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.

TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3.

Previously, we have shown that TAL1 and the LIM-only protein gene (LMO) are regularly coactivated in T-cell acute lymphoblastic leukemia (T-ALL). This observation is likely to relate to the findings that TAL1 and LMO are highly synergistic in T-cell tumorigenesis in double-transgenic mice. To understand the molecular mechanisms of functional synergy between TAL1 and LMO in tumorigenesis and transcriptional regulation, we tried to identify downstream target genes regulated by TAL1 and LMO by a subtractive PCR method. One of the isolated genes, that for retinaldehyde dehydrogenase 2 (RALDH2), was regularly expressed in most of the T-ALL cell lines that coexpressed TAL1 and LMO. Exogenously transfected TAL1 and LMO, but not either alone, induced RALDH2 expression in a T-ALL cell line, HPB-ALL, not expressing endogeneous TAL1 or LMO. The RALDH2 transcripts in T-ALL were, however, mostly initiated within the second intron. Promoter analysis revealed that a GATA site in a cryptic promoter in the second intron was essential and sufficient for the TAL1- and LMO-dependent transcriptional activation, and GATA3 binds to this site. In addition, forced expression of GATA3 potentiated the induction of RALDH2 by TAL1 and LMO, and these three factors formed a complex in vivo. Furthermore, a TAL1 mutant not binding to DNA also activated the transcription of RALDH2 in the presence of LMO and GATA3. Collectively, we have identified the RALDH2 gene as a first example of direct transcriptional target genes regulated by TAL1 and LMO in T-ALL. In this case, TAL1 and LMO act as cofactors for GATA3 to activate the transcription of RALDH2.

Distal myopathy: histochemical and ultrastructural studies.

In three familial cases and one sporadic case of late-onset distal myopathy, muscle wasting started in the distal portions of the lower extremities. The most striking change seen by light microscopy was the appearance of rimmed vacuoles. These were presumed to be autophagic, because they were found by electron microscopy to contain membranous lamellar structures and other heterogenous materials enclosed by a limiting membrane. On the other hand, lysosomal activity was markedly increased in skeletal muscle. In 6% to 22% of affected muscle fibers there were acid phosphatase-positive granules deep in the sarcoplasm, whereas control muscles had no such granules. The degenerative process in distal myopathy may be different from that in other muscular dystrophies.

A patient with dementia with Lewy bodies and codon 232 mutation of PRNP.

The authors describe a patient who had a point mutation at codon 232 of the prion protein gene, resulting in the substitution of methionine for arginine (M232R). The patient developed dementia and died 6 years after its onset. Autopsy revealed dementia with Lewy bodies, not Creutzfeldt-Jakob disease. Although the M232R mutation has been reported to cause Creutzfeldt-Jakob disease, findings in our patient suggest that not all patients presenting progressive dementia with M232R mutation have Creutzfeldt-Jakob disease.

A Creutzfeldt-Jakob disease agent (Echigo-1 strain) recovered from brain tissue showing the 'panencephalopathic type' disease.

We used histologic evidence of degenerative changes in both the gray and white matter of the brain to diagnose a patient as having the panencephalopathic type of Creutzfeldt-Jakob disease (CJD). This type of CJD is relatively common in Japan, but not in North America or Europe. We recovered a transmissible pathogen (Echigo-1 strain) from an autopsy specimen of the patient's brain and passed it serially in Hartley guinea pigs. After a long latent period, it caused degenerative changes, mainly in the thalamic area of the guinea pig brain. On the 4th passage, a substrain emerged with a short latent period. When cross-transmitted to Golden Syrian hamsters, this substrain induced severe degeneration in both the thalamus and cerebral cortex. We compare our results with those for other experimental CJDs produced by other types of this disease.

Uniform tissue distribution of tRNA(Lys) mutation in mitochondrial DNA in MERRF patients.

We documented the presence of a point mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA) in various postmortem tissues from two patients with myoclonus epilepsy associated with ragged-red fibers (MERRF). The percentages of the mutant mtDNA were similar (93 to 99%) in both clinically affected and unaffected tissues, suggesting that preferential clinical involvement of certain tissues in MERRF is based not only on the variation of distribution of the mutant mtDNA, but also on other factors such as differences in the threshold in various CNS regions and organs.

