Nobutada Tachi

The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin.

The newly recognized ataxia–ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3′- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.

Homozygosity Mapping of Portuguese and Japanese Forms of Ataxia-Oculomotor Apraxia to 9p13, and Evidence for Genetic Heterogeneity

Ataxia with oculomotor apraxia (AOA) is characterized by early-onset cerebellar ataxia, ocular apraxia, early areflexia, late peripheral neuropathy, slow progression, severe motor handicap, and absence of both telangiectasias and immunodeficiency. We studied 13 Portuguese families with AOA and found that the two largest families show linkage to 9p, with LOD scores of 4.13 and 3.82, respectively, at a recombination fraction of 0. These and three smaller families, all from northern Portugal, showed homozygosity and haplotype sharing over a 2-cM region on 9p13, demonstrating the existence of both a founding event and linkage to this locus, AOA1, in the five families. Three other families were excluded from this locus, demonstrating nonallelic heterogeneity in AOA. Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA), so far described only in Japan, is characterized by marked cerebellar atrophy, peripheral neuropathy, mental retardation, and, occasionally, oculomotor apraxia. Two unrelated Japanese families with EOCA-HA were analyzed and appeared to show linkage to the AOA1 locus. Subsequently, hypoalbuminemia was found in all five Portuguese patients with AOA1 with a long disease duration, suggesting that AOA1 and EOCA-HA correspond to the same entity that accounts for a significant proportion of all recessive ataxias. The narrow localization of AOA1 should prompt the identification of the defective gene.

Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities

We report the histopathologic findings of 3 sural nerve biopsies and 1 muscle biopsy from 3 patients with Rett syndrome. The 3 sural nerve biopsies demonstrated a few ultrastructural abnormalities, including the presence of many Pi-granules and mitochondrial changes in the cytoplasm of Schwann cells, occasional bands of Büngner and onion-bulb formations, and mitochondrial alterations in myelinated axons. Morphometric analysis disclosed reduction in the number of large myelinated fibers with normal densities in comparison to those of an age-matched normal control. Light microscopic examination of the biopsied muscle from a 6-year-old patient with Rett syndrome revealed the existence of many small, dark, angulated fibers with NADH-TR staining. Ultrastructural investigation of the muscle confirmed the presence of the dumbbell-shaped mitochondria. Peripheral nerve involvement and the possibility of mitochondrial abnormalities in Rett syndrome were suggested by the results.

Glycogen storage disease with normal acid maltase: Skeletal and cardiac muscles

We report a 5-year-old boy with lysosomal glycogen storage disease and normal acid maltase activity. This patient, the fourth reported in the literature, was referred to our hospital for evaluation of elevated serum GOT, GPT, and CK activities. He had neither muscle weakness nor atrophy. Echocardiography demonstrated marked thickening of the intraventricular septum and left ventricular wall which indicated hypertrophic cardiomyopathy. Biopsied skeletal muscle disclosed massive accumulation of glycogen and autophagic vacuoles. Electron microscopy of biopsied cardiac muscle revealed severe myofibrillar disruption with marked accumulation of free and intralysosomal glycogen. Activities of all major glycolytic enzymes in skeletal muscle, including acid maltase, were normal. It is unknown why muscle lysosomes appeared to be unable to digest the trapped glycogen despite the presence of acid maltase. Our findings illustrate the importance of performing skeletal muscle investigation during childhood in patients with hypertrophic cardiomyopathy.

Congenital myotonic dystrophy transmitted from an asymptomatic father with a DM-specific gene

We present the first report of paternal transmission of congenital myotonic dystrophy (DM). The patients had typical congenital DM and showed unstable CTG repeats on Southern blot analysis. The mother had no expansion of the DM gene, but the asymptomatic father had minimal expansion of the CTG repeats.

Tomaculous neuropathy in Charcot-Marie-Tooth disease with myelin protein zero gene mutation

Mutation of the myelin protein zero (MPZ) gene is associated with a small number of Charcot-Marie-Tooth (CMT) patients. We present a patient with Lys 130 Arg substitution in the extracellular domain who showed tomacula formation in biopsied sural nerve. CMT patients with mutations Ly 96 Glu, Lys 130 Arg and Ile 135 Leu showed tomaculous neuropathy. Present and previously reported investigations suggest that the pathological phenotypes of peripheral nerve are probably related to the mutations of the MPZ gene.

