A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy

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Ann Neurol. 2009 Apr 13;66(6):759-770.

A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy.

Yum SW, Zhang J, Mo K, Li J, Scherer SS.

Section of Neurology, St. 's Hospital for Children, Drexel University

College of Medicine, Philadelphia, PA.

OBJECTIVE: To report the first cases of a homozygous recessive mutation in NEFL,

the gene that encodes the light subunit of neurofilaments.

METHODS: Clinical and electrophysiologic data were evaluated, and a sural nerve

biopsy from one affected child was examined by immunohistochemistry and electron

microscopy. The ability of the mutant protein to form filaments was

characterized in an established cell culture system.

RESULTS: Four of five siblings developed of a severe, progressive neuropathy

beginning in early childhood. Serial nerve conduction studies showed

progressively reduced amplitudes with age and pronounced slowing at all ages.

Visual-evoked responses were slowed in three children, indicating that central

nervous system axons were subclinically involved. All four affected children

were homozygous for a nonsense mutation at glutamate 210 (E210X) in the NEFL

gene; both parents were heterozygous carriers. A sural nerve biopsy from an

affected patient showed markedly reduced numbers of myelinated axons; the

remaining myelinated axons were small and lacked intermediate filaments. The

E210X mutant protein did not form an intermediate filament network and did not

interfere with the filament formation by wild-type human light subunit of

neurofilaments in SW-13 vim(-) cells.

INTERPRETATION: This is the first demonstration of a recessive NEFL mutation,

which appears to cause a simple loss of function, resulting in a severe,

early-onset axonal neuropathy with unique features. These results confirm that

neurofilaments are the main determinant of axonal caliber and conduction

velocity, and demonstrate for the first time that neurofilaments are required

for the maintenance of myelinated peripheral nervous system axons.