Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei.

We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy (DMD) gene. Most of these dystrophinopathy patients had had an erroneous or ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed clinical severity by a standardized protocol, measured X-chromosome inactivation patterns in blood and muscle DNA, and quantitated the dystrophin protein content of muscle. We found that patients could be separated into two groups: those showing equal numbers of normal and mutant dystrophin genes in peripheral blood DNA ("random" X-inactivation), and those showing preferential use of the mutant dystrophin gene ("skewed" X-inactivation). In the random X-inactivation carriers, the clinical phenotype ranged from asymptomatic to mild disability, the dystrophin content of muscle was > 60% of normal, and there were only minor histopathologic changes. In the skewed X-inactivation patients, clinical manifestations ranged from mild to severe, but the patients with mild disease were young (5 to 10 years old). The low levels of dystrophin (< 30% on average) and the severe symptoms of the older patients suggested a poor prognosis for those with skewed X-inactivation, and they all showed morphologic changes of dystrophy. The random inactivation patients showed evidence of biochemical "normalization," with higher dystrophin content in muscle than predicted by the number of normal dystrophin genes. Seventy-nine percent of skewed X-inactivation patients (11/14) showed genetic "normalization," with proportionally more dystrophin-positive nuclei in muscle than in blood. In 65% of the skewed X-inactivation patients, dystrophin was not produced by dystrophin-positive nuclei; an average of 20% of myofiber nuclei were genetically dystrophin-positive but did not produce stable dystrophin. Biochemical normalization seems to be the main mechanism for rescue of fibers from dystrophin deficiency in the random X-inactivation patients. In the skewed X-inactivation patients, genetic normalization is active, but production failure of dystrophin by dystrophin-normal nuclei may counteract any effect of biochemical normalization. In the skewed X-inactivation patients, the remodeling of the muscle through cycles of degeneration and regeneration led to threefold increase in the number of dystrophin-competent nuclei in muscle myofibers (3.3 +/- 4.6), while dystrophin content was on the average 1.5-fold less then expected (-1.54 +/- 3.38). Our results permit more accurate prognistic assessment of isolated female dystrophinopathy patients and provide important data with which to estimate the potential effect of gene delivery (gene therapy) in DMD.

Hemolytic uremic syndrome with particular involvement of basal ganglia and favorable outcome.

Two children with hemolytic uremic syndrome and extrapyramidal complications are presented. Neuroimaging studies demonstrated bilateral basal ganglia (striatal) involvement with favorable recovery in both patients. The pathophysiology of the neurologic complications in hemolytic uremic syndrome are probably multifactorial. Our patients suggest a reversible process because both patients recovered clinically and radiographically. Neurologic complications do not always portend a poor prognosis and, in general, involvement of the basal ganglia is associated with favorable outcome.

Evolution of neonatal seizures.

The evolution of the diagnosis, etiology, management, and prognosis of neonatal seizures over the past two decades is reviewed. Seizures in the neonate are unique and require special classification. They result from acquired or congenital abnormalities of the central nervous system. Clustering of prognostic parameters, including seizure characteristics, perinatal factors, neurologic signs, cause, and neuroimaging and electroencephalographic abnormalities, allows neonatal seizures to be viewed as clinical syndromes with predictable outcomes.

Identical mitochondrial DNA deletion in mother with progressive external ophthalmoplegia and son with Pearson marrow-pancreas syndrome.

We describe a family in which the mother has progressive external ophthalmoplegia with the common 4977 base pair deletion, and her son has a syndrome similar to the Pearson marrow-pancreas syndrome with the identical deletion. This case extends the clinical phenotype of the Pearson syndrome and raises the possibility that developmentally regulated tissue-specific nuclear factors are responsible for the differential phenotypic expression of these two mitochondrial disorders.

Gastrointestinal hemorrhage associated with gastric polyps in Menkes disease.

We describe two infants with Menkes disease who had serious gastrointestinal bleeding from solitary gastric polyps. Hemorrhage in one patient was acute and proved fatal. Histopathologic examinations showed submucosal vascular ectasia with mucosal hyperplasia, edema, and ulceration. Gastric polyps may represent an underappreciated clinical abnormality in Menkes disease.