Adrenoleukodystrophy: a clinical variant presenting as olivopontocerebellar atrophy.

A 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.

Regulation of the development of allodynia by intrathecally administered P2 purinoceptor agonists and antagonists in mice.

Effects of agonists and antagonists of P2X-purinoceptors on the regulation of the development of allodynia were examined in mice; the drugs were administered intrathecally to the spinal cord. Suramin (5, 10 microg) and pyridoxalphosphate-6-azophenyl-2', 4'-disulfonic acid (PPADS), antagonists of P2X receptors, inhibited prostaglandin (PG) E(2)-induced allodynia. PPADS did not block glutamate-induced allodynia. alpha,beta-Methylene ATP (alpha, beta-meATP), an agonist of P2X receptor, elicited allodynia. alpha, beta-me ATP-induced allodynia was blocked by co-administration of alpha,beta-meATP with PPADS, MK 801 or N(omega)-nitro-L-arginine methyl ester (L-NAME). Suramin at higher doses (20, 40 microg) induced allodynia, which was inhibited by MK 801 or L-NAME. These results suggest that ATP P2X receptors in the spinal cord are involved in the regulation of tactile allodynia. Glutamate receptor and nitric oxide systems play an important role in the development of allodynia produced by alpha,beta-meATP and suramin.

A new myopathy with tubulomembranous inclusions.

A muscle biopsy performed on a 16-year-old boy with progressive myopathy revealed hitherto unrecognized peculiar inclusions which consisted of 3 types of structures. The first type consisted of laminated tubulomembranous structures and most of the inclusions belonged to this type. The lamellae were regularly spaced with a periodicity of 8.5--9 nm and curving a little, and were observed as concentric lamellae according to the plane of sectioning. The second type of inclusions consisted of curvifilamentous material. The third type had the appearance of moderately electron-dense granular material surrounded by a single unit membrane. The origin and nature of these inclusions is obscure, but the diagnosis of some kind of storage myopathy was suspected in this case.

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 Friedreich's 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 Friedreich's 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.

Quantitative study of intermediolateral column cell counts in Machado-Joseph disease.

The number of intermediolateral column (ILC) neurons in 6 alternating segments from the 2nd to 12th thoracic segment of the spinal cord were studied in 4 cases with Machado-Joseph disease (MJD), 3 cases with olivopontocerebellar atrophy (OPCA), a case with Shy-Drager syndrome (SDS), and 5 normal controls. We counted the number of ILC neurons with clearly defined nucleoli in 12 sections of each segment, each section 20 microns thick and taken at 100 microns intervals and then divided the 6 alternating segments into 3 groups, upper (Th2, 4), middle (Th6, 8) and lower (Th10, 12). In each of the three groups of normal control cases, the number of ILC neurons had decreased with aging. In all MJD cases, the number of ILC neurons had moderately decreased in comparison with age-matched controls. One of the MJD cases showed a marked decrease in the number of ILC neurons, as did the SDS case. The ILCs of the entire thoracic spinal cord in the MJD cases were moderately involved.

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.

An autopsy case of mitochondrial encephalomyopathy: biochemical and electron microscopic studies of the brain.

A 29-year-old single woman had recurrent stroke-like episodes. She developed loss of consciousness, myoclonic seizures, and lactic acidosis. She died at the age of 30. A muscle biopsy study revealed mitochondrial myopathy, and the postmortem biochemical analysis demonstrated decreased cytochrome c oxidase activity in the skeletal muscles by 20% of normal control. The brain had multiple ischemic lesions in the cerebral cortex without major vascular occlusions. We present this case as an autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with a partial deficiency of cytochrome c oxidase. The analytical electron microscopic study of the calcified small vessels in the globus pallidus revealed increased calcium, phosphorus and iron. No accumulation of chromium, nickel or zinc was noted in this case, which was different from the previously reported cases of basal ganglia calcification.

Neurological complications of the ring (22) syndrome: a case report.

The first Japanese case of the ring (22) syndrome was described. The patient had diffuse neurological involvement of the central, peripheral nerves and muscles in addition to the phenotypical characteristics of this syndrome.

A family with adult type ceroid lipofuscinosis (Kufs' disease) and heart muscle disease: report of two autopsy cases.

