Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients--10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

Hypercapnic respiratory failure due to L-tryptophan-induced eosinophilic polymyositis.

A 24-year-old man presenting with fever, rash, and myalgias subsequently developed hypercapnic respiratory failure and severe limb muscle weakness. Muscle biopsy revealed eosinophilic myositis, due to the ingestion of large quantities of L-tryptophan as a dietary supplement. Complete recovery occurred with corticosteroid administration. Significant involvement of the respiratory muscles can be a predominant feature of this newly described disease entity.

Eosinophilic myositis an expression of L-tryptophan toxicity?

Eosinophilia-myalgia syndrome possibly due to L-tryptophan is a new clinical entity that has been recently reported. We describe the clinical presentation of eosinophilia, eosinophilic pustular folliculitis, myalgia, and eosinophilic myositis, that led to respiratory failure in a young man taking an L-tryptophan containing compound.

Photodynamic therapy of normal cerebral tissue in the cat: a noninvasive model for cerebrovascular thrombosis.

The early neuropathological response of normal cat brain to photodynamic therapy was investigated. Photofrin II was injected (IV) into a cat and photoactivated with red light from a filtered incandescent lamp. Animals were subjected to phototherapy either through the intact skull or with energy deposition onto the intact dura. Following photoactivation the animals were maintained for 6 h after which time the brain was removed and sections submitted for electron microscopic and or light microscopic study. Gross anatomical analysis of the photoactivated brain revealed hemorrhagic dusky discoloration limited to the area of the tissue illuminated. Animals that failed to show a lesion were cats characterized by low Photofrin II dosage and low photoactivation intensity. The microscopic cortical features of cats with lesions included prominent capillary congestion and regions of marked vacuolization and rarefaction. Blood vessels were structurally altered and the lumen of many vessels was completely filled with tightly packed erythrocytes. Our study suggests that the acute neuropathological response of cerebral tissue to photoactivation resembles that of microvascular thrombosis. It is thus reasonable to explore PDT of normal tissue as a non invasive model of cerebrovascular thrombosis in the cat.

Myopathy and hypersensitivity to phenytoin.

A 19-year-old man with a generalized seizure disorder was treated with phenytoin. A hypersensitivity reaction was marked by hepatitis, severe myalgia, proximal arm weakness, and high serum creatine kinase. Biopsy was diagnostic of myopathy. Patients demonstrating abnormalities of immune responsiveness may best be managed by use of an alternative anticonvulsant.

Myopathies.

This paper reviews the recent advances in our knowledge of muscle disease. The use of muscle biopsy for diagnosis is discussed. The etiology, pathogenesis, and treatment of polymyositis/dermatomyositis are considered. The author discusses the clinical patterns, inheritance, and pathogenesis of progressive muscular dystrophies, especially Duchenne muscular dystrophy; myotonic disorders; glycogen storage diseases; disorders of lipid metabolism; mitochondrial diseases; and congenital muscle diseases. (Neurosurgery, 5: 747--758, 1979).