neurologic test, including brain computed tomographic (CT) scan (n = 283), electroencephalography (n = 253), carotid Doppler echocardiography (n = 185), and brain magnetic resonance imaging (n = 10). Only brain CT scan and electroencephalography yielded diagnoses in 5 (2%) and 6 patients (2%), respectively with history consistent with seizures or stroke. Cardiovascular tests providing the highest diagnostic yields (postural blood pressure check in 52 [30%], head-up tilt-table test in 32 [24%], and electrophysiologic study in 5 [16%]) were used in 176 (27%), 132 (20%), and 31 patients (5%), respectively. Differences in the use of some tests were noted at the participating hospitals and over time (1994 vs 1998). The total number of diagnosed cases was similar for patients undergoing evaluation by primary care physicians alone (65/103 [63%]), compared with cardiology (48/85 [56%]), neurology (29/48 [60%]), or both (81/141 [57%]). After a mean (+/-SD) length of stay of 5 +/- 4 days, 320 (49%) of 649 cases remained undiagnosed. Despite a reduction in the use of some tests (eg, brain CT scan and carotid Doppler) over time, lower-yield neurologic tests were overused and higher-yield cardiovascular tests were likely underused. The untargeted, seemingly random use of specialty evaluations did not seem to contribute to an increase in the overall number of diagnosed cases. Increased use of specific tests directed by history and results of physical examination may improve diagnostic yield and decrease the cost of evaluating syncope.

Computed tomography of the head

Even in emergency situations, when a head injury is minor as determined by a physician's evaluation and based on established guidelines, CT of the head should be avoided for adults and delayed pending clinical observation in the emergency department for children. Many people visit emergency departments for minor head injuries. CT scans of the head can confirm a diagnosis of skull fracture or brain bleeding, but even in the emergency department, such things are uncommon and not minor injuries, so CT of the head is usually not necessary. Clinical trials have shown the efficacy and safety of using CT of the head in emergency settings only when indicated, which would be at the indication of evidence-based guidelines following the physical examination and a review of the person's history.

Recurrent syncope in a hypertensive subject with vascular cognitive impairment and permanent pacemaker.

Syncope following permanent pacemaker (PM) implantation is a nightmare for electrophysiologists. We describe a case of daily recurrent syncope in an 84-year-old man having a dual-chamber pacemaker implanted for complete atrio-ventricular block occurred 4 years before the admission to our department. He had a history of arterial hypertension, parossistic atrial fibrillation, chronic obstructive pulmonary disease, stage-III chronic renal failure, mild vascular cognitive impairment and glaucoma. The initial work-up including electrocardiogram (ECG), repeated PM interrogations, Holter electrocardiogram, blood pressure measurement in orthostatic position, complete blood count, serum glycaemia, electrolytes and thyroid function tests showed normal findings. Syncope occurred in lying position and during 90° left clockwise neck rotation and was associated to pallor, sweating, tonic-clonic seizures and transient self-limited loss of consciousness lasting a few seconds. Electroencephalogram was normal. During continuous ECG monitoring, the right rotation of the head determined a ventricular asystolic pause lasting 9 seconds associated with loss of consciousness. Restoration of sinus rhythm was observed after bringing back the head in axis. The PM interrogation, performed during pacing failure, recorded low impedance of bipolar ventricular lead, suggesting a damage in lead insulation. It is likely that lead movements during clockwise neck rotation produced an intermittent short circuit that prevented sufficient energy delivery to the myocardium with a consequence of sudden loss of capture.

Confirmation of brain death with portable isotope angiography: a review of 204 consecutive cases.

Intravenous isotope angiography is a rapid, safe, and specific bedside test for confirming brain death by demonstrating the lack of critical cerebral perfusion that occurs in this condition, regardless of etiology. A review of 204 consecutive cases of suspected brain death studied with isotope angiography has reaffirmed our confidence in the specificity of the technique and has convinced us to make less stringent our radiographic criteria for confirming brain death by this method. A technically satisfactory single flow study that shows arrest of the carotid circulation at the base of the skull and absence of the intracranial arterial circulation may be considered confirmatory of a carefully established clinical diagnosis of brain death, even though there may be some visualization of the intracranial venous sinuses. Arbitrary waiting periods, withdrawal of sedative drugs, and electrophysiological studies are not needed when this technique is used.

Efficacy of implantable loop recorders in establishing symptom-rhythm correlation in young patients with syncope and palpitations.

