Polymyalgia rheumatica. Classic example I suppose, and it is seen in the clinic in droves. Older woman with normocitic anemia and clear ferrokinetic pattern of chronic disorder (hyposideremia but hyperferritinemia). The only one that fits, and it fits perfectly, is number 3; they only needed to give us a high ESR. 1: if it is a recent loss, the MCV could remain normal, but the ferritin should be affected, and certainly not elevated. 2: the same. If it is due to Fe malabsorption, ferritin should be low. And if it were due to B12 malabsorption, the MCV would be clearly higher. 4: 70 tachycardia and normal MCV. This one is too much.

Polymyalgia rheumatica. Classic example I suppose, and it is seen in the clinic in droves. Older woman with normocitic anemia and clear ferrokinetic pattern of chronic disorder (hyposideremia but hyperferritinemia). [HIDDEN] they only needed to give us a high ESR. [HIDDEN] 2: the same. [HIDDEN] And if it were due to B12 malabsorption, the MCV would be clearly higher. [HIDDEN] This one is too much.

The determination in a 70-year-old woman of hematocrit 32%, Hb 9.6 g/dL, MCV 85 fL (70-99), Fe 25 ug/dL (37-145) and ferritin 350 ng/mL (15-150), is more suggestive of:

Recent blood loss through the digestive tract.

[Iron deficiency anemia is not always simple].

Malabsorption of oraliron is rare, and more frequently suspected than proved. It could be due to prolonged iron deficiency. Case no. 1: A boy was admitted at the age of 5 months for recurrent bronchitis. His hemoglobin was 8.2 g/dl, mean corpuscular volume (MCV) 60 micron3, mean corpuscular hemoglobin (MCH) 15 ng and mean corpuscular hemoglobin concentration (MCHC) 25 gHb/dl. The serum iron was 1 microgram/dl, iron binding capacity (IBC) was 284 micrograms/dl and ferritin was 14.9 ng/ml. Dietary iron was inadequate. The patient was given ferrous sulfate but iron deficiency persisted at the ages of 11 months and 3 years, probably due to poor compliance. Similar hematologic data (Hb: 6.4 g/dl, MCV 55 micrograms/m3, MCH 13.9 ng, MCHC 24 gHb/dl) were found at the age of 9 years. The patient was then given ferrous sulfate orally as test but the serum iron levels were unchanged during the 4 hours following ingestion. A parenteral iron preparation (iron-dextran, 500 mg) improved the hematologic data. 6 months later, a new oral test with ferrous sulfate improved the serum iron level. Case no. 2: A boy with complex congenital cardiopathy was operated on in the neonatal period and given oral iron at the age of 9 months because of anemia with microcytosis and hypochromia. This anemia was still present at 17 months and was associated with normal or high serum ferritin. Electrophoresis of hemoglobin was normal. At the age of 4 yr 5 mo, Hb was 9.7 g/dl, MCV 62.8 micrograms/m3, MCH 18.4 ng, iron 16 micrograms/dl and ferritin 94.1 ng/ml. An oral test with ferrous sulfate failed to increase the serum iron. The patient was then given parenteral iron-dextran without benefit, and a second oral test remained ineffective. After a second course of parenteral iron-dextran, Hb was 11.5 g/dl, MCV 74.1 micrograms/m3, MCH 23.7 ng while the serum iron remained low (23 micrograms/dl) and ferritin increased to 587 ng/ml. A third oral test with ferrous sulfate was still ineffective, as was a test using 4 mg/kg iron. The first patient suffered from iron malabsorption, presumably due to iron deficiency. The second patient could have abnormal metabolism and/or abnormal ferritin.

Hematinic deficiencies and anemia statuses in oral mucosal disease patients with folic acid deficiency.

Folic acid deficiency (FAD) may result in macrocytic anemia. This study assessed the hematinic deficiencies and anemia statuses in oral mucosal disease patients with FAD (defined as folic acid ≤ 6 ng/mL). The blood hemoglobin (Hb), iron, vitamin B12, and folic acid concentrations, serum gastric parietal cell antibody level, and mean corpuscular volume (MCV) in 198 oral mucosal disease patients with FAD were measured. Based on World Health Organization (WHO) criteria, anemia or Hb deficiency was defined as having an Hb concentration of <13 g/dL for men and <12 g/dL for women. In this study, macrocytic anemia due to FAD was defined as having an MCV ≥100 fL and folic acid ≤6 ng/mL; pernicious anemia as having MCV ≥100 fL, vitamin B12 < 200 pg/mL, and serum gastric parietal cell antibody positivity; iron deficiency anemia as having MCV <80 fL and iron <60 μg/dL; and thalassemia trait as having MCV <74 fL, red blood cell (RBC) count > 5.0 × 10(12)/L, and Mentzer index (MCV/RBC) < 13. We found that by WHO definitions, 73 (36.9%), 41 (20.7%), and 10 (5.1%) of our 198 FAD patients had concomitant Hb, iron, and vitamin B12 deficiencies, respectively. Of 73 anemic FAD patients, three had macrocytic anemia due to FAD, one had pernicious anemia, 14 had iron deficiency anemia, eight had thalassemia trait, and the resting 47 had normocytic anemia. In addition to macrocytic anemia (2.0%), FAD patients may have concomitant normocytic (23.7%) or microcytic (11.1%) anemia.

[Effect of Helicobacter pylori eradication on iron deficiency anemia of unknown origin].

Iron deficiency anemia of unknown origin is a frequent cause of anemia in which etiological diagnosis is often not achieved, despite currently available diagnostic techniques. Recent studies suggest that, in the absence of digestive tract lesions, Helicobacter pylori infection could be the cause of iron deficiency anemia, due to the alterations produced in gastric iron absorption. To evaluate whether H. pylori eradication resolves iron deficiency anemia and removes the need for oral iron administration. We performed an observational descriptive study in patients with iron deficiency anemia refractory to treatment with oral iron administration and with out causes that could explain their anemia. Gastroscopy, ileocolonoscopy, intestinal transit study and/or endoscopic capsule were performed. Female patients also underwent gynecological study. All patients were H. pylori-positive and standard eradication therapy was administered until elimination was achieved. The patients were followed-up for a minimum of 3 months after H. pylori eradication and the need for oral iron intake after eradication was evaluated. Ten patients, aged 53+/-8.2 years, were included. Hemoglobin (Hbg) before treatment was 10.06+/-0.53 mg/dl, mean corpuscular volume (MCV) was 75.43+/-6.02 fl and ferritin was 6.1+/-3.28 ng/ml. Eradication therapy was administered until elimination of H. pylori. The mean time before disappearance of anemia was 4.5 months. Laboratory parameters after treatment were as follows: Hgb 12.86+/-0.75 mg/dl, MCV 85.02+/-4.8 fl and ferritin 28+/-22.19 ng/dl. In the absence of lesions that could explain iron deficiency anemia, this disease can be related to H. pylori infection. Eradication of this infection is closely followed by disappearance of anemia and ferropenia.

Mean corpuscular volume

Interpretation The normal reference range is typically 80-100 fL. High In pernicious anemia (macrocytic), MCV can range up to 150 femtolitres. (as are an elevated GGT and an AST/ALT ratio of 2:1). Vitamin B12 and/or folic acid deficiency has also been associated with macrocytic anemia (high MCV numbers). Low The most common causes of microcytic anemia are iron deficiency (due to inadequate dietary intake, gastrointestinal blood loss, or menstrual blood loss), thalassemia, sideroblastic anemia or chronic disease. In iron deficiency anemia (microcytic anemia), it can be as low as 60 to 70 femtolitres. In some cases of thalassemia, the MCV may be low even though the patient is not iron deficient. Worked example

InternalMed_Harrison

When moderate anemia is present (hemoglobin 10–13 g/dL), the bone marrow remains hypoproliferative. With more severe anemia (hemoglobin 7–8 g/dL), hypochromia and microcytosis become more prominent, target cells and misshapen red cells (poikilocytes) appear on the blood smear as cigaror pencil-shaped forms, and the erythroid marrow becomes increasingly ineffective. Consequently, with severe prolonged iron-deficiency anemia, erythroid hyperplasia of the marrow develops, rather than hypoproliferation. Conditions that increase demand for iron, increase iron loss, or decrease iron intake or absorption can produce iron deficiency (Table 126-2). Chronic blood loss Menses Acute blood loss Blood donation Phlebotomy as treatment for polycythemia vera Malabsorption from disease (sprue, Crohn’s disease) Malabsorption from surgery (gastrectomy and some forms of bariatric surgery)

Latent iron deficiency

The normal range for hemoglobin is 13.8 to 17.2 grams per deciliter (g/dL) for men and 12.1 to 15.1 g/dL for women. Low hemoglobin indicates anemia but will be normal for LID. Normal serum iron is between 60 and 170 micrograms per deciliter (μg/dL). Normal total iron-binding capacity for both sexes is 240 to 450 μg/dL. Total iron-binding capacity increases when iron deficiency exists. Serum ferritin levels reflect the iron stores available in the body. The normal range is 20 to 200 ng/mL for men and 15 to 150 ng/mL for women. Low levels (< 12 ng/mL) are specific for iron deficiency. However, inflammatory and neoplastic disorders can cause ferritin levels to increase - this may be seen in cases of hepatitis, leukemia, Hodgkin lymphoma, and GI tract tumors. The most sensitive and specific criterion for iron-deficient erythropoiesis is depleted iron stores in the bone marrow. However, in practice, a bone marrow examination is rarely needed.

