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PubMed2001

Familial infantile myoclonic epilepsy: clinical features in a large kindred with autosomal recessive inheritance.

PURPOSE: To describe the clinical features of a large kindred with familial infantile myoclonic epilepsy (FIME) with autosomal recessive inheritance, and to discuss the nosology of the early infantile myoclonic epilepsies (IMEs). METHODS: The family descends from the intermarriage of two couples of siblings. In a previous study, we mapped the genetic locus to chromosome 16p13. We analyzed results of family records and personal history, psychomotor development, neurologic examination, epilepsy features, and EEG recordings for each subject. RESULTS: FIME has a strong penetrance (eight affected of 14 subjects) and a homogeneous clinical picture. Like the benign form of infantile myoclonic epilepsy (BIME), FIME is a true idiopathic IME with unremarkable history, no neurologic or mental impairment, good response to treatment, and normal interictal EEG pattern. Conversely, onset with generalized epileptic seizures without fever (four patients) or with fever (one patient), frequency and duration of the myoclonic seizures, occurrence of generalized tonic--clonic seizures (GTCSs) in all patients and persistence of seizures into adulthood are characteristics of the severe infantile myoclonic epilepsy (SIME). CONCLUSIONS: Clinical overlap probably exists among the myoclonic epilepsies of infancy. FIME differs from other forms of IME in its phenotypic features. The peculiar mode of inheritance is explained by the genetic background of the family. Genetic studies suggest linkage to chromosome 16 in familial cases of true IME.

Adult↗
PubMed2003

Inherited platelet-based bleeding disorders.

Inherited platelet-based bleeding disorders include abnormalities of platelet number and function, and are generally classified based on the abnormal functions or responses. However, a clear distinction is problematic, and in this review, the classification has been based on abnormalities of platelet components that share common characteristics. Inherited thrombocytopenias are rare, but probably underdiagnosed. They are usually classified according to both platelet size and the presence or absence of clinical features other than those deriving from the platelet defect. Hereditary disorders of platelet function can be classified as resulting from: (i) abnormalities of the platelet receptors for adhesive proteins; (ii) abnormalities of the platelet receptors for soluble agonists; (iii) abnormalities of the platelet granules; (iv) abnormalities of the signal-transduction pathways; (v) abnormalities of the membrane phospholipids; and (vi) miscellaneous abnormalities of platelet function. The literature on these disorders is reviewed, and the underlying defects discussed.

Blood Platelet Disorders↗
PubMed2003

Thrombophilic families with inheritably associated high levels of coagulation factors VIII, IX and XI.

We describe six families in which associated high levels of coagulation factors (F) XI, FIX and FVIII (each with a plasma concentration higher than the 95th percentile found in a control group of 500 asymptomatic individuals: respectively, 135, 145 and 155 IU dL-1) were inherited as a dominant autosomic genetic traits. In these six families, this syndrome is associated with venous thromboembolic events (Odds ratio 41 [4.9-353], P = 0.0006). It seems to predispose to idiopathic events and, as age increases, is often associated with recurrence. First thrombotic episodes occur in young patients (50% of the carriers are symptomatic at the age of 32 years) and in women, can be unmasked by hormonal treatments, mainly oral contraceptives. The association of high levels of coagulation FXI, FIX and FVIII is thus a new rare high-risk inherited thrombophilia syndrome.

Adolescent↗
PubMed2001

Mitochondrial diabetes, DIDMOAD and other inherited diabetes syndromes.

Inherited diabetes syndromes are individually rare but collectively make up a significant proportion of patients attending diabetes clinics, some of whom have multiple handicaps. This chapter focuses on syndromes in which major advances have been made in our understanding of the underlying molecular genetics. These conditions demonstrate novel genetic mechanisms such as maternal inheritance and genetic imprinting. They are also fascinating as they aid our understanding of insulin metabolism, both normal and abnormal. As the causative genes are identified, future issues will be the availability of genetic testing, their contribution to the genetic heterogeneity of the more common types of diabetes, and functional studies of the relevant proteins. It is probable that other subtypes of diabetes will be identified as the relevant metabolic pathways are characterized. This is an exciting time to be a diabetes physician as diabetology returns to being a diagnostic rather than a mainly management-based speciality.

