Biochemical analysis of decreased ornithine transport activity in the liver mitochondria from patients with hyperornithinemia, hyperammonemia and homocitrullinuria.

Hyperornithinemia, hyperammonemia and homocitrullinuria (HHH disorder) is an inherited metabolic disorder which shows peculiar amino acid changes in the serum and urine. The primary defect is considered to be the transport of ornithine across the mitochondrial membrane, but there is no direct evidence for this so far. We have analyzed ornithine transport activities in the liver mitochondria from three patients with HHH disorder. In coupled liver mitochondria we demonstrated low activities of citrulline synthesis and low rates of ornithine uptake. However, there were no abnormalities in carbamoyl-phosphate synthetase activity, ornithine carbamoyltransferase activity, N-acetylglutamate levels or O2 uptake with succinate. We also performed a kinetic study of citrulline synthesis as a function of ornithine concentration. We found increased Km values for ornithine and varied Vmax values of citrulline synthesis, which suggested the presence of a mutant transport protein. From these results we conclude that the defect of hyperornithinemia, hyperammonemia and homocitrullinuria lies in the transport of ornithine across the mitochondrial membrane.

A genetic variant of Emery-Dreifuss disease. Muscular dystrophy with humeropelvic distribution, early joint contracture, and permanent atrial paralysis.

A 38-year-old woman, a product of consanguineous parents, had been observed to have limited neck flexion and elbow joints contracture since early childhood. In addition, she experienced humeropelvic muscular weakness and atrophy, so that she was unable to walk by age 27. At 34 years of age, she required a permanent pacemaker to treat complete atrioventricular block with ventricular bradycardia. A myocardial biopsy confirmed cardiomyopathy. The clinical features of the present case are similar to those of the Emery-Dreifuss syndrome; however, this case may be inherited through an autosomal recessive trait.

Multiple sclerosis co-existent with myxedema. An autopsy case report.

A 64-year-old woman developed impaired consciousness and vision, sensorimotor paresis, hypothermia, bradycardia, and edema. Symptoms fluctuated with seasonal exacerbations in winter and terminated in coma with respiratory insufficiency at age 69. High CSF protein content and low serum T4 and TSH levels were noted. Treatment with prednisolone and thyroxin considerably improved her consciousness and edema. The patient suddenly expired of pulmonary embolism. Postmortem examination revealed a marked atrophy of pituitary and thyroid glands, while multiple demyelinating plaques were disclosed in the optic tract and cervical cord. A review of the literature indicates that this is the first report of the co-existence of two such disorders.

Concanavalin A binding sites on the erythrocytes of normal and genetically dystrophic chickens.

Red blood cells (RBCs) were obtained from genetically dystrophic chickens (Dy) and age-matched controls (C). Dy-RBCs had a lower titer of agglutination to concanavalin A (Con A) compared to C-RBCs. In order to ascertain the difference in agglutination, Con A binding on RBCs was studied, using 125I-labeled Con A ([125I]Con A) and ferritin conjugate to Con A (Fer-Con A). Kinetic analysis of [125I]Con A binding to Dy-RBCs showed a reduction of major binding sites of Con A. There was no difference in the apparent association constant for the major binding sites of Con A between Dy-RBCs and C-RBCs. Quantitative analysis of Con A binding site distribution on RBCs using Fer-Con A showed a remarkable diminution of ferritin particles tagged on the surface of Dy-RBCs. There was no significant difference in the distribution pattern of ferritin particles between Dy-RBCs and C-RBCs.

Creatine kinase (CK)-linked IgA in Isaacs' syndrome. An immune complex disease?

Electrophoresis of serum from a patient with Isaacs' syndrome revealed an atypical creatine kinase (CK) isoenzyme pattern which contained an extra band migrating between CK2(MB) and CK3(MM). Immunofixation demonstrated that the extra band was a complex of CK3(MM) and IgA. The presence of this complex seemed to correlate with increased serum CK levels which were associated with the aggravation of symptoms. Immunofluorescence studies on muscle biopsy samples revealed the presence of the complex in the muscle fiber membrane and motor endplate. The existence of CK-linked IgA in an Isaacs' syndrome suggests that an immunological abnormality may play a role in the pathological process of this rare syndrome.

Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations.

The clinical efficacy, dose-response relationship, and safety of TRH-T (thyrotropin releasing hormone tartrate) were assessed in 290 patients with spinocerebellar degeneration (SCD) in a 2-week, double-blind study using placebo as control. 254 patients satisfied the criteria for inclusion in evaluation of the drug efficacy. The patients were treated with TRH-T in an intramuscular dose of 2 mg, 0.5 mg or 0 mg (placebo) as TRH once a day for 2 weeks. Clinical responses to these treatments were evaluated 3 times: at the end of weeks 1 and 2 of treatment and a week after the end of treatment. The results of "global improvement rating" as well as those of "ataxia improvement rating" showed that both 2 mg and 0.5 mg TRH-T treatments were significantly superior to placebo treatment in patients with predominantly cerebellar form of SCD. The effect was well maintained a week after the end of the 2-week treatment in the patients who were given TRH-T in daily dose of 2 mg and showed improvement at the end of treatment. The results of "improvement rating of each symptom" revealed that 2 mg treatment was significantly more effective than placebo for disorders of standing, gait, speech and writing. In the patients who had no pyramidal involvement or disorder of deep sensation, the drug efficacy and dose-response relationship were evident. Adverse reactions to the drug such as headache, feeling febrile and nausea were observed in 50% of the patients on 2 mg treatment, in 38% of those on 0.5 mg treatment and in 21% of those on placebo patient, however, discontinued treatment because of adverse reactions.