Keiichi Nakahara

Therapeutic trials in 200 patients with HTLV-Iassociated myelopathy/tropical spastic paraparesis

We report here the results of therapeutic trials in 200 patients with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) conducted in our department between 1986 and 1993. Motor disability grades were improved by more than one grade in 69.5% (91/131) of patients by oral administration of prednisolone, 50% (3/6) by eperisone hydrochloride only, 43.8% (7/16) by blood purification (lymphocytapheresis and plasmapheresis), 40.0% (2/5) by intrathecal injection of hydrocortisone, 30.0% (3/10) by intravenous injection of high-dose methylprednisolone, 23.3% (10/43) by interferon-alpha (intramuscular injection and inhalation), 22.2% (2/9) by azathioprine, 20.0% (4/20) by high-dose vitamin C, 16.0% (4/25) by erythromycin, 12.5% (3/24) by salazosulfapyridine, 11.8% (2/17) by mizoribine, 7.1% (1/14) by fosfomycin, and 6.3% (1/16) by thyrotropin releasing hormone. No critical side effects of these therapies were seen with the exceptions of one patient with adult respiratory distress syndrome due to cytomegalovirus infection and one patient with drug-induced hepatitis/hepatic failure. Selection of these treatments for patients with HAM/ TSP must be considered on the basis of age, sex, disease severity and complications to reduce adverse events and to improve quality of life. Although the results were a synopsis of different treatments given to 200 patients with HAM/ TSP as an open trial, we consider this the first report of a large-scale therapeutic trial in patients with HAM/TSP. The results of this study indicate that immunomodulatory therapies have some beneficial effects in HAM/TSP, and the functions of these agents are related to the pathophysiology of this disease.

Experimental simvastatin-induced myopathy in rabbits

We induced experimental myopathy in rabbits by giving simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. After oral administration of simvastatin (50 mg/kg/day) for 2 weeks, serum CK was elevated in 5 of 7 rabbits; degenerating or necrotic fibers were seen in 3 rabbits. Using electromyography, myotonic discharges were found in the 2 rabbits examined. The combination of myotonic discharges, necrosis and raised serum CK levels suggests that the myopathy was induced by lesions of the muscle surface membrane.

Epidemiology of Progressive Muscular Dystrophy in Okinawa, Japan

We studied the prevalence of various types of progressive muscular dystrophy (PMD) in Okinawa, Japan on December 31, 1989 and the incidence of Duchenne muscular dystrophy (DMD) in 5-year periods from 1957 to 1985. We classified patients with PMD clinically, electrophysiologically, molecular biologically and immunohistochemically with antidystrophin antibody, especially for sporadic cases of DMD, Becker muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LG). The prevalence for all PMD in Okinawa was 7.13 X 10(-5) for DMD, 1.82 X 10(-5) for BMD in the male population, 1.55 X 10(-5) for LG, 1.14 X 10(-5) for congenital muscular dystrophy, 2.03 X 10(-5) for facioscapulohumeral muscular dystrophy (FSH), and 9.13 X 10(-5) for myotonic dystrophy (MD) in the total population. The incidence of DMD in the period 1957-1985 was 15.41 X 10(-5) live-born males (LBM) and 3.21 X 10(-5) LBM for BMD. The incidence has apparently declined in Okinawa since 1975. The prevalence of BMD, FSH and MD was rather high in Okinawa compared with previous reports. Molecular biological techniques for classifying patients were indispensable for the epidemiological study of PMD.

Cardiomyopathy, mental retardation, and autophagic vacuolar myopathy. Abnormal MRI findings in the head.

A 21-year-old man with childhood-onset mental retardation, non-obstructive hypertrophic cardiomyopathy, and vacuolar myopathy is presented. A histopathological study of biopsied skeletal muscle showed lysosomal glycogen storage mimicking acid maltase deficiency, but biochemical analysis showed normal acid alpha-glucosidase activity. Glycogenosomes were also recognized in endothelial cells on electronmicroscopic examination of biopsied skeletal muscle. Magnetic resonance imaging (MRI) findings in the head revealed the involvement of the central nervous system. This is a new type of lysosomal glycogen storage disease with multisystemic involvement. The specific biochemical defect in this disorder remains to be elucidated.

Experimental germanium myopathy

SummaryThe long-term administration of germanium dioxide (GeO2) to rats produced Ge myopathy characterized by the formation of ragged-red fibers. The earliest pathological changes in experimental Ge myopathy were a decrease in cytochrome c oxidase activity and accumulation of high electron-dense materials in mitochondria. These findings suggest that a mitochondrial dysfunction may be most important in the genesis of experimental Ge myopathy, which could be a useful animal model for the investigation of and therapeutic trials for human mitochondrial myopathies.