Adult↗
PubMed2001

Evidence-based diagnosis of familial non-X-linked dilated cardiomyopathy. Prevalence, inheritance and characteristics.

AIMS: To assess the prevalence of familial non-X-linked dilated cardiomyopathy, to diagnose early asymptomatic cases evaluate inheritance and characterize clinical phenotypes. METHODS AND RESULTS: We screened 472 relatives of 104 consecutive patients diagnosed with dilated cardiomyopathy; males with X-linked dilated cardiomyopathy were excluded based on systematic immunohistochemical and molecular analysis. Relatives underwent clinical examination, electrocardiography, echocardiography and serum creatine-phosphokinase determination. Twenty-six index patients (25%) had familial disease: four youths (< or = 20 years) had rapidly progressive outcome and underwent emergency transplantation. In a sib-pair, the onset was with atrioventricular block. Inheritance was autosomal dominant in 15, undetermined in seven (four sib-pairs); mitochondrial DNA pathological mutations were found in four. The screening identified 23 newly diagnosed relatives in the familial group. Transplantation (P = 0.04) and atrial fibrillation (P = 0.04) were more frequent, and left bundle branch block (P = 0.04) less frequent in index patients with familial than in those with non-familial disease. Several non-affected relatives had instrumental abnormalities potentially useful as pre-clinical markers: their prevalence was similar in both groups. CONCLUSIONS: The prevalence of familial, non X-linked dilated cardiomyopathy was 25%. The immediate benefits of screening family members of index patients was early diagnosis in unaware symptomless affected relatives.

Adult↗
PubMed2006

Diamond blackfan anemia: New paradigms for a "not so pure" inherited red cell aplasia.

Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous disorder characterized by erythroid failure, congenital anomalies, and a predisposition to cancer. Faulty ribosome biogenesis is hypothesized to be the underlying defect, leading to erythroid failure due to accelerated apoptosis in affected erythroid progenitors/precursors. Since first observed in DBA, pro-apoptotic hematopoiesis has been recognized as a common mechanism for hematopoietic failure in virtually all of the inherited bone marrow failure syndromes. Inherited as an autosomal dominant trait, one of what appears to be multiple DBA genes, coding for ribosomal protein RPS19, has been cloned. The discovery of additional genes will no doubt clarify the molecular pathophysiology of this disorder. Even within families, individuals may vary dramatically as to the degree of anemia, treatment response, and the presence of congenital anomalies. The study of DBA has been facilitated by the creation of international patient registries that provide more reliable information regarding clinical presentation, genetics, and outcome, as well as descriptions of congenital malformations and cancer predisposition, than can be culled from the literature. Analysis of registry data has led to improvements in clinical care and provides patients and research specimens for clinical and laboratory investigations.

Anemia, Diamond-Blackfan↗
PubMed2006

Inherited thrombocytopenia: Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii.

Thrombocytopenia in the newborn period can signify an inherited platelet disorder. Congenital amegakaryocytic thrombocytopenia (CAMT) and thrombocytopenia with absent radii (TAR) share features of isolated thrombocytopenia, reduced or absent marrow megakaryocytes, impaired responsiveness to thrombopoietin (TPO), and high plasma TPO levels. These disorders are most readily distinguished from each other by the finding of radial aplasia in TAR and the presence of c-MPL mutations in CAMT. In addition, their long-term outcomes are strikingly different: the development of trilineage marrow failure in CAMT in contrast to the general improvement of thrombocytopenia in TAR. The differential diagnosis for CAMT and TAR also includes other congenital disorders in which thrombocytopenia and radial abnormalities can be seen. In this article we will review our molecular and clinical understanding of these two inherited disorders of amegakaryocytosis.