To evaluate efficacy of the recently introduced implantable loop recorder (ILR) in establishing symptom-rhythm correlation in young patients with syncope, near syncope, palpitations, and acute life-threatening events (ALTEs). A retrospective study was conducted with patients with ILR from 3 pediatric centers. Inclusion criteria were age <or=25 years and a minimum follow-up of 1 month. All ILR-stored events were analyzed regularly for the presence or absence of an arrhythmia at the time of the symptomatic event. Twenty-one patients (12 male, 9 female) with an average age of 12.3 +/- 5.3 years (range: 0.8-22 years) were included in the study. Five (24%) patients had structural heart disease, 2 (10%) had a family history of sudden cardiac death, 3 (14%) had QT prolongation on electrocardiogram, and 11 had no cardiovascular disease. Indications for ILR were recurrent syncope and near syncope (n = 15), palpitations (n = 2), and ALTE (n = 2). Fourteen (67%) patients continued to have symptoms, and 7 (33%) had no symptoms after ILR over a follow-up period of 8.4 +/- 4.7 months (range: 1.9-16 months). Symptom-rhythm correlation was possible in all 14 patients who continued to have symptoms (supraventricular tachycardia in 4, ventricular tachycardia in 2, torsades de points in 1, asystole in 1, junctional bradycardia in 1, and sinus rhythm in 5). ILR is useful in determining the presence or absence of an arrhythmia during symptoms of syncope, near syncope, and palpitations as well as ALTEs in patients with and without structural heart disease when conventional diagnostic testing, such as electrocardiogram, Holter monitoring, and/or external loop recording, is inconclusive.

The fainting patient. First and foremost, a meticulous evaluation.

It is sobering to consider the vast spectrum of causes of syncope. It is fortunate, however, that 30% to 74% of cases are assigned the correct cause on the basis of a thorough history and physical examination. However, a shotgun approach to evaluation is costly and may expose the patient to unnecessary risk and concern. Examples of diagnostic excess are routine CT scanning of the head and routine EEG, both of which have a very low yield on routine use. These procedures should only be used if they are necessary to answer questions raised by the initial evaluation.

S1-induced vasospastic angina-diagnostic utility of Holter ECG: a report of a case.

Vasospastic angina is a rare but potentially life-threatening adverse event (AE) of S1, an oral fluoropyrimidine anticancer agent. However, this AE is not well known owing to its low incidence. We report herein a case of a patient who suffered from vasospastic angina associated with S1 chemotherapy for unresectable gastric adenocarcinoma, along with a review of the literature. A 68-year-old woman was endoscopically diagnosed with gastric adenocarcinoma of the diffuse type. Abdominal pelvic contrast-enhanced computed tomography (CT) revealed small nodules in the omentum and ascites in the pouch of Douglas. The patient was clinically diagnosed with unresectable gastric adenocarcinoma with peritoneal metastasis, and primary chemotherapy with S1 plus cisplatin was selected. Around midnight of day 1, the patient complained of sudden oppressive chest pain. The pain disappeared spontaneously after 3-5 min, but similar events happened every midnight thereafter. No significant change was found on bedside electrocardiograms (ECGs) recorded immediately after the pain attacks. The patient was suspected to have unstable angina and underwent Holter ECG on day 4 of treatment. Holter ECG revealed ST segment elevations and short-run ventricular tachycardia during a pain attack. S1 chemotherapy was discontinued, and no attack was observed thereafter. Coronary CT angiography showed no significant stenosis of coronary arteries. Clinicians should be aware of vasospastic angina as a serious AE in the chemotherapy with S1. Holter ECG is useful for the early diagnosis of this rare and clinically important AE.


The maternal grandmother carried the mutation in one copy of the gene on an X chromosome (we are not told that she had the disease, but a son of hers, Isabel's maternal uncle, did have the disease). Isabel's mother continues to carry it, since one of Isabel's brothers has suffered from the disease but not her father. Thus, Isabel has a 50% chance of having inherited the mutated gene from her mother (as her children are all healthy, we are not sure if she is a carrier), and therefore her daughter has a 25% chance of having inherited the mutated gene from her grandmother.

Elizabeth has three sons and one daughter (Mary), all of whom are healthy. A brother and a maternal uncle of Isabel died of Duchenne disease: an X-linked recessive disease. At present, Maria wants to become pregnant and wants to know the risk of transmitting the disease to her offspring. With the data collected, what is the probability that Maria is a carrier of Duchenne disease?

Preimplantation genetic diagnosis

In the case of families at risk for X-linked diseases, patients are provided with a single PGD assay of gender identification. Gender selection offers a solution to individuals with X-linked diseases who are in the process of getting pregnant. The selection of a female embryo offspring is used in order to prevent the transmission of X-linked Mendelian recessive diseases. Such X-linked Mendelian diseases include Duchenne muscular dystrophy (DMD), and hemophilia A and B, which are rarely seen in females because the offspring is unlikely to inherit two copies of the recessive allele. Since two copies of the mutant X allele are required for the disease to be passed on to the female offspring, females will at worst be carriers for the disease but may not necessarily have a dominant gene for the disease. Males on the other hand only require one copy of the mutant X allele for the disease to occur in one's phenotype and therefore, the male offspring of a carrier mother has a 50% chance of

[The use of Bayes theorum in genetic counseling in cases of Duchenne muscular dystrophy].

