Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and lewy body-like hyaline inclusions.

BACKGROUND: Mutations in the SOD1 gene are responsible for approximately 25% of all familial amyotrophic lateral sclerosis (ALS) cases. However, the correlation between the clinical and pathological features and the various SOD1 gene mutations has not been well characterized. OBJECTIVES: To screen the SOD1 gene in search of potential mutations and to obtain clinical and pathological data for 2 Japanese families with ALS. DESIGN: Clinical histories and neurological findings, gross and microscopic pathological features, and DNA analysis of the SOD1 gene. RESULTS: The 2 families with ALS showed a novel missense mutation in the SOD1 gene, which was heterozygous for point mutation TTG to TCG, causing substitution of leucine for serine at codon 126 (Leu126Ser) in exon 5. Clinically, patients showed slower disease progression and lack of upper motor neuron signs. Neuropathologically, the autopsied patient showed the form of familial ALS with posterior column involvement, and the pontocerebellar tract and the dentate nuclei of the cerebellum were also involved. Furthermore, abundant Lewy body-like hyaline inclusions were observed in the affected motor and nonmotor neurons. CONCLUSIONS: Familial ALS with a novel Leu126Ser mutation in the SOD1 gene showed mild clinical features and lack of upper motor neuron signs. We believe that Leu126Ser might be associated with the clinical features and that the mutation site in the SOD1 gene and disease duration might be associated with the formation of Lewy body-like hyaline inclusions.

A case of chronic GM1 gangliosidosis presenting as dystonia: clinical and biochemical studies.

Clinical and biochemical studies are reported on a 32-year-old man with GM1 gangliosidosis who presented with a slowly progressive dystonia that began when he was aged 7 years and eventually became almost totally incapacitating at the age of 35. There was only mild intellectual deterioration, but myoclonus, seizures and macular cherry-red spots were never observed. Proton-density and T2-weighted MRI scans showed symmetrical hyperintense lesions of both putamina. No increase of GM1 ganglioside was found in plasma or cerebrospinal fluid, and the metabolism of GM1 ganglioside in cultured skin fibroblasts from the patient was also almost normal, although the residual activity of GM1 ganglioside beta-galactosidase activity was only 10% of normal. These findings suggest that impaired GM1 ganglioside metabolism is not present systemically as it is in the infantile and juvenile types of the disorder, but is mainly confined to the central nervous system in chronic GM1 gangliosidosis.

Free radicals, lipid peroxides and antioxidants in blood of patients with myotonic dystrophy.

We studied the levels of free radicals, lipid peroxides and antioxidants, as well as superoxide dismutase (SOD) activity in the blood of six patients with myotonic dystrophy (MyD) (mean age 52.8, SD 5.0 years) and seven controls (mean age 48.8, SD 6.3 years). Electron spin resonance was used to assess the free radicals by the spin-trapping method using 5,5-dimethyl-1-pyrroline-1-oxide. The levels of C centre radical (P < 0.05) and H radical (P < 0.05) in blood from the six MyD patients were significantly higher than those in the seven controls. The SOD activities in red blood cells and serum from the six MyD patients showed no significant difference from those in the seven controls. The serum lipid peroxide concentration was increased in five of the MyD patients and tended to increase further as the disease progressed. The serum vitamin E level was low in two patients and in the low normal range in three. Serum coenzyme Q10 was decreased in four patients. The serum selenium level was decreased in two patients and that of serum albumin was decreased in three. Therefore we conclude that increased levels of free radicals and lipid peroxides and decreased antioxidant levels play an important role in the pathogenesis of MyD.

Superoxide dismutase and free radicals in sporadic amyotrophic lateral sclerosis: relationship to clinical data.

We studied the relationships between the superoxide dismutase (SOD) activity, free radical (FR) levels and clinical data in patients with sporadic amyotrophic lateral sclerosis (SALS). The SOD activities and blood FR levels of 16 patients with SALS (mean age 58.6 +/- 10.2 years), 11 with other neurological disease, including myotonic dystrophy (ND, mean age 53.5 +/- 9.1 years), and 15 normal control subjects (mean age 56.2 +/- 7.3 years) were measured. The mean levels of FR in blood from the patients with SALS and ND and the SOD activities in red blood cells (RBC) from those with ND were significantly higher than the corresponding control values. There was a positive correlation between the SOD activities in RBC and blood hydroxyl radical levels in the patients with ND, but neither the patients with SALS nor the controls showed such a correlation. The SALS patients without pyramidal signs showed slow disease progression and their mean RBC SOD activity was significantly higher than the corresponding control value. We compared the FR levels and SOD activities of 8 patients who needed a respirator within 40 months after the onset of SALS (SALS40, mean age 58.7 +/- 9.4 years), 3 who needed a respirator over 100 months after the onset of SALS (SALS100, mean age 58.3 +/- 15.9 years) and the controls. The mean blood FR levels of the SALS40 and SALS100 patients were significantly higher than the corresponding control values. The mean SOD activity in RBC from the SALS100 group was significantly higher than the SALS40 and control group values. Therefore, we concluded that elevated blood FR levels do not induce RBC SOD in SALS patients and that the disease progressed more rapidly in SALS patients with low than high RBS SOD activities.

