Hiroshi Iwashita

Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

A family of McLeod syndrome, masquerading as chorea-acanthocytosis

A man, aged 52, is reported to show (1) adult onset, (2) progressive orofacial dyskinesia and choreic movements of the extremities, (3) tongue biting, (4) denervation of the peripheral nerves, (5) acanthocytosis, and (6) increased serum creatine kinase, which are characteristic of chorea-acanthocytosis. The Kell blood group examination on erythrocytes disclosed that the propositus had McLeod phenotype, and his mother and one of his sisters were carriers of the McLeod phenotype. Thus, he was diagnosed as having McLeod syndrome. A criterion of exclusion of McLeod phenotype on erythrocytes should be added to the diagnostic criteria of chorea-acanthocytosis. Moreover, chronic neurogenic changes instead of myogenic changes were electromyographically and histopathologically verified in the muscle.

Adrenoleukodystrophy Abnormality of very long‐chain fatty acids in erythrocyte membrane phospholipids

Long-chain fatty acids in erythrocyte membrane phospholipids were analyzed in three patients with adrenoleukodystrophy (ALD) and four diseased controls with other neurologic diseases by high performance liquid chromatography (HPLC). HPLC chromatograms showed the increase of a very long-chain fatty acid C26:0 in glycerophospholipids of ALD erythrocyte membranes, which was not so prominent in sphingomyelin. The ratio of C26:0 to C22:0 increased in glycerophospholipids as well as sphingomyelin in ALD. These results suggest that ALD has a generalized abnormal metabolism of very long-chain saturated fatty acids.

Elevated cerebrospinal fluid lactate/pyruvate ratio in Machado‐Joseph disease

To identify the metabolic alterations related to mitochondrial functions in Machado‐Joseph disease (MJD), we analyzed the cerebrospinal fluid (CSF) levels of lactate, pyruvate, and citric acid cycle intermediates by high performance liquid chromatography (HPLC) in 7 Japanese patients with that disease and then measured some mitochondrial enzymes. Their mean age was 46 years. Diseased controls were matched by age to the patients studied. The CSF level of lactate was significantly elevated, pyruvate was significantly decreased, and the lactate/pyruvate (L/P) ratio was significantly elevated in the patients with MJD. There were no significant differences of citric acid cycle intermediates of the CSF between the patients and the controls. We measured the native and dichloroacetate (DCA)‐activated pyruvate dehydrogenase complex (PDHC) activities, and mitochondrial electron transport activities in 3 patients with MJD, and found these activities to be normal. Therefore, the increased CSF lactate, increased lactate/pyruvate ratio, and decreased pyruvate may reflect the decreased regional cerebral blood flow rather than metabolic derangement of the mitochondria.

Clinical studies of multiple sclerosis in Japan

SummaryOf 69 consecutive Japanese patients with probable multiple sclerosis (MS), 34 patients showed visual impairment at the initial bout. 16 out of these 34 patients manifested only the optic symptoms at the onset, without other clinical evidence of MS, and the condition was diagnosed as retrobulbar neuritis (RBN) initially. The clinical pictures of these 16 patients are described and analyzed. This series showed a female preference with the male-to-female ratio of 1 to 4.3. The age at onset was 27 years on the average, which is not significantly different from that of the whole MS series (31 years). The interval from the end of the initial RBN to the second bout ranged from 1 month to 13 years, but was less than 4 years in all cases but 2. The laterality, mode of onset, severity and duration of the initial visual impairment, or the degree of recovery from the initial bout did not seem to influence the subsequent occurrence of other clinical evidences of MS. It is noteworthy that in 11 out of the 16 patients the symptom at the second bout was, or at least also included, visual impairment. Comparison of MS patients, who started with visual impairment as the sole initial symptom, between the Oriental and Western countries is warranted.Zusammenfassung34 von 69 japanischen Patienten mit wahrscheinlicher multipler Sklerose (MS) zeigten Sehstörungen beim ersten Krankheitsschub. Bei 16 dieser 34 Patienten waren die Opticus-Symptome das einzige Symptom. Diese Fälle wurden als retrobulbäre Neuritis (RBN) diagnostiziert. Die klinischen Bilder dieser 16 Patienten wurden geschildert und analysiert. In dieser Serie überwogen weibliche Patienten im Verhältnis 4,3:1. Das Durchschnittsalter betrug bei Krankheitsbeginn 27 Jahre. Das Intervall zwischen dem Ende der ersten RBN zum nächsten Schub reichte von 1 Monat bis zu 13 Jahren. Seite und Art der Erkrankung, Schwere und Dauer der ersten Sehstörungen oder Grad der Besserung scheinen die folgende Entwicklung der anderen klinischen Symptome von MS nicht zu beeinflussen. Es ist bemerkenswert, daß 11 dieser 16 Patienten eine Sehstörung auch während des zweiten Schubes zeigten. Ein Vergleich der MS-Patienten, die eine Sehstörung als einziges Initialsymptom aufweisen, zwischen den östlichen und westlichen Ländern wäre in Zukunft wünschenswert.