Bayes' law or theorem (1763) allows the expression of a posterior probability of heterozygosity for an X-linked gene, from two different kinds of information, namely: 1. the prior probability for the mother of an isolated case of Duchenne muscular dystrophy: --to be a carrier by mutation of the gene in one of her parents, or by segregation from earlier generations; --to be herself the origin of the mutation; 2. conditional probabilities, taking into consideration the existence of this woman's normal brothers, sons or maternal uncles and the serum creatine-kinase levels in the possible carrier(s) of the mutant gene. In some situations, these calculations give a recurrence risk which is lower than expected at first and allows sometimes to reassure anxious consultants on their genetic risk.

[Carrier detection of Duchenne/Becker muscular dystrophy by analysis of STRs loci linked to the gene of dystrophin in Venezuelan families].

The Duchenne/Becker Muscular Dystrophy (DMD/BMD) is an X linked recessive lethal disease. The female carrier will transmit the disease gene to half of her sons and half of her daughters; half of the daughters will be carriers, while half will be normal. Half of the sons will be normal and, on average, half will have the disease. It is of particular relevance to be able to detect carrier status among female relatives of the patients for genetic counseling and prenatal diagnosis. The method of Short Tandem Repeat (STR) sequence polymorphism analysis can determine haplotype at normal status or at risk status and, to establish genetic linkage between the mutated gene and the segregated haplotype. We have analyzed 105 members from 15 unrelated Venezuelan families with one or more siblings affected with DMD/DMB and 7 unrelated males. Of the 105, 37 were male (26 affected and 11 normal) and 68 were female. STR sequences (STR44, STR45, STR49, STR50, STR3'DYS) of the gene of the Dystrophin were amplified by polymerase chain reaction (PCR) to analyze allelic polymorphism in the families. Five of the 15 families (33%) had a deletion of one or several of the exons. Of the 68 females, 27 (39.7%) were carriers, 27 (39.7%) were non-carriers and in 14 cases (20.58%) it was not possible to reach a definitive diagnosis. The definitive diagnosis could be established in 79% of the females. This analysis also shows that the mutation occurred on the grandpaternal X chromosome in one family. Hemizygocity was detected and carrier status ascertained in the mother of other patient and in one family we were able to do prenatal diagnosis. The germinal mosaicism could not be excluded in 3 patients.

Obstentrics_Williams

Incest is defined as a sexual relationship between first-degree relatives such as parent-child or brother-sister and is universally illegal. Progeny of such unions carry the highest risk of abnormal outcomes, and older studies reported that up to 40 percent of ofspring were abnormal as a result of recessive and multifactorial disorders (Baird, 1982; Freire-Maia, 1984). Most X-linked diseases are recessive. Common examples include color blindness, hemophilia A and B, and Duchenne and Becker muscular dystrophy. Males with an X-linked recessive gene are usually afected by the disease it causes, because they lack a second X chromosome to express the normal dominant gene. A male with an X-linked disease cannot have afected sons because they cannot receive his X chromosome. When a woman carries a gene causing an X-linked recessive condition, each of her sons has a 50-percent risk of being afected, and each daughter has a 50-percent chance of being a carrier.

[Carrier diagnosis and prenatal prognosis using DNA analysis in X-chromosome-linked Duchenne and Becker muscular dystrophy].

Haplotypes for 7 flanking and 16 "intragenic" X-linked DNA polymorphisms were determined in 204 members of 31 families with Duchenne (DMD) and 27 members of 4 families with Becker type muscular dystrophy (BMD) and combined with CK and pedigree data to estimate carrier and fetal risks. All of the 27 younger female relatives of the familial cases (8 DMD, 2 BMD) could either be identified (11) or ruled out (16) as carriers with 95% or higher probability. Out of 49 possible carriers in the 23 DMD and 2 BMD families with isolated cases, 19 were classified as carriers and 18 as homozygote-normal females. In 3 families the mutation could be traced indirectly to a defined ancestor (mother, grand-parent), and in 5 families a molecular deletion was found. In all identified carriers and in medium risk females an informative DNA-constellation for prenatal predictions was present for at least one "intragenic" or two flanking markers. Prenatal DNA-investigations were carried out during pregnancy in 9 possible DMD carriers. There was one termination due to an XYY karyotype. Of the remaining 8 cases, the carrier state could be ruled out in 4 mothers, the fetal sex was female in another 3, and one male fetus was predicted normal. All babies (3 boys, 5 girls) are healthy. The practical significance of these findings with regard to the prevention of DMD/BMD and the present diagnostic strategies are discussed.

