Fuminobu Sugai

Benefit of valproic acid in suppressing disease progression of ALS model mice.

Valproic acid (VPA) has long been used as an antiepileptic drug and recently as a mood stabilizer, and evidence is increasing that VPA exerts neuroprotective effects through changes in a variety of intracellular signalling pathways including upregulation of Bcl‐2 protein with an antiapoptotic property and inhibiting glycogen synthase kinase 3‐β, which is considered to promote cell survival. Although the neuroprotective effects of VPA have been demonstrated in a murine model of human immunodeficiency virus‐1 encephalitis, there have been no reports on the effect of VPA in chronic progressing neurodegenerative disease models including amyotrophic lateral sclerosis (ALS). ALS is a devastating disease selectively affecting motoneurons, and its disease model mice bear a close resemblance to ALS symptomatically and pathologically. First, we used an organotypic slice culture using mouse spinal cord, and showed that VPA protected spinal motoneurons against death from glutamate toxicity in vitro. Then, we treated ALS model mice with VPA at the dose effective level for epileptic model mice after 45 days of age (pre‐onset treatment) or the day of the disease onset (post‐onset treatment). We found a significant prolongation of the disease duration in ALS model mice in both methods of treatment. Considering the long usage of VPA for epileptic patients with good tolerance and safety, these data strongly support the clinical application of VPA for ALS treatment.

Rapid disease progression correlates with instability of mutant SOD1 in familial ALS.

Studies on the clinical course of familial ALS suggest that the duration of illness is relatively consistent for each mutation but variable among the different mutations. The authors analyzed the relative amount of mutant compared with normal SOD1 protein in the erythrocytes from 29 patients with ALS with 22 different mutations. Turnover of mutant SOD1 correlated with a shorter disease survival time.

The "pulvinar sign" in a case of paraneoplastic limbic encephalitis associated with non-Hodgkin's lymphoma.

This paper reports a 59 year old woman with paraneoplastic limbic encephalitis associated with diffuse large B cell lymphoma. Her brain magnetic resonance imaging scan showed bilateral posterior thalamic hyperintensities, similar to the “pulvinar sign”. Her symptoms included progressive psychiatric disturbance and resembled the initial symptoms of variant Creutzfeldt–Jakob disease (vCJD). Clinicians should consider this treatable disorder in the differential diagnosis of vCJD.

HTLV-I-associated myelopathy manifested after renal transplantation

We report a patient with HTLV-I-associated myelopathy (HAM), who developed symptoms of myelopathy 4 years after cadaveric renal transplantation. Since he was seronegative before the transplantation, it is suggested that HTLV-I infection was transmitted via renal graft transplantation. He has been treated with immunosuppressive agents such as cyclosporin A (CsA), mycophenolate mofetil (MMF), and prednisolone (PSL) to prevent graft rejection. This case suggested that these immunosuppressive agents are poorly effective in suppressing either the onset or progression of HAM/TSP.

Identification of two novel mutations in the Cu/Zn superoxide dismutase gene with familial amyotrophic lateral sclerosis: mass spectrometric and genomic analyses.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of patients are sporadic cases, while 5-10% of the patients have a family history of ALS (fALS). Mutations in the gene that encodes cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 25% of fALS cases. Although the precise pathogenesis of ALS is still unknown, experimental studies including animal models suggest that fALS is caused by the toxic gain-of-function of the SOD1 mutant. We have analyzed not only SOD1 gene mutation by genomic sequencing, but also SOD1 mutant protein by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). We analyzed 33 fALS patients and found 10 mutations in SOD1 gene, in which two were novel: Asp101His substitution in exon 4 and Gly141Glu substitution in exon 5. Here, we present their mass spectrometric protein analyses and clinical features.

Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase.

We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content.