Cell Lineage↗
PubMed2002

The genetics of inherited sideroblastic anemias.

The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders defined by the presence of pathologic iron deposits in erythroblast mitochondria. While the pathogenesis of almost all cases of acquired sideroblastic anemia is unknown, the molecular genetic basis for several of the inherited forms have now been described. Initially, mutations in ALAS2 in X-linked sideroblastic anemia (XLSA) focused attention on the heme biosynthetic pathway as a primary cause of sideroblastic anemia. However, the subsequent description of the genes involved in XLSA with ataxia, thiamine-responsive megaloblastic anemia, and Pearson marrow-pancreas syndrome have implicated other pathways, including mitochondrial oxidative phosphorylation, thiamine metabolism, and iron-sulfur cluster biosynthesis, as primary defects in sideroblastic anemias that may only secondarily impact heme metabolism.

Anemia, Sideroblastic↗
PubMed2002

Considerations in genetic counseling for inherited breast cancer predisposition.

Of the 190000 women estimated to have been diagnosed with breast cancer in 2001, between 5% and 10% of them are likely to have developed their disease as the result of an inherited susceptibility. Although breast cancer is a component tumor of several familial cancer predisposition syndromes, mutations in BRCA1 and BRCA2 are the most commonly identified germline changes. Recognition of hereditary breast cancer is critical to allow the implementation of appropriate treatment, screening, and prevention strategies for the affected woman and her family members. Genetic testing may play an important role in refining risk assessment, identifying individuals at risk before cancer has developed, and relieving anxiety in family members who have not inherited the predisposition.

Breast Neoplasms↗
PubMed1996

The molecular basis and clinical characteristics of Maternally Inherited Diabetes and Deafness (MIDD), a recently recognized diabetic subtype.

Diabetes mellitus comprises a number of diseases with hyperglycemia as hallmark. Currently, multiple genetic factors are being recognized which contribute to the development of diabetes or which may modulate its clinical expression. This review presents an overview of our current knowledge on a diabetic subtype which associates with a single mutation in mitochondrial DNA. Based on the triad of Maternal Inheritance, Diabetes and Deafness we propose the name Maternally Inherited Diabetes and Deafness (MIDD) for this syndrome. In Northwestern Europe MIDD affects approximately 1.3% of all diabetic individuals.

Adult↗
PubMed2000

Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism.

Hyperhomocysteinemia is an established risk factor for deep vein thrombosis. Factor V Leiden has been reported to potentiate the thrombotic risk related with severe hyperhomocysteinemia, being more represented in thrombotic patients with homocystinuria as compared with patients without a history of thrombosis. The results concerning the interaction between moderate hyperhomocysteinemia and inherited thrombophilic factors such as Factor V Leiden or the prothrombin G20210A mutation are contradictory. The relative risk for venous thrombosis has been reported to be increased 10- to 50-fold in patients carrying both hyperhomocysteinemia and inherited thrombophilia in comparison with normal controls, suggesting a synergistic interaction, yet other studies failed to confirm such conclusion. The heterogeneity of these findings is in part due to the small number of individuals with double defects, leading to statistically unreliable results. Genotyping for mutations that are possible causes of moderate hyperhomocysteinemia, such as the thermolabile variant (C677T) of methylenetetrahydrofolate reductase (MTHFR), does not seem useful to identify individuals at higher risk for venous thromboembolism. In fact, in most of the studies the presence of the C677T MTHFR homozygous genotype does not increase the thrombotic risk associated with Factor V Leiden or the prothrombin mutation.

3' Untranslated Regions↗
PubMed2003

Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications.

