Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene.

Friedreich ataxia (FRDA), the most common autosomal recessive neurodegenerative disease among Europeans and people of European descent, is characterized by an early onset (usually before the age of 25), progressive ataxia, sensory loss, absence of tendon reflexes and pyramidal weakness of the legs. We have recently identified a unique group of patients whose clinical presentations are characterized by autosomal recessive inheritance, early age of onset, FRDA-like clinical presentations and hypoalbuminemia. Linkage to the FRDA locus, however, was excluded. Given the similarities of the clinical presentations to those of the recently described ataxia with oculomotor apraxia (AOA) linked to chromosome 9p13, we confirmed that the disorder of our patients is also linked to the same locus. We narrowed the candidate region and have identified a new gene encoding a member of the histidine triad (HIT) superfamily as the 'causative' gene. We have called its product aprataxin; the gene symbol is APTX. Although many HIT proteins have been identified, aprataxin is the first to be linked to a distinct phenotype.

Structural proteins of the opaque muscle fibers in Duchenne muscular dystrophy.

We studied the structural proteins of the "opaque fibers" (OFs) in muscle biopsies from 12 patients, aged 4 to 24 years, with Duchenne muscular dystrophy. The electrophoretic patterns of myofibrillar proteins indicated three groups of opaque fibers: the first (OF a) had an almost normal electrophoretogram, the second (OF b1) showed a clear decrease of 55,000 dalton protein (desmin), and the third (OF b2) exhibited a great reduction in alpha-actinin and desmin. The data suggest that some OFs are pathologic fibers in the degenerative process of Duchenne dystrophy.

High single-dose alternate-day corticosteroid regimens in treatment of polymyositis.

High single-dose alternate-day prednisolone therapy (ADT) was compared with daily-dose prednisolone therapy (DDT) for treatment of polymyositis. Thirty patients with polymyositis were treated with ADT for an average of 33.9 months. The combined number of improvements was 21 out of 30, a response rate of 70%. Side-effects were very rare and mild. On the other hand, 9 of 17 patients treated with DDT for an average 18.5 months improved, a response rate of 53%. The incidence of side-effects was strikingly higher than with ADT. ADT is therefore strongly advocated for treatment of polymyositis to avoid infectious complications and lessen cushingoid side-effects.

Alpha 2-adrenergic receptor in familial amyloidotic polyneuropathy.

alpha 2-Adrenergic receptor binding has been studied in platelet membranes from 16 patients with type 1 familial amyloidotic polyneuropathy (FAP) at various clinical stages and 15 normal subjects. Binding of the radioligand [3H]yohimbine to platelet membranes was used to examine alpha 2-adrenergic receptors. The number of alpha 2-adrenergic receptors were significantly lower in patients of the early stage than in normal subjects. Then, the numbers tended to be higher than those of normal subjects in the intermediate stage, and they were higher in the single advanced-stage patient studied. The reduction in alpha 2-adrenergic receptor numbers in platelet membranes from patients of the early stage might be explained by the down-regulation of the receptors in vascular smooth muscle, but it remains uncertain whether a high number of alpha 2-adrenergic receptors observed in the single advanced-stage patient might be explained by the up-regulation of the receptors.

[A hereditary ataxia associated with hypoalbuminemia and hyperlipidemia--a variant form of Friedreich's disease or a new clinical entity?].

The patients belonged to three different families and were products of consanguineous marriage. The neurological symptoms and signs in these patients began in infancy or childhood and included gait disturbance, horizontal nystagmus, distention tremor of the hands, muscular wasting and sensory impairment of the hands and legs. CT-scan and/or MRI showed atrophy of the cerebellum. Serum biochemical analyses revealed hypoalbuminemia with hyperlipidemia. There were no abnormalities in the heart, liver, kidney, gastrointestinal tract, or endocrine systems. The autopsy revealed degenerative changes in the spinal cord including posterior column and lateral pyramidal tract, as well as in the peripheral nerves and cerebellar cortex. Although we have speculated that the disease presented here would be a clinical variants of Friedreich's disease, it would make a new clinical entity because there was no report about the association to hypoalbuminemia and hyperlipidemia with spinocerebellar degeneration.

Deferoxamine mesylate inhibits bacterial growth in vivo.

Iron is one of the essential element for bacterial growth. To study the effect of chelation of iron on bacterial growth, 17 different strains of bacteria were cultured in chocolate-agar medium in the presence or absence of deferoxamine methylate (DM), a potent chelating agent for iron. A fairly low concentration of DM (10 mg/ml) in the culture medium markedly inhibited the growth rates of the three bacterial strains, B. catarrhalis, N. meningiditis and N. gonorrhoeae. In vivo effect of DM was also tested in mice that were intraperitoneally inoculated with a lethal number of N. meningiditis (2 x 10(8)/animal). After 40 h of inoculation, more than 90% of the control animals died for acute peritonitis. In contrast, animals which were intraperitoneally administered with DM showed a marked resistance to the inoculated bacteria without showing toxic effects of the agent: less than 30% of animals died of acute peritonitis caused by infection within 40 h. The results suggest that, in addition to the currently used antibiotics. DM might also be an useful therapeutic agent for treatment of bacterial infection.

Single muscle fiber analysis of myoclonus epilepsy with ragged-red fibers.

We examined two muscle biopsy specimens from a proband and her mother with myoclonus epilepsy with ragged-red fibers (MERRF), both obtained at an interval of about 10 years, using histochemistry, in situ hybridization, and single-fiber polymerase chain reaction. Total (wild-type and mutant) mitochondrial DNAs (mtDNAs) were greatly increased in ragged-red fibers (RRF) over non-RRF in all muscle specimens analyzed. The proportion of mutant mtDNA was also significantly higher in RRF than in non-RRF. By comparing the first and second muscle biopsied specimens in each patient, we found that while the proportion of RRF, cytochrome coxidase deficient fibers, and mutant DNA in muscle changed over a 10-year period, the proportion of wild-type and mutant mtDNAs in RRF and in non-RRF was similar between the two specimens. These results suggest that the ratio of wild-type to mutant mtDNAs in RRF and non-RRF in MERRF is at a steady state level in each muscle fiber, without replicative advantage of mutant mtDNA.

Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15A13-15.

To date, three loci for autosomal recessive hereditary spastic paraplegia (ARHSP) linked to chromosomes 8p12-q13, 16qter, and 15q13-15 have been characterized. We have clinically characterized 13 Japanese ARHSP families and performed genetic linkage analyses. All 13 families were classified as having the "complicated" form, which manifests with mental impairment and thin corpus callosum. Linkage to the 8p12-q13 and 16qter loci was excluded, although 10 of the 13 families showed marker data consistent with linkage to the 15q13-15 locus. The multipoint LOD score of the 10 families linked to chromosome 15 was above 9.00 in the 3-centimorgan segment flanked by D15S994 and D15S659, with a maximum multipoint LOD score of 9.68 at a position 1.2 centimorgans telomeric from D15S994 to D15S659. We have shown that ARHSP with thin corpus callosum, a subtype of recessive spastic paraplegia, maps to chromosome 15q13-15.