Further evidence for genetic heterogeneity of distal HMN type V, CMT2 with predominant hand involvement and Silver syndrome

Institute of Human Genetics, Medical University Graz, Austria.
Journal of the Neurological Sciences (Impact Factor: 2.26). 01/2008; 263(1-2):100-6. DOI: 10.1016/j.jns.2007.06.047
Source: PubMed

ABSTRACT Distal hereditary motor neuropathy type V (dHMN-V) and Charcot-Marie-Tooth syndrome (CMT) type 2 presenting with predominant hand involvement, also known as CMT2D and Silver syndrome (SS) are rare phenotypically overlapping diseases which can be caused by mutations in the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and in the glycyl-tRNA synthetase encoding (GARS) genes. Mutations in the heat-shock proteins HSPB1 and HSPB8 can cause related distal hereditary motor neuropathies (dHMN) and are considered candidates for dHMN-V, CMT2, and SS.
To define the frequency and distribution of mutations in the GARS, BSCL2, HSPB1 and HSPB8 genes we screened 33 unrelated sporadic and familial patients diagnosed as either dHMN-V, CMT2D or SS. Exon 3 of the BSCL2 gene was screened in further 69 individuals with an unclassified dHMN phenotype or diagnosed as hereditary spastic paraplegia (HSP) complicated by pure motor neuropathy.
Four patients diagnosed with dHMN-V or SS carried known heterozygous BSCL2 mutations (N88S and S90L). In one dHMN-V patient we detected a putative GARS mutation (A57V). No mutations were detected in HSPB1 and HSPB8. The diagnostic yield gained in the series of 33 probands was 12% for BSCL2 mutations and 3% for GARS mutations. In the series of unclassified dHMN and complicated HSP cases no mutations were found.
Our data confirm that most likely only two mutations (N88S, S90L) in exon 3 of BSCL2 may lead to dHMN-V or SS phenotypes. Mutations in GARS, HSPB1 and HSPB8. are not a common cause of dHMN-V, SS and CMT2D. We would therefore suggest that a genetic testing of dHMN-V and SS patients should begin with screening of exon 3 of the BSCL2 gene. Screening of the GARS gene is useful in patients with CMT2 with predominant hand involvement and dHMN-V. The rather low frequencies of BSCL2, GARS, HSPB1 and HSPB8 mutations in dHMN-V, CMT2D and SS patients strongly point to further genetic heterogeneity of these related disorders.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Atypical manifestations of peripheral neuropathy are not rare, challenging the differential diagnosis. In the past, the diagnosis of hereditary neuropathy was mainly based on the clinical and electromyographic (EMG) findings and, occasionally, biopsy. Nowadays, the genetic tests allow us to identify more than 40 different genes/loci associated with Charcot-Marie-Tooth (CMT) disease, although some subtypes are clinically indistinguishable. We have followed a patient with a clinical diagnosis of apparent sporadic and atypical CMT and recently diagnosed genetically as distal hereditary motor neuropathy, type V (dHMN-V). Case Report: Thirty-five years ago, a 16 years old patient complained muscular weakness and wasting at the hands small muscles. Sporadic fasciculations were observed whereas deep ten-don reflexes and sensation were normal. EMG examination revealed neurogenic muscular denervation in the distribu-tion of C7, C8 and T1 segments bilaterally. Muscular biopsy of the left Biceps Brachii showed rare atrophic fibers and some cellular atypia. The disease has undergone a clinical and EMG progression and diffusion over the years, involving the lower limbs and leading to a bilateral steppage. A more slight diffuse axonal motor neuropathy was also identified in the proband's son and second cousin. The genetic study found a known missense mutation in BSCL2 gene related to a dHMN-V. Interestingly, there was a remarkable intra-familiar phenotypic variability, especially in the clinical onset and severity. Discussion: Atypical manifestations of hereditary neuropathies often overlap with other conditions. The pre-sent case highlights how a comprehensive clinical evaluation and a careful follow-up have led to a correct diagnosis even 35 years later and have allowed to identify other affected family members. The apparent lack of familiarity was probably due to the very soft presentation in the proband's relatives. Although the genetic study was not available at that time, the first clinical diagnosis was not disavowed. The main differential diagnoses and a brief review of similar reported cases are discussed.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by overexpressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that overexpressed Seipin is partly co-localized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency but not the amplitudes of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs). The amplitude of both evoked EPSC and IPSC are also compromised by mutant Seipin overexpression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons overexpressing Seipin-N88S, while neither γ-amino butyric acid (GABA) nor α-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 12/2013; DOI:10.1111/jnc.12638 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Charcot-Marie-Tooth disease type 2D (CMT2D) is an autosomal dominant axonal peripheral neuropathy characterized by impaired motor and sensory function in the distal extremities. Mutations in the glycyl-tRNA synthetase (GARS) gene cause CMT2D. GARS is a member of the ubiquitously expressed aminoacyl-tRNA synthetase (ARS) family and is responsible for charging tRNA with glycine. To date, thirteen GARS mutations have been identified in patients with CMT disease. While functional studies have revealed loss-of-function characteristics, only four GARS mutations have been rigorously studied. Here, we report the functional evaluation of nine CMT-associated GARS mutations in tRNA charging, yeast complementation, and subcellular localization assays. Our results demonstrate that impaired function is a common characteristic of CMT-associated GARS mutations. Additionally, one mutation previously associated with CMT disease (p.Ser581Leu) does not demonstrate impaired function, was identified in the general population, and failed to segregate with disease in two newly identified families with CMT disease. Thus, we propose that this variant is not a disease-causing mutation. Together, our data indicate that impaired function is a key component of GARS-mediated CMT disease and emphasize the need for careful genetic and functional evaluation before implicating a variant in disease onset.This article is protected by copyright. All rights reserved
    Human Mutation 08/2014; 35(11). DOI:10.1002/humu.22681 · 5.05 Impact Factor

Full-text (2 Sources)

Available from
Jun 10, 2014