Lesch–Nyhan syndrome

If a woman is the first in her family with an affected son, Haldane's rule predicts a 2/3 chance that she is a carrier and a 1/3 chance that the son has a new germline mutation. The risk to siblings of an affected individual depends upon the carrier status of the mother herself. A 50% chance is given to any female who is a carrier to transmit the HPRT1 mutation in each pregnancy. Sons who inherit the mutation will be affected while daughters who inherit the mutation are carriers. Therefore, with each pregnancy, a carrier female has a 25% chance of having a male that is affected, a 25% chance of having a female that is a carrier, and a 50% chance of having a normal male or female. Males with LNS do not reproduce due to the characteristics of the disease. However, if a male with a less severe phenotype reproduces, all of his daughters are carriers, and none of his sons will be affected. Pathophysiology

How does the mode of inheritance of a genetic condition influence families? A study of guilt, blame, stigma, and understanding of inheritance and reproductive risks in families with X-linked and autosomal recessive diseases.

While the mode of inheritance of a genetic condition has long been considered to have not only medical, but also psychosocial consequences for families, this supposition has never been tested. We surveyed 112 members of 51 families (59% response) with chronic granulomatous disease to determine the influence of mode of inheritance on parents', siblings', and patients' (1) knowledge of inheritance and reproductive risk; (2) concern about risk to future family-members; (3) feelings of guilt and blame; and (4) feelings of stigmatization. Ninety-six members of 51 families (49% response) with Duchenne/Becker muscular dystrophy and spinal muscular atrophy types II/III were also studied. X-linked families had better understanding of inheritance (P < 0.001) and reproductive risks (P < 0.01). X-linked mothers worried more about risks to future generations; other autosomal-recessive family members were as worried. X-linked mothers were more likely to feel guilty (P < 0.01) and blame themselves (P < 0.001). X-linked fathers blamed their child's mother (P < 0.05) and X-linked mothers felt more blamed by the father (P < 0.01). X-linked family-members were more likely to consider being a carrier stigmatizing (P < 0.05). When providing genetic counseling, attention should be given to guilt and blame in X-linked families and understanding reproductive risks in autosomal recessive families.

[Genetic counseling of parents of children with eye diseases].

What is the empirical risk for children to be born with a disease or a malformation? In healthy families, the parents being normal, the probability is 2 to 4% and when the parents are first cousins, although healthy, it is 5%. Of course, the risk is greater in affected families. When the mother or the father is affected and when there is no consanguinity, the risk is 20%, but when the parents are first cousins, it is 32,5%. When the two parents are affected, it is 100%. When the parents are normal, but when already one child is affected, the risk for the other children is 25%. When the mother or the father is affected and when there is already one child affected, the risk for the other children is 50%. When a grand parent is affected, the risk for the grand children is 10%. When an aunt or an uncle is affected, the risk for the nephews and nieces is 7%. In the case of genetic counseling, the parents must understand that no physician can guarantee that a child will be normal. On the other side, they must understand that the mendelian risks are the same for each pregnancy. Finally, they must know that at each birth there is a risk of 2 to 4% of having a major congenital anomaly. On the human and psychological point of view, the physician must convince the parents that they are not responsible and that, if a woman may be a gene carrier, the husband may also carry pathological genes, as each individual carries 2 to 10 pathological recessive genes. Finally, it is not the geneticist who has to impose a procreative decision. Only the parents have to decide if they want or do not want other children.

Genetic disorder

X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch–Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red–green color blindness. X-linked recessive conditions can sometimes manifest in females due to

[Manifesting carriers of Duchenne muscular dystrophy over two generations].

We report a family with manifesting DMD carriers over two generations. Sixty years old female (case 1) suffered from slowly progressive weakness since her thirties. Her youngest daughter aged 30 (case 2) had cramping calf muscle pain since her 5 years old. Progressive muscle weakness developed and lost her ambulation by the age of 20. Grandson of case 1 (son of case 1's eldest daughter who has no clinical symptoms) was diagnosed as DMD with deletion of exon 19-21 in dystrophin gene. Case 1 and case 2 were revealed to be DMD carriers. We speculate that, in this family, X-inactivation process was not random and paternal X was preferentially inactivated by maternal mutant X.

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients--10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

DUCHEN: an interactive computer program for calculating heterozygosity (carrier) risks in X-linked recessive lethal diseases, and its application in Duchenne muscular dystrophy.

