The spastin jigsaw puzzle: another missing piece found.
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Adenosine Triphosphatases↗
Biomedical subjects
Peter Hedera
Publications and source records attributed to Peter Hedera.
Mutations in the GABRA1 and EFHC1 genes are rare in familial juvenile myoclonic epilepsy.
Juvenile myoclonic epilepsy (JME), accounting for approximately 25% of idiopathic generalized epilepsies, is genetically heterogeneous. Mutations in the alpha-1 subunit of the GABAA receptor (GABRA1) and EFHC1 genes have been reported in a few families with autosomal dominant (AD) JME. We have investigated the contribution of these two genes to familial JME in our cohort of 54 JME Caucasian families. Syndromic classification of JME was based on previously published criteria. We considered kindreds with at least one affected first-degree relative and the evidence of a vertical transmission as definite AD JME, and families with at least one affected second-degree relative as probable AD JME. We included 33 families meeting criteria for definitive AD JME and 21 that were classified as probable AD JME. None of these families were considered informative enough to analyze candidate loci for JME using linkage analysis. We have systematically screened coding exons of these two genes using temperature gradient capillary electrophoresis. Every heteroduplex with an abnormal mobility was sequenced. No disease-causing mutations in the GABRA1 gene were identified. Analysis of EFHC1 gene found one putative disease-causing mutation R221H that was previously reported as a tandem mutation. Several synonymous and non-synonymous coding polymorphisms were identified but the allelic frequency did not differ between controls and affected individuals. Our data suggests that the majority of familial AD JME is not caused by mutations in the GABRA1 and EFHC1 genes.
Calcium-Binding Proteins↗
Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia.
Autosomal dominant hereditary spastic paraplegia (AD HSP) linked to chromosome 12q (SPG10) is caused by mutations in the neuronal kinesin heavy-chain KIF5A gene. This is a rare cause of AD HSP, and only two disease-causing mutations have been reported thus far. In both instances, affected individuals harboring mutations in the KIF5A gene displayed symptom onset at a very early age. Here we present the results of clinical and genetic analyses of a large kindred with uncomplicated AD HSP. We were able to establish a definitive linkage to the SPG10 locus, and sequencing of the KIF5A gene revealed a heterozygous missense mutation 1,035 A>G in exon 10, resulting in tyrosine-to-cysteine substitution. This mutation is located in a highly conserved kinesin motor domain of the neuronal kinesin heavy-chain protein, but in contrast to two previously reported missense mutations, the age of symptom onset in our family was much later, with an average age of 36.1+/-4 years. Our results demonstrate that mutations in the KIF5A gene can also be associated with an adult age of onset of AD HSP.
Adult↗
Treatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease.
OBJECTIVE: To compare tetrathiomolybdate and trientine in treating patients with the neurologic presentation of Wilson disease for the frequency of neurologic worsening, adverse effects, and degree of neurologic recovery. DESIGN: A randomized, double-blind, controlled, 2-arm study of 48 patients with the neurologic presentation of Wilson disease. Patients either received 500 mg of trientine hydrochloride 2 times per day or 20 mg of tetrathiomolybdate 3 times per day with meals and 20 mg 3 times per day between meals for 8 weeks. All patients received 50 mg of zinc 2 times per day. Patients were hospitalized for 8 weeks, with neurologic and speech function assessed weekly; discharged taking 50 mg of zinc 3 times per day, and returned annually for follow-up. SETTING: A university hospital referral setting. PATIENTS: Primarily newly diagnosed patients with Wilson disease presenting with neurologic symptoms who had not been treated longer than 4 weeks with an anticopper drug. INTERVENTION: Treatment with either trientine plus zinc or tetrathiomolybdate plus zinc. MAIN OUTCOME MEASURES: Neurologic function was assessed by semiquantitative neurologic and speech examinations. Drug adverse events were evaluated by blood cell counts and biochemical measures. RESULTS: Six of 23 patients in the trientine arm and 1 of 25 patients in the tetrathiomolybdate arm underwent neurologic deterioration (P<.05). Three patients receiving tetrathiomolybdate had adverse effects of anemia and/or leukopenia, and 4 had further transaminase elevations. One patient receiving trientine had an adverse effect of anemia. Four patients receiving trientine died during follow-up, 3 having shown initial neurologic deterioration. Neurologic and speech recovery during a 3-year follow-up period were quite good. CONCLUSION: Tetrathiomolybdate is a better choice than trientine for preserving neurologic function in patients who present with neurologic disease.