Demyelinating peripheral neuropathy in cockayne syndrome: a histopathologic and morphometric study

The clinical and histopathological features of Cockayne syndrome in a 2-year-old girl are reported. Sural nerve biopsy revealed segmental demyelination and remyelination. The density of myelinated fibers, especially small ones, was decreased in comparison with an age-matched control. Although the total number of unmyelinated fibers showed no difference from that in the control, the number of small unmyelinated fibers was slightly increased. A study of teased fibers from the patients nerve revealed that 1% of the fibers had segmental demyelination, and 7% showed remyelination. Ultrastructurally, demyelinated fibers were present sporadically. No degeneration of axons was evident. Our pathological and morphometric data for the sural nerve suggest the presence of primary demyelination in early childhood.

Congenital muscular dystrophy in Marinesco-Sjögren syndrome

The histochemical and immunocytochemical findings of biopsied muscle in a 2-year-old girl with Marinesco-Sjögren syndrome are reported. Muscle histology consisted of mild muscular dystrophy, such as that found in limb-girdle or non-Fukuyama congenital muscular dystrophy. By immunocytochemical stain using anti-dystrophin antibody, Duchenne and Becker muscular dystrophies were excluded. In addition to characteristic clinical features, including ataxia, congenital cataract, and psychomotor retardation, muscle involvement is essential to the diagnosis of Marinesco-Sjögren syndrome.

Electron microscopic study of the biopsied cardiac muscle in Duchenne muscular dystrophy

Cardiac muscular biopsies were performed on 4 patients with Duchenne muscular dystrophy (DMD). None of the patients had cardiac symptoms and all of them exhibited normal electro- and echocardiographic findings. Electron microscopic examination of cardiac muscles from 4 patients with DMD disclosed proliferation of the mitochondria, changes in the cristae, abnormalities of the Z-bands, dilatation of the sarcoplasmic reticulum, deposition of glycogen, and changes in the nuclei. The most striking finding in these patients was that the residual bodies were increased and were observed mainly in the perinuclear region. These ultrastructural features suggest that an extreme exhaustion had already been present in myocardial tissue of the patients prior to the onset of cardiac symptoms.

Clinicopathological and virological analyses of familial human T-lymphotropic virus type I–associated polyneuropathy

Human T-lymphotropic virus type I (HTLV-I) is known to be the causative agent of the chronic myelopathy, HTLV-I-associated myelopathy (HAM), and on rare occasions infection is also associated with the development of polyneuropathy. Here the authors present an HTLV-I-positive family of whom four members developed a chronic demyelinating polyneuropathy without HAM. Four female patients in a family from Hokkaido in Japan developed distal dominant paresthesia and muscle weakness in the second and third decades of their life. Neurological findings at ages ranging from 50 to 65 years included mild painful sensorimotor disturbances with atrophy of the distal parts of the extremities but without pyramidal signs or hyperactive tendon reflexes. Magnetic resonance imaging (MRI) findings of brain and spinal cord were unremarkable. Serum HTLV-I antibody levels were elevated at 1:8,192 to 1:32,768, whereas those in cerebrospinal fluid were low at 1:4 to 1:8. Electrophysiological studies revealed polyphasic compound muscle action potentials with denervation potentials on nerve conduction studies and neurogenic patterns by electromyography, which were consistent with signs of chronic motor dominant demyelinating polyneuropathy. Sural nerve biopsy showed decreased myelinated fibers, occurrence of globule formation, myelin ovoid and remyelinated fibers, and an infiltration of CD68-positive macrophages with occasional CD4-positive T cells in the nerve fascicles. The polyneuropathy was responsive to steroid therapy. Analyses of serological human leukocyte antigen (HLA) types indicated that none of the patients possessed a high-risk HLA type known to be associated with adult T-cell leukemia (ATL), whereas they did have high responsive alleles to HTLV-I env similar to that observed in HAM. Nucleotide sequence analysis of the HTLV-I tax region demonstrated the B subgroup in all patients. This study suggests that HTLV-I infection can result in the development of a familial form of polyneuropathy that is associated with distinct HLA class I alleles, which might possibly involve a distinct virus subtype.