A family of familial hypercholesterolemia with cerebral infarction and without coronary heart disease. An unusual case with corneal opacity, polyneuropathy and carpal tunnel syndrome in the family: therapy with probucol and tocopherol nicotinate.

A study is presented of a 48-year-old female patient and her three siblings with familial hypercholesterolemia. The family members had episodes of cerebral infarction and apparently had atherosclerosis of the internal carotid artery, but no coronary heart disease due to their almost normal level of cholesterol. The laboratory studies of the family members revealed the elevations of serum lipid peroxides, serum lipoprotein(a), leukotriene C4 in blood, the thromboxane B2/6-keto-prostaglandin F1 alpha ratio in plasma and serum hydroxyl radical. Therefore, it is suspected that these factors accelerating atherosclerotic process caused the cerebral infarction. The patient demonstrated corneal opacities, palpebral xanthomas, thickened Achilles tendons, polyneuropathy and the carpal tunnel syndrome. Laboratory studies revealed an elevation in the OKT4/8 ratio, monocyte dysfunction with respect to phagocytosis and chemotaxis, and the presence of the 46XX/45XO mosaic chromosome. Lipid deposits were observed in the Achilles tendon, the transverse carpal ligament, the Schwann's cells and axons of the sural nerve, and in the keratocytes and stroma of the cornea. Following the administration of tocopherol nicotinate and probucol, the patient's serum lipid peroxide normalized and there was improvement in her palpebral xanthomas, thickening of the Achilles tendons and polyneuropathy. We conclude that the lipid deposits in this patient were due to the abnormal oxidative metabolism of low-density lipoprotein and a disturbance of the scavenger pathway due to the monocyte dysfunction.

Cerebrospinal fluid corticotropin-releasing hormone in neurodegenerative diseases: reduction in spinocerebellar degeneration.

Levels of corticotropin-releasing hormone (CRH) in cerebrospinal fluid (CSF) were examined in patients with spinocerebellar degeneration (SCD) including olivopontocerebellar atrophy (OPCA), dentatorubropallidoluysian atrophy (DRPLA) and Friedreich's ataxia, Parkinson's disease (PD) and senile dementia of the Alzheimer type (SDAT), and normal aged subjects. CRH concentrations in CSF were significantly reduced in SCD compared to SDAT, PD and CSF and normal aged subjects. It is likely that degeneration not only of the cerebral cortex and the limbic system but also of the subcortical structures such as the brainstem and the cerebellum alters levels of CRH in CSF. Together with the recent anatomical and physiological evidence, the results suggest pathophysiological relevance of CRH for the cerebellar symptoms in SCD.

Synthesis of betaine-homocysteine S-methyltransferase is continuously enhanced in fatty livers of thyroidectomized chickens.

We examined thyroidectomized chickens in terms of plasma lipid concentration and protein expression within the liver. Although the body weight of thyroidectomized chickens was remarkably low due to growth retardation, the livers were enlarged and fatty compared to those of sham-operated chickens. An increase in phospholipid, triglyceride, and total cholesterol levels within the blood plasma of thyroidectomized chickens was observed, clearly reflecting increased lipid synthesis within the liver. Overexpression of some proteins, for example, 29- and 45-kDa proteins, was observed in thyroidectomized chicken livers by means of electrophoresis. A peptide map was made for the protein that exhibited the greatest degree of overexpression. One of them demonstrated a molecular mass of 45 kDa and an isoelectric point (pI) between 7.5 and 8.0, depending on its form. Partial N-terminal amino acid sequences were determined from three random peptides of this protein. The amino acid sequence of this protein showed a high degree of homology with the betaine-homocysteine S-methyltransferase (BHMT, EC 2.1.1.5) of some mammalian species. We identified this protein as chicken BHMT because, in addition to its sequence homology with mammalian BHMT, there were similarities were also observed between this 45-kDa protein and mammalian BHMT with respect to molecular mass and isoelectric behavior. In the liver, 10 d after thyroidectomy, the synthesis of hepatic BHMT had already been enhanced, and the high expression was maintained at 50 d of age. Generally, BHMT catalyzes the transfer of a methyl group from betaine to L-homocysteine. In addition, it seems that this enzyme is also closely related to lipid metabolism in the liver; in this study expression of BHMT in the liver corresponded to plasma lipid levels. Moreover, hypothyroidism may be directly or indirectly related to overexpression of BHMT. Due to similarities between the BHMT of chickens and mammalian species, the chicken model might provide a useful means by which to study BHMT, its role in lipid metabolism, and methods of targeting the expression of BHMT. Another 29-kDa protein was unidentified in the homology search.