Inherited thrombophilia has been reported to be associated with an increased risk for complications of pregnancy, including venous thromboembolism (VTE) as well as preeclampsia (PEC), fetal loss (FL), fetal growth retardation (FGR), and abruptio placentae (AP), the latter probably due to inadequate placental perfusion. The estimate of risk largely depends on the kind of thrombophilia and on the criteria applied for the selection of the patients, producing in some cases contradictory results. Convincing evidence is available that deficiency of antithrombin III (AT), protein C (PC), and protein S (PS) is a risk factor for VTE and late FL. Factor V (Leiden) is associated with an increased risk for VTE, unexplained recurrent FL, late FL, and perhaps PEC; prothrombin G20210A is a weak risk factor for VTE. So far, the data available for FGR and AP are scarce. However, the absolute risk for VTE during pregnancy and puerperium is between 1 and 3%, in comparison with the baseline risk of 0.08%. Antithrombotic prophylaxis with subcutaneous heparin is warranted during puerperium in all women with thrombophilia and throughout all pregnancy in women at higher risk (AT deficiency, homozygosity for factor VLeiden, and perhaps PC and PS deficiencies); treatment with subcutaneous heparin for prevention of FL among women with thombophilia is under investigation. Presence of inherited thrombophilia increases the risk for VTE due to oral contraceptives up to an absolute risk of 3 per 1000 person-years, in comparison with the baseline risk of 3 to 6 per 10000 person-years; the risk is further increased by first usage, the use of preparations containing third-generation progestins, and thrombophilia due to AT, PC, and PS deficiency as well as homozygous factor V (Leiden) and combined defects.

Blood Coagulation Factors↗
PubMed2003

Oral contraceptives and inherited thrombophilia: a gene-environment interaction with a risk of venous thrombosis?

There are indications in the literature that asymptomatic women with an inherited thrombophilic defect who use oral contraceptive have an increased risk of venous thrombosis. There are no consistent data regarding the thrombotic risk in users of oral contraceptives with an inherited thrombophilic defect and personal history of venous thrombosis. Selective genetic screening on the basis of clinical judgment, and family and personal history, instead of universal screening, may be useful before oral contraceptives are prescribed. Nonetheless, the actual risks and benefits of such practice remain to be examined.

Contraceptives, Oral↗
PubMed2004

Inherited thrombocytopenias: molecular mechanisms.

Each megakaryocyte forms 10(3) platelets and 10(11) platelets are replenished daily. The unique and amazing mechanisms that allow megakaryocytes to become giant and polyploid and to release such a large number of platelets are still poorly understood. The study of inherited thrombocytopenias offers the possibility to gain new information on these processes because several different forms, deriving from defective megakaryocytic commitment, differentiation, maturation, or platelet formation, have been identified. Moreover, in the presence of some genetic defects, megakaryocytes produce platelets with a shortened life span. In this review, we summarize what we have learned about inherited thrombocytopenias in the last few years.

Bernard-Soulier Syndrome↗
PubMed2005

Inheritance of R337H p53 gene mutation in children with sporadic adrenocortical tumor.

Adrenocortical tumors (ACTs) are frequent in Brazil. The mechanisms of adrenal tumorigenesis remain poorly established; the R337H germline mutation in the p53 gene has previously been associated with ACTs in Brazilian children. We investigated the frequency and inheritance of R337H p53 mutation as well as genotype and phenotype correlation in 21 children and 5 adult patients with ACTs. DNA was extracted from peripheral blood cells and/or tumor tissue for sequencing exon 10 of the p53 gene. Nine sets of parents of patients with p53 mutation were also submitted to mutational analysis. Virilization was the most common clinical sign in children with or without Cushing's syndrome. Two members of the adult group showed asymptomatic adrenal incidentalomas, two showed virilization, and one presented with Cushing's syndrome. Sixteen children with ACTs had peripheral blood available, and twelve of them (75%) showed the heterozygous R337H p53 gene mutation. The R337H mutation was found in fifteen samples of the nineteen tumor specimens available (78.9%). Among the nine sets of parents of the patients with R337H mutation, eight showed the same mutation with heterozygosity in one of the parents. None of the parents showed ACTs or any other neoplasia at the time of the study. Only one adult patient with an ACT revealed the same R337H p53 germline mutation. There was no association between the presence of germline or tissue R337H p53 mutation and malignancy at diagnosis. We confirmed the high frequency of R337H p53 mutation in Brazilian children with sporadic ACTs. The R337H p53 mutation was inherited from one of the parents of the patients, and there was no association between the presence of this mutation and tumor malignancy in children. The founder effect of R337H p53 mutation and the role of environmental mutagens contributing to the geographical clustering and high prevalence of ACTs in Brazilian children remain to be established.