Adrenoleukodystrophy: fatty acid analysis of total glycerophospholipids in erythrocyte membranes

ABSTRACT – The saturated fatty acids released from the erythrocyte membranes of four patients with adrenoleukodystrophy (ALD) and 14 diseased controls were analyzed by high performance liquid chromatography. The ratios of C26:0 to other saturated fatty acids in ALD were higher than those of diseased controls, and neither false‐positive nor false‐negative samples were observed. These results suggest that a study of fatty acids of total glycerophospholipids in erythrocyte membranes by high performance liquid chromatography is a useful diagnostic method of ALD.

Very long-chain fatty acids in neutral lipids and glycerophospholipids of adrenoleukodystrophy-cultured skin fibroblasts

Three major lipid fractions, i.e., cholesterol ester, triacylglycerol and glycerophospholipids, were investigated cultured fibroblasts to clarify whether very long-chain fatty acids were accumulated or not. Abnormally accumulated very long-chain fatty acids were confirmed in all three lipid fractions. Our results support our previous report that there may be a generalized abnormal metabolism of very long-chain fatty acids in adrenoleukodystrophy.

A Study on Erythrocyte Membrane Plasmalogen in Myotonic Dystrophy

Phospholipid classes that included plasmalogens of erythrocyte membranes in seven myotonic dystrophy (MyD) patients and seven normal controls were analyzed by HPLC. No significant difference in phospholipid classes was found between patients with MyD and normal controls, but there was a visible difference in peak profiles of compounds of the phosphatidylethanolamine class. In the study of plasmalogens, we used two preparation methods: exposure to HCl and deacylation with mild alkaline. The area ratio of the plasmalogen form to the diacyl form in the phosphatidylethanolamine class of MyD erythrocyte membranes was significantly lower than that of normal controls. Fatty acid analyses showed that fatty acids of both phosphatidylethanolamine subclasses have less unsaturation in MyD.

A comparison of erythrocytes, lymphocytes and blood plasma as samples in fatty acid analysis for the diagnosis of adrenoleukodystrophy

We studied the very-long-chain fatty acids of blood plasma, erythrocyte membranes and lymphocytes in 4 adrenoleukodystrophy patients, 5 adrenoleukodystrophy obligate carriers, 12 normal controls and 81 patients with various neurological disorders by high-performance liquid chromatography and compared the reliabilities in the diagnosis of adrenoleukodystrophy of these 3 components of peripheral blood. Of 81 patients with various neurological disorders, 2 myotonic dystrophy and 2 spinocerebellar degeneration patients showed increased ratios of C26:0 to C22:0 in erythrocyte membranes, but not in blood plasma and lymphocytes. None of the 12 normal controls showed increased ratios of C26:0 to C22:0 in erythrocyte membranes, blood plasma and lymphocytes. These results suggest that fatty acid analysis for the diagnosis of adrenoleukodystrophy is more reliable when blood plasma and lymphocytes are used than when erythrocyte membranes are used.

Familial hypo-β-lipoproteinaemia

Abstract A family with partial deficiency of serum β-lipoprotein and serum cholesterol is reported, in which 7 of the 8 members examined presented with a similar biochemical abnormality. The pedigree indicated an autosomal dominant inheritance for this abnormality. None of the family members presented acanthocytosis. The profile of the concentrations of serum lipids in this family was somewhat different from those of the reported families with hypo-β-lipoproteinaemia. Only one patient in this family presented neurological manifestations consisting of polyneuritis and papilloedema, which were dissimilar to those of the patients seen in the reported families. The clinical manifestations of this patient resemble the Guillain-Barre syndrome except for the very chronic evolution of the symptoms. The lack of neurological symptoms in other members of this family suggested that the neurological manifestations of the propositus could be a fortuitous association and that only the unusual chronic evolution of the symptoms was related to the hypo-β-lipoproteinaemia. However, it cannot be excluded also that the neurological manifestations were a direct consequence of the familial metabolic error.