Beta Thalassemia -- Evaluation

The complete blood count (CBC) of a patient with beta-thalassemia major will show microcytic hypochromic anemia with Hb levels less than 7g/dl, the mean corpuscular volume between (MCV) 50 and 70 fl, and mean corpuscular Hb (MCH) between 12 and 20pg. Beta- thalassemia intermedia presents with values of Hb between 7 and 10 g/dl, MCV 50 to 80 fl, and MCH 16 to 24pg. In beta-thalassemia minor, the red cell number is often elevated, reduced MCV, MCH, and the red cell distribution width (RDW) will typically show low elevations. The normal to mildly elevated RDW can help differentiate thalassemias from other microcytic hypochromic anemias, such as iron deficiency anemia and sideroblastic anemia where the RDW is typically very high. The peripheral blood smear will show microcytic hypochromic anemia with target cells, teardrop cells, and often coarse basophilic stippling (see Image 1). In severe forms of beta-thalassemia, there is anisopoikilocytosis with bizarre red cell morphology and numerous nucleated red blood cells. [2]

Congenital dyserythropoietic anemia

Treatment of individuals with CDA usually consist of frequent blood transfusions, but this can vary depending on the type that the individual has. Patients report going every 2–3 weeks for blood transfusions. In addition, they must undertake chelation therapy to survive; either deferoxamine, deferasirox, or deferiprone to eliminate the excess iron that accumulates. Removal of the spleen and gallbladder are common. Hemoglobin levels can run anywhere between 8.0 g/dl and 11.0 g/dl in untransfused patients, the amount of blood received by the patient is not as important as their baseline pre-transfusion hemoglobin level. This is true for ferritin levels and iron levels in the organs as well, it is important for patients to go regularly for transfusions in order to maximize good health, normal ferritin levels run anywhere between 24 and 336 ng/ml, hematologists generally do not begin chelation therapy until ferritin levels reach at least 1000 ng/ml. It is more important to check iron

Iron status of one-year-old infants in a well baby clinic.

Seventy-two healthy infants (37 males, 35 females) attending a private well baby clinic were enrolled in the study. Their mean birthweights and body weights at one year of age were 3,079 grams and 10 kilograms, respectively. Blood samples were drawn approximately on their first birthday for evaluating the iron status. Complete blood count, hemoglobin (Hb) typing and DNA analysis for common carrier status of thalassemia and hemoglobinopathis were also determined. According to the infants of serum ferritin, the patients were classified into 4 groups: group 1, iron deficiency anemia (Hb <11 g/dl and ferritin <12 ng/L) in 1 infants (1.4%); group 2, iron deficiency without anemia (Hb >11 g/dl and ferritin <12 ng/L) in 5 infants (6.9%); group 3, borderline iron depletion (ferritin 12-30 ng/L) in 39 infants (54.2%); group 4, iron sufficiency (ferritin >30 ng/L) in 27 infants (37.5%). The iron deficiency state emerged as 8.3 per cent (6/72). There was no significant difference of levels of Hb and mean corpuscular volume (MCV) among the infants with iron deficiency without anemia, borderline iron depletion and iron sufficiency. The results also revealed that 25 out of 72 (34.7%) infants were carriers of thalassemia and hemoglobinopathies. The carrier infants had significant lower Hb and MCV than those of the non-carrier infants with the p-values of 0.004 and 0.000, respectively; while their serum ferritin levels were not significantly different. Additionally, the association of carrier and iron deficiency state was further evaluated. The Hb and MCV among carrier infants with and without iron deficiency were not significantly different. Six infants with carrier state were found to have slightly decreased levels of Hb ranging from 10.3 to 10.9 g/dl with the ferritin ranging from 18.7 to 382.9 ng/L while the remainders had Hb of >11 g/dl. Therefore, 7 out of 72 (9.2%) infants had anemia (Hb <11 g/dl) which was caused by the carrier state of thalassemia and hemoglobinopathies (n=6) and iron deficiency anemia (n=1). The risk factors of iron deficiency status were associated with feeding regimen including continuation of breast feeding until one year of age without adequate haem iron supplement, exclusive formula feeding, inadequacy of solid food supplement with only one meal per day and excluding haem iron from animal liver without substitution. The infants with risk factors had significantly lower levels of serum ferritin (mean 14.1 +/- 1.7 ng/L) than those without risk factors (mean 31.9 +/- 1.9 ng/L) with a p-value of 0.000. In conclusion, adequate haem iron supplement in 3 meals of solid food is essential for the prevention of iron deficiency status in one-year-old infants.

Patients over 45 years with iron deficiency require investigation.

Iron deficiency anaemia (IDA) that occurs in patients above the age of 45 years is often caused by gastrointestinal blood loss, and guidelines on the appropriate investigation of these patients have been published. There are few data regarding patients with iron deficiency who are not anaemic and it is not clear how these patients should be managed. We set out to investigate the hypothesis that similar pathologies are likely to underlie iron deficiency and IDA, and to assess whether IDA was being investigated according to the guidelines published by the British Society of Gastroenterology (BSG). The pathology computer identified 153 consecutive patients over the age of 45 years who had serum ferritin levels below 20 microg/dl (normal range 20-200 microg/dl) in a 2 month period (i.e., October and November 2000). Medical records were examined and we recorded all investigations, the diagnoses reached, and the investigating specialty. The results were compared using odds ratios (ORs) and 95% confidence intervals (CIs). The study shows that the causes of iron deficiency and IDA are similar, but IDA is investigated more thoroughly than iron deficiency, OR 2.07 (CI 1.08-3.97). Ten patients with iron deficiency without anaemia were found to have coeliac disease, a significant result, OR 6.71 (CI 1.38-32.6). The majority of patients with IDA are not under the care of a gastroenterologist and this group are significantly less likely to be investigated according to the BSG guidelines, OR 0.15 (0.04-0.6). The study shows that the yield of investigation of iron deficiency is high and, hence, it should be investigated in all patients over the age of 45 years. Despite guidelines published by the BSG, IDA is investigated sub-optimally and measures other than the issuing of guidelines are needed to change practice.

Response to parenteral iron therapy distinguish unexplained refractory iron deficiency anemia from iron-refractory iron deficiency anemia.

We evaluated that response to parenteral iron therapy could be helpful in distinguishing the types of iron deficiency anemia. This study analyzed responses to IV iron sucrose therapy of 15 children with unexplained refractory iron deficiency anemia (URIDA). We compared the results at diagnosis, 6 weeks and 6 months after the therapy. Results were compared with responses of 11 patients' results with iron-refractory iron deficiency anemia (IRIDA) from our previous study. Six weeks after the start of treatment, ferritin, MCV, MCH and Hb values were in normal range in 10 patients. The increase in Hb, MCH, MCV, and ferritin values ranged 2.6-3.5 g/dL, 1.7-4.2 pg, 2-9 fL, and 13-25 ng/mL, respectively. In five patients, Hb, MCH, and MCV mean (range) values [11.2 g/dL (11-12.2), 24.5 pg (24-25.6), and 67 fL (65-70)] were nearly normal but ferritin mean (range) values [9.8 ng/mL (8-11)] were below normal. Six weeks after the start of treatment, Hb, MCH, MCV and ferritin values of patients with IRIDA were increased. The increase in Hb, MCH, MCV, and ferritin values ranged 0.8-2.7 g/dL, 1.7-4.2 pg, 2-9 fL, and 13-25 ng/mL, respectively. IRIDA is only partially responsive to parenteral iron supplementation. In conclusion, this study demonstrated that the response to intravenous iron therapy for the URIDA cases improved blood parameters more effectively than hereditary IRIDA. Response to parenteral iron therapy would be helpful to distinguish unexplained refractory IDA from hereditary IRIDA for clinicians who do not have access to hepcidin or TMPRS6 mutation analysis.

