Progressive muscular dystrophy in childhood

The words of Gowers are as true today as they were nearly a century ago. My interest in muscular dystrophy started in 1957 when, as Senior House Officer at Queen Mary's Hospital for Children, Carshalton, Surrey, I first observed a large number of children suffering from this tragic disease. The frustration of helplessly, watching its inevitable course stimulated the present study.After obtaining an initial impression or' the collection from my clinical observations and a review of the hospital records between 1920 and 1950, I started a more systematic enquiry. The present investigation compromises my personal observations on 65 cases ranging in age from 3 to 16 years. Of these, 57 were seen and followed up at Queen Mary's Hospital for Children, and 8 at the Southern Hospital, Dartford, Kent

Genomic Variation and Gene Conversion in Spinal Muscular Atrophy: Implications for Disease Process and Clinical Phenotype

SummaryAutosomal recessive spinal muscular atrophy (SMA) is classified, on the basis of age at onset and severity, into three types: type I, severe; type II, intermediate; and type III, mild. The critical region in 5q13 contains an inverted repeat harboring several genes, including the survival motor neuron (SMN) gene, the neuronal apoptosis inhibitory protein (NAIP) gene, and the p44 gene, which encodes a transcription-factor subunit. Deletion of NAIP and p44 is observed more often in severe SMA, but there is no evidence that these genes play a role in the pathology of the disease. In > 90% of all SMA patients, exons 7 and 8 of the telomeric SMN gene (SMNtel) are not detectable, and this is also observed in some normal siblings and parents. Point mutations and gene conversions in SMNtel suggest that it plays a major role in the disease. To define a correlation between genotype and phenotype, we mapped deletions, using pulsed-field gel electrophoresis. Surprisingly, our data show that mutations in SMA types II and III, previously classed as deletions, are in fact due to gene-conversion events in which SMNtel is replaced by its centromeric counterpart, SMNcen. This results in a greater number of SMNcen copies in type II and type III patients compared with type I patients and enables a genotype/phenotype correlation to be made. We also demonstrate individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explains why no consensus map of this region has been produced. This DNA variation may be due to a midisatellite repeat array, which would promote the observed high deletion and gene-conversion rate