Proximal spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann disease (type II) and Kugelberg-Welander disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus. Research has been hindered because the underlying biochemical defect is unknown, and there are insufficient large pedigrees with the most common and severe form (type I) available for study. Therefore, we have undertaken a genetic linkage analysis of the chronic forms of the disease (types II and III) as an initial step towards the ultimate goal of characterizing the gene(s) responsible for all three types. We report here the assignment of the locus for the chronic forms to the long arm of chromosome 5 (5q12-q14), with the anonymous DNA marker D5S39, in 24 multiplex families of distinct ethnic origin. Furthermore, no evidence for genetic heterogeneity was found for types II and III in our study, suggesting that these two forms are allelic disorders.

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Case reportThe patient was a white male aged 10 years at the time of the first metabolic study. Early psychomotor development was uneventful, with an apparently normal acquisition of language. A progressive decline of verbal fluency was first noted at age five, and complete mutism became established in a few months. This severe aphasia was associated with verbal auditory agnosia, aggressive behaviour, hyperkinesis, and clumsiness. During this period at least one atypical absence with palpebral myoclonic jerks was seen. The child was considered to be psychotic, however, and remained unmedicated. A CT scan, performed at age seven, revealed the presence of an extraparenchymal cystic mass containing fluid in the left middle cranial fossa, extending over the cerebral convexity to the frontoparietal region. Although the portion of the skull covering the cyst was bulging and thinned, there was no distortion of the midline, nor apparent displacement of adjacent brain structures and the collection was considered to be a benign arachnoid cyst. Studies by EEG disclosed bilateral multifocal spike and spike-wave complexes, with a slight predominance over the left temporal region.

We report the clinical, electrophysiological, and morphological observations of five infants with an unusual form of spinal muscular atrophy (SMA). In these infants muscular weakness and atrophy were initially restricted to the distal limbs and this pattern was associated with paralysis of the diaphragm. The difference between the clinical manifestations of this syndrome and the classical form of infantile spinal muscular atrophy (SMA type 1) as well as other congenital hereditary neuropathies is discussed.