Difficulty identifying spinocerebellar ataxia 17 from preceding psychiatric symptoms

SPINOCEREBELLAR ATAXIA (SCA) with preceding psychiatric symptoms has only ever been reported for SCA17. SCA17, a rare autosomal dominant disorder, is characterized by various neurological symptoms and/or psychiatric symptoms. SCA17 with psychiatric symptoms is often diagnosed as a variety of psychiatric disorders such as schizophrenia and bipolar disorder before the onset of neurological symptoms. SCA17 is a polyglutamine disease caused by expanded CAG/CAA repeats in the TATA boxbinding protein (TBP) gene. Here, we report two rare cases of undefined hereditary SCA other than SCA17 with preceding psychiatric symptoms. A 65-year-old man had presented with hypomanic and depressive episodes on more than 10 occasions since the age of 18. He was diagnosed with bipolar disorder at the age of 45. The patient noticed progressive unsteadiness of gait from 58 years of age, with double vision and difficulties in fastening a button. A 54-year-old man had exhibited social withdrawal since he was in high school. He complained of cenesthopathy and persecutory delusion since his 30s, and was diagnosed with schizophrenia. He complained of feeling vertigo since 47 years of age, and subsequently reported further symptoms, such as double vision, gait disturbance, dysphagia and slurred speech. There were past histories of paralytic ileus and aspiration pneumonia at 53 years of age. He had autonomic symptoms, such as mild orthostatic hypotension and severe constipation. Both patients had limb and gait ataxia, intention tremor, saccades during slow pursuit, gaze nystagmus and convergent disturbance, and had mild rigidity only in the former patient. They had no other neurological symptoms. They had several biological relatives with SCA. The latter had relatives with progressive muscular dystrophy and schizophrenia. Brain magnetic resonance imaging indicated atrophy of the cerebellum (hemisphere and vermis) in both cases; additionally lower pons in the latter case. They were diagnosed with SCA in their late 50s. Mutation analysis failed to identify any mutations in well-known causative genes reported in Japan for SCA1, SCA2, DRPLA, SCA3 and SCA6 in the former patient. No abnormally expanded triplet repeats were identified in the TBP gene (SCA17) in both patients. Their mental state is relatively stable with medication (patient 1, paroxetine 40 mg/day and taltirelin hydrate 10 mg/day; patient 2, aripiprazole 12 mg/day), while their neurological symptoms and cerebral atrophy are gradually progressing. These patients met the diagnostic criteria for schizophrenia or bipolar disorder from DSM-IV and matched the criteria of SCA from the Japanese Ministry of Health, Labor and Welfare. Informed consent was obtained from both patients. Because the presence of pre-existing psychiatric symptoms was consistent with SCA17, we suspected that these symptoms were referable to SCA17, but SCA17 was excluded in both cases on genetic analysis. SCA is a heterogeneous syndrome with similar clinical phenotypes, such as ataxia and cerebellar atrophy, and is caused by different genetic abnormalities at different chromosomal loci. Some characteristic symptoms are considered to be useful to distinguish several subtypes of SCA. This approach failed to identify the subtype of SCA in the present patients. We suggest that it is difficult to identify SCA17 on the basis of preceding psychiatric symptoms.

A case of central nervous system relapse in acute promyelocytic leukemia.

A 70-year-old woman who have achieved complete remission (CR) of acute promyelocytic leukemia (APL) with all-trans retinoic acid and chemotherapy presented with abnormal sensation in the right lateral thigh and the bilateral legs. In addition, neurological examination revealed weakness of the left shoulder abduction, the right hand, and the bilateral lower limbs. Atypical promyelocytes were detected in the cerebrospinal fluid, in spite of normal finding in the peripheral blood smear. Magnetic resonance imaging showed gadolinium-enhanced multiple intradural/extramedullary lesions in the whole spine. Nerve conduction studies of the right limbs revealed sensorimotor conduction abnormalities, conspicuously in the posterior tibial and sural nerves. As a result, she was diagnosed as having intrathecal relapse of APL, associated with multiple mononeuropathy. The neurological symptoms were completely disappeared by intrathecal chemotherapy and whole-spine radiotherapy, suggesting that the neuropathy was possibly caused by meningeal infiltration affecting multiple spinal nerve roots. Since extramedullary or intrathecal relapse is extremely rare in APL compared with other types of leukemia, precise neurological evaluations and suitable treatment should be performed immediately, when APL patients with CR manifest some neurological symptoms.