Adrenal Cortex Neoplasms↗
PubMed2005

Laboratory detection of inherited thrombophilia: a historical perspective.

Considerable progress has been made in determining the molecular bases of inherited thrombophilia in the last 25 years. There are several genetic abnormalities that can be detected in the laboratory and are currently recognized to be unequivocally associated with an increased tendency to develop venous thrombosis. Testing for inherited and acquired causes of thrombophilia may make counseling more focused in ostensibly healthy members of thrombophilic families (i.e., those in which a measurable abnormality was identified in one or more asymptomatic persons). In other situations, including women who start taking oral contraceptives, become pregnant, or consider hormone replacement therapy, screening is generally not useful. It is hoped that because we currently have such simple and clinically useful global tests of hypocoagulability as the prothrombin time and activated partial thromboplastin time, it may soon become possible to measure multifactorial thrombophilia without resorting to the multiplicity of tests now necessary.

Blood Coagulation↗
PubMed2006

Diagnosis of inherited von Willebrand disease: a clinical perspective.

von Willebrand disease (VWD) is the most frequent inherited disorder of hemostasis and is due to quantitative (types 1 and 3) or qualitative (type 2) defects of von Willebrand factor (VWF). Due to the large heterogeneity of VWF defects and to the external variables influencing VWF levels in the circulation, VWD diagnosis can be difficult, especially in relatively mild forms. Three criteria should be always satisfied for a correct VWD diagnosis: (1) a positive bleeding history since childhood; (2) reduced levels of VWF activity in plasma; and (3) autosomal dominant or recessive inheritance patterns within the family (in most cases). According to clinical prospective studies, a bleeding history in VWD patients should be derived from a detailed questionnaire, with calculated bleeding scores. The ristocetin cofactor activity is the most useful test for VWD screening in the general population because it reproduces in vitro the first VWF interactions with its platelet receptor; however other assays are required to identify and classify VWD types. The current classification (types 1, 2A, 2B, 2M, 2N, and 3) is important to understand the basic mechanisms of VWF defects, to determine the risk of bleeding, and to select the best therapeutic approach. Molecular screening can be important to confirm phenotypic diagnosis for tracking VWF defects within families. Compared with hemophilia, most VWD patients show relatively mild bleeding symptoms. Therefore, prenatal diagnosis is required only for women already known to be carriers of VWD type 3. No spontaneous bleedings usually occur at birth in severe type 3 VWD. Neonatal diagnosis of VWD should always be compared with other affected members within the same family. Given that young children with VWD type 3 might carry deletions of VWF gene that predispose to the alloantibodies to VWF, every new child with VWD type 3 should be investigated intensively for VWF gene deletions before starting extensive therapy with exogenous VWF concentrates.

Child↗
PubMed1997

Maternally inherited diabetes and deafness: a diabetic subtype associated with a mutation in mitochondrial DNA.

Diabetes mellitus is a common disease with variations in its clinical expression and different modes of pathogenesis. The purpose of this review is to discuss a recently identified diabetic subtype. Based on the triad diabetes, maternal inheritance and impaired hearing in this subtype we have proposed the name Maternally Inherited Diabetes and Deafness (MIDD). This diabetic subtype associates in the vast majority of cases with a single mutation in mitochondrial DNA, at position 3243. The clinical presentation of MIDD which can be IDDM-like or NIDDM-like, its frequency of occurrence, possible pathogenic mechanisms and the contribution of other mitochondrial DNA mutations to the development of diabetes will be discussed.

DNA, Mitochondrial↗