Type 2E neurofilament light chain early onset mutations research

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ABSTRACT from Brain 2003 Mar;126(Pt 3):590-597

Mutations in the neurofilament light chain gene (NEFL) cause early onset

severe Charcot-Marie-Tooth disease.

Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E,

Ceuterick C, JJ, IJ, Mancias P, Papasozomenos SC,

Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky

I, Lupski JR, Timmerman V.

Molecular Genetics Department, Flanders Interuniversity Institute for

Biotechnology and Laboratory of Neuropathology and Electronmicroscopy,

Born-Bunge Foundation, University of Antwerp, Antwerp, Division of

Neurology, University Hospital of Antwerp,

Edegem, Belgium, Departments of Molecular and Human Genetics, and

Pediatrics, Baylor College of Medicine, Houston, TX, Departments of

Neurology and Pathology and Laboratory Medicine, The University of

Texas-Houston Medical School, Texas, Department of Genetics, Credit

Valley Hospital, Ontario, Department of Neurology, Wayne State

University School of Medicine, Detroit, MI, Lutheran General Hospital,

Park Ridge, IL, USA, Laboratory of Molecular Pathology and Department of

Neurology, Sofia Medical University, Sofia, Bulgaria.

Neurofilament light chain polypeptide (NEFL) is one of the most abundant

cytoskeletal components of the neuron. Mutations in the NEFL gene were

recently reported as a cause for autosomal dominant Charcot-Marie-Tooth

type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the

frequency and phenotypic consequences of NEFL mutations, we screened 323

patients with CMT or related peripheral neuropathies. We detected six

disease associated missense mutations and one 3-bp in-frame deletion

clustered in functionally defined domains of the NEFL protein.

Patients have an early onset and often a severe clinical phenotype.

Electrophysiological examination shows moderately to severely slowed

nerve conduction velocities. We report the first nerve biopsy of a CMT

patient with a de novo missense mutation in NEFL, and found an axonal

pathology with axonal regeneration clusters and onion bulb formations.

Our findings provide further evidence that the clinical

variation observed in CMT depends on the gene mutated and the specific

type of mutation, and we also suggest that NEFL mutations need to be

considered in the molecular evaluation of patients with sporadic or

dominantly inherited CMT.