The program DUCHEN calculates the probability that a woman is a carrier of an X-linked, lethal recessive disease on the basis of information in the woman's family and any available biochemical data. It is easily used by persons without computer knowledge or experience. The present version can accommodate families consisting of up to 100 people in seven generations. Risks may be estimated on the basis of pedigree information only, or with the inclusion of one or more types of biochemical test results. Biochemical data are incorporated with pedigree information into final risks using the powerful statistical technique of logistic discrimination, a procedure particularly suited for the separation of non-normal populations on the basis of overlapping quantitative characteristics. Mutation rates are specified separately for males and females. DUCHEN is available in FORTRAN 77, IBM BASIC, and Applesoft BASIC, and may be used on a variety of mainframe or microcomputers. The model was used to calculate risks for 375 girls and women in 46 families with Duchenne muscular dystrophy (DMD); serum creatine kinase tests had been carried out on 167 of these subjects who were of reproductive age. Carrier probabilities equal to or lower than the population risk (0.0004) were obtained for 21% of the aunts and 43% of the cousins of affected boys from families with an isolated case of DMD and for 14% of the cousins of affected boys from families with a known DMD history. DUCHEN should assist counsellors in determining which members of large families should be further examined using either standard biochemical carrier detection methods or DNA marker studies.(ABSTRACT TRUNCATED AT 250 WORDS)

First_Aid_Step1

Aa  risk in consanguineous families. Unaffected individual with affected sibling has 2/3 probability of being a carrier. X-linked recessive Sons of heterozygous mothers have a 50% Commonly more severe in males. Females chance of being affected. No male-to-male usually must be homozygous to be affected. transmission. Skips generations. transmit to all daughters but no sons. XXXXXXXYXYXYXXXXXXXYXYXY X-linked dominant Transmitted through both parents. Mothers Examples: fragile X syndrome, Alport syndrome, transmit to 50% of daughters and sons; fathers hypophosphatemic rickets (also called X-linked hypophosphatemia)—phosphate wasting at proximal tubule • rickets-like presentation. Mitochondrial Transmitted only through the mother. All inheritance offspring of affected females may show signs of disease. Variable expression in a population or even within a family due to heteroplasmy.

Recurrence risk due to germ line mosaicism: Duchenne and Becker muscular dystrophy.

The presence of multiple affected offspring from apparently non-carrier parents is caused by germ line mosaicism. Although germ line mosaicism has been reported for many diseases, figures for recurrence risks are known for only a few of them. In X-linked Duchenne and Becker muscular dystrophies (DMD/BMD), the recurrence risk for non-carrier females due to germ line mosaicism has been estimated to be between 14% and 20% (95% confidence interval 3-30) if the risk haplotype is transmitted. In this study, we have analyzed 318 DMD/BMD cases in which the detected mutation was de novo with the aim of obtaining a better estimate of the 'true' number of germ line mosaics and a more precise recurrence risk. This knowledge is essential for genetic counseling. Our data indicate a recurrence risk of 8.6% (4.8-12.2) if the risk haplotype is transmitted, but there is a remarkable difference between proximal (15.6%) (4.1-27.0) and distal (6.4%) (2.1-10.6) deletions. Overall, most mutations originated in the female. Deletions occur more often on the X chromosome of the maternal grandmother, whereas point mutations occur on the X chromosome of the maternal grandfather. In unhaplotyped de novo DMD/BMD families, the risk of recurrence of the mutation is 4.3%.

Obligate carrier

In X-linked recessive disorders, only females can be the carriers of the recessive mutation, making them obligate carriers of this type of disease. Females acquire one X-chromosome from their father and one from their mother, and this means they can either be heterozygous for the mutated allele or homozygous. If heterozygous, she is a carrier of the mutated allele because the disease is recessive. If homozygous, she has the disease. An affected father with an X-linked recessive trait will always pass the trait on to the daughter. Therefore, all daughters of an affected male are obligate carriers. On the other hand, a carrier mother has a 50% chance of passing her mutated X-chromosome to the daughter. This makes all daughters of carrier mothers possible carriers but not necessarily obligate carriers. Males cannot be obligate or possible carriers of X-linked recessive traits because they only have one X-chromosome, and so are always phenotypically affected when receiving the mutated

Genetic counseling of isolated carriers of Duchenne muscular dystrophy.

It has recently become possible to detect female carriers of Duchenne muscular dystrophy with no affected male relative in the family. These "isolated carriers" represent about 10% of women with high serum creatine phosphokinase (CPK) levels and clinical evidence of a muscle disease. Most isolated carriers ascertained by clinical and/or CPK levels and diagnosed by dystrophin immunostaining of muscle biopsy show symptoms of a muscular dystrophy, and often carry the diagnosis of recessive "limb-girdle muscular dystrophy" prior to dystrophin analysis. It has been difficult to offer genetic counseling and prenatal diagnosis for Duchenne muscular dystrophy in the families of these isolated carriers, largely due to the difficulty in determining which of the dystrophin alleles segregating in the family harbors the mutation in the heterozygote. Here we report genetic counseling of three isolated carriers and their families. In two cases, prenatal diagnosis of at-risk pregnancies was conducted. We determined X inactivation patterns and inheritance of X chromosomes in each family, and used this information to define the at-risk dystrophin gene. In all three families, the mutation was a de novo event, two in the paternal germ-line, and one in the maternal germ-line. In each case we show that sibs of the heterozygous woman are at population risk, while pregnancies of each propositus are at high risk. Our results show that accurate genetic counseling and prenatal diagnosis can be offered to these families.

