Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: Clinical, electrophysiologic, and genetic aspects of a large family

We describe 10 patients from a large family with early onset motor and sensory neuropathy. Six were still living at the time of the study. In all cases, early motor milestones had been achieved. Mean age at onset of symptoms was 34 months; these included progressive distal and proximal muscle weakness of lower limbs. Pes equinovarus developed in all patients during childhood. Slight facial weakness was present in four patients, and one of them also had bilateral facial synkinesia. Intellectual function was normal in all cases. There was no evidence of thickened peripheral nerves. All three adult patients (mean age, 27 years) were seriously handicapped and wheelchair-bound. Death occurred in the fourth to fifth decade of life and the duration of the illness varied from 27 to 39 years. Motor nerve conduction velocities ranged from 15 to 17 dsec in the upper limbs of the youngest patients, and were undetectable in the adult patients. Sensitive action potentials were almost always absent. In all patients, auditory evoked potentials showed abnormally delayed interpeak I-III latencies. The most prominent pathologic finding was a highly unusual myelin abnormality consisting of irregular redundant loops and folding of the myelin sheath. The genealogic study gave strong evidence of autosomal-recessive inheritance. The molecular analysis failed to demonstrate either duplication in the chromosome 17p11.2-12, point mutations in the four exons of the PMP-22 (17p11.2) and the six exons of the PO (1q21–q25) genes, or linkage to chromosome 8q13–21.1. The classification of demyelinating hereditary motor and sensory neuropathies (HMSN) is still a matter of debate. 1,2 Autosomal dominant HMSN (Charcot-Marie-Tooth disease [CMT]) shows the typical neuropathologic findings of demyelination and onion-bulb formation. CMT is heterogeneous, 3–8 with loci described on chromosome 17 (CMTIA), chromosome 1 (CMTIB), and an unknown possible third locus (CMTIC). There are duplications and point mutations at the peripheral myelin protein 22 (PMP-22) locus in patients with CMTIA 3–6 and several point mutations in the protein zero (Po) in patients with CMTl B. 7,8 Autosomal-recessive demyelinating HMSN includes different disorders with a broad spectrum of clinical severity. 1,2,9 Three pathologic forms are now recognized, 1,2 two with classic or basal lamina onion bulbs, and a third characterized by focally folded myelin sheaths. Only the gene responsible for the form characterized morphologically by basal lamina onion bulbs, namely CMT4A, has been mapped in the 8q13-21.1 region. l0 Although the existence of HMSN with focally folded myelin sheaths has been established, 1,2 clinical features and natural history remain ill-defined. In addition, despite the postulated autosomal recessive mode of inheritance, 1,2 only few familial cases have been described 11–14 and no multigenerational pedigree has been available, making it difficult to assess the pattern of inheritance. In this study, we present 10 patients from a large family with this form of HMSN and describe the full clinical, electrophysiologic, and pathologic findings and the natural clinical history of this type of disease. We also carried out a genetic study to assess Mendelian inheritance, and searched for the most common mutations in the PMP-22 and Po genes, which cause demyelinating HMSN 3–8 and linkage to chromosome 8 where the CMT4A gene has been mapped. 10