Serious gastrointestinal pathology found in patients with serum ferritin values < or = 50 ng/ml.

Our aim was to evaluate the gastrointestinal tract in patients with serum ferritin values < or = 50 ng/ml for the presence of serious gastrointestinal pathology, including neoplasia and acid peptic disease. In this prospective observational study, patients with serum ferritin values < or = 50 ng/ml who did not have an obvious cause of iron deficiency underwent colonoscopy and/or esophagogastroduodenoscopy. Between October 1, 1994, and February 29, 1996, 725 of 3015 patients who had serum ferritin determinations were found to have values < or = 50 ng/ml. To date, 143 patients have been fully evaluated and 77 were found to have serious gastrointestinal pathology including acid peptic disease (N = 46), cancer (N = 15), and large adenomas (N = 6). Colon cancer was discovered in five asymptomatic patients. The prevalences of serious gastrointestinal pathology did not differ between patients with serum ferritin values < or = 20 ng/ml and those with values between 21-50 ng/ml (63% vs 48%, p = 0.07). However, multivariate analysis showed that the presence of upper or lower gastrointestinal symptoms and serum ferritin value < or = 20 ng/ml is predictive of finding serious pathology (p = 0.0002 for the whole model), with odds ratios of 3.8 (95% confidence interval of 1.84-7.70) for presence of gastrointestinal symptoms and 2.2 (95% confidence interval of 1.09-4.57) for serum ferritin value < or = 20 ng/ml. Endoscopic examination is warranted in patients with serum ferritin values < or = 50 ng/ml to detect serious gastrointestinal pathology, present in 54% of such patients.

Low isolated ferritin levels without anemia: is gastrointestinal tract endoscopy sufficient to explain the cause?

The present study assesses the diagnostic significance of low ferritin levels in gastrointestinal diseases by evaluating the endoscopic findings of patients with low ferritin levels without anemia. The study included patients aged 0-18 years who underwent an upper and lower gastrointestinal system endoscopy in the Pediatric Gastroenterology Department of our hospital. The patients were divided into three groups based on hemoglobin, and ferritin levels at the time of initial presentation and endoscopic and histopathological findings were recorded retrospectively. In the present study, 2391 pediatric patients were reviewed, among which 29% (n = 699) had anemia, 23% (n = 549) had low ferritin levels without anemia, and 48% (n = 1143) did not have anemia. The most common symptoms were abdominal pain, dyspepsia, and growth retardation. When the endoscopy findings were compared with those of patients with non-anemic group, Helicobacter pylori gastritis (24%/17.6%) and celiac disease (6%/2.2%) were more common in low ferritin levels without anemia, which indicated a statistically significant difference (p = 0.000/p = 0.04). Helicobacter pylori gastritis and celiac disease were more commonly observed in association with low ferritin levels. Low ferritin levels without anemia can be an early and silent sign of celiac disease.

Prevalence of hematinics deficiency amongst female students and its correction.

Nutritional anemia (NA) is common in India. While iron deficiency (ID) is a well recognized cause of NA, prevalence of deficiencies of other hematinics is not systematically investigated. Seventy students of a junior class of a polytechnic and 202 inmates of girl students home were taken up for study. Students were given a questionnaire to elicit anemia related symptoms. Blood was collected for complete blood count (CBC), serum ferritin, folic acid and vitamin B12. Students of polytechnic received hematinic at bed time during their menstrual periods whereas inmates of students home received hematinic at bed time, 3 days in a week. After 6 months blood tests were repeated in those who completed the treatment. CBC was done on Coulter counter and ferritin, folic acid and vitamin B12 were assayed by chemiluminescence. Students were divided into three groups-(1) Control group with Hb 12.0 g/dl or more and ferritin 15.0 ng/ml or more; (2) ID Group with Hb 12.0 g/dl or more and ferritin less than 15.0 ng/ml; and (3) Iron Deficiency Anemia (IDA) group with Hb less tha 12.0 g/dl and ferritin less than 15.0 ng/ml. Basal parameters of three groups were compared using students t test. Change in parameters with treatment was compared using paired students t test. Median age-16 years (range 10-25). Anemia ( Hb < 12.0 g/dl)-94 (34.6%); MCV < 80 fl-153 (56.3%); MCH < 27 pg-167 (61.4%); Ferritin < 15.0 ng/ml-161 (59.2%); Folic acid < 3.5 ng/ml-34 (12.5%); Vitamin B12 < 258 pg/ml-133 (48.9%) Pre-therapy: (1) Hb, MCV, MCH and ferritin significantly lower in ID and IDA Groups compared to control group. (2) Hb, MCV, MCH and Ferritin significantly lower in IDA Group as compared to ID Group.  POST-THERAPY: (1) IDA group showed significant increase in Hb, MCV, MCH, ferritin, folic acid and vitamin B12. (2) final Hb (11.26+1.07) and ferritin (7.46+4.81) in IDA Group were subnormal. (3) MCV, MCH, ferritin, folic acid and vitamin B12 increased significantly in ID Group and control group. (1) Nutritional anemia is common amongst asymptomatic young female students. (2) Deficiencies of iron, folic acid and vitamin B12 are common and coexist. (3) 105 mg elemental iron for 3 days in a week for 6 months is not adequate to correct IDA. (4) 105 mg iron for 3 days in a week is enough to correct ID. (5) Non-anemic individuals with ID have iron deficient erythropoiesis. (6) Non-anemic individuals without ID, in this cohort, also had iron deficient eryhtropoiesis.

[Method for determining the amount of blood loss using the storage iron decrease rate as obtained from serum ferritin after intravenous iron therapy].

This is to introduce a new method for determining the amount of blood loss by measuring the storage iron decrease rate (SID), as obtained by following serum ferritin after intravenous iron therapy in a patient with iron deficiency anemia due to intestinal blood loss. The patient was followed from the day S, when iron therapy started, to the day E, when serum ferritin decreased to 12 microg/l, indicating the exhaustion of the iron stores. The SID was calculated from the formula: SID=(T-R)/D, where, T mg = total amount of injected iron, R mg = the difference in the iron in the hemoglobin (deltaHb) between day S and E, and D = days from S to E. The SID was thought to be iron loss only, as the contribution of iron absorption and iron loss to the SID, with the exception of bleeding, was believed to be negligible and as the serum ferritin decrease curve was exponentially linear. Using the formula, V = iron loss/iron in mean Hb, the amount of blood loss: V=29 ml/day was obtained. This method can also be used for the quantitation of blood loss in other patients with chronic blood loss, because the SID could also be determined in 12 cases of post-treatment iron deficiency anemia with chronic blood loss.

The Role of Advanced Practitioners in Optimizing Clinical Management and Support of Patients With Polycythemia Vera.

<bCASE STUDY</b Mr. M, a 65-year-old male, presented to his primary care physician with progressive fatigue, difficulty sleeping, and daily headaches for the past 3 weeks. His headaches were not associated with visual disturbances, cognitive deficits, or nausea/vomiting, and he had no history of migraines. He had a history of hypertension and hyperlipidemia, did not smoke, rarely drank alcohol, and had no recent illnesses or hospitalizations. His previous physical examination and laboratory studies 2 years ago were normal. The current physical examination revealed a plethoric yet well-appearing, well-nourished male in no acute distress. His lungs were clear to auscultation bilaterally without wheezes, rales, or rhonchi. He had a regular heart rate and rhythm without murmur. His abdomen was soft, without tenderness, distension, or palpable hepatosplenomegaly. Examination of the extremities was negative for edema. Distal pulses and sensation in the hands and feet were intact and equal bilaterally. Cranial nerves II to XII were deemed intact, and no gross focal deficits were observed. Complete blood count (CBC) revealed a slightly elevated white blood cell (WBC) count (14.6 × 10<sup9</sup/L [normal range, 3.9-10.7 × 10<sup9</sup/L; Wians, 2015]), erythrocytosis (red blood cell [RBC] count, 6.5 × 1012/L [normal range, 4.2-5.9 × 1012/L; Wians, 2015], hemoglobin, 19 g/dL [normal range, 14-17 g/dL; Wians, 2015], and hematocrit, 54.3% [normal range, 41%-51%; Wians, 2015]), thrombocytosis (platelet count, 500 × 109/L [normal range, 150-350 × 10<sup9</sup/L; Wians, 2015]), and microcytosis (mean cell volume [MCV], 75 fL [80-100 fL; Wians, 2015]), which combined were cause for referral to a hematology/oncology clinic. During his hematology/oncology evaluation, Mr. M described "never feeling rested" and being unable to sleep with uncertain snoring habits. He was experiencing itching during hot showers yet did not have rashes and had not recently introduced a new soap. He had no family history of blood disorders and no personal history of blood clots. The second CBC and laboratory tests confirmed erythrocytosis (RBC count, 6.5 × 1012/L; hemoglobin, 18.9 g/dL; hematocrit, 54%) and microcytosis (MCV, 75 fL). Serum iron (22 μg/dL [normal range, 60-160 μg/dL]) and ferritin (5 ng/mL [normal range, 15-200 ng/mL]) were suggestive of iron deficiency, serum erythropoietin was 8 mU/mL (normal range, 4.0-18.5 mU/mL), and a Janus kinase 2 (JAK2) mutation analysis was positive for JAK2V617F. Platelet count remained 500 × 109/L and WBC count was 10.2 × 10<sup9</sup/L.

