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.

Lower motor neuron syndromes defined by patterns of weakness, nerve conduction abnormalities, and high titers of antiglycolipid antibodies.

We studied 74 patients with progressive, asymmetrical lower motor neuron syndromes. Clinical features of these patients, including age, sex, disease duration, patterns of weakness, and reflex changes, were evaluated by review of records. In each patient the clinical features were compared to the type of nerve conduction abnormalities and to the specificities of high-titer serum antiglycolipid antibodies. Antibody specificities were determined by an enzyme-linked immunosorbent assay using purified glycolipids and carbohydrates as substrates. Our results show that high titers of antibodies to glycolipids are common in sera of patients with lower motor neuron syndromes. Selective patterns of reactivity indicate that specific carbohydrate epitopes on the glycolipids are the targets of the high-titer antibodies in individual patients with lower motor neuron syndromes. Several distinct lower motor neuron syndromes can be identified based on clinical, physiological, and antiglycolipid antibody characteristics. These syndromes include multifocal motor neuropathy with evidence of multifocal conduction block on motor, but not sensory, axons and frequent (84%) high titers of anti-GM1 ganglioside antibodies; a lower motor neuron syndrome with predominantly distal weakness early in the disease course, no conduction block, and a high incidence (64%) of anti-GM1 antibodies; and a lower motor neuron syndrome with predominant early weakness in proximal muscles and serum antibodies to asialo-GM1 that do not cross-react with GM1 ganglioside.

Kearns-Sayre syndrome: biochemical studies of mitochondrial metabolism.

Examination of oxidative metabolism in mitochondria isolated from quadriceps skeletal muscle biopsy specimens of 4 patients with Kearns-Sayre syndrome has shown that the mitochondria were tightly coupled, with maximal respiratory rates depending on the presence of adenosine diphosphate (ADP), Ca2+, or uncoupler. The state 3 respiratory rates with nicotinamide adenine dinucleotide (NAD)-linked substrates and succinate were much lower than those of control subjects. The cytochrome oxidase activities (measured with ascorbate + phenazine methosulfate as substrates) were also decreased, but this segment of the respiratory chain was not rate-limiting for succinate or NAD-linked substrate oxidation. Analyses of the steady-state reduction kinetics of the respiratory chain carriers revealed that the rate-limiting step of the impaired respiration with succinate or NAD-linked substrates lies between the c cytochromes and cytochrome oxidase. Measurement of the total substrate-reducible (at anaerobiosis) and chemically reducible levels of the cytochromes in mitochondria from 3 patients showed a severe deficiency of cytochrome a + a3 and an excess of the c cytochromes. To our knowledge, this is the first instance in which a mitochondrial electron transfer defect and cytochrome oxidase deficiency has been shown to be associated with an excess of the c cytochromes.

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.

The influence of rat suspension-hypokinesia on the gastrocnemius muscle.

Hind-limb hypokinesia was induced in rats by the Morey method to characterize the response of the gastrocnemius muscle. A comparison of rats suspended for 2 weeks with weight, sex, and litter-matched control rats indicate no difference in gastrocnemius wet weight, contraction, or one-half relaxation times, but less contractile function as indicated by lowered dP/dt. Myosin ATPase staining identified uniform Type I (slow-twitch) and II (fast-twitch) atrophy in the muscles from 4 of 10 rats suspended for 2 weeks and 1 of 12 rats suspended for 4 weeks; muscles from three other rats of the 4-week group displayed greater Type I atrophy. Other histochemical changes were characteristic of a neuropathy. These data together with recently acquired soleus data (29) indicate the Morey model, like space flight, evokes greater changes in the Type I or slow twitch fibers of the gastrocnemius and soleus muscles.

Influence of suspension hypokinesia on rat soleus muscle.

Hindlimb hypokinesia was induced in rats by the Morey method to characterize the response of the soleus muscle. Rats suspended for 1-4 wk exhibited continuous and significant declines in soleus mass, function, and contractile duration. Soleus speeding was in part explained by an alteration in fiber type. The normal incidence of 70-90% type I fibers in the soleus muscle was reduced after 4 wk of suspension to 50% or less in 9 of 11 rats. A significant decline in type I myosin isozyme content occurred without a change in that of type II. Other observed histochemical changes were characteristic of denervation. Consistent with soleus atrophy, there was a significant increase in lysosomal (acid) protease activity. One week of recovery after a 2-wk suspension was characterized by a return to values not significantly different from control for muscle wet weights, peak contraction force, one-half relaxation time, and type I myosin. Persistent differences from control were observed in maximal rate of tension development, contraction time, and denervation-like changes.

Pharmacology and neurotoxicity of cis-diamminedichloroplatinum, bleomycin, 5-fluorouracil, and cyclophosphamide administration following osmotic blood-brain barrier modification.

cis-Platinum, bleomycin, 5-fluorouracil, and cyclophosphamide were administered to rodent and canine models of osmotic blood-brain barrier modification to evaluate the relationship between tissue drug concentration in brain and the physiological and neuropathological effects of the drug. The toxicity studies were carried out in the canine, and the pharmacological studies were carried out in the rodent. Even without the osmotic procedure, intracarotid cis-platinum, in contrast to the other drugs, produced modification of the blood-brain barrier with resultant severe neurotoxicity. Osmotic blood-brain barrier modification was used to increase delivery of bleomycin and 5-fluorouracil to the ipsilateral brain region, but the increased delivery was associated with evident neurotoxicity. Cyclophosphamide administration in association with osmotic blood-brain barrier opening did not cause significant neural toxicity. These studies indicate that some chemotherapeutic agents given in association with osmotic blood-brain barrier opening can result in neurotoxicity. The corollary of the known limited neurotoxicity when these chemotherapeutic agents are used in a conventional manner appears to be due to the presence of the blood-brain barrier.