Adolescent↗
Familial essential tremor with apparent autosomal dominant inheritance: should we also consider other inheritance modes?
A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors.
Adolescent↗
Identification of a novel locus for febrile seizures and epilepsy on chromosome 21q22.
PURPOSE: To report results of linkage analysis in a large family with autosomal dominant (AD) febrile seizures (FS) and epilepsy. BACKGROUND: AD FS and epilepsy is clinically and genetically a heterogeneous group of epilepsies, frequently inherited. The most notable, generalized epilepsy with febrile seizures plus (GEFS+), is characterized by heterogeneous phenotypes including FS persisting beyond the usual age of remission or coexisting with afebrile seizures. Mutations in three subunits of sodium channel genes and one GABA(A)-receptor subunit gene have been identified in some GEFS+ pedigrees. Six genetic loci for FS have been reported so far, but the molecular basis of FS remains unknown. METHODS: We identified a five-generation family with 13 individuals affected by FS. Evidence was found for coexisting afebrile seizures in some affected individuals. Evaluation included a detailed history and neurologic examination, as well as collection of DNA. After excluding previously identified loci associated with FS and epilepsy, a genome-wide search was performed. RESULTS: Two affected individuals reported only a single FS, whereas the other affected individuals had a history of repeated FS. Coexisting afebrile seizures developed in three individuals. The mode of inheritance was consistent with AD inheritance with an incomplete penetrance. Tight linkage to a group of markers on chromosome 21q22 was identified with flanking markers D21S1909 and D21S1444, and maximum 2-point lod score 3.35 for markers D21S1910 and D21S1894. We excluded four ion-channel genes within this 6.5-cM locus as a cause of FS and epilepsy in this family. CONCLUSIONS: We report a novel locus on chromosome 21q22 for AD FS. Identification of the gene causing epilepsy on chromosome 21q22 will advance our understanding of inherited epilepsy and FS, and possibly other types of epilepsies.
Adult↗
Mutations in GABRA1, GABRA5, GABRG2 and GABRD receptor genes are not a major factor in the pathogenesis of familial focal epilepsy preceded by febrile seizures.
GABA(A) receptors mutations have been reported in few epilepsy families with febrile seizures (FS) followed by generalized epilepsy. It is not known if such mutations may underlie FS followed by partial epilepsy, which is a more common type of epilepsy. We searched for disease-causing mutations in the genes of the alpha1, alpha5, gamma2 and delta subunits of the GABA-A receptor that were previously shown to contain epilepsy-causing mutations or epilepsy susceptibility polymorphisms. All coding and untranslated exons of these four GABA(A) subunit genes were screened in 74 unrelated patients with familial partial epilepsy preceded by FS. Most patients had temporal lobe epilepsy (TLE). We did not detect any disease-causing mutations that would be consistent with missense, nonsense or splice site mutations in any of the four analyzed genes. We conclude that these genes are not a major genetic factor in familial TLE preceded by FS.
Adult↗
The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures.
