Rapidly progressive asymmetrical weakness in Charcot–Marie–Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy

doi:10.1016/j.nmd.2013.01.010

Neuromuscular Disorders

Volume 23, Issue 5, May 2013, Pages 399-403

https://doi.org/10.1016/j.nmd.2013.01.010 Get rights and content

Abstract

Charcot–Marie–Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4 sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy, especially if there is a background history of a more slowly progressive neuropathy.

Introduction

Charcot–Marie–Tooth disease (CMT) disease is a clinically and genetically heterogeneous group of disorders characterised by predominantly distal weakness, muscle wasting and sensory loss. CMT is the commonest inherited neuromuscular disorder affecting around 1 in 2500 individuals [1]. Based on upper limb motor conduction velocities (MCV), CMT is divided into CMT1 (MCV < 38 m/s) and CMT2 (MCV > 38 m/s) [2]. It is usually straightforward to differentiate CMT1 from chronic inflammatory demyelinating polyradiculopathy (CIDP) which typically presents acutely, often with a patchy non-homogeneous predominantly motor neuropathy with associated demyelinating features on nerve conduction studies, but occasionally it can present difficulties. We have previously published reports of patients with inherited neuropathies due to GJB1, SH3TC2 and SPTLC1 mutations who had been initially diagnosed as inflammatory demyelinating neuropathy [3], [4], [5]. CMT4J, a rare form of demyelinating CMT, caused by recessive mutations in the phosphoinositide phosphatase FIG4, is characterised by progressive proximal and distal weakness and evidence of chronic denervation in both proximal and distal muscles [6]. We describe a patient with the classical features of CMT4J, in addition to the rapid progression of weakness in a single limb resembling an acquired inflammatory neuropathy.

Section snippets

Case report

A 26-year old man was referred to our clinic with the rapid development of a wasted left arm over a period of 2 years. He had been previously diagnosed with a congenital hypomyelinating neuropathy (CMT1), with early onset progressive weakness in all 4 limbs. Following a normal pregnancy and delivery, he had walked late at 26 months of age. Progressive weakness, starting distally and advancing proximally, was noticed in early childhood and he started using a wheelchair at 13 years of age. He was

FIG4 sequencing

The exons and exon–intron boundaries of FIG4 were amplified using a standard PCR reaction. A sequencing reaction was performed and samples were separated on the 3730xl DNA analyzer. The resulting data was manually analysed with the seqScape v2.5 program. FIG4 sequencing showed an I41T point mutation in exon 2 and an 8-bp deletion in exon 8 causing the frameshift protein truncation mutation p.K278YfsX5 (Fig. 3).

Discussion

Inherited neuropathies may mimic CIDP when they present with proximal or asymmetrical weakness, or when nerve conduction studies show patchy slowing of motor conduction with conduction block and temporal dispersion. We have previously published reports of patients with inherited neuropathies due to GJB1, SH3TC2 and SPTLC1 mutations initially diagnosed as CIDP [3], [4], [5]. Abnormal temporal dispersion and proximal motor conduction block are part of the electrodiagnostic criteria for CIDP, but

Competing interests

None.

Funding

MPM was supported by a Churchill Fellowship from the Winston Churchill Memorial Trust. AR is in receipt of a fellowship from the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712). MMR is grateful to the Medical Research Council (MRC) and the National Institutes of Neurological Diseases and Stroke and office of Rare Diseases (U54NS065712) for their support. This work was undertaken at University College London Hospitals/University College London,

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Citation Excerpt :
Indeed, conduction blocks, raised CSF protein levels and the occurrence of a proximal weakness may lead to discuss the diagnosis of chronic inflammatory polyradiculoneuropathy leading to the prescription of intravenous immunoglobulins, steroids or other immunosuppressive therapies. As such, this have been described in different forms of CMT, either dominant, X-kinked or recessive: i.e. CMT4J, caused by recessive mutations in the phosphoinositide phosphatase FIG4 gene CMT1B with MPZ mutations, CMT1C due to LITAF mutations, CMTX due to GJB1 mutations or CMT4C caused by recessive SH3TC2 mutations [20–25]. CK levels in two of our patients were strikingly elevated as seen in two previously reported patients[6], which may be part of the spectrum of PLEKHG5-related neuropathies.
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Case reportRapidly progressive asymmetrical weakness in Charcot–Marie–Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy

Abstract

Introduction

Section snippets

Case report

FIG4 sequencing

Discussion

Competing interests

Funding

Neuromuscul Disord

Neuromuscul Disord

Am J Hum Genet

Genetic and clinical aspects of Charcot–Marie–Tooth’s disease

Clin Genet

The clinical features of hereditary motor and sensory neuropathy types I and II

Brain

Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I)

Brain

Case report
Rapidly progressive asymmetrical weakness in Charcot–Marie–Tooth disease type 4J resembles chronic inflammatory demyelinating polyneuropathy