Clinical features of the localized girdle sensation of mid-trunk (false localizing sign) appeared in cervical compressive myelopathy patients

Cervical compressive myelopathy patients sometimes show localized girdle sensation in the mid trunk (so-called false localizing sign). This symptom often confuses physicians, but the clinical features and mechanism of this symptom are still unclear. We investigated the clinical features and possible mechanism. In each of five cases of cervical compressive myelopathy disease with and without mid-truncal girdle sensation, the clinical features, degree and shape of cord compression were analysed. The girdle sensation was expressed as a vague or burning sensation, and was localized with a width of 3 or 4 dermatomes from the T3 to T11 level. There was no correlation between the appearance of the girdle sensation and etiology and level of cervical cord compression. Pyramidal tract signs and disturbance of superficial sensation were observed in all cases. Furthermore, on axial MRI, the midline ventral surface of the cervical cord was remarkably compressed in cases with girdle sensation, as if the compressive lesion entered the anterior medial fissure of the cervical cord. From these findings, this false localizing sign may be caused by severe compression of midline ventral structure of the cervical cord. Ischemia of the thoracic watershed zone of the anterior spinal artery from the compression of the anterior spinal artery at the cervical level might also be considered to be a possible cause.

Three cases of juvenile onset HTLV-I-associated myelopathy with pseudohypoparathyroidism

Among 201 patients diagnosed with HAM/TSP at Kagoshima University, 21 juvenile onset patients had manifested clinical signs and symptoms at less than 15 years of age. They appeared to have common characteristics such as short stature and slight mental retardation. These signs prompted us to investigate five of them endocrinologically; and three patients with pseudohypoparathyroidism (PHP) were confirmed. Serum calcium levels were low, and human parathyroid hormone (PTH) infusion (Ellsworth-Howard test) caused low response in urinary cyclic AMP and phosphorus excretion. The first case had IgA nephropathy, which is generally associated with infectious diseases, while the second case had muscular lymphocytic infiltration. The mothers of cases 1 and 2, who were both seropositive for HTLV-I, were suspected to have abnormal calcium metabolism based on Ellsworth-Howard test. A brother of case 1 and two sisters of case 3 had also HAM/TSP and short stature. The early clinical onset of HAM/TSP may be due to PTH receptor anomaly and a low level of 1,25-dihydroxyvitamin D, which is deficient in PHP and is involved in the regulation of the immune response. The association with IgA nephropathy or myositis may result from progressive HTLV-I infection.

Blood Dolichols in a Patient with Abetalipoproteinaemia

Dolichol and dolichyl derivatives have an important function as glycosyl carriers in the assembly of the N-asparaginyllinked oligosaccharide core region of glycoproteins. Dolichols are synthesized through the cholesterol biosynthesis pathway in all mammalian organs and are present in all tissues, and are also associated with lipoproteins in the blood circulation. However, the origin and metabolic pathway of blood dolichols remain unknown. Abetalipoproteinaemia is a disorder of the secretion of very low-density lipoprotein (VLDL) from the liver and of chylomicrons from the intestine into the blood circulation. Therefore, examination of blood dolichols in this disorder may provide valuable information on their origin and metabolic pathway. Dolichols were exclusively associated with the high-density lipoprotein (HDL) fraction (80·7±6·3% of total dolichols) in control human blood. Serum from a patient also contained dolichols in the HDL fraction (82·8% of total dolichols). The total amount of dolichols was higher in the patient (207·0 ng/mL) than in the controls (106·2±22·7 ng/mL, n = 14). The compositions of dolichols were very similar to each other. These results indicated that, at least in the patient with abetalipoproteinaemia, the HDL-associated dolichols were possibly derived from the liver not through other lipoproteins but through dolichol transfer protein, or were possibly taken up and carried by HDL from peripheral tissues.

