Congenital muscular dystrophy with rigid spine syndrome: A clinical, pathological, radiological, and genetic study

Rigid spine syndrome is a term first proposed by Dubowitz to describe a sub set of patients affected by myopathy with early spinal contractures as a pr ominent feature. While spinal rigidity is a nonspecific feature, found in E mery-Dreifuss muscular dystrophy and in some congenital myopathies, it is a lso a prominent feature in a group of patients with merosin-positive congen ital muscular dystrophy, where it is generally associated with stable or on ly slowly progressive weakness and early respiratory insufficiency. Recentl y, the first locus for congenital muscular dystrophy in association with ri gid spine syndrome was mapped to chromosome 1p35-p36 in consanguineous Moro ccan, Turkish, and Iranian families. We present here a detailed phenotypic description of the familial syndrome linked to this locus, describing 4 sib lings (3 boys and 1 girl) of Northern European-American heritage who are th e offspring of a nonconsanguineous marriage. All 4 siblings were affected b y hypotonia and prominent neck weakness in infancy, early spinal rigidity, and early scoliosis. After initial improvement, muscle strength stabilizes or slowly declines, and skeletal deformities and respiratory insufficiency supervene, Muscle biopsy in an affected child at age 9 months revealed mini mal, nonspecific myopathic changes, leading to a diagnosis of "minimal chan ge myopathy." Muscle biopsy in his sibling, at the age of 14 years, reveale d chronic and severe myopathic (dystrophic) changes, with normal staining f or laminin-2 and for proteins of the dystrophin-glycoprotein complex. A pos sible explanation for these biopsy findings is that magnetic resonance imag ing of the thighs reveals stereotyped selective muscle involvement, with th e selectivity more pronounced early in the disease course followed by wides pread muscular signal abnormalities in the late stages of the disease. In t his family, linkage to the chromosome 1p rigid spine syndrome locus (RSMD1) is supported by maximum LOD scores for several markers of 1.81 at O = 0, r epresenting the maximum statistical power possible for this family. In comb ination with the previous report, this syndrome is linked to the RSMD1 locu s with a summated maximum LOD score of 6.29, and analysis of recombination events in our family narrows the previously reported RSMD1 locus to 3 centi Morgans.