A novel NGFB point mutation: a phenotype study of heterozygous patients.

OBJECTIVE

A family with neurological findings similar to hereditary sensory and autonomic neuropathy type V having a point mutation in the nerve growth factor beta (NGFB) gene was recently described. The homozygous genotype gives disabling symptoms. The purpose of the present study was to evaluate the symptoms in heterozygous patients.

METHODS

26 patients heterozygous for the NGFB mutation (12 men, mean age 50 (13-90) years) were examined clinically and answered a health status questionnaire, including the Michigan Neuropathy Screening Instrument (MNSI). 28 relatives (15 men, mean age 44 (15-86) years) without the mutation served as controls in the clinical examination part. 23 of the heterozygotes were examined neurophysiologically and six heterozygous patients underwent a sural nerve biopsy.

RESULTS

The heterozygous phenotype ranged from eight patients with Charcot arthropathy starting in adult age and associated with variable symptoms of neuropathy but without complete insensitivity to pain, anhidrosis or mental retardation, to 10 symptom free patients. There was no difference in MNSI between the young heterozygous cases (<55 years old) and the controls. Six of 23 heterozygous patients had impaired cutaneous thermal perception and 11 of 23 had signs of carpal tunnel syndrome. Sural nerve biopsies showed a moderate reduction of both small myelinated (Adelta) and unmyelinated (C) fibres. No apparent correlation of small fibre reduction to symptoms was found.

CONCLUSIONS

The NGFB mutation in its heterozygous form results in a milder disease than in homozygotes, with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps lifestyle factors also, may influence the development of clinical polyneuropathy.