Suppression of lymphocyte spontaneous proliferative response by proteolipid protein peptide in patients with HAM/TSP

To understand the immune mechanism suggested in HTLV-I-associated myelopathy (HAM/TSP), we investigated T cell response to proteolipid protein (PLP). Because of high autologous proliferative response (APR) of peripheral blood mononuclear cells (PBMC) in culture, the lymphocyte proliferation assay was not useful in this disease. Unexpectedly, however, APR was profoundly (70–98%) suppressed in 6 of 9 cases when PLP peptide 105-124 was added in the culture. PLP peptide 85-104 or 145-159 also suppressed APR in a few cases. Time course study showed that the peptide-mediated suppression became apparent after day 4 in culture. The results can be interpreted as that suppressor cells recognizing the PLP peptides were present in the PBMC of HAM/TSP patients and suppressed the APR as the consequence of antigen specific response. This may indicate that a T cell response to certain PLP determinants is involved in the pathomechanism of HAM/TSP at least in part. Molecular mimicry between PLP and HTLV-I mayaccount for the T cell sensitization to PLP in HAM/TSP.

New mutation of gap junction protein beta1 (GJB1) gene in X-linked hereditary motor and sensory neuropathy.

Dear Editor, Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy (HMSN) comprises hereditary disorders of the peripheral nervous system with autosomal or X-linked inheritance. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein b1 (GJB1), the gene encoding connexin 32 (Cx32) (Bergoffen et al., 1993). Cx32 has been localized in non-compact peripheral myelin, probably forming gap junctions between adjacent myelin wraps of the same Schwann cells (Scherer et al., 1995). Because the first mutations were reported in 1993, over 200 different mutations in GJB1 associated with CMTX have been identified. These include missense, frameshift, deletion, and non-sense mutations. In this letter, we report a novel 10 base pair (bp) deletion in the GJB1 gene in a patient with CMTX. A 52-year-old man presented with a 10-year history of progressive gait disturbance due to leg muscle weakness. Since the age of 46, he noticed muscle weakness in upper limbs and finger tremor. The patient’s maternal nephew had similar symptoms. Neurological examinations in the patient revealed normal intelligence. Cranial nerves were intact. Manual muscle strength test revealed distal dominant muscle weakness in the extremities. Postural finger tremor was prominent in the upper limbs. He had pes cavus, atrophy of distal leg muscles, and intrinsic hand muscles. Co-ordination was moderately unskillful. Deep tendon reflexes were absent in all extremities. In the sensory system, vibration was severely disturbed in the lower extremities. Gait was characterized by steppage. Romberg sign was present. Motor nerve conduction study revealed diffuse slowing of motor nerve conduction velocity (MCV) with low-amplitude compound muscle action potentials (CMAPs) (median nerve, MCV 32 m/s, CMAP 3.0 mV, F-wave latency 43.5 ms; tibial nerve, MCV 29 m/ s, CMAP 3.7 mV, F-wave latency 70.0 ms). Sensory nerve action potentials (SNAPs) were decreased, and sensory nerve conduction velocity (SCV) was delayed in all nerves tested (median nerve, SCV 37.8 ms, SNAP 1.8 mV; sural nerve, SCV 34 m/s, SNAP 4.7 mV). Sural nerve biopsy was performed with the patient’s consent. The densities of large and small myelinated fibers were moderately decreased (5,243/mm) (Fig. 1A). The majority of fibers had relatively thin myelin, and many myelinated fibers were aggregated in clusters. Several fibers had excessive myelin folding. In teased fiber analysis, the frequency of fibers with paranodal demyelination was 4%, the frequency of fibers with segmental demyelination with variable myelin thickness between internodes more than 50%, demyelination, and remyelination was 28%, the frequency of axonal degeneration was 4%, and the frequency of fibers with focal myelin thickenings was 8%. Informed consent for conducting GJB1 gene analysis was obtained from the patient. Direct testing for GJB1 sequence was performed by PCR amplification and automated sequencing of both genomic strands which code for the entire mature protein. Sequencing demonstrated a heterozygous 10-bp deletion frameshifting mutation 8 nucleotide position (466–475) (Fig. 1B), which is predicted to result in alteration and truncation of the Cx32 protein structure. This is the report of a patient with CMTX having a new truncating frameshift mutation of GJB1 gene. The clinical features of the present case are consistent with mild form of CMTX (Ionasescu et al., 1996). Sural nerve pathology in the present case showed the following features: (1) prominent clusters of thinly myelinated fibers; (2) frequent alterations of paranodal myelin; and (3) abnormalities of adaxonal and innermost Schwann cell cytoplasm. These changes were previously described in CMTX (Vital et al., 2001). Taken together, this new mutation of GJB1 gene may be the cause of neuropathy in the present case. Address correspondence to: Dr Fujio Umehara, The Department of Neurology and Geriatrics, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, Japan. Tel: þ81-99-275-5332; Fax: þ81-99-265-7164; E-mail: umehara@ m2.kufm.kagoshima-u.ac.jp Journal of the Peripheral Nervous System 11:96–97 (2006)