[alpha-thalassemia accompanied with Gilbert's syndrome].

A 15-year-old boy was admitted to our hospital because of microcytic hypochromic erythrocytosis and hyperbilirubinemia in October 1996. The laboratory findings were RBC: 597 x 10(4)/microliter, Hb: 13.1 g/dl, Ht: 40.8%, MCV: 70fl, MCH: 22pg, total bilirubin: 3.2 mg/dl (indirect: 2.2 mg/dl), s-Fe: 99 micrograms/dl, and ferritin: 25 ng/ml. Routine liver function tests were normal. There were no findings of hemolysis except for an increase in serum indirect bilirubin and reticulocytes. Decreased erythrocyte osmotic fragility was observed. The patient's mother and sister also showed microcytic hypochromic erythrocytosis. PCR analysis of genomic DNA from this patient, his mother, and his sister confirmed the diagnosis of the alpha-thalassemia trait. However, the bilirubin-UDP-glucuronosyltransferase 1 (B-UGT 1) gene mutation and the findings of the fasting test indicated the simultaneous presence of Gilbert's syndrome. The association of these two diseases in the same patient appears to be rare, especially in Japan because of the low incidence of thalassemia in this country. We concluded that the hyperbilirubinemia was caused by decreased bilirubin clearance, not by increased erythrocyte destruction.

Anaemia in patients with arthritis: are simple investigations helpful?

The level of haemoglobin, serum iron, total iron binding capacity and ferritin were measured in patients with rheumatological conditions who were anaemic at the time of upper gastrointestinal endoscopy. These parameters were similar in patients with or without lesions of their upper gastrointestinal tract, and in patients with a positive or negative faecal occult blood result. Lesions of the upper gastrointestinal tract were not more frequent in patients with a microcytic anaemia when compared to those with a normocytic anaemia, nor were they found more frequently in patients with a positive faecal occult blood test. Lesions visible at upper gastrointestinal endoscopy are not an important cause of microcytic anaemia in patients with arthritis. The finding that patients with normocytic anaemia are more likely to proceed to lower bowel examination than patients with microcytic anaemia is a reflection of the difficulty in interpretation of these simple haematological tests and showed they were unhelpful in determining which patients warrant investigation of the lower bowel. The frequency of further investigation of the lower bowel was significantly reduced by a positive endoscopy report, irrespective of the nature of the lesion, but was not significantly increased by finding faecal occult blood. We suggest that patients with arthritis selected for investigation of possible gastrointestinal blood loss should follow an organized plan of investigation that includes examination of both upper and lower bowel, and which should proceed uninfluenced by pro tem results. Unfortunately the selection of patients for such further investigation is hampered by a lack of simple discriminatory tests.

Identification of a new mutation on the beta-globin gene: codons 8/9 (+AGAA); GAG.AAG.TCT(Glu-Lys-Ser)>GAG. AAAGAAG, in a patient from the north of France with a phenotype of beta-thalassemia minor.

A 37-year-old man presented a slight debility. The hemogram showed a phenotype of beta-thalassemia minor: Hb (13.1 g/dL), mean corpuscular volume (MCV) (62 fL) with low mean corpuscular hemoglobin (MCH) (20.8 pg), associated with a high level of Hb A(2) of 5.3%. The serum ferritin level was 1,072 ng/mL. The sequencing of the mutated fragment revealed a duplication of four bases of codons 7/8 involving a shift in the open reading frame starting from codon 9 with a TGA stop codon at codon 23: codons 7/8/9 (+AGAA); GAG.AAG.TCT(Gly-Lys-Ser)>GAG.AAAGAAG. The human hemoglobin (Hb) instability tests were negative. The patient did not present the high iron Fe (HFE) mutation (C282Y, H63D). The same mutation was found in five other unrelated families (representing a total of 23 patients). All of their ancestors came from the north of France. This mutation has not been described before and could have its origins in the native populations of Northern France.

Mean Corpuscular Volume -- Differential Diagnosis

Differential diagnoses of MCV under 80 include iron deficiency anemia causes, anemia of chronic disease causes, sideroblastic anemia causes, H. pylori infection, and thalassemias. Iron deficiency anemia can have many different differential diagnoses including menorrhagia, colorectal adenocarcinoma, bleeding colonic polyp, bleeding peptic ulcer disease, Helicobacter pylori infection, hematemesis, chronic epistaxis, and duodenal malabsorption or resection. Anemia of chronic disease can have differential diagnoses including malignancy, rheumatologic conditions such as SLE and rheumatoid arthritis, autoimmune diseases such as primary biliary cirrhosis or multiple sclerosis, chronic kidney disease, and chronic infection. Chronic alcoholism, vitamin B6 deficiency, isoniazid use, myelodysplastic disorder, lead poisoning, copper deficiency, and congenital sideroblastic anemia are all differential diagnoses for sideroblastic anemia, causing microcytic anemia. The main types of thalassemia are alpha1, alpha2, alpha3/ hemoglobin H disease, alpha4, which is fatal, beta-thalassemia minor, beta-thalassemia major, and HbS/β thalassemia heterozygote.

[PREVALENCE OF IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA IN INFANTS AGED 9 TO 15 MONTHS IN A LOW INCOME POPULATION (2005-2010)].

Iron deficiency (ID) is a common nutritional deficiency. To estimate the prevalence and causes of ID and iron deficiency anemia (IDA) and to report the iron status in Israeli Arab infants. Data on iron status was taken from 410 infants, aged 9 to 15 months, who were randomly selected from 2400 infants born between 2005-2010. Hemoglobin (Hb) <11 g/dL, ferritin <12 μg/L and mean corpuscular volume (MCV) <70 fL were the criteria for establishing IDA, and ferritin<12 μg/L and MCV <70 fL for establishing ID. Of the 410 infants, 116 (28%) had Hb <11 g/dL, and 68 (17%) had MCV<70 fL. We were able to analyze the samples of 368 infants for ferritin: 27 (7%) had ferritin <12 μg/L. Iron deficiency anemia (Hb <11 g/dL and ferritin <12 μg/L) was diagnosed in 15/368 infants (4%).The IDA rate was 2% (10/368 infants) when the criteria of three factors (Hb <11 g/dL and ferritin <12 μg/L, MCV <70 fL) were used. Infants who were breastfed >6 months were significantly less prone to have anemia (P > 0.002) and infants who received >6 months of iron supplements were also less prone to have anemia (P < 0.05). Studies are needed for establishing valid cutoff points for diagnosing ID and IDA and for identifying the causes of the high rate of anemia in the absence of ID. Breastfeeding and iron preparation supplementation are recommended and the test of ferritin at one year of age could be considered.

[Diagnosis of chronic hemorrhage in diseases of the small intestine].

In a period of 10 years 38 patients received treatment in the clinic for iron deficiency anemia in whom the source of chronic blood loss was revealed in the small intestine. The radionuclide method for detecting concealed blood loss was most informative for the diagnosis (98%) of chronic intestinal hemorrhages, and was particularly important in cases with iron deficiency anemia of unclear genesis. Oral enterography was the most available method and sufficiently informative (32%) in the diagnosis of chronic hemorrhages from the small intestine. In 3-4 day, blood loss of more than 10 ml/24 h from the gastrointestinal tract verified by the radionuclide method but with the source of the bleeding not identified by instrumental methods, the indications for diagnostic laparotomy must be widened for careful examination of the small intestine.

Effect of breastfeeding versus infant formula on iron status of infants with beta thalassemia major.

