The phenotype of Charcot–Marie–Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy
Introduction
Charcot–Marie–Tooth disease (CMT) is a clinically and genetically heterogeneous group of disorders and is the most common inherited neuromuscular disorder, with an estimated overall prevalence of one in 2500 individuals [1]. Inheritance can be autosomal dominant (AD) recessive (AR) or X-linked. The number of genes for AR CMT has rapidly increased over the last few years, so far 13 different genes have been identified (11 for the demyelinating forms and 2 for the axonal forms). The AR CMT phenotype is usually more severe and has an earlier onset than AD CMT [2], [3], there are often additional clinical features such as scoliosis, vocal cord problems or cranial neuropathies that can give clinical clues to the genetic cause [4], [5].
The demyelinating forms are called CMT4. In 1996 LeGuern et al. assigned the locus for CMT4C to chromosome 5q23-33 in two consanguineous Algerian families with typical childhood/adolescent onset CMT with the associated feature of pes cavus and scoliosis in many individuals. There was also a discrepancy between the rapid worsening of deformities and the relatively slow progression of the motor deficit. Nerve conduction studies suggested demyelination and in the majority of patients the median motor conduction velocity was only moderate with a MCV of between 20 and 32 m/s. A particular feature that seemed specific to CMT4C was the sural nerve pathology showing very thin myelin sheaths with extensive Schwann cell proliferation with multiple small onion bulbs [6]. The CMT4C genetic region was further refined in families from Europe and North Africa [7], [8].
Senderek et al. [9] identified 11 mutations in an uncharacterised transcript, KIAA1985 in 12 CMT4C families from Turkey, Germany, Italy, Greece and Iran. Protein homology studies suggest two N-terminal SH3 domains and 10 TPR (tetratricopeptide repeat) motifs for the KIAA1985 protein [9] which has also been called SH3TC2. A further KIAA1985 mutation (homozygous R1190X) was identified with a founder effect in Spanish Gypsies, where this mutation and the R954X mutation were the most prevalent [10], [11] and a total of 21 SH3TC2 mutations have been identified to date with over half being present in exon 11 of the gene.
The clinical phenotype associated with SH3TC2 mutations is mainly characterised by early onset and frequent scoliosis [12]; cranial nerve abnormalities comprising deafness, nystagmus and facial weakness have been commented upon in some individuals [9]. In addition, interesting histopathological variability with giant axon in one family has been reported [12]. Recently founder mutations in SH3TC2 (R954X) have been identified 10 French-Canadian families [13].
To assess the frequency of SH3TC2 mutations in English AR demyelinating CMT families we analysed 23 AR CMT families identifying five families with mutations. The genetics and variable clinical, electrophysiological and neuropathological phenotype are discussed here. We also describe a case with a 20-year history of a presumed inflammatory neuropathy that was superimposed onto the common English R954X SH3TC2 mutation.
Section snippets
Patients
Ethics approval was obtained from the joint medical and ethics committee at The National Hospital for Neurology and Neurosurgery to perform this clinical and genetic study. Twenty three cases with AR demyelinating CMT were analysed and gave informed consent and were ascertained through either the genetic peripheral nerve clinic (MMR) in the National Hospital for Neurology and Neurosurgery (NHNN), the Neurogenetics clinic (NHNN) (HH) or at the Paediatric Neurology Department of the Evelina
Genetic analyses
In our cohort of 23 AR English CMT cases we identified five families with SH3TC2 mutations. Four families were homozygous for the R954X (n. 2860 C to T) mutation (Families 1–4) and one family (Family 5) had two compound heterozygous mutations, R954X (n. 2860 C to T) and a E657K (n. 1969 G to A) mutation. We only sequenced the SH3TC2 hotspot of exon 11 and the surrounding exons 10 and 12 in these cases. The mutations segregated with the disease in families 1 and 2, each with two affected
Discussion
We identified 5 British families with CMT4C due to SH3TC2 gene mutations out of a total of 23 AR demyelinating CMT cases screened. All typical clinico-pathologically diagnosed CMT4C patients had SH3TC2 mutations. The R954X mutation was present in all families indicating this mutation is common in AR CMT in the UK as well as being found in Algeria, Europe and the French-Canadian populations [12], [13]. The finding of the R954X mutation in several populations and the founder effect in 10 isolated
Acknowledgements
We are grateful to Dr. Gabreels-Festens for her help with the family 1 nerve biopsy interpretation. We are also grateful to the families for their help with this work. We acknowledge the Medical Research Council (MRC) and the Muscular Dystrophy Campaign for funding support. This work also received funding from a UCLH/UCL Comprehensive Biomedical Research Centre (CBRC) grant and was undertaken at University College London Hospitals/University College London, which received a proportion of
References (19)
Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot–Marie–Tooth type 4C neuropathy
Am J Hum Genet
(2003)Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster
Neuromuscular Disord
(2008)- et al.
Anti-PMP22 antibodies in patients with inflammatory neuropathy
J Neuroimmunol
(2000) - et al.
Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients
Lancet Neurol
(2004) - Skre H, Genetic and clinical aspects of Charcot–Marie–Tooth’s disease. In: Proceedings of the third international...
- et al.
Autosomal recessive forms of hereditary motor and sensory neuropathy
J Neurol Neurosur Psy
(1980) Autosomal recessive hereditary motor and sensory neuropathy
Curr Opin Neurol
(2000)Autosomal-recessive Charcot–Marie–Tooth diseases
J Neuropathol Exp Neurol
(2005)Mutations in the 5′ region of the myotubularin-related protein 2 (MTMR2) gene in autosomal recessive hereditary neuropathy with focally folded myelin
Brain
(2001)