Objective: We recently described a family with neurological findings similar to HSAN (Hereditary sensory and autonomic neuropathy) type V having a point mutation in the Nerve growth factor beta (NGFB) gene. The homozygous genotype gives disabling symptoms. The purpose of the present study is 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 6 heterozygous patients underwent a sural nerve biopsy.
Results: The heterozygous phenotype ranged from 8 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 (<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 (Aä) and unmyelinated (C) fibres. We found no apparent correlation of small fibre reduction to symptoms.
Conclusions: The NGFB mutation in its heterozygous form results in a milder disease than in homozygots with a variable clinical picture, ranging from asymptomatic cases to those with Charcot arthropathy appearing in adult age. Particularly age, but perhaps also life style factors, may influence the development of clinical polyneuropathy.