From enigmatic to problematic

In recent years many of the most novel and fascinating surprises of the molecular revolution in medicine have emerged from investigations of the neuromuscular diseases. First came the discovery of the massive dystrophin gene in Duchenne muscular dystrophy, then the trinucleotide expansions of Kennedy syndrome and myotonic dystrophy, and, most recently, the dissimilar effects that excess or insufficient PMP22 gene dosage have in producing either Charcot-Marie-Tooth type 1A or hereditary neuropathy with liability to pressure palsies. Childhood spinal muscular atrophy (SMA)--the last major enigma of the common genetic neuromuscular disorders--may soon contribute to this list of surprises, since recent studies by three different groups [1-3] suggest a disorder characterized by its own distinctive molecular and genetic pathophysiology. The genetics of SMA has been stunningly complex. Two groups of researchers looking for the SMA gene have reported evidence that supports unrelated but neighboring candidate genes, either of which, if discovered by itself, would have been hailed as a strong candidate. Each fulfills the criterion that has been useful in identifying candidate genes for other disorders: the close association between disabling mutations of the gene and the disease. But each of these reports harbors inconsistencies that require unconventional explanations to preserve the candidacy status of their gene--a suspension of disbelief that most investigators would be willing to grant were it not for the other group's findings. Some of the confusion surrounding the molecular genetics of SMA is no doubt due to our present incomplete understanding, but the very complexity of the SMA-containing region of chromosome 5 itself is responsible for many of the pathogenic mutations. Genetic complexity is thus at once the reason for our present confusion, the spur for further research, and a major cause of the disease. First described just over a century ago, SMA is, in its severe form, …