Thalassemia major or Cooley's anemia is the most severe form of beta thalassemia in which the complete lack of beta protein in the hemoglobin causes a life-threatening anemia requiring regular blood transfusions and extensive ongoing medical care. These extensive, lifelong blood transfusions lead to iron-overload that must be treated with chelation therapy to prevent early death from organ failure. We compared serum iron and ferritin levels amongst infants aged up to one year with beta thalassemia major according to their feeding types, including exclusively breastfed, exclusively formula fed and combined (both breast and formula) fed types. Sixty out of 176 screened infants with transfusion dependant beta thalassemia major were recruited from the outpatient clinic of thalassemia at Zagazig University Hospital in Egypt, between 2007 and 2014. Patients were classified into three groups (20 patients per group) according to type of feeding. Group 1: exclusive breastfeeding, around 6-8 feeds per day; group 2: exclusive infant formula feeding, 120-150 ml of formula per kilogram of body weight per day divided into 6-8 feeds and group 3: combined breastfeeding and formula per day. Serum iron and ferritin levels were lower in group 1 compared to groups 2 and 3. The mean serum iron for group 1 was 73, 87 and 96 ug/dl at 6, 9 and 12 months respectively, while that for group 2 was 85, 99 and 112 ug/dl at 6, 9 and 12 months respectively and for group 3 was 78, 92 and 99 ug/dl at 6, 9 and 12 months respectively. The mean serum ferritin for group 1 was 283, 327 and 497 ng/ml at 6, 9 and 12 months respectively, while that for group 2 was 310, 389 and 591 ng/ml at 6, 9 and 12 months respectively and for group 3 was 291, 345 and 515 ng/ml at 6, 9 and 12 months respectively. The differences were not statistically significant. Breastfed infants with beta thalassemia major may accumulate less iron than infants fed iron fortified formula anticipating later onset of iron overload in the breastfed infants. Larger studies are needed to support these findings.

[Endemic sprue: its first diagnosis based on bleeding complications].

A 47-year-old man without previously known illness was admitted to hospital because of acute haematomas in the legs: the history revealed no cause. The pale-looking patient reported having large and foul-smelling stools once or twice daily. There were large haematomas and swellings on both legs. His general and nutritional state was reduced. "Bleeding of unknown origin" was suspected at this time. Haemoglobin concentration was 5.6 g/dl, while iron was normal and ferritin reduced. Quick value was below 5%, activated partial thromboplastin time prolonged to 180 s. Vitamin A and E concentrations were reduced; coumarin derivatives were not demonstrated in blood. Abdominal ultrasonography showed clearly thickened intestinal walls. Four units of erythrocyte concentrate were immediately administered, together with 2000 IU factors II, VII, X and anti-haemophilic factor B (PPSB), and 10 mg vitamin K intravenously. As intestinal malabsorption was suspected, a vitamin A absorption test was performed: it indicated malabsorption. Upper intestinal endoscopy showed coeliac disease, as did a biopsy. The patient's state quickly improved after he had been given vitamins A, D, E and K and put on a gluten-free diet. Coeliac disease can take a clinically unremarkable course for a long time and may finally become manifest through an isolated abnormality, such as bleeding.

Incidence and risk factors of iron deficiency anemia in term infants.

To compare the incidence of iron deficiency anemia (IDA) between breast-fed (BF) and formula-fed (FF) infants and to identify the risk factors of IDA in these infants. Cohort study. A study of 140 full- term infants (70 BF and 70 FF) was conducted at BMA Medical College and Vajira Hospital from February 2002 to November 2003. All infants were followed at the age of 1, 2, 4, 6, 9 and 12 months for growth and developmental assessment. Blood samples were analyzed for hemoglobin (Hb), hematocrit (Hct) and mean corpuscular volume (MCV) at 9 - 12 months; and infants with Hb < 11.0 g/dl were further investigated for the cause of anemia. The mean values of Hb, Hct, MCV and serum ferritin of BF infants were 10.8 g/dl, 32.8%, 70.9fl and 16.7 ng/ml respectively, which were significantly lower than those of FF infants (11.4 g/dl, 35.1%, 73.3fl, and 36.9 ng/ml, p < 0. 05). Anemia was found in 27 BF infants (38.6%) compared with 10 FF infants (14.39%). The incidence of IDA in BF infants was significantly higher than FF infants (25.7% vs 2.9%, p < 0.001). Risk factors of IDA included low birth weight, breastfeeding and inadequate complementary food (adjusted RR (95% CI): 3.1(1.1 - 9.1), 6.3(1.5 - 25.0), 7.7(2.8 - 20.0), respectively). IDA is more prevalent in BF than FF infants. Risk factors of IDA are low birth weight, breastfeeding and inadequate complementary food. Prevention of IDA in infants should be achieved through adequate iron-rich complementary food and screening for Hb or Hct at 9 - 12 months of age in high risk infants.

Identification of clinical and simple laboratory variables predicting responsible gastrointestinal lesions in patients with iron deficiency anemia.

Iron deficiency anemia (IDA) is a frequent disorder. Also, it may be a sign of underlying serious diseases. Iron deficiency points to an occult or frank bleeding lesion when occurred in men or postmenopausal women. In this study, we aimed to evaluate the diagnostic yield of endoscopy in patients with IDA and to define predictive factors of gastrointestinal (GI) lesions causing IDA. Ninety-one patients (77 women, 14 men; mean age: 43 years) who were decided to have esophago-duodenoscopy and/or colonoscopy for iron deficiency anemia were interviewed and responded to a questionnaire that included clinical and biochemical variables. The endoscopic findings were recorded as GI lesions causing IDA or not causing IDA. Endoscopy revealed a source of IDA in 18.6 % of cases. The risk factors for finding GI lesions causing IDA were as follows: male gender (p= 0.004), advanced age (> 50 years) (p= 0.010), weight loss (over 20% of total body weight lost in last 6 month) (p= 0.020), chronic diarrhea (p= 0.006), change of bowel habits (p= 0.043), epigastric tenderness (p= 0.037), raised carcinoembryonic antigen (CEA) level (normal range: 0-7 ng/mL) (p= 0.039), < 10 gr/dl hemoglobin (Hb) level (p=0.054). None of these risk factors had been present in 21 (23%) women younger than 51 years. In this group, no patient had any GI lesion likely to cause IDA (negative predictive value= 100%). In multivariate analysis, advanced age (p=0.017), male gender (p< 0.01) and weight lost (p=0.012) found that associated with GI lesions in all patients. It may be an appropriate clinical approach to consider these risk factors when deciding for gastrointestinal endoscopic evaluation in iron deficiency anemia.

[An elderly woman with macrocytic anemia and acute high-output heart failure following acute bleeding due to a gastric ulcer].

Although macrocytic anemia can develop in patients with acute blood loss, such anemia in very old patients is uncommon. In this report, we describe the course of an 89-year-old woman who had a rapid recovery from macrocytic anemia by medication only after acute blood loss due to a gastric ulcer. She had been treated with antihypertensive drugs for the previous 28 years at our outpatient clinic, and was admitted because of acute anemia 6 days after she had experienced tarry stool. Her hemoglobin (Hb) count and mean corpuscular volume (MCV) were 8.4 g/dl, and 103 fl, respectively. A gastroscopic examination indicated that the tarry stool originated from a fresh gastric ulcer. She was treated with an iron preparation, a diuretic and a proton pump inhibitor. The anemia was rapidly improved to Hb 10.5 g/dl and MCV 106 fl in one week, and to Hb 14.5 g/dl and MCV 99 fl in 4 weeks. At admission, she had slight pleural effusion and slight edema associated with an increase in her plasma brain natriuretic peptide (BNP) level (323 pg/ml), and her left ventricular ejection fraction was 76% based on the echocardiography findings, which are signs of the high-output heart failure without remarkable left ventricular diastolic dysfunction (E/e': 11.2). However, these signs improved rapidly, and her BNP level thereafter decreased to 114 pg/ml within four weeks.

