Leukoencephalopathy With Metaphyseal Chondrodysplasia

Clinical Features

Neubauer et al. (2006) reported a 3-generation family from northern Germany in which 4 males had a disorder characterized by early-onset leukoencephalopathy associated with metaphyseal chondrodysplasia. Inheritance was consistent with an X-linked recessive pattern. The proband developed normally until age 2 to 3 years, when he developed slow gait and toe-walking. Broad knees and wrists were noted. In the following years, he developed a fine tremor and deteriorating vision. Examination at age 11 years showed spastic paraplegia, hyperreflexia with extensor plantar responses, action tremor, and an IQ of 65 to 70. He had a low nasal bridge, mild midface hypoplasia, and anteverted nares. A younger brother had a similar course. A 36-year-old maternal uncle developed spastic paraplegia, tremor, and thick knees at age 5 years. He also had horizontal nystagmus and almost complete loss of vision. He died at age 37 of aspiration pneumonia in a bilateral decorticate rigid state. An affected grandfather had a similar disease course and died at age 26 years. Brain MRI of the brothers and uncle showed homogeneous increased high signal intensities in the white matter. Plain radiographs showed areas of marked radiolucency in the distal metaphyses of the ulna and radius. Postmortem examination of the uncle showed cerebral atrophy, hypoplastic corpus callosum, thin optic nerves, and atrophic pyramidal tracts. Astrocytes were markedly increased. Bone mineralization was diffusely decreased. Neubauer et al. (2006) observed that the disorder in this family was slowly progressive and implicated demyelination.

Mapping

In the family reported by Neubauer et al. (2006), linkage analysis of the X chromosome identified a 14-cM candidate region on Xq25-q27 between DXS8093 and DXS1232. Two-point linkage analysis resulted in positive lod scores of 0.89 to 1.41, the latter of which was the maximum score obtainable for the family structure. The PLP1 gene (300401) and 23 other genes in the region were excluded.