Novel SPG10 mutation associated with dysautonomia, spinal cord atrophy, and skin biopsy abnormality.

BACKGROUND: SPG10 is a rare form of autosomic dominant hereditary spastic paraplegia (HSP) caused by mutations in the KIF5A gene, which may be involved in axonal transport. METHODS: We report the characteristics of a French family with a novel missense mutation c.580 G>C in exon 7 of the KIF5A gene. RESULTS: The proband and his sister presented with an adult onset HSP, a sensory spinal cord-like syndrome, dysautonomia, and severe axonal polyneuropathy. Contrary to the proband, his sister presented a secondary improvement in spasticity and walking. In the proband, MRI findings consisted in spinal cord atrophy and symmetric cerebral demyelination, whereas the skin biopsy suggested a defect in the number of vesicles and synaptophysin density at the pre-synaptic membrane. CONCLUSION: This study extends the phenotype of SPG10 and argues for abnormalities in the axonal vesicular transport.

First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.

The gene for autosomal dominant cerebellar ataxia with pigmentary macular dystrophy maps to chromosome 3p12-p21.1.

Autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) is a rare neurodegenerative disorder with marked anticipation. We have mapped the ADCA type II locus to chromosome 3 by linkage analysis in a genome-wide search and found no evidence for genetic heterogeneity among four families of different geographic origins. Haplotype reconstruction initially restricted the locus to the 33 cM interval flanked by D3S1300 and D3S1276 located at 3p12-p21.1. Combined multipoint analysis, using the Zmax-1 method, further reduced the candidate interval to an 8 cM region around D3S1285. Our results show that ADCA type II is a genetically homogenous disorder, independent of the heterogeneous group of type I cerebellar ataxias.

Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2.

A gene mutated in Charcot-Marie-Tooth disease type 4B (CMT4B), an autosomal recessive demyelinating neuropathy with myelin outfoldings, has been mapped on chromosome 11q22. Using a positional-cloning strategy, we identified in unrelated CMT4B patients mutations occurring in the gene MTMR2, encoding myotubularin-related protein-2, a dual specificity phosphatase (DSP).

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.

INTRODUCTION: Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI). OBJECTIVE: To characterise in more detail the mutation spectrum associated with Dravet syndrome. METHODS: A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened. RESULTS: SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients. CONCLUSION: These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.

Familial cortical myoclonic tremor with epilepsy (FCMTE): Clinical characteristics and exclusion of linkages to 8q and 2p in a large French family.

INTRODUCTION: Familial cortical myoclonic tremor with epilepsy (FCMTE) is defined by an autosomal-dominant inheritance, adult onset of myoclonus of the extremities, infrequent epileptic seizures, a non-progressive course, polyspikes on electroencephalography (EEG), photosensitivity, giant somatosensory-evoked potentials (SEP), enhancement of C-reflex and a premyoclonus spike detected by jerk-locked EEG back-averaging. Two genes yet to be identified are mapped to 8q23.3-q24.1 and 2p11.1-q12.2. METHODS: The present study involved five generations of a French family presenting with FCMTE, including 76 family members. Clinical analyses were performed in 39 living subjects and electrophysiological studies in five patients. Altogether, 27 relatives (21 living and six deceased) had the clinical characteristics of FCMTE, 17 of whom were analyzed. Linkage analyses were performed with microsatellites encompassing the two known loci (8q 23.3-q24.1 and 2p11.1-q12.2). RESULTS: Mean age at onset in the 17 living patients was 28.8 years (range 24-41). All had myoclonus/cortical tremor, and 11/17 had generalized tonic-clonic seizures. Other clinical symptoms were photosensitivity (16 cases), partial seizures (five cases), sensitivity to starvation/exercise (six cases) and vibration (four cases), ophthalmic migraine (six cases) and gait disorders (10 cases). Electrophysiological studies confirmed the FCMTE diagnosis in the five studied patients. Of the remaining relatives, 14 were considered healthy (asymptomatic subjects aged more than 40years) and eight were of unknown status (asymptomatic aged lesser than 40years). The pattern of inheritance was consistent with autosomal-dominant inheritance, although the two loci responsible for FCMTE were excluded. CONCLUSION: This large family highlights some unusual clinical characteristics and suggests the presence of a third gene. Genetic research is ongoing to identify the mutated gene.

K-complex-induced seizures in autosomal dominant nocturnal frontal lobe epilepsy.

