Molecular analysis of the myoadenylate deaminase deficiencies

Myoadenylate deaminase (mAMPD) deficiency in a clinically heterogeous metabolic myopathy consisting of primary (inherited) and secondary (acquired) forms based on a variety of clinical and laboratory findings. To provide a basis for delineating the underlying molecular defects in mAMPD deficiency, and as a means to test the proposal for multiple forms of the resulting disease, Northern blot analyses were performed with RNA isolated from individual patients with classified primary and secondary deficiency utilizing human mAMPD cDNA probes isolated from adult skeletal muscle libraries. Analysis of nine patients with primary mAMPD deficiency indicates normal abundance of mAMPD transcript. No immunoreactive mAMPD polypeptide is detected in Western blot analyses of skeletal muscle extracts prepared from these patients. Specificity to mAMPD is demonstrated by normal creatine kinase (CK) activities and M-creatine kinase (M-CK) transcript abundance. Similar analyses of four individuals with secondary mAMPD deficiency reveal heterogeneity in this subgroup of patients. Whereas two of these patients exhibit normal mAMPD transcript abundance, two others associated with inflammatory myopathy display reductions in mAMPD and M-CK transcript abundance. Examination of tissue sections derived from the same biopsies utilized in the isolation of RNA demonstrates the integrity of the skeletal muscle in those patients with associated inflammatory myopathy. Combined, these data support the proposal for multiple forms of mAMPD deficiency, and indicate that the primary condition is most commonly characterized by specific point mutations or small deletions/rearrangements in the ampd1 gene, whereas some patients with secondary mAMPD deficiency display more generalized aberrations in gene expression.