DNA and Protein Sequence Analysis

there is unlikely to be major confusion between the two groups. The limb-girdle muscular dystrophies (LGMD) are a group of autosomally inherited progressive myopathic diseases. Eight different genetic types of LGMD have so far been identified, of which two are dominantly inherited and the other six recessively inherited.' Of the genes so far identified, three encode structural proteins of the dystrophin associated glycoprotein complex and one encodes the muscle specific calpain. Clinically, there are insufficient data so far to distinguish between the different forms of LGMD. In the past, LGMD has been confused with other forms of muscle disease. Patients previously diagnosed as suffering from LGMD have in some cases been shown by molecular analysis to have a dystrophinopathy (X linked) or mitochondrial or metabolic disease. Given the extreme heterogeneity of LGMD, it is important to ensure that resources applied to track down the primary genetic defect in any particular family or case are appropriately directed by careful exclusion of all possible alternative diagnoses. It has been postulated that the milder forms of spinal muscular atrophy (type III SMA) may be a source of diagnostic confusion in recessive or sporadic cases. Phenotypically, both diseases show proximal muscle weakness and wasting, creatine kinase levels may be raised in SMA, and EMG and muscle biopsy analysis may show conflicting or confusing results. It is now possible to perform molecular tests for the genetic faults which are associated with chromosome 5 linked SMA. We examined a panel of 95 patients with a diagnosis of LGMD. These patients were from a variety of different sources both in the UK and abroad. Some referred themselves to our department because of our research interest in LGMD, others were referred from recognised neuromuscular units. All, according to the information available, had clinical characteristics and investigations which were consistent with a diagnosis of LGMD according to the latest diagnostic criteria.2 We analysed DNA samples for deletions of exons 7 and 8 of the survival motor neurone (SMN) gene (deleted in approximately 94% of milder SMA cases)' and also for deletions of exons 5 and 6 of the neuronal apoptosis inhibitory protein (NAIP) gene (deleted in about 67% of SMA type 1 cases and 42% of type 2 and 3 cases).4 We found deletions in SMN and NAIP in only one family. Haplotype analysis confirmed that the affected sibs in this family did share the chromosome 5 region containing the SMN and NAIP genes. The three children from this family had childhood onset of a predominantly proximal muscle weakness and wasting diagnosed clinically and on investigation as a limb-girdle muscular dystrophy. Recent re-evaluation of serum creatine kinase showed that the level remained high (576 IU/1, normal up to 180 IU/1) even many years after the onset. All had relatively slow progression of disease and normal intelligence. We conclude that spinal muscular atrophy associated with deletions of SMN and NAIP is not a common source of confusion in the diagnosis of LGMD. The investigation may, however, still be useful in those families in which there is genuine diagnostic confusion on the basis either of equivocal creatine kinase levels or conflicting results from EMG or muscle biopsy. We are very grateful to the patients and clinicians who have helped collect the samples for this and other studies. Financial support has been provided by the Medical Research Council of Great Britain, the Muscular Dystrophy Group of Great Britain and Northern Ireland, and the British Medical Association.