OBJECTIVE: To examine in detail the relations between seizures and K-complexes in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). METHODS: Prolonged continuous video-EEG recording and analysis of 30 seizures in an 18-year-old woman suffering from ADNFLE with a CHRNA4 gene mutation. RESULTS: Twenty-seven of 30 recorded seizures started just after a K-complex. In nine cases a sound induced a K-complex that was immediately followed by the seizure. Most seizures preceded repetitive and brief ictal restarts. CONCLUSIONS: Three new characteristics have been observed in this ADNFLE patient: a K-complex is almost invariably present at seizure onset; sounds trigger some seizures; ictal restarts occur often. SIGNIFICANCE: These new observations--the presence of K-complexes at seizure onset and occurrence of sound-triggered seizures--support the view that ADNFLE seizures may be initiated by K-complexes.

Autism, language delay and mental retardation in a patient with 7q11 duplication.

BACKGROUND: Chromosomal rearrangements, arising from unequal recombination between repeated sequences, are found in a subset of patients with autism. Duplications involving loci associated with behavioural disturbances constitute an especially good candidate mechanism. The Williams-Beuren critical region (WBCR), located at 7q11.23, is commonly deleted in Williams-Beuren microdeletion syndrome (WBS). However, only four patients with a duplication of the WBCR have been reported to date: one with severe language delay and the three others with variable developmental, psychomotor and language delay. OBJECTIVE AND METHODS: In this study, we screened 206 patients with autism spectrum disorders for the WBCR duplication by quantitative microsatellite analysis and multiple ligation-dependent probe amplification. RESULTS: We identified one male patient with a de novo interstitial duplication of the entire WBCR of paternal origin. The patient had autistic disorder, severe language delay and mental retardation, with very mild dysmorphic features. CONCLUSION: We report the first patient with autistic disorder and a WBCR duplication. This observation indicates that the 7q11.23 duplication could be involved in complex clinical phenotypes, ranging from developmental or language delay to mental retardation and autism, and extends the phenotype initially reported. These findings also support the existence of one or several genes in 7q11.23 sensitive to gene dosage and involved in the development of language and social interaction.

Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease.

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families in the European CMT population but are more frequent in the Mediterranean basin and the Middle East because of more widespread consanguinity. Until now, demyelinating ARCMT was more extensively studied at the genetic level than the axonal form. Since 1999, the number of localized or identified genes responsible for demyelinating ARCMT has greatly increased. Eight genes, EGR2, GDAP1, KIAA1985, MTMR2, MTMR13, NDRG1, PRX, and CTDP1, have been identified and two new loci mapped to chromosomes 10q23 and 12p11-q13. In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis.

The involvement of the trans-generational effect in the high incidence of the hydatidiform mole in Africa.

INTRODUCTION: While the incidence of various chromosomal anomalies observed, including triploid partial moles is independent of the socio-economic level, higher incidences of complete hydatidiform mole "CHM" is generally associated with under developed areas. Moreover, studies have shown that some nutritional deficiencies are related to the abnormal development of oocytes and placenta. In Senegal and Morocco, the annual seasonal cycle contains one period with food shortages and the incidence of complete moles is significant. Accordingly, accurate statistical analyses have been performed in these two countries. METHODS: Each month during a one year period, we investigated the occurrence of normal conceptions, molar conceptions and the conception of the future patients in Senegal and Morocco. The comparisons of the conception dates for these three types of conception were analyzed using the Chi-squared test. RESULTS: 94% of the patients were conceived just prior to the period in the year with food shortages. Consequently, the development of the female embryos occurred under nutritional constraints, which negatively affect the recruitment of the vital factors required for the normal synthesis of DNA, proteins and placental differentiation. DISCUSSIONS: A nutritional deficiency in the mother at conception of their daughter (future patient) is implicated in the higher incidence of CHM in their daughters' filiation. These nutritional deficiencies during the first weeks of pregnancy will have repercussions on the normal development of the oocytes. Accordingly, these developmental impairments take place during the embryonic life of the future mothers of complete moles and not during the conception of the moles themselves.

A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length.