BACKGROUND: Polymorphism G1465A in the GABBR1 gene has been suggested as a risk factor for non-lesional temporal lobe epilepsy (TLE); however, this genetic association study has not been independently replicated. We attempted to replicate this study in our cohort of patients with TLE. Furthermore, we also analyzed the coding sequence of this gene and searched for disease-causing mutations. METHODS: We included 120 unrelated individuals with TLE that was preceded by febrile seizures (FS) who did not have any evidence of structural lesions suggesting secondary epilepsy. 66 individuals had positive family history of TLE epilepsy and 54 were sporadic. Each patient was genotyped for the presence of G1465A polymorphism. All exons of the GABBR1 gene were screened by single strand confirmation polymorphism method. Genotypes were compared with two independent matched control groups. RESULTS: We detected two A alleles of the G1465A polymorphism in one homozygous control subject (0.87% of all alleles) and one A allele in a patient with TLE (0.45%, not significant). Other detected polymorphisms in coding regions had similar frequencies in epilepsy patients and control groups. No disease causing mutations in the GABBR1 gene were detected in patients with sporadic or familial TLE. CONCLUSION: Our results indicate that TLE preceded by FS is not associated with the polymorphisms or mutations in the GABBR1 gene, including the G1465A polymorphism. The proportion of TLE patients with FS in the original study, reporting this positive association, did not differ between allele A negative and positive cases. Thus, our failure to reproduce this result is likely applicable to all non-lesional TLE epilepsies.
Adult↗
Autosomal recessive primary generalized dystonia in two siblings from a consanguineous family.
We describe the clinical features of a brother and sister with non-dopa-responsive, childhood-onset, generalized dystonia. The children were born to consanguineous parents, had no family history of neurologic disease, no evidence of structural or metabolic causes of dystonia, and negative testing for the GAG946 deletion mutation in the DYT1 gene. This report supports the existence of a generalized type of dystonia with autosomal recessive inheritance (DYT2).
Child↗
Skewed X-inactivation in carriers establishes linkage in an X-linked deafness-mental retardation syndrome.
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Chromosomes, Human, X↗
Two patients with monomelic ulnar duplication with mirror hand polydactyly: segmental Laurin-Sandrow syndrome.
We have studied two unrelated boys with isolated left mirror hand and ulnar duplication. Neither had facial anomalies and family histories were unremarkable. We suggest that these boys have segmental Laurin-Sandrow syndrome, or mirror-image duplication, due to somatic mutation involving precursor cells of the left upper limb and that the facial and digital abnormalities in Laurin-Sandrow syndrome are consistent with ectopic anterior hedgehog signaling in the developing limb bud and in the maxillary processes of the face, which closely resemble findings in the Doublefoot (Dbf) mouse mutant.
Abnormalities, Multiple↗
Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).
We previously linked Laing-type early-onset autosomal dominant distal myopathy (MPD1) to a 22-cM region of chromosome 14. One candidate gene in the region, MYH7, which is mutated in cardiomyopathy and myosin storage myopathy, codes for the myosin heavy chain of type I skeletal muscle fibers and cardiac ventricles. We have identified five novel heterozygous mutations--Arg1500Pro, Lys1617del, Ala1663Pro, Leu1706Pro, and Lys1729del in exons 32, 34, 35, and 36 of MYH7--in six families with early-onset distal myopathy. All five mutations are predicted, by in silico analysis, to locally disrupt the ability of the myosin tail to form the coiled coil, which is its normal structure. These findings demonstrate that heterozygous mutations toward the 3' end of MYH7 cause Laing-type early-onset distal myopathy. MYH7 is the fourth distal-myopathy gene to have been identified.
Child↗
Novel mutation in the SPG3A gene in an African American family with an early onset of hereditary spastic paraplegia.
