The phenotype of Charcot–Marie–Tooth disease type 4C due to SH3TC2 mutations and possible predisposition to an inflammatory neuropathy

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Abstract

Charcot–Marie–Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. The locus responsible for CMT4C was previously assigned to the chromosome 5q23 region by homozygosity mapping and mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly in families around the Mediterranean basin but also frequently in European Gypsies. No English families have been reported to date. To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2 mutations we screened 23 English autosomal recessive (AR) demyelinating CMT families. Five families with AR demyelinating CMT and SH3TC2 mutations were identified, four families were homozygous for the R954X mutation and the fifth family was compound heterozygous for the R954X and E657K mutations. There was significant clinical variation between these families with some cases presenting with a severe childhood onset neuropathy with respiratory and cranial nerve involvement, compared to other families with mild scoliosis and foot deformity. Characteristic sural nerve neuropathology was seen in three families with frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming basal lamina onion bulbs and abnormally long and attenuated Schwann cell processes. One patient homozygous for the R954X mutation had a 20-year history of an inflammatory neuropathy that was superimposed onto the hereditary form, indicating that structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation.

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

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