Nobuyoshi Fukuhara

Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): Disease entity or a syndrome? ☆: Light- and electron-microscopic studies of two cases and review of literature

A report is given of an association of dyssynergia cerebellaris myoclonica associated with Friedreichs ataxia and mitochondrial myopathy in 2 patients. They had suffered from gradually increasing bursts of myoclonus since the wage of 14 and childhood, respectively. The other striking clinical features included generalized convulsions, mental deterioration, intention tremor, ataxia, muscular atrophy and deformity of feet. Muscle biopsies revealed ragged-red fibres in both cases. On electron microscopy these fibres contained subsarcolemnal aggregations of abundant abnormal mitochondria with proliferation of inner membranes or paracrystalline inclusions. One of these patients showed elevated blood lactate and pyruvate with an increased lactate/pyruvate ration, apparently of primary origin. These 2 cases resemble those reported briefly by Tsairis et al. (1974). An association of dyssynergia cerebellaris myoclonica associated with Friedreichs ataxia and mitochondrial myopathy in these 2 patients is unlikely to be coincidental but may represent one nosological entity. This myoclonus epilepsy syndrome associated with ragged-red fibres is compared with other possibly related mitochondrial encephalomyopathies.

Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein

Early‐onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is an autosomal recessive neurodegenerative disorder characterized by early‐onset ataxia, ocular motor apraxia, and hypoalbuminemia. Recently, the causative gene for EAOH, APTX, has been identified. Of the two splicing variants of APTX mRNA, the short and the long forms, long‐form APTX mRNA was found to be the major isoform. Aprataxin is mainly located in the nucleus, and, furthermore, the first nuclear localization signal located near the amino terminus of the long‐form aprataxin is essential for its nuclear localization. We found, based on the yeast two‐hybrid and coimmunoprecipitation experiments, that the long‐form but not the short‐form aprataxin interacts with XRCC1 (x‐ray repair cross‐complementing group 1). Interestingly the amino terminus of the long‐form aprataxin is homologous with polynucleotidekinase‐3′‐phosphatase, which has been demonstrated to be involved in base excision repair, a subtype of single‐strand DNA break repair, through interaction with XRCC1, DNA polymerase β, and DNA ligase III. These results strongly support the possibility that aprataxin and XRCC1 constitute a multiprotein complex and are involved in single‐strand DNA break repair, and furthermore, that accumulation of unrepaired damaged DNA underlies the pathophysiological mechanisms of EAOH.

Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases

Point mutations in mitochondrial (mt) tRNA genes are associated with a variety of human mitochondrial diseases. We have shown previously that mt tRNALeu(UUR) with a MELAS A3243G mutation and mt tRNALys with a MERRF A8344G mutation derived from HeLa background cybrid cells are deficient in normal taurine‐containing modifications [τm5(s2)U; 5‐taurinomethyl‐(2‐thio)uridine] at the anticodon wobble position in both cases. The wobble modification deficiency results in defective translation. We report here wobble modification deficiencies of mutant mt tRNAs from cybrid cells with different nuclear backgrounds, as well as from patient tissues. These findings demonstrate the generality of the wobble modification deficiency in mutant tRNAs in MELAS and MERRF.

Human Cerebellar Activation in Relation to Saccadic Eye Movements: A Functional Magnetic Resonance Imaging Study

Purpose: The functional organization of the human cerebellum involved in saccadic eye movements was investigated using functional magnetic resonance imaging (fMRI). Methods: The subjects were 7 normal volunteers aged 18–34 years. Visual stimuli were back-projected onto a screen placed at the subjects’ feet. The stimulation period of 30 s consisted of a saccade target jumping back and forth horizontally by 20° once per second. The control period of 30 s consisted of a fixed target. The stimulation and control periods were alternated 10 times during the presentation. Functional images were collected with a 1.5-tesla clinical MRI scanner. The significance of activation was determined by Statistical Parametric Mapping (SPM 99) at a threshold of p < 0.001 (uncorrected), and significantly activated areas were superimposed on the T1-weighted images. Results: Significantly activated areas related to visually guided saccades were observed in the cerebellar vermis (declive and folium), in the bilateral cerebellar hemispheres (mainly the superior semilunar lobule) of the cerebellum, in the frontal eye field, in the supplementary eye field and in parts of the parietal lobule of the cerebrum. Conclusion: Our results suggest that the cerebellar posterior vermis and bilateral hemispheres are related to saccades in humans. These results are consistent with neurophysiological data obtained in primates.