BACKGROUND: Mutations in a novel GTPase gene SPG3A cause an autosomal dominant hereditary spastic paraplegia linked to chromosome 14q (SPG3), which accounts for approximately 10% to 15% of all autosomal dominant hereditary spastic paraplegia cases. The mutational spectrum of the SPG3A gene and the phenotype/genotype correlations have not yet been established. OBJECTIVE: To describe a kindred with an infantile onset of hereditary spastic paraplegia caused by a novel mutation in the SPG3A gene. PATIENTS: Complete neurological examination and genetic analysis were performed on 6 affected members of a small African American kindred. Linkage analysis to genetic markers near autosomal dominant hereditary spastic paraplegia loci on chromosomes 2p and 14q was performed. The coding sequence of the SPG3A gene was analyzed, and the identified change in the sequence was tested for being a benign polymorphism by sequencing 200 chromosomes from normal controls. RESULTS: Every affected individual had signs of uncomplicated spastic paraparesis without additional neurological abnormalities. None of the affected family members had ever walked normally. The history was consistent with an infantile onset, despite the normal acquisition of motor milestones. Genetic analysis suggested linkage to the SPG3A locus on chromosome 14q. Analysis of the SPG3A gene revealed a missense mutation C635T, predicted to result in a threonine to isoleucine substitution at codon 156. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. CONCLUSION: We report a novel mutation in the SPG3A gene in an African American family with an infantile onset of autosomal dominant hereditary spastic paraplegia.
Adolescent↗
Autosomal dominant lateral temporal epilepsy: two families with novel mutations in the LGI1 gene.
PURPOSE: Mutations in the leucine rich, glioma inactivated gene (LGI1) were recently described in a small number of families with autosomal dominant lateral temporal epilepsy (ADLTE). ADLTE is characterized by partial seizures with symptoms suggestive of a lateral temporal onset, including frequent auditory aura. Here we report the results of clinical and genetic analyses of two newly identified families with ADTLE. METHODS: We identified two families whose seizure semiology was suggestive of ADLTE. Evaluation included a detailed history and neurologic examination, as well as collection of DNA. The coding sequence of the LGI1 gene from affected subjects from both families was analyzed for evidence of mutation. RESULTS: Each patient had a history of partial seizures, often with secondary generalization earlier in the course. Auditory aura was reported by approximately two thirds of affected patients in each pedigree. Novel mutations in LGI1 were detected in both families. A heterozygous single-nucleotide deletion at position 329 (del 329C) was detected in affected individuals from one family, whereas patients from the second family had a nonsynonymous variation, corresponding to C435G. CONCLUSIONS: We identified two novel mutations in the LGI1 gene. The phenotype of these two families was similar to that of other kindreds with ADLTE, as auditory aura was absent in one third of affected individuals. Our results further support that LGI1 mutations should be considered in patients with a history of partial seizures if the semiology of seizures is consistent with the onset in the lateral temporal lobe.
Adult↗
Oculo-facio-cardio-dental syndrome: skewed X chromosome inactivation in mother and daughter suggest X-linked dominant Inheritance.
Oculo-facio-cardio-dental syndrome (OFCD) is an uncommon multiple congenital anomaly syndrome that is characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects, and dental anomalies including canine radiculomegaly and oligodontia. Although most cases of OFCD are sporadic, since all reported OFCD individuals have been female, it has been suggested that OFCD is an X-linked dominant trait. Here we report two affected female patients with OFCD, a mother and daughter, who both had congenital cataracts, microphthalmia, characteristic dental anomalies, and typical facial dysmorphisms. These features were diagnostic for OFCD; thus, these cases represent the second documented instance of mother-to-daughter OFCD transmission. In addition to the clinical features typically seen in OFCD individuals, the affected daughter exhibited several additional congenital anomalies including intestinal malrotation and hypoplastic thumbs. Thus, these cases further define and expand the OFCD clinical phenotype. These two individuals also displayed a skewed pattern of X chromosome inactivation. Together, these data strongly support the hypothesis that OFCD is inherited as an X-linked dominant condition.
Abnormalities, Multiple↗
Juberg-Hayward syndrome: report of a new patient with severe phenotype and novel clinical features.
