Hypermyelinating neuropathy, mental retardation and epilepsy in a case of merosin deficiency

Children with a deficiency of laminin alpha2 chain generally show an involvement of skeletal muscles, cerebral white matter and peripheral nerves. Among these patients, however, there is increasing evidence of molecular and phenotype heterogeneity. We report a 19-year-old girl with distal weakness, mental retardation and refractory epilepsy in whom elevated serum CK suggested a myopathy. Electrophysiological and neuroimaging examinations as well as studies of nerve and muscle biopsies were performed. Nerve conduction velocities were definitely reduced and brain MRI demonstrated a diffuse white matter involvement. The muscle biopsy showed both myopathic and neurogenic features. By immunohistochemistry laminin alpha2 chain was mildly reduced in muscle and virtually absent in peripheral nerve. Teasing of sural nerve fibers showed a 'globular' hypermyelination characteristically located at the paranodal regions. A mild loss of myelinated fiber's, without any demyelination-remyelination changes was found. Haplotype analysis suggested linkage to the LAMA2 locus. Our case is peculiar as the putative mutation probably affects the expression of laminin alpha2 chain is affected in a tissue specific manner: the protein is virtually absent in peripheral nerves but only mildly reduced in skeletal muscle. As to the disorder of nerve myelination, an absence or abnormal functioning of laminin a2 chain can alter the feed-back control during myelinogenesis, leading to an over-ensheathment of axon. Alternatively, a compensatory up-regaulation of other laminins can induce the hyperproduction of myelin sheaths. This case provides new evidence of the phenotypical heterogeneity of the LAMA2 gene and sheds light in understanding the role of laminin alpha2 chain in myelination of peripheral nerve. (C) 2002 Elsevier Science B.V. All rights reserved.