Shaking rat Kawasaki (SRK), a newly discovered neurological mutant rat in the Wistar strain, is described. The abnormalities of SRK rats are transmitted as an autosomal recessive trait. The neurological signs are shaking of the body and an ataxic-paretic gait from day 10 postnatal. The affected rats survive for about 1 month. Macroscopically, the cerebellum is small and frequently the vermis and paraflocculus lacking. The most conspicuous histological finding in the central nervous system is malposition of the neurons in the cerebral cortex, hippocampus and cerebellum. Myelination and synapse formation are intact. Abnormal myelinated fibers are present in the molecular layer of the cerebral cortex and in the central gray matter of the spinal cord. These morphological abnormalities resemble those reported in the reeler mutant mouse. SRK rats are another good animal model of human congenital malformations with neuronal migration disorders.

Abstract:We have immunocytochemically shown a significant reduction in the amount of laminin M (or merosin; a tissue-restricted basal lamina protein expressed in striated muscle, Schwann cells, and placental trophoblast) in the skeletal muscle of Fukuyama type congenital muscular dystrophy (FCMD).1) To inquire into the role of laminin M in the process of muscular dystrophies, we examined laminin M in several animal models that cause muscular dystrophy. Immunofluorescent, immunoblotting, and electron microscopic analyses have revealed that laminin M is missing from skeletal and cardiac muscles and peripheral nerve in the affected homozygous C57BL/6J-dy/dy mice, but not in the non-affected heterozygous Dy/dy and the other dystrophic animal models including mdx mice, BIO 14.6 hamsters, and line 413 chickens. In the dy/dy mice, laminin M mRNA is not detected by Northern blotting, but becomes detectable by RT-PCR amplification. Other components of the basal lamina such as laminin B, beta-integrin, type IV collagen, and fibronectin are normally expressed in all animals examined, including the dy/dy mice. These observations strongly suggest that laminin M defect is primarily responsible for the pathogenesis of muscle fiber damage and dysmyelination of the dystrophic dy/dy mice.

We analyzed urinary valproate (VPA) metabolites and carnitine concentrations in a child who accidentally ingested 400 mg/kg VPA. The concentration of 4-en VPA, the presumed major factor in VPA-induced hepatotoxicity, was markedly increased, without liver dysfunction or hyperammonemia. The other major abnormality was decreased beta-oxidation and markedly increased omega-oxidation. After L-carnitine supplementation, VPA metabolism returned to normal. The level of valproylcarnitine was not increased and therefore was not affected by L-carnitine. L-Carnitine may be useful in treating patients with coma after VPA overdose.

In a new family with X-linked congenital autophagic vacuolar myopathy (AVM), seven affected boys presented with congenital hypotonia, dyspnea, and dysphagia with delayed motor milestones. Muscle pathology revealed autophagic vacuoles with sarcolemmal features, multilayered basal lamina with marked sarcolemmal deposition of C5-9 membrane attack complex and calcium, histologically indistinguishable from childhood-onset X-linked myopathy with excessive autophagy (XMEA). Haplotype analysis suggests that this new AVM and XMEA may be allelic despite different clinical presentations.

Chronic injections of valproic acid (VPA), VPA with phenobarbital (PB), and PB were studied for their effects on liver mitochondrial morphology and carnitine metabolism in rats. Mitochondrial enlargement was induced by the administration of VPA (500 mg/kg/day) for a period of 7 consecutive days. The administration of VPA (500 mg/kg/day)-plus-PB (20 mg/kg/day) for 7 days, however, did not induce megamitochondrial formation, but in these livers an unusual increase was observed in the number of liver mitochondria, microvesicular steatoses, and myeloid bodies. VPA-treated rats had significantly lower levels of serum-free and total carnitine and higher levels of acylcarnitine and acyl to free ratio than those of the controls. The free carnitine concentrations in serum and liver of the rats treated with VPA-plus-PB were much lower as compared with those treated with either VPA or PB. These morphological and biochemical results, especially of carnitine metabolism, suggest that inhibition of beta-oxidation in liver mitochondria occurred in rats treated with VPA and PB and that, in particular, polytherapy with VPA-plus-PB could be clinically hazardous in causing hepatic injury.