Our study aims to provide a comprehensive view of the endocrine features in Kennedy's disease (KD). Twenty-two men with KD underwent detailed endocrine investigations. Clinical signs of partial androgen resistance were present in more than 80% of the patients, with gynecomastia being the most prominent. Gynecomastia was postpubertal but appeared before muscular weakness in most cases. Thirteen patients had alteration of testicular exocrine function. Hormonal profile of partial androgen resistance was present in 86% of the patients, with an elevated testosterone level in 68%. Androgen insensitivity seems to appear later in life in KD, similar to the development of neurological signs. Although we confirm the previously reported correlation between the CAG repeat length and the early onset of the neurological disease, we describe a significant correlation between repeat length and the age of onset of gynecomastia as well as biological indexes of androgen insensitivity. This is supported by numerous in vitro data correlating variations in the CAG tract with androgen receptor activity; the longer the CAG repeats, the weaker the receptor transactivation. Ours is the first study to show such a clear and prominent pattern of androgen insensitivity in KD. In clinical practice, KD patients are often misdiagnosed as having amyotrophic lateral sclerosis. Careful examination of the endocrine component could avoid such a deleterious misdiagnosis.

Prenatal detection of a 17p11.2 duplication resulting from a rare recombination event and novel PCR-based strategy for molecular identification of Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease, type 1A (CMT1A) is caused in most cases by a 1.5 Mb duplication on chromosome 17p11.2 arising after unequal crossing-over between repeated sequences called CMT1A-REPs, flanking the 1.5 Mb unit. A 3.2 kb recombination hot spot has been defined, resulting in a junction fragment between EcoRI (distal CMT1A-REP) and SacI (proximal CMT1A-REP). This was further reduced to a 1.7kb EcoRI-NsiI fragment, and recently to a 731 bp hot spot region within this fragment. We describe the CMT1A-REPs-based PCR method used to identify CMT1A duplications and report on a family case in which a 29-year-old pregnant woman requested prenatal diagnosis for two successive pregnancies because her husband was affected with CMT1A. Our method enabled us to characterise the duplication in both foetuses and demonstrate that it arose from a rare recombination event taking place outside the 1.7 kb region. Since our approach is simple and enables the entire set of duplications occurring after recombination in the enlarged 3.2kb region including the hot spot to be detected, we suggest it might be considered for use in primary screening for pre- and postnatal diagnosis of CMT1A.

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: exclusion of candidate genes including EGR1.

Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.

A clinical, electrophysiologic, neuropathologic, and genetic study of two large Algerian families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease.

The hereditary sensory and motor neuropathies form a clinically heterogenous group of disorders, the most frequent of which is Charcot-Marie-Tooth disease (CMT). The autosomal dominant forms of CMT are well characterized, but the nosology of autosomal recessive CMT is still controversial. We report two large consanguineous Algerian families with an autosomal recessive demyelinating CMT and similar clinical manifestations. The clinical, electrophysiologic, and neuropathologic features resemble those of autosomal dominant CMT1, but the early onset and rapid progression of deformities are specific. We excluded by linkage analysis the three loci CMT1A (17p11.2), CMT1B (1q22-23), and CMT4A (8q11-21.1) responsible for demyelinating forms of CMT. These findings suggest a subtype of autosomal recessive neuropathy, the locus of which is undetermined.

Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct clinical, electrophysiologic, and genetic entities.

Hereditary neuralgic amyotrophy (HNA) is an autosomal disease characterized by painful episodes of brachial palsy. The presence of tomacula in some patients suggested that HNA might be genetically related to hereditary neuropathy with liability to pressure palsies (HNPP), caused by point mutations in the PMP22 gene or deletion of the region containing this gene. In a clinical, electrophysiologic, and molecular study of two families with HNA, we show that the PMP22 gene is not deleted, duplicated, or mutated in HNA and that the disease is not linked to any other gene in the HNPP deleted region. We conclude that HNA and HNPP are distinct genetic entities.

Clinical, electrophysiologic, and molecular correlations in 13 families with hereditary neuropathy with liability to pressure palsies and a chromosome 17p11.2 deletion.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disease characterized by recurrent episodes of acute nerve palsies. We performed a clinical, electrophysiologic, and molecular study of 13 French families with HNPP associated with a chromosome 17p11.2 deletion in 36 individuals. There were electrophysiologic abnormalities in all symptomatic (n = 28) and asymptomatic (n = 8) deletion carriers, even in childhood. Bilateral delayed distal motor latency of the median nerve at the wrist, reduced sensory velocity in the palm-wrist segment, and delayed distal motor latency or reduced motor velocity in the peroneal nerve was diagnostic in at-risk relatives. This large series confirms the reliability of molecular analysis combined with a simplified electrophysiologic examination for the diagnosis of HNPP associated with 17p11.2 deletion.