Duchenne Muscular Dystrophy: a Survey of Perspectives on Carrier Testing and Communication Within the Family.

Carrier testing is widely available for multiple genetic conditions, and several professional organizations have created practice guidelines regarding appropriate clinical application and the testing of minors. Previous research has focused on carrier screening, predictive testing, and testing for X-linked conditions. However, family perspectives on carrier testing for X-linked lethal diseases have yet to be described. In this study, we explored communication within the family about carrier testing and the perspectives of mothers of sons with an X-linked lethal disease, Duchenne muscular dystrophy (DMD). Twenty-five mothers of sons with DMD participated in an anonymous online survey. Survey questions included multiple choice, Likert scale, and open ended, short answer questions. Analysis of the multiple choice and Likert scale questions revealed that most mothers preferred a gradual style of communication with their daughters regarding risk status. In addition, most participants reported having consulted with a genetic counselor and found it helpful. Comparisons between groups, analyzed using Fisher's exact tests, found no differences in preferred style due to mother's carrier status or having a daughter. Thematic analysis was conducted on responses to open ended questions. Themes identified included the impact of family implications, age and maturity, and a desire for autonomy regarding the decision to discuss and undergo carrier testing with at-risk daughters, particularly timing of these discussions. Implications for genetic counseling practice are discussed.

Genetics, X-Linked Inheritance -- Introduction -- X linked Recessive Inheritance

RISK CALCULATION: The X chromosome from a male is transmitted to daughters, and the Y chromosome is transferred to sons. If an affected male has kids with a healthy female, none of his male offsprings will be affected, but all of his female offspring will be carriers.  If a carrier female has kids with a healthy male, each male offspring has a 50% chance of being affected, and female offspring have a 50% chance of being a carrier.

Preimplantation genetic diagnosis

the disease. Males on the other hand only require one copy of the mutant X allele for the disease to occur in one's phenotype and therefore, the male offspring of a carrier mother has a 50% chance of having the disease. Reasons may include the rarity of the condition or because affected males are reproductively disadvantaged. Therefore, medical uses of PGD for selection of a female offspring to prevent the transmission of X-linked Mendelian recessive disorders are often applied. Preimplantation genetic diagnosis applied for gender selection can be used for non-Mendelian disorders that are significantly more prevalent in one sex. Three assessments are made prior to the initiation of the PGD process for the prevention of these inherited disorders. In order to validate the use of PGD, gender selection is based on the seriousness of the inherited condition, the risk ratio in either sex, or the options for disease treatment.

InternalMed_Harrison

x-linkeD DisorDers Males have only one X chromosome; consequently, a daughter always inherits her father’s X chromosome in addition to one of her mother’s two X chromosomes. A son inherits the Y chromosome from his father and one maternal X chromosome. Thus, the characteristic features of X-linked inheritance are (1) the absence of father-to-son transmission, and (2) the fact that all daughters of an affected male are obligate carriers of the mutant allele (Fig. 82-13C). The risk of developing disease due to a mutant X-chromosomal gene differs in the two sexes. Because males have only one X chromosome, they are hemizygous for the mutant allele; thus, they are more likely to develop the mutant phenotype, regardless of whether the mutation is dominant or recessive. A female may be either heterozygous or homozygous for the mutant allele, which may be dominant or recessive. The terms X-linked dominant or X-linked recessive are therefore only applicable to expression of the mutant

Prenatal diagnosis and detection of carriers with DNA probes in Duchenne's muscular dystrophy.

We performed genetic analyses for the prenatal diagnosis of Duchenne's muscular dystrophy and detection of the carrier state in five families with seven pregnancies at risk for the disease. As genetic markers for the disorder, we used DNA-sequence polymorphisms detected with 12 different DNA probes derived from the vicinity of the Duchenne's muscular dystrophy locus or from within the gene, on the X chromosome. One male fetus of a proved carrier mother was predicted to be unaffected, and this was confirmed after birth. Another male fetus was predicted to be unaffected (probability, 95 percent or greater), although a crossover event had been identified in a region of the X chromosome thought to be distal to the Duchenne gene. Unfortunately, an elevated serum creatine kinase level after birth indicated that the infant had inherited the Duchenne mutation. Three male fetuses predicted to be affected with 66 percent or 95 percent probabilities were aborted, and the presence of the DNA-marker alleles was confirmed in fetal tissues. In one family, in which the maternal grandparents were unavailable, the initial genetic interpretation had to be revised after a second male fetus was analyzed with intragenic probes. Our experience suggests that despite the large number of intragenic and flanking DNA polymorphisms available, uncertainties often remain in the prenatal diagnosis of Duchenne's muscular dystrophy. Pitfalls are presented by the large size of the region in which Duchenne's mutations can occur. Crossover events in this region, which result in an exchange of DNA between two X chromosomes, can render DNA-marker studies inaccurate. Also, an autosomal recessive mutation can produce the same clinical picture.