Two cases in a family with Kufs' disease had lethal arrhythmias and heart muscle disease. Autopsy findings showed an abundant accumulation of lipofuscin-like lipopigments in most neurons in the central nervous system (CNS). The heart showed a slight increase in the accumulation of the lipofuscin-like lipopigments in the myocardial fibers, slight to severe fibrosis and infiltration of fat cells in the myocardium. The lipopigments both in the heart and in neurons of the CNS had curvilinear profiles on electron microscope and reacted immunohistochemically to polyclonal antibodies against subunit c of mitochondrial adenosine triphosphate (ATP) synthase. The degenerative process in this heart muscle disease might be attributable to the same metabolic abnormality as seen in the neuronal degeneration associated with Kufs' disease.

Thymic carcinoma associated with pinealoma and terminating with peroxidase-negative acute myeloid leukemia.

Thymoma is associated with a wide variety of syndromes. However, an association with peroxidase-negative acute myeloid leukemia and pinealoma, although feasible due to the marked influence of this tumor on the lymphoid system, has not been described previously. A patient with thymic carcinoma and pinealoma who developed peroxidase-negative acute myeloid leukemia as a late event is presented in this report.

Clinical experiences of stenting in patients with esophago-bronchial fistula: report of four cases.

The esophagorespiratory fistula is difficult to treat, and the patients' quality of life is generally poor due to suffering from dysphagia and dyspnea. We performed stent therapy in four cases of the esophagorespiratory fistula associated with esophageal cancer. Three of four patients showed improved symptoms, enabling oral liquid or food intake, although one died of dyspnea despite the therapy. The findings suggest that stent therapy is an effective method to close the esophagorespiratory fistula and to improve the patients' quality of life, although it is temporary and not a radical treatment.

Survival of mice and hematopoietic stem cells in bone marrow after intermittent total body irradiation.

As a preparative procedure for bone marrow transplantation, intermittent total body irradiation (TBI) has been used in our hospital. The biological significance of this method, in which the instantaneous dose rate is high but the average dose rate is low, has not been evaluated to date. The hematopoietic responses caused by both intermittent and continuous TBI were compared. In the intermittent irradiation, mice in a moving irradiation chamber were exposed under a small field (2 X 35 cm2), and the instantaneous and average dose rates were 1 Gy/min and 0.25-0.12 Gy/min, respectively. The average dose rate was adjusted to the same level in both irradiation methods. LD50/30 and survival of colony-forming units (CFU) in culture and survival of endogenous CFU in the spleen from female BDF1 mice were the same with the two methods. These results show that the response of hematopoietic stem cells depends on the average dose rate, not on the instantaneous dose rate. Our findings suggest that intermittent irradiation, as well as the continuous method, would be useful for preparing patients before bone marrow transplantation.

MERRF: a clinicopathological study. Relationships between myoclonus epilepsies and mitochondrial myopathies.

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a degenerative disease involving dentate nuclei of the cerebellum, globus pallidus, the posterior columns and spinocerebellar tracts of the spinal cord, and skeletal muscles. Abnormal mitochondria were observed in the cells of the cerebellar cortex and of the dentate nuclei. The main symptoms of this disease include cerebellar ataxia and myoclonus in addition to muscular wasting. Patients with MELAS occasionally have myoclonus, but they never have myoclonus as their initial symptoms. Most of the patients with both clinical features of MERRF and MELAS were regarded as belonging to the category of MELAS.

[A case report of psittacosis and chlamydial isolation from a patient].

A 48-year-old female was seen at our hospital after having a severe fever of nearly 40 degrees C, for a period of 9 days. She complained of pain in the left side of her chest. An X-ray examination revealed a slight infiltration of the upper and middle lung fields. At this time, it was learned that the women's pet bird had recently died. This case was diagnosed as acute pneumonia due to psittacosis. Therefore the administration of Roxithromycin was started. After a few day her condition improved. During the course of treatment, serum was taken and a throat swab was done. A micro-immunofluorescence (MIF) test was performed to check the serum antibody levels against Chlamydia psittaci. The serum titer rose from 1:8 to 1:256 in 15 days after admission. The final diagnosis was made after positive isolation of C. psittaci by means of the cell culture method.