Mean Corpuscular Volume -- Evaluation

For microcytic anemia, the presentation will determine the types of studies. If a patient is a menstruating woman with an MCV under 80, a Von Willebrand Factor and/or thyroid panel may be obtained to determine the underlying cause of menorrhagia as well as full menstrual history. On the contrary, a patient with microcytic anemia over the age of 50, is required to obtain a colonoscopy to determine if the iron deficiency originates from a polyp or neoplasm within the colon. Other investigations include urea breath test and an upper endoscopy to test for Helicobacter pylori infection if the patient complains of gastritis type pain. Anemia of chronic disease requires myriad tests if the underlying cause is unknown. Many of these tests include rheumatoid factor, Anti-double stranded DNA antibodies, Anti-neutrophil cytoplastic antibodies , anti-myeloperoxidase antibodies, a urine spot test to determine the renal function with GFR, creatinine, and blood urea nitrogen, HLA-B27 screening, and many more rheumatologic antibodies. Also, screening for malignancies with a CT scan or chest X-ray might be a consideration for the anemia of chronic disease. If lead poisoning is a possibility, a blood lead level is the gold-standard test. However, if other causes of sideroblastic anemia are suspected, a bone marrow biopsy is required. Medical history is very important to uncover the underlying etiology. In this case, the patient may be able to avoid a bone marrow biopsy. If beta-thalassemia is suspected based on history and physical examination, hemoglobin electrophoresis will help determine the amount of AA vs. A2 hemoglobin is present.  Genetic analysis is superior tests for alpha-thalassemia.

Relationship between glycosylated hemoglobin and iron deficiency anemia: A common but overlooked problem.

Both diabetes mellitus (DM) and iron deficiency anemia (IDA) are prevalent in every area of the world, and so, the possibility of these two diseases co-existing is also very high. It is our belief that clinical results of any correlation between iron status of the body and glycosylated haemoglobin (HbA1c) would be beneficial to many patients, therefore in this study, the effect of IDA on HbA1c was investigated. A total of 146 patients with DM and IDA were evaluated prospectively. While the patients were administered 270 mg/day of ferrous sulphate (80 mg elemental iron) orally for three months for the treatment of IDA, no interventions were made for the treatment of DM. Patient levels of hemoglobin (Hb), hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), platelet, white blood cells (WBC), serum iron, serum iron binding capacity (SIBC), ferritin, fasting plasma glucose (FPG), HbA1c, body mass index (BMI), C-reactive protein (CRP) values were measured at baseline and at the third month of treatment with iron, and were compared. The median age of our patients was 45 (40-50) and median duration of diabetes was 3 years (1,75-5). While the baseline median Hb was 10.4 (mg/dL) (9.5-11.1), MCV was 74 (fL) (70.8-77), ferritin was 4 (ug/L) (3-6) at three months, Hb was measured at 12.6 (mg/dL) (12.1-13.2), MCV was measured at 82 (fL) (80-86), ferritin was measured at 15 (ug/L) (9-21.2) and was significantly higher compared to baseline values (p < 0.001). The baseline median HBA1c of patients was 7.09 ± 0.51 (%) and three month HBA1c was 6.69 ± 0.53 (%), which was significantly lower than when comparing baseline values with values at third month (p < 0.001). Baseline and three month values for FPG were 118 (mg/dL) (108-132) and 116 (mg/dL) (106-125) respectively, and there was no significant difference (p:0.07). A 2.2 mg/dL (1.5-3.5) increase in median Hb level accompanied a 0.4 % (0.2-0.6) decrease in median HbA1c levels (Spearman rho = -0.362; p < 0.001). Our study has shown conclusivly that IDA is related to increased HbA1c concentrations and HbA1c decreases significantly following treatment with iron. IDA should be considered before making any decisions regarding diagnosis or treatment according to HbA1c.

Can haematological indices predict positive findings at endoscopy in anaemic patients?

Patients with anaemia are commonly referred for bidirectional endoscopy. The aim of this study was to determine if any haematological parameters could predict positive findings at endoscopy. A total of 209 patients had bidirectional endoscopies performed for anaemia between September 2002 and March 2004. The endoscopy reports, histology and full blood count results (haemoglobin [Hb], red blood cells [RBCs], packed cell volume [PCV], mean cell volume [MCV] and mean cell haemoglobin [MCH]) were then reviewed. Statistical analysis was performed using non-parametric tests. Overall, 197 patients had successful bidirectional endoscopies with 12 requiring completion barium enema. In 48 (23%) of these patients, a cause of anaemia was found with 15 (7.2%) carcinomas detected (2 upper GI and 13 lower GI). There was a significant difference in haemoglobin (9.2 g/dl versus 10.1 g/dl; P = 0.0044), RBCs (3.56 x 10(12)/l versus 3.83 x 10(12)/l; P = 0.0325) and PCV (0.279 l/l versus 0.31 l/l; P = 0.0112) between patients with positive findings at endoscopy and those with a normal investigation. Cancer patients had significantly lower haemoglobin (8.65 g/dl versus 10.1 g/dl; P = 0.0103), RBCs (3.45 x 10(12)/l versus 3.83 x 10(12)/l; P = 0.0179) and PCV (0.27 l/l versus 0.31 l/l; P = 0.0298) compared with patients with normal endoscopies. There was no significant difference in the other haematological parameters between those found to have positive findings and those that had normal endoscopies. Based on this study, the yield of bidirectional endoscopy is low, with haemoglobin and PCV being the most useful haematological indices of significant pathology. Ferritin and MCV did not predict the likelihood of finding a gastrointestinal cause for the anaemia.

Descriptive analysis of the prevalence of anemia in a randomly selected sample of elderly people living at home: some results of an Italian multicentric study.

We studied hematological indexes (RBC, HB, HT, MCV), serum iron and serum ferritin values in 1784 randomly selected subjects aged 65 and over (725 males and 1059 females) divided into five age groups (65-69, 70-74, 75-79, 80-84, > or = 85 years). The subjects were classified as anemic and normochromic according to the criteria for a "geriatric" level of anemia (HB < or = 12 g/dL in both sexes) as well as "W.H.O." levels for anemia (HB < 13 g/dL in males and < 12 g/dL in females). Macrocytosis (MCV > 100 fl) and low serum ferritin level (< or = 12 ng/dL) were classified according to MCV and serum ferritin values. Mean HB values in males were 14.85 +/- 1.33; 14.82 +/- 1.40; 14.77 +/- 1.43; 14.59 +/- 1.47 and 13.83 +/- 1.13 in the five age groups (65-69, 70-74, 75-79, 80-84 and > or = 85 years) respectively; in females, they were 13.77 +/- 1.15; 13.75 +/- 1.27; 13.44 +/- 1.39; 13.44 +/- 1.52 and 13.34 +/- 1.61, respectively. There was a low frequency of anemia in the entire sample: 2.9% in males and 9.9% in females according to the "geriatric" level, and 9.4% in males and 8.8% in females according to the "W.H.O." level. There was a higher prevalence of macrocytosis in males (6.3%) than in females (3.3%). We conclude that red cell parameters tend to decrease in aging, and further investigations are needed that exclude persons with existing chronic conditions, and incorporate data on nutritional status.

Predictors of gastrointestinal lesions on endoscopy in iron deficiency anemia without gastrointestinal symptoms.

Iron deficiency anaemia (IDA) due to occult gastrointestinal (GI) blood loss usually remains unnoticed until patient become symptomatic. There is sparse data in IDA patients without gastrointestinal symptoms. This study was designed to find out the frequency and predictors of endoscopic lesions in IDA without gastrointestinal symptoms. Cross-sectional study performed on a convenience sample of consecutive subjects. Ninety five consecutive patients with laboratory based diagnosis of IDA having no gastrointestinal symptoms were interviewed and their clinical and biochemical variables were recorded. All the study patients underwent esophago-gastroduodenoscopy (EGD) and colonoscopy. Endoscopic findings were documented as presence/absence of bleeding related lesion and presence/absence of cause of IDA. Multiple logistic regressions were performed to identify variables significantly related to outcome variables. Possible cause of anaemia was found in 71% and bleeding related lesions were found in 53% of patients. Upper gastrointestinal tract lesions were found in 41% of patients with bleeding related lesions. On multivariable logistic regression; advancing age, low mean corpuscular volume (MCV<or=60 fl), and positive fecal occult blood test were predictive factors for bleeding related GI lesions and cause of IDA CONCLUSION: Clinical and Biochemical markers can predict gastrointestinal lesions on endoscopy in IDA patients without gastrointestinal symptoms. High proportion of upper gastrointestinal involvement warrants EGD as initial endoscopic procedure however, this needs validation by further studies.


It is the male who presents the disease, which we are told is X-linked, so there are only two options left: 2 and 3. 2 is not because the males will receive the Y chromosome from the father and the X from the mother, who is healthy, so the daughters will be able to carry the disease (correct option 3).

It is the male who presents the disease, which we are told is X-linked, so there are only two options left: 2 and 3. 2 is not because the males will receive the Y chromosome from the father and the X from the mother, who is healthy, so the daughters will be able to carry the disease ([HIDDEN]).