The Process of Disclosure: Mothers' Experiences of Communicating X-Linked Carrier Risk Information to At-Risk Daughters.

When a boy is diagnosed with an X-linked condition such as Duchenne or Becker muscular dystrophy (D/BMD), the mother learns not only of her own potential carrier risk but also that of her daughters. Before the daughters are seen in the Genetics Clinic, responsibility for disclosing carrier risk information falls mainly to their mothers. We know little about if when and how these daughters are being told about their risk, and how mothers find the experience. Should we be doing more to help and support them? Using qualitative methods, six mothers known to the Manchester Centre for Genomic Medicine were interviewed about the disclosure of D/BMD carrier risk information to their daughters. The four key themes that arose are presented: communication process, facilitators of disclosure, barriers to disclosure and support and information. Despite the participants' endeavours to be open and honest with their daughters and their belief that they had fully disclosed, key information was often withheld. Major barriers to discussion of the future, including reproductive options, were apparent. These were partly overcome by the involvement of genetic counsellors (GCs). The participants suggested a greater involvement of GCs, proactively sending appointments and written information, and offering carrier testing more flexibly.

Sex differences in medicine

Prostate cancer, testicular cancer and other diseases of the male reproductive system occur in men. Diseases of X-linked recessive inheritance, such as colour blindness, occur more frequently in men, and haemophilia A and B occur almost exclusively in men. The presence of a single X chromosome in males (rather than two in females) may explain why males are more susceptible to genetic diseases linked to the X chromosome, including hemophilia, Duchenne muscular dystrophy, and Hunter syndrome. Certain neurodegenerative diseases (Parkinson's disease (2:1 ratio) and Lewy body dementia (4:1 ratio)) are more prevalent in males. Parkinson's also displays phenotypic differences: males are more likely to present with sleep disturbances and deficits in verbal fluency and facial expression. Abdominal aortic aneurysms are six times more common in men, and thus some countries have introduced screening for males at risk of suffering the condition.

CLCN5

Genetic testing is useful to determine the status of healthy carrier in the mother of an affected male. In fact, being Dent disease an X-linked recessive disorder, males are more frequently affected than females, and females may be heterozygous healthy carrier. Due to skewed X-inactivation, female carriers may present some mild symptoms of Dent disease such as low-molecular-weight proteinuria or hypercalciuria. Carriers will transmit the disease to half of their sons whereas half of their daughters will be carriers. Affected males do not transmit the disease to their sons since they pass Y chromosome to males, but all their daughters will inherited mutated X chromosome. Preimplant and prenatal genetic testing is not advised for Dent disease 1 since the prognosis for the majority of the patients is good and a clear correlation between genotype and phenotype is lacking. See also Chloride channel Notes References Further reading External links Ion channels

Prenatal diagnosis of hemophilia A by DNA analysis of chorionic villi.

Hemophilia A is an X-linked recessive single gene disease. If a female is a carrier, her sons have a 50% risk of being affected. Five gravidas, each with a positive family history of hemophilia A, were collected for prenatal diagnosis using DNA analysis on chorionic villi. We used two closely linked extragenic DNA markers, St14 and DX13, and three restriction enzymes, TaqI, MspI, and BglII, to study four restriction fragment length polymorphisms in the Xq28 region. From family analysis, haplotypes were constructed to track the inheritance of X-chromosomes. In family 1, the male fetus inherited the X-chromosome from his normal grandfather, thus his probability of being affected was predicted to be less than 5%. In families 2 and 3, the gravidas inherited the maternal X-chromosome with a different haplotype from that of the affected brother or nephew, thus they both have a low probability (less than 5%) of being carriers. In family 4, the gravida and her male fetus inherited the same X-chromosome as her affected brother. With coagulation assay also showing a high probability of the gravida being a carrier, the fetus was at high risk for the disease. On pregnancy termination, fetal plasma analysis confirmed the diagnosis. In family 5, the gravida's mother had homozygous haplotypes, making the distinction between two X-chromosomes impossible. Coagulation assay classified the gravida as a probable carrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Duchenne muscular dystrophy in Wales: a 15 year study, 1971 to 1986.

A register of families with Duchenne muscular dystrophy (DMD) in Wales was set up in 1973 and has been regularly maintained ever since. All women at significant risk in these families were offered estimation of their carrier status by creatine kinase and pedigree analysis. A total of 225 of the 512 women tested was assigned a risk of carrying the DMD gene of less than 5%. One hundred and twenty live births from this group were notified to the register and only one was an affected male. This was the expected number and shows that the risks given were largely accurate. Women given a risk of 5% or greater were offered fetal sexing with termination of any male. Amniocentesis was of limited value and chorionic villus sampling, introduced in 1984, was acceptable to more women at risk. The incidence of DMD in Wales dropped from one in 3435 at the beginning of the study to one in 4046 by 1982, and the proportion of recurrent cases from 40% to 22%. Common reasons for recurrence were birth of a second affected boy before diagnosis of the first, and failure of families with affected dead members in previous generations to be notified to the register. Maintaining an accurate register of DMD families is an essential tool in their management.

