Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation

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Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.

Ann Neurol 2005;57:415-424.

Auer-Grumbach M, Schlotter-Weigel B, Lochmuller H, Strobl-Wildemann G,

Auer-Grumbach P, Fischer R, Offenbacher H, Zwick EB, Robl T, Hartl G, Hartung

HP, Wagner K, Windpassinger C.

Institute of Medical Biology and Human Genetics, Medical University Graz, Graz,

Austria.

Recently, two missense mutations (N88S, S90L) in the Berardinelli-Seip

congenital lipodystrophy gene have been identified in autosomal dominant distal

hereditary motor neuropathy and Silver syndrome. We report the phenotypic

consequences of the N88S mutation in 90 patients of 1 large Austrian family and

two unrelated German families. Variation in the clinical and

electrophysiological phenotype enabled us to distinguish six subtypes. In 4.4%,

the disorder was not penetrant. Twenty percent of the patients were

subclinically affected; some of these patients could only be detected by

pathological nerve conduction studies. A distal hereditary motor neuropathy type

V phenotype characterized by predominant hand muscle involvement was found in

31.1%, whereas 14.5% showed typical Silver syndrome with amyotrophy of the small

hand muscles and spasticity of the lower extremities. Moreover, the phenotype

present in 20% was compatible with Charcot-Marie-Tooth disease. In 10%, the

clinical diagnosis of pure or complicated hereditary spastic paraparesis was

made. Electrophysiological studies showed an axonal neuropathy but also

chronodispersion of compound motor action potentials and conduction blocks.

Sensory nerve conduction studies were rarely pathological. Our study indicates

that the dominant N88S mutation in the Berardinelli-Seip congenital

lipodystrophy gene 2 leads to a broad spectrum of motor neuron disorders.