[Study on purple pigmentation in five cases with purple urine bag syndrome].

We reported five patients with purple urine bag syndrome (PUBS). Four patients had indicanuria, and, in three of them, purple pigmentation was reproduced by inoculating urinary isolates, in the broth with indoxyl sulfate. Klebsiella pneumoniae, Pseudomonas aeruginosa and Enterococcus avium were considered to produce the purple pigment in three patients. However, attempts to reproduce the purple pigment failed in two patients, and one of them did not have indicanuria. These results suggest that indicanuria is not necessarily required for the development of PUBS.

[Flora in the anterior nares of patients in the neurologic ward: the influence of nasogastric intubation and mechanical ventilation].

MRSA has been isolated frequently from patients in the neurologic ward of Minami-Okayama Hospital. We examined the flora in the anterior nares of 37 patients in the neurologic ward and 36 patients in the medical ward. Existence of dysphagia and nasogastric intubation is considered to make a marked difference between nasal flora of neurologic patients and that of medical patients. Patients with nasogastric intubation had higher incidences of colonization with S. aureus, and gram-negative rods. All patients colonized with MRSA had received nasal tube-feeding. Nasogastric intubation is considered to be a significant risk factor for MRSA colonization. The study in patients with nasogastric intubation demonstrated that patients with mechanical ventilation had a significantly higher incidence of colonization with gram-negative rods, such as P. aeruginosa, and a lower incidence of colonization with S. aureus. A incidence of MRSA colonization in patients with mechanical ventilation was significantly low. Mechanical ventilation is not necessarily considered to be a risk factor for MRSA colonization.

[Relation between cerebral white matter damage on CT and MRI and clinical data in DRPLA (pseudo-Huntington form)].

We studied the relation between cerebral white matter damage and clinical data in nine patients with dentatorubropallidoluysian atrophy (DRPLA). All patients showed pseudo-Huntington form. The study produced five results. (1) The four of the nine patients showed diffuse hypodensity of the cerebral white matter on CT. We studied one of this four patients by MRI. The hypodensity area on CT showed marked high signal intensity by T2-weighted image on MRI. (2) The onset age was later in the patients with cerebral white matter damage as compared with the patients without this damage. (3) All patients showed subcortical dementia, which was more remarkable in the patient with white matter damage. This suggests the relation between cerebral white matter damage and progression rate of subcortical dementia in DRPLA. (4) Gait disturbance progressed more rapidly in the patients with cerebral white matter damage. (5) The homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) concentration in CSF decreased more remarkably in the patients with white matter damage.

[Free radical, lipid peroxide and antioxidant in mitochondrial encephalomyopathy].

We studied free radical, lipid peroxide (LPO) and antioxidant levels of blood in three cases with mitochondrial encephalomyopathy. Case 1 was a 17-year-old man with MELAS. Serum vitamin E levels were decreased and LPO levels were increased after stroke-like episodes in case 1. Case 2 was a 68-year-old woman with MELAS and a maternal elder aunt of case 1. She showed an elevated serum LPO levels (6.58 nmol/ml) in the absence of stroke-like episode and serum CoQ10 level was 0.54 microgram/ml before therapy. By CoQ10, idebenone and tocopherol nicotinate therapy, serum LPO levels decreased gradually in parallel with the decrease of lactate and pyruvate levels. Free radicals were measured in case 2 and controls by spin trapping method. Hydroxyl radical and C center radical were increased and H radical was normal in blood. But these free radicals in serum were all normal. Her serum antioxidants revealed an elevated percent inhibition of SOD and a decreased transfferin level. Case 3 was a 52-year-old woman with MERRF. She showed an elevation of serum LPO (12.8 nmol/ml). Her serum antioxidants revealed an elevated vitamin E and ceruloplasmin levels and percent inhibition of SOD.

The influence of long-term treatment with povidone-iodine on thyroid function.

Povidone-iodine (PVP-I) is generally very safe, but cases of thyroid dysfunction induced by PVP-I have been reported. The effect of long-term treatment with PVP-I on thyroid function was to be assessed. In 40 inpatients of the department of neurology, the status of the use of PVP-I preparations and their effects on serum inorganic iodine levels and thyroid functions were investigated. In 27 patients treated with PVP-I for a long term, inorganic iodine levels were significantly increased as compared to those in 13 patients without PVP-I treatment. Out of 27 patients treated with PVP-I in the long term, subclinical hypothroidism was seen in 3 patients, mild hyperthroidism was seen in 1 patient, and subclinical hyperthyroidism was suspected in 7 patients. Patients treated with PVP-I for a long time should be observed carefully for any manifestation of thyroid dysfunction.