A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood and sparing of the quadricep muscles. The UDP‐N‐acetylglucosamine‐2‐epimerase/N‐acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM). To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees.

Fabry's disease on the mechanism of the peripheral nerve involvement.

SummaryA sural nerve biopsy of a patient with Fabrys disease showed depletion of larger myelinated fibres, but smaller myelinated and unmyelinated fibres were intact. Epineurial and to a lesser degree endoneurial vessels revealed abundant lamellar inclusions in the endothelial and perithelial cells. Larger myelinated nerve fibres contained glycogen granules in the vacuoles caused by splitting of the adaxonal membranes. A skin biopsy revealed abundant inclusions in the secretory cells and myoepithelial cells of the sweat glands. The lumen of the gland was packed with inclusions like those in the vessel walls. The pain and anhydrosis might be caused by accumulation of glycolipid in the vasa nervorum and sweat glands and not by autonomic nerve involvement.

Hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA): a new disease

Seven patients with hereditary motor and sensory neuropathy associated with cerebellar atrophy (HMSNCA) are presented. This is the first comprehensive evaluation of what is a unique disorder, half way between the cerebellar atrophies and the hereditary motor and sensory neuropathies. In addition to cerebellar ataxia and peripheral neuropathy, the most frequent features in HMSNCA were nystagmus, dysarthria, mental impairment and tremor. Pyramidal signs or autonomic nerve dysfunction was never revealed. Scoliosis or kyphoscoliosis was not noted. Progression of the disorder was very slow, most of the patients being ambulatory more than 10 years after the onset. Most of the patients had hypoalbuminemia. Half-life periods of serum albumin were normal and decreased synthesis of albumin in the liver was suspected. An autosomal recessive inheritance was strongly suggested, because of healthy consanguineous parents and affected siblings in these families. The segregation ratio was 0.32 +/- 0.10 and was close to the expected ratio of 0.25 in an autosomal recessive inheritance.

Adrenoleukodystrophy: a clinical variant presenting as olivopontocerebellar atrophy.

SummaryA case of adrenoleukodystrophy showing neurological features of olivopontocerebellar atrophy is described. A CT scan demonstrated marked atrophy in both cerebellum and pons. ACTH stimulation produced no rise in the plasma cortisol level but a significant rise in the plasma aldosterone level. The ratios of C26:0 to C22:0 in fatty acids of sphingomyelin from erythrocyte membrane and plasma were increased.

Nemaline myopathy: Histological, histochemical and ultrastructural studies

SummaryHistological, histochemical and ultrastructural studies were performed on muscle biopsies from three siblings with congenital nemaline myopathy. Histological studies revealed type I fibre atrophy and type II fibre paucity. Ultrastructural studies of intramuscular nerves showed that the axonal diameters were very narrow compared with the width of myelin lamellae. Granular or membranous osmiophilic material occurred in the adaxonal Schwann cell cytoplasm and had a periodicity of 33–38Å. The neuromuscular junctions showed degenerative features such as glycogen granules or myelin figures in 27.1% of total terminal axons. The secondary synaptic clefts were markedly decreased in number and short in length. Myotendinous junction-like structures were found in 5.5% of the muscle fibres near the neuromuscular junctions, and often near sites of fibre-splitting. Rods in nemaline myopathy might be caused as a result of longitudinal splitting and disruption of fibres due to deficient regeneration of the muscle fibres associated with neurotrophic abnormalities.

Core/targetoid fibres and multiple cytoplasmic bodies in organophosphate neuropathy.

SummaryFrom correlated histochemical and ultrastructural investigations of biopsy specimens of a rare case with delayed-onset neuropathy due to organophosphate (Dipterex) intoxication, several pathological characteristics were recognized in the muscle fibres. Most striking was a concurrence of core/targetoids and multiple cytoplasmic bodies in the same fibres. Foci of markedly reduced or absent oxidative enzyme activity were revealed in 71.6% of type I fibres and in 3.4% of type II fibres. Most of those foci were two-zoned core/targetoids. Cytoplasmic bodies were also revealed selectively in type I fibres contrary to the previous reports. Targets, targetoids, cores and multicores were suggested to be strongly related to each other pathogenetically and to be due to the disturbance of some neurotrophic influences. In the biopsy specimen taken 220 days after exposure to the drug, numerous sarcoplasmic masses were revealed, and they were very likely to represent special forms of regeneration.