Duchenne muscular dystrophy: data from family studies.

In an extensive epidemiological survey of Duchenne muscular dystrophy carried out in Venetia (Italy) the incidence was found to be 28.2 X 10(-5) and female gamete mutation rate was estimated by the direct method between 61 and 35 X 10(-6). The percentage of isolated cases was 0.54. Indirect and direct estimates of this proportion suggest, however, that only a minor fraction arises from maternal mutation (from 0.11 to 0.18 of the total number of cases). Studies on pedigrees collected in the course of the survey indicate that there is a higher frequency of Duchenne carrier females than normal females in affected sibships. Additional evidence supporting the hypothesis of a reproductive heterozygote advantage and gametic selection is reported.

Klinefelter syndrome

The testicles of affected males are usually less than 2 cm in length (and always shorter than 3.5 cm), 1 cm in width, and 4 ml in volume. XXY males are more likely than other men to have certain health problems, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis. In contrast to these potentially increased risks, rare X-linked recessive conditions are thought to occur less frequently in XXY males than in XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

No reason for a reduction in the number of offspring per sperm donor because of possible transmission of autosomal dominant diseases.

A limit of 25 offspring per sperm donor has been imposed in The Netherlands since 1992, in order to prevent children from donors having a greater risk of consanguineous relationships than would occur in random individuals. An incident with a donor who developed a serious hereditary brain disease raised the question whether the limit of 25 should be reduced. Here I consider this suggestion from a genetic, psychological and legal standpoint. There appears to be no valid population genetics argument for limiting the number of donor offspring to below the figure that would prevent an increased chance of inbreeding. Reduction of the number of children per donor theoretically only results in transmission of greater diversity to donor offspring. Moreover, as within the general population, the total number of children conceived from sperm donors is negligible, the impact of donor offspring on the population genetics is anyhow insignificant. From a psychological standpoint, it should be noted that individuals making use of a donor, or their offspring, have no knowledge of other offspring conceived with their particular donor. This implies that the number of offspring per donor is of no relevance to them (provided of course there is an acceptably low chance of inbreeding). The new Dutch law on disclosure of donor identity to donor-insemination children, also produces no compelling reasons for a general reduction in the number of offspring per donor. Reduction desired by individual donors can be obtained by means of mutual agreements between sperm banks and donors. In conclusion neither the possible transmission of late-onset autosomal dominant diseases, nor other considerations necessitate a reduction in the offspring limit calculated to prevent increased risks of inbreeding among donor offspring.

Preimplantation genetic diagnosis

Monogenic disorders PGD is available for a large number of monogenic disorders—that is, disorders due to a single gene only (autosomal recessive, autosomal dominant or X-linked)—or of chromosomal structural aberrations (such as a balanced translocation). PGD helps these couples identify embryos carrying a genetic disease or a chromosome abnormality, thus avoiding diseased offspring. The most frequently diagnosed autosomal recessive disorders are cystic fibrosis, Beta-thalassemia, sickle cell disease and spinal muscular atrophy type 1. The most common dominant diseases are myotonic dystrophy, Huntington's disease and Charcot–Marie–Tooth disease; and in the case of the X-linked diseases, most of the cycles are performed for fragile X syndrome, haemophilia A and Duchenne muscular dystrophy. Though it is quite infrequent, some centers report PGD for mitochondrial disorders or two indications simultaneously.

A simple method for calculating risks before DNA analysis.

Calculation of carrier risk of an X linked disease may be performed on a small computer after DNA analysis, but a method for rapid hand estimation of the risk is still useful for a quick check of the results and weighing the relative importance of each element of information, such as the determination of a haplotype. Each risk estimation is a function of a prior risk and the product of likelihood ratios and these terms are derived themselves from parameters such as fitness or the relative mutation rate in male and female gametes. Even if it is often difficult to have strong experimental estimation of these variables, the existence of a normal father or grandfather must be considered whenever male fitness is not null. The likelihood ratio for a woman for not being a carrier, when her father is not affected and her mother has herself a likelihood R for not having the mutated gene, may be expressed as the ratio 2R/(CmR + 1), with Cm being a function of male fitness and relative mutation rate. Cm represents the odds ratio for the mother of a carrier not to be a carrier, given that the father of the known carrier is not affected. This formula can be used recurrently and reduces to 2R/(R + 1) in lethal X linked disease. When likelihood ratios are expressed as an algebraic function, maximum values are easily determined, hence fixing the limits of DNA analysis.

Ezutromid

Ezutromid is an orally administered small molecule utrophin modulator currently involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different