Neurotoxicity of chemotherapeutic agents after blood-brain barrier modification: neuropathological studies.

We examined in 47 dogs the effects of 5-fluorouracil, Adriamycin (doxorubicin hydrochloride), cis-platinum (cis-diamminedichloroplatinum) cyclophosphamide, and bleomycin given in association with osmotic blood-brain barrier modification. The dose of drug ranged from 100% to as little as 5 to 10% of the conventional systemic dosage. Serial neurological observation and subsequent postmortem neuropathological evaluation at times varying from 2.5 hours to 52 days after drug administration showed that cis-platinum and Adriamycin were highly neurotoxic, as evidenced by neurological deficits and pathological changes in the central nervous system parenchyma; 5-fluorouracil and bleomycin had much less, but consequential neurotoxicity; and cyclophosphamide was not associated with substantial toxicity. Intracarotid cis-platinum, unlike the other drugs, damaged the blood-brain barrier and resulted in marked neurotoxicity in the absence of osmotic blood-brain barrier opening. The neural lesions produced by these agents were not specific but were manifested as foci of hemorrhagic necrosis and edema. In addition, secondary brainstem hemorrhage was observed in animals that developed transtentorial herniation. On the basis of these studies, of five drugs studied at a wide range of doses, only cyclophosphamide appears to be safe enough to evaluate in clinical trials that utilize blood-brain barrier modification to enhance drug delivery. These studies also suggest that the lack of neurotoxicity associated with the usual administration of most chemotherapeutic agents probably stems from limited entry of drug into the brain through an intact blood-brain barrier.

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.

Peripheral neuropathy and starvation after gastric partitioning for morbid obesity.

Three months after gastric partitioning for morbid obesity, two patients developed an unusual and severe form of polyneuropathy that affected their sense of position maximally. This disorder produced severe ataxia of the upper extremities and trunk, and pseudochorea. One patient died and the autopsy showed an extensive demyelinating polyneuropathy. Neuronal cell bodies in the anterior horns and dorsal root ganglia showed extensive accumulations of lipofuscin and Schwann cells showed extensive accumulations of lipid. This neuronal and Schwann cell lipidosis appears to result from starvation of the obese and has never been reported in other forms of human starvation or nutritional deficiency.

Sources of error in the diagnosis of Guillain-Barre syndrome.

A careful monitoring of the accuracy of diagnosis in six cases of Guillain-Barre syndrome has shown that a substantial proportion of these patients initially diagnosed as having Guillain-Barre syndrome on the basis of characteristic clinical findings and an elevated level of protein in the spinal fluid had a neuropathy caused by another etiology. The pitfalls in the laboratory and clinical diagnosis of disorders that were confused with Guillain-Barre syndrome were several: the pattern of neurological dysfunction in the Guillain-Barre syndrome was not unique to that disorder; no specific laboratory test existed to confirm the diagnosis of Guillain-Barre syndrome; and the laboratory diagnosis of other causes of similar neurological disorders (especially heavy metal intoxication) depended upon tests that are very unreliable.

Osmotic blood-brain barrier disruption in the posterior fossa of the dog.

Transient reversible osmotic blood-brain barrier disruption was produced in the posterior fossa of 33 dogs. A percutaneous catheter technique was used for the infusion of hypertonic mannitol into the vertebral artery. Neither the catheter technique nor the osmotic barrier modification resulted in interference with brain-stem function in most animals. The degree of barrier modification achieved by osmotic disruption in the posterior fossa is similar to that previously described for barrier modification of the supratentorial parenchyma. Methotrexate delivered to the brain via the vertebral artery resulted in a drug concentration of 100 to 300 ng/gm brain tissue. When the same amount of drug was given following osmotic blood-brain barrier disruption, brain tissue contained 1100 to 5000 ng of methotrexate/gm of brain tissue. Finally, the adequacy of the blood-brain barrier modification in the posterior fossa was shown to be quantifiable by the amount of enhancement on computerized tomographic scans.

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).

Malignant pineal region tumors. A clinico-pathological study.

Eight patients with primary malignant pineal tumors have been seen at this institution over the past 6 years; six of them underwent definitive surgical exploration. Complete gross microsurgical excision of well encapsulated tumors was possible in four of these patients. In two cases of pineal germinomas, a biopsy and a subtotal resection were carried out because of the known radiosensitivity of this tumor. These six surgical patients all received postoperative craniospinal radiation and continue to do well up to 6 years postoperatively. Two nonoperative patients were initially treated at other institutions by ventriculoperitoneal shunt and radiation and were the only ones to develop metastatic disease. One patient had metastasis of her pineoblastoma to her unirradiated spinal canal and the other patient had metastasis of his germinoma to the peritoneum. The former patient was quadriplegic on admission, although her pineal tumor was no longer visible on computerized tomography (CT), and she died of pneumonia. The latter patient's tumor secreted the beta chain of human chorionic gonadotropin (HCG). This patient's massive metastatic tumor burden completely regressed as determined by body CT scan and HCG levels after four courses of chemotherapy with bleomycin, vinblastine, and cis-platinum. In 20 patients with lesions of the pineal region, craniotomy was associated with only one death (a patient with metastatic adenocarcinoma). Thus, microsurgery for pineal tumors provides either a reasonably safe potential for complete tumor extirpation and possible cure, or a tissue diagnosis which is necessary for appropriate therapeutic planning for radiotherapy and/or chemotherapy. The traditional therapeutic approach of empiric radiotherapy without a tissue diagnosis for pineal lesions may no longer be warranted.