A man has a partial deletion in the dystrophin gene (chromosome Xp21) which causes the semiology of Becker muscular dystrophy. He goes to the genetic consultation with his wife, to assess the risks of transmission of the disease. What correct information will be provided in the course of the genetic counseling?

According to autosomal dominant inheritance, half of her children will inherit the disease and without distinction of sexes.

Their daughters will not inherit the disease, but all their future sons will be carriers and can transmit the mutation to 50%.

Their sons will not inherit the disease, but all their future daughters will be carriers and can transmit the mutation to 50%.

There is no risk: the inheritance of the disease is of the mitochondrial type, never transmitted by males.

According to autosomal recessive inheritance, 25% of their children will manifest the disease in childhood, regardless of sex.

Becker muscular dystrophy

Genetics The disorder is inherited with an X-linked recessive inheritance pattern. The gene is located on the X chromosome. Since women have two X chromosomes, if one X chromosome has the non-working gene, the second X chromosome will have a working copy of the gene to compensate, because of this ability to compensate, women rarely develop symptoms. All dystrophinopathies are inherited in an X-linked recessive manner. The risk to the siblings of an affected individual depends upon the carrier status of the mother. Carrier females have a 50% chance of passing the DMD mutation in each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation will be carriers. Men who have Becker muscular dystrophy can have children, and all their daughters are carriers, but none of the sons will inherit their father's mutation.

X-linked dominant inheritance

Inheritance In X-linked dominant inheritance, when the mother alone is the carrier of a mutated, or defective gene associated with a disease or disorder; she herself will have the disorder. Her children will inherit the disorder as follows: Of her daughters and sons: 50% will have the disorder, 50% will be completely unaffected. Children of either sex have an even chance of receiving either of their mother's two X chromosomes, one of which contains the defective gene in question. When the father alone is the carrier of a defective gene associated with a disease or disorder, he too will have the disorder. His children will inherit the disorder as follows: Of his daughters: 100% will have the disorder, since all of his daughters will receive one copy of his single X chromosome. Of his sons: none will have the disorder; sons do not receive an X chromosome from their father.

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.

[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.

Duchenne muscular dystrophy

DMD is inherited in an X-linked recessive pattern. Females typically are carriers of the genetic trait while males are affected. A female carrier will be unaware she carries a mutation until she has an affected son. The son of a carrier mother has a 50% chance of inheriting the defective gene from his mother. The daughter of a carrier mother has a 50% chance of being a carrier and a 50% chance of having two normal copies of the gene. In all cases, an unaffected father either passes a normal Y to his son or a normal X to his daughter. Female carriers of an X-linked recessive condition, such as DMD, can show symptoms depending on their pattern of X-inactivation.

Autosome

Autosomal genetic disorders Autosomal genetic disorders can arise due to a number of causes, some of the most common being nondisjunction in parental germ cells or Mendelian inheritance of deleterious alleles from parents. Autosomal genetic disorders which exhibit Mendelian inheritance can be inherited either in an autosomal dominant or recessive fashion. These disorders manifest in and are passed on by either sex with equal frequency. Autosomal dominant disorders are often present in both parent and child, as the child needs to inherit only one copy of the deleterious allele to manifest the disease. Autosomal recessive diseases, however, require two copies of the deleterious allele for the disease to manifest. Because it is possible to possess one copy of a deleterious allele without presenting a disease phenotype, two phenotypically normal parents can have a child with the disease if both parents are carriers (also known as heterozygotes) for the condition.

Brother/sister pairs affected with early-onset, progressive muscular dystrophy: molecular studies reveal etiologic heterogeneity.

An autosomal recessive (AR) form of muscular dystrophy that clinically resembles Duchenne/Becker types exists, but its frequency is unknown. We have studied three unrelated affected brother/sister pairs and their families for deletions and polymorphisms with the entire dystrophin cDNA and other DNA probes from the Xp21 region to test for involvement of the DMD locus. In family 1 a large intragenic deletion was found in the affected male. The affected sister was heterozygous for this deletion, but the mother was not, implying germinal mosaicism. In family 2, no deletion was detected in the affected male. RFLP analysis revealed that the affected male and an unaffected sister shared a complete Xp21 haplotype while the affected sister had inherited a recombinant Xp21 region resulting from a crossover between pERT 87-15 and J-Bir. Only the 5' region of the dystrophin gene was shared with the affected boy. X-inactivation studies using a polymorphism in the 5'-flanking region of the HPRT gene, in conjunction with methylation-sensitive enzymes, revealed random X inactivation in the affected girl's leukocytes. In a muscle biopsy from the affected male, the dystrophin protein was present in normal amount and size. Family 3 was informative for four RFLPs detected with dystrophin cDNA probes which span the entire gene. The affected male was found to share the complete dystrophin RFLP haplotype with his unaffected brother, while his affected sister had inherited the other maternal haplotype. It is concluded that the clinical presentation of early-onset, progressive muscular dystrophy in a male and in his karyotypically normal sister can be caused by mutations at different loci. While in family 1 a deletion in the dystrophin gene is responsible, this gene does not appear to be involved in families 2 and 3.

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

Hereditary carrier

A hereditary carrier (genetic carrier or just carrier), is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, however, able to pass the allele onto their offspring, who may then express the genetic trait. Carriers in autosomal inheritances Autosomal dominant-recessive inheritance is made possible by the fact that the individuals of most species (including all higher animals and plants) have two alleles of most hereditary predispositions because the chromosomes in the cell nucleus are usually present in pairs (diploid). Carriers can be female or male as the autosoms are homologous independently from the sex.

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

Human genetics

Inheritance of traits for humans are based upon Gregor Mendel's model of inheritance. Mendel deduced that inheritance depends upon discrete units of inheritance, called factors or genes. Autosomal dominant inheritance Autosomal traits are associated with a single gene on an autosome (non-sex chromosome)—they are called "dominant" because a single copy—inherited from either parent—is enough to cause this trait to appear. This often means that one of the parents must also have the same trait, unless it has arisen due to an unlikely new mutation. Examples of autosomal dominant traits and disorders are Huntington's disease and achondroplasia. Autosomal recessive inheritance

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

Smith–Fineman–Myers syndrome

Genetics SFMS is an X-linked disease by chromosome Xq13. X-linked diseases map to the human X chromosome because this syndrome is an X chromosome linked females who have two chromosomes are not affected but because males only have one X chromosome, they are more likely to be affected and show the full clinical symptoms. This disease only requires one copy of the abnormal X-linked gene to display the syndrome. Since females have two X chromosomes, the effect of one X chromosome is recessive and the second chromosome masks the affected chromosome. Affected fathers can never pass this X-linked disease to their sons but affected fathers can pass the X-linked gene to their daughters who has a 50% chance to pass this disease-causing gene to each of her children. Since females who inherit this gene do not show symptoms, they are called carriers. Each of the female's carrier's son has a 50% chance to display the symptoms but none of the female carrier's daughters would display any symptoms.

Genodermatosis

Autosomal recessive inheritance The second kind is autosomal recessive inheritance, in this kind of inheritance, patients can be of any sex and inbreeding tends to lead to this inheritance. Cases of skin disease that may be inherited in this kind of mode include epidermolysis bullosa, xeroderma pigmentosum, acrodermatitis enteropathica, ichthyosis and so on. X-linked dominant inheritance The third kind is X-linked dominant inheritance, in this kind of inheritance, patients can be of any sex. Male patients can pass the disease on to their sons and the chances of female patients passing it to their daughters or sons are almost equal. Cases of skin disease that may be inherited in this kind of mode include incontinentia pigmenti, focal dermal hypoplasia and so on.

Neurological disorders with autosomal dominant transmission.

Neurofibromatosis, Huntington's disease, and myotonic dystrophy are three hereditary disorders affecting the nervous system. They have in common the basic principles of autosomal dominant inheritance: an affected individual has one parent with the disorder; the disorder affects males and females in approximately equal numbers; and an affected individual has a 50 percent risk of transmitting the disorder to every child. Furthermore, each of the three disorders have additional features that complicate genetic counseling and decisions about reproduction. Neurofibromatosis has an extremely variable expressivity, making the identification of affected individuals difficult and allowing for some reduction in the risk figures; although there is a 50 percent risk of a child inheriting the mutant gene, only one-fourth to one-third of these will experience serious consequences. Huntington's disease has a fairly typical course with degeneration occurring over 10 to 20 years. The frequent late onset of the disorder and the lack of any preclinical test for detecting carriers create problems for those at risk who wish to have children but do not want to pass the disorder to future generations. Both variable expressivity and variable onset are found in myotonic dystrophy. In addition, there is a risk of the severe early onset myotonic dystrophy when the mother is the affected parent. Genetic counseling should be available to patients and families with these three disorders. Nurses who have an understanding of the dynamics of these particular disorders can be empathetic to patients who face personal and family problems caused by the conditions. Alert nursing staff, in casual discussion with patients, may learn of hereditary disorders in a family or may notice symptoms that could lead to diagnosis of one of these disorders. Finally, nurses who are aware of the variations in genetic transmission of these disorders, may be in position to instruct and reinforce genetic counseling that the family has received.

