Elsevier

Neuromuscular Disorders

Volume 19, Issue 10, October 2009, Pages 701-703
Neuromuscular Disorders

Case report
Hereditary motor and sensory neuropathy caused by a novel mutation in LITAF

https://doi.org/10.1016/j.nmd.2009.05.006Get rights and content

Abstract

Hereditary motor-sensory neuropathy (HMSN) Type 1/CMT 1 is a disorder of the peripheral nervous system. The underlying genetic cause is heterogeneous, and mutations in LITAF (Lipopolysaccharide-induced TNF-α factor) represent a rare cause of CMT Type 1. In this report, a novel missense mutation is presented in the LITAF gene (c.430G > A p.V144M) in a German CMT family exhibiting typical electrophysiological features of a demyelinating neuropathy with conduction blocks and variable age at onset. Molecular genetic characterization of demyelinating HMSN should therefore include screening of the LITAF gene if typical signs of a non-homogenous demyelinating neuropathy combined with dominant familial occurrence are evident.

Introduction

Hereditary motor and sensory neuropathy (HMSN), also referred to as Charcot-Marie-Tooth disease (CMT) is characterized by progressive distal muscle weakness, foot deformities as well as progressive sensory loss affecting the distal extremities. HMSN can be divided into primary demyelinating (type 1) or axonal forms (type 2) according to the nerve conduction velocities that are severely reduced in demyelinating forms but rather unaffected in axonal disease [1]. HMSN type 1A is the most common type of demyelinating HMSN, caused by a duplication on chromosome 17p11.2-p12 including the PMP22 genomic region. Besides involvement of the GJB1/Connexin32 gene, mutations in the myelin protein zero (MPZ/P0) gene (CMT 1B) and the peripheral myelin protein 22 (PMP22) gene (CMT 1E) are common causes for hereditary motor sensory neuropathies of the demyelinating type [2]. These genes encode a structural component of the myelin sheath and hence, are directly involved in the composition of peripheral nerves. In contrast, mutations in genes involved in gene regulation are a rare cause of HMSN (for overview see Inherited Peripheral Neuropathies Mutation Database available at http://www.molgen.ua.ac.be/CMTMutations). In addition to the transcription factor epidermal growth response 2 (EGR2), one of these genes is lipopolysaccharide-induced TNF-α factor (LITAF), which in most cases has been associated with demyelinating peripheral neuropathy (CMT 1C #MIM 603795). LITAF is located on chromosome 16p13.3-p12 [3] and encoded by 4 exons. The gene product of LITAF is a transcripiton factor regulating tumor necrosis factor α (TNF-α) gene expression and was identified as a sole gene due to a sequencing error and hence, LITAF is alternatively referred to as SIMPLE (small integral membrane protein of the lysosome/late endosome) [4].

Mutations in LITAF were reported to cause demyelinating neuropathy with an autosomal dominant inheritance mode [5]. Yet, only few cases with mutations in LITAF have been reported with a detailed clinical evaluation. In this case report, a German family exhibiting typical signs of a demyelinating neuropathy is presented suggesting molecular genetic evaluation of LITAF in familial cases with CMT 1 neuropathy.

Section snippets

Case report

A 57-year-old female patient was admitted to the Neuromuscular Unit of the Department of Neurology at the University Hospital Göttingen complaining of distal paresthesia and painful feet sensations since 6–12 months. Additionally, slowly progressive ataxia was observed. Neurological evaluation revealed normal cranial nerve function and intellectual status. Extremity deformities were present in terms of pes excavatus and manual muscle testing revealed paresis of MRC grade 5 in distal lower limbs.

Discussion

Mutations in LITAF are a rare cause of HMSN Type 1, yet eight different mutations within the coding region of LITAF have been reported to be associated with CMT 1 phenotype (Inherited Peripheral Neuropathies Mutation Database: http://www.molgen.ua.ac.be/CMTMutations/). Only few studies are available investigating LITAF in CMT [e.g. [5], [6], [7] since mutations in LITAF have been shown to be associated with CMT 1 [3]. In CMT1 70% of patients harbour the CMT1A duplication [2] whereas mutations

Acknowledgments

We thank the patients for their agreement to publish this case.

References (8)

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