We report a patient with severe mental retardation (MR), microcephaly, Dandy-Walker malformation, bilateral lip/palate clefts, hypertrophied sublingual frenulum, lobular tongue, absent thumbs, and other skeletal abnormalities, including Y-shaped metacarpals and urogenital abnormalities. High-resolution karyotype and subtelomeric fluorescence in situ hybridization were normal. We propose that his clinical picture is most consistent with Juberg-Hayward or orocraniodigital syndrome. Several clinical features present in our patient (unilateral distal displacement of elbow position, second-site radioulnar synostosis, bilateral Y-shaped metacarpal, lobular tongue, hypertrophic frenuli, Dandy-Walker malformation) have not previously been reported in this condition, thus expanding the phenotypic spectrum of this rare condition. The presence of these novel findings suggests possible overlap with other syndromes, such as orofaciodigital and Malpuech syndromes.
Adolescent↗
Treatment of Wilson disease with ammonium tetrathiomolybdate: III. Initial therapy in a total of 55 neurologically affected patients and follow-up with zinc therapy.
BACKGROUND: It is unclear what anticopper drug to use for patients with Wilson disease who present with neurologic manifestations because penicillamine often makes them neurologically worse and zinc is slow acting. OBJECTIVE: To evaluate the frequency of neurologic worsening and drug adverse effects with ammonium tetrathiomolybdate. DESIGN: Open-label study of 55 untreated patients (22 of them new) presenting with neurologic Wilson disease treated with tetrathiomolybdate varying from 120 to 410 mg/d for 8 weeks and then followed up for 3 years. Neurologic function was assessed with scored neurologic and speech tests. SETTING: A university hospital referral setting. PATIENTS: All untreated, newly diagnosed patients with neurologic Wilson disease. INTERVENTION: Treatment with tetrathiomolybdate. MAIN OUTCOME MEASURES: Neurologic function was evaluated by neurologic and speech examinations. Drug adverse effects were evaluated by complete blood cell counts and biochemical measures. RESULTS: Only 2 (4%) of 55 patients treated with tetrathiomolybdate showed neurologic deterioration, compared with an estimated 50% of penicillamine-treated patients. Five of the 22 new patients exhibited bone marrow suppression and 3 had aminotransferase elevations. These numbers are higher than in the original 33 patients and appear to be due primarily to a more rapid dose escalation. CONCLUSIONS: Tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur.
Adult↗
Myelopolyneuropathy and pancytopenia due to copper deficiency and high zinc levels of unknown origin: further support for existence of a new zinc overload syndrome.
OBJECTIVE: To describe a patient with idiopathic zinc overload without an identifiable source and secondary copper deficiency causing myelopolyneuropathy and pancytopenia. DESIGN: Case report. PATIENT AND RESULTS: A 46-year-old man presented with severe bone marrow suppression and subsequently developed progressive myelopathy with sensory ataxia. No identifiable cause of myelopathy was detected, and his neuroimaging findings were unremarkable. Plasma analysis demonstrated a low copper level and an increased zinc level (<10 micro g/dL [<12.6-18.9 micro mol/L] and 184 micro g/dL [28.2 micro mol/L], respectively; normal range for both, 80-120 micro g/dL [12.6-18.9 micro mol/L and 12.3-18.4 micro mol/L, respectively) and a low level of ceruloplasmin. There was no evidence for an external source of zinc. Daily oral supplementation with 2 mg resulted in the prompt reversal of hematologic abnormalities, improved but still subnormal plasma copper levels, and normalization of ceruloplasmin values. The patient's neurologic condition deteriorated further, with worsening of myelopathy and development of polyneuropathy. Analyses of plasma copper and zinc levels demonstrated persisting hyperzincemia and subnormal copper levels during 4 years of follow-up. Increased copper supplementation to 8 mg/d partially reversed his neurologic signs. A clinical investigation of 6 siblings and 1 surviving parent did not identify family members with similar abnormalities. CONCLUSIONS: Persistent hyperzincemia without an identifiable external source appears to be a primary metabolic defect, while copper deficiency is a secondary phenomenon, causing hematologic and neurologic abnormalities. Two unrelated patients with similar idiopathic hyperzincemia and hypocupremia have been recently described. This suggests the existence of a new metabolic disorder with idiopathic zinc overload.
Copper↗