Dystrophin muscle enhancer 1 is implicated in the activation of non-muscle isoforms in the skeletal muscle of patients with X-linked dilated cardiomyopathy.

X-linked dilated cardiomyopathy (XLDC) is a dystrophinopathy characterized by severe cardiomyopathy with no skeletal muscle involvement. Several XLDC patients have been described with mutations that abolish dystrophin muscle (M) isoform expression. The absence of skeletal muscle degeneration normally associated with loss of dystrophin function was shown to be due to increased expression of brain (B) and cerebellar Purkinje (CP) isoforms of the gene exclusively in the skeletal muscle of these patients. This suggested that the B and CP promoters have an inherent capacity to function in skeletal muscle or that they are up-regulated by a skeletal muscle-specific enhancer unaffected by the mutations in these patients. In this work we have analyzed the deletion breakpoints of two XLDC patients with deletions removing the M promoter and exon 1, but not affecting the B and CP promoters. Despite the presence of several muscle-specific regulatory motifs, the B and CP promoters were found to be essentially inactive in muscle cell lines and primary cultures. As dystrophin muscle enhancer 1 (DME1), the only known muscle-specific enhancer within the dystrophin gene, is preserved in these patients, we tested its ability to up-regulate the B and CP promoters in muscle cells. B and CP promoter activity was significantly increased in the presence of DME1, and more importantly, activation was observed exclusively in cells presenting a skeletal muscle phenotype. These results point to a role for DME1 in the induction of B and CP isoform expression in the skeletal muscle of XLDC patients defective for M isoform expression.

A 6-year-old boy with hyperammonaemia: partial N-acetylglutamate synthase deficiency or portosystemic encephalopathy?

UNLABELLED: We describe a 6-year-old boy admitted with lethargy and somnolence. Laboratory tests showed hyperammonaemia (arterial level 186 micromol/l) and slightly elevated prothrombin time. The patient was treated with sodium benzoate, lactulose and a protein-restricted diet. This resulted in an insufficient decrease in blood ammonia levels. Metabolic investigations were unrevealing apart from a slightly elevated urinary glutamine concentration. Liver tissue showed steatosis and mildly decreased activity of N-acetylglutamate synthase suggesting partial deficiency. Treatment with N-carbamyl glutamate did not affect serum ammonia levels. Colour Doppler sonography and MR angiography demonstrated a patent ductus venosus. After surgical ligation of the ductus venosus, serum ammonia levels returned to normal and mental and motor performance improved markedly. CONCLUSION: In late onset hyperammonaemia, partial N-acetylglutamate synthase deficiency and portocaval shunt should be ruled out.

Quantitation of skin vasomotor control in normal subjects and in diabetic patients with autonomic neuropathy.

Peripheral autonomic neuropathy in diabetes has been difficult to evaluate. We have developed a test to quantitate sympathetic skin vasomotor function in the extremities. Skin vasomotor reflexes were investigated after warming and cooling the left arm and recording changes in skin temperature as a measure of skin blood flow in the right hand and both feet. Twenty-three diabetic patients with cardiac autonomic neuropathy and 28 healthy control subjects were examined. In contrast to the healthy subjects, the diabetic patients showed reduced or even absent responses in skin temperature to both warming and cooling. The rate of skin temperature decrease for the hand and feet during cooling, which was used as the actual parameter to quantitate skin vasomotor control, was significantly reduced in the diabetic group as compared with the healthy control subjects. We conclude that this technique provides a simple non-invasive method for quantitating skin vasomotor function in the extremities of diabetic patients.