Genetics, Autosomal Recessive -- Mechanism

The most common situation of an autosomal recessive disease occurs when the parents are each carrier or heterozygous (Dd). Children of carrier parents have a 25% chance of inheriting the disorder. This value is obtained by using the Punnet square model used in genetics. Each parent has a 50% chance of passing on the disease allele. Using the multiplication rule of probability, there is a 50% chance that the father passes on his disease allele and a 50% chance that the mother passes on her disease allele; 50% x 50% = 25%. So with the mating of carrier parents, there is a 25% chance that the child will be affected, a 50% chance that the child would be a carrier, and 25% chance that they would be homozygous dominant and unaffected.

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

Generally, it manifests only in males. A male with an affected allele on his single X chromosome is hemizygous and can not transmit the disorder to their male offsprings, but all his daughters would be obligate carriers. Healthy heterozygous carrier females pass the disorder to affected sons. So from affected males, it can be transmitted to male grandchildren through carrier daughter ('diagonal' or 'Knight's move' transmission).

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

Neonatal diabetes

Autosomal Recessive -Autosomal recessive-Generally, every cells have two copies of each gene-one gene is inherited from the mother and one gene is inherited from the father. Autosomal recessive inheritance pattern is defined as a mutation present in both copies if the gene in order for a person to be affected and each parent much pass on a mutated gene for a child to be affected. However, if an infant or child has only one copy, he or she are a carrier of the mutation. If both parents are carriers of the recessive gene mutation, each child have a 25% chance of inheriting the gene. Spontaneous: A new mutation or change occurs within the gene. X-linked: When a trait or disease happens in a person who has inherited a mutated gene on the X chromosome (one of the sex chromosome).

Norrie disease

Genetics Norrie disease is a rare genetic disorder caused by mutations in the NDP gene, located on Xp11.4 (GeneID: 4693). It is inherited in an X-linked recessive manner. This means that almost only males are affected. Sons of affected men will not have the mutation, while all of their daughters will be genetic carriers of the mutation. Female carriers usually show no clinical symptoms, but will pass the mutation to 50% of their offspring. Daughters with the mutated gene will also be, like their mother, asymptomatic carriers, but 50% of their sons will express clinical symptoms.

[X-linked recessively inherited peroneal muscular atrophy].

This article presents a pedigree of 80 members of which there are 13 patients (13 males) with peroneal muscular atrophy. The analysis of this pedigree shows that an affected male married to a normal female will have normal son(s) and carrier-daughter(s). The normal son(s) will have normal offspring, but half the sons of the carrier-daughter(s) will be affected. The pathogenic genes of affected males are transmitted to their daughters, but not to their sons. So this inheritance is of X-linked recessive type. This is the first report of X-linked recessively inherited peroneal muscular atrophy in china.

InternalMed_Harrison

In most instances, an affected individual is the offspring of heterozygous parents. In this situation, there is a 25% chance that the offspring will have a normal genotype, a 50% probability of a heterozygous state, and a 25% risk of homozygosity for the recessive alleles (Figs. 82-10, 82-13B). In the case of one unaffected heterozygous and one affected homozygous parent, the probability of disease increases to 50% for each child. In this instance, the pedigree analysis mimics an autosomal dominant mode of inheritance (pseudodominance). In contrast to autosomal dominant disorders, new mutations in recessive alleles are rarely manifest because they usually result in an asymptomatic carrier state.

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.

InternalMed_Harrison

genes that result in disease. Because each individual has two copies of each chromosome (one inherited from the mother and one inherited from the father), he or she can have only two alleles at a given locus. However, there can be many different alleles in the population. The normal or common allele is usually referred to as wild type. When alleles at a given locus are identical, the individual is homozygous. Inheriting identical copies of a mutant allele occurs in many autosomal recessive disorders, particularly in circumstances of consanguinity or isolated populations. If the alleles are different on the maternal and the paternal copy of the gene, the individual is heterozygous at this locus (Fig. 82-10). If two different mutant alleles are inherited at a given locus, the individual is said to be a compound heterozygote. Hemizygous is used to describe males with a mutation in an X chromosomal gene or a female with a loss of one X chromosomal locus.

Identification of duchenne muscular dystrophy female carriers by fluorescence in situ hybridization and RT-PCR.

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder caused by mutations in the dystrophin DMD gene located at Xp21.1 region. Up to 65% of the patients present dystrophin gene deletions. Mothers of DMD patients have a two-thirds chance of carrying a dystrophin mutation. The female carrier will transmit the disease gene to half of her sons and half of her daughters. As the recurrence risk for the disease is extremely high, it is very important to detect carrier status among female relatives of the patients to bring an adequate genetic counseling. In this work, results from two methods to identify female carriers are presented. One method is a multicolor fluorescence in situ hybridization (FISH) assay, and the other is reverse transcriptase-polymerase chain reaction (RT-PCR). We showed that FISH is an efficient, sensitive method that brings confident results to detect DMD female carriers as compared to RT-PCR.

InternalMed_Harrison

In autosomal dominant disorders, individuals are affected in successive generations; the disease does not occur in the offspring of unaffected individuals. Males and females are affected with equal frequency because the defective gene resides on one of the 22 autosomes (Fig. 82-13A). Autosomal dominant mutations alter one of the two alleles at a given locus. Because the alleles segregate randomly at meiosis, the probability that an offspring will be affected is 50%. Unless there is a new germline mutation, an affected individual has an affected parent. Children with a normal genotype do not transmit the disorder. Due to differences in penetrance or expressivity (see above), the Chapter 82 Principles of Human Genetics Heterozygous Heterozygous Female male female carrier of X-linked trait FIGURE 82-11 Standard pedigree symbols.

Human genetics

Autosomal recessive inheritance Autosomal recessive traits is one pattern of inheritance for a trait, disease, or disorder to be passed on through families. For a recessive trait or disease to be displayed two copies of the trait or disorder needs to be presented. The trait or gene will be located on a non-sex chromosome. Because it takes two copies of a trait to display a trait, many people can unknowingly be carriers of a disease. From an evolutionary perspective, a recessive disease or trait can remain hidden for several generations before displaying the phenotype. Examples of autosomal recessive disorders are albinism, cystic fibrosis.

Oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene. Autosomal dominant inheritance is the most common form of inheritance. Less commonly, OPMD can be inherited in an autosomal recessive pattern, which means that two copies of the mutated gene need to be present in each cell, both parents need to be carriers of the mutated gene, and usually show no signs or symptoms. The PABPN1 mutation contains a GCG trinucleotide repeat at the 5' end of the coding region, and expansion of this repeat which then leads to autosomal dominant oculopharyngeal muscular dystrophy (OPMD) disease. Signs and symptoms

LMNA-related congenital muscular dystrophy

This illness implies, like other muscular dystrophies, muscle weakness, motor difficulties and lack of control in the movement of the head, respiratory failure and cardiac abnormalities. It is an autosomal dominant inherited disease that affects both male and female. It is dominantly inherited because the abnormal gene would dominate beyond the normal one and it would transmit the disease. But it can also be recessive inheritance, which means that parents would carry the disease but it would not appear. Moreover, this disease is also caused by de novo mutations, which are spontaneous mutations. Therefore, although parents have normal genes, children who are affected by mutations will have kids that would suffer the same disease as it is transmitted through heredity. This dystrophy was discovered thanks to geneticist, Gisèle Bonne, who identified the first mutation of the LMNA gene in 1999.

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.

Human mitochondrial genetics

Inheritance patterns Because mitochondrial diseases (diseases due to malfunction of mitochondria) can be inherited both maternally and through chromosomal inheritance, the way in which they are passed on from generation to generation can vary greatly depending on the disease. Mitochondrial genetic mutations that occur in the nuclear DNA can occur in any of the chromosomes (depending on the species). Mutations inherited through the chromosomes can be autosomal dominant or recessive and can also be sex-linked dominant or recessive. Chromosomal inheritance follows normal Mendelian laws, despite the fact that the phenotype of the disease may be masked.

[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.