Shiro Yorifuji

Treatment of Kearns‐Sayre syndrome with coenzyme Q10

We studied the metabolism of coenzyme Q10 (CoQ) and the effects of CoQ therapy in five patients with Kearns-Sayre syndrome (KSS). Although the mitochondrial fraction was increased in muscles from KSS patients, CoQ content was slightly low. CoQ synthesis was normal in fibroblasts from KSS patients. Administration of 120 to 150 mg/d of CoQ improved abnormal metabolism of pyruvate and NADH oxidation in skeletal muscle. CoQ therapy decreased CSF protein concentration and CSF lactate/pyruvate ratio. ECG abnormalities and neurologic symptoms also improved.

Cognitive function in amyotrophic lateral sclerosis

Cognitive function in patients with amyotrophic lateral sclerosis (ALS) has drawn recent attention. However, the pathogenesis of cognitive dysfunction in patients with ALS remains uncertain. To explore the underlying mechanism for cognitive dysfunction further, we studied 26 patients with ALS (15 male and 11 female; age from 36 to 67 years) by using neuropsychological batteries, magnetic resonance imaging (MRI) and single photon emission computed tomography (SPECT). We also evaluated these patients and an additional 26 age- and sex-matched normal controls using neuropsychological batteries with special attention to the frontal lobe function. On the basis of neuropsychological examination, we classified patients into three groups using cluster analysis. Age, education level and severity were comparable across these subgroups. Neuropathologic examination was subsequently carried out in six patients. Patients in Group 1 and 2 had low scores on all measures compared to patients in Group 3 and normal controls. Patients in Group 1 and 2 had frontal atrophy on MRI and reduced isotope uptake in the frontal region on SPECT, which was more evident in patients in Group 1. On neuropathologic examination, patients in Group 1 showed spongy degeneration and neuronal loss in the frontal lobe. Patients in Group 3 showed no notable pathology in the frontal region. The gradient distribution of the scores for attention and executive function, as well as SPECT findings suggested the presence of a continuum of cognitive disability in patients with ALS corresponding to the pathologic process in the frontal lobe ranging from significant impairment to normality. We, therefore, believe that inattention and executive dysfunction alternatives may evolve in patients with ALS corresponding to the pathologic process in the frontal lobe.

Determination of language dominance with synthetic aperture magnetometry: comparison with the Wada test.

Cerebral dominance for language function was investigated with synthetic aperture magnetometry (SAM). The results were compared with those of the Wada test. SAM is a spatial filtering technique that enables demonstration of the spatiotemporal distribution of oscillatory changes (synchronization and desynchronization) in magnetoencephalography (MEG) signals elicited by specific brain activation. MEG was conducted during a silent reading task in 20 consecutive preoperative neurosurgical patients who also underwent a Wada test. The spatial distribution of oscillatory changes related to silent reading was shown tomographically with SAM as statistical images. Language dominance was estimated by the laterality index, which scales the lateralization of the beta (13-25 Hz) and low gamma (25-50 Hz) band desynchronizations in the inferior frontal gyrus (IFG) or middle frontal gyrus (MFG). Oscillatory changes were distributed multifocally and bilaterally in the occipital cortex, IFG or MFG, and temporo-parieto-occipital border regions. In 19 patients (95%), language lateralization estimated by the laterality index was congruent with the result of the Wada test. In left-handed patients, SAM analysis clearly differentiated language dominance (left, right, or bilateral), and the findings were confirmed by the Wada test. Lateralization of beta or low gamma band desynchronizations in the IFG or MFG is a good indicator of the side of language dominance. Reliability of MEG imaging with SAM is sufficient to evaluate language dominance preoperatively in neurosurgical patients.

Long‐term coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome c oxidase deficiency A 31P NMR study

For 2 years we administered high doses of coenzyme Q10 (CoQ) to a patient having mitochondrial encephalomyopathy with cytochrome c oxidase deficiency. Abnormal elevation of the serum lactate per pyruvate ratio and the increased concentration of serum lactate plus pyruvate induced by exercise decreased with CoQ treatment. This therapeutic effect continued for 2 years. 31P nuclear magnetic resonance spectroscopy showed acceleration of the postexercise recovery of the ratio of phosphocreatine to inorganic phosphate in muscle during CoQ treatment. These observations support the beneficial effect of CoQ on the impaired mitochondrial oxidative metabolism in muscle. Also, impaired central and peripheral nerve conductivities consistently improved during CoQ treatment. These results indicate that CoQ has clinical value in the long-term management of patients with mitochondrial encephalomyopathies, even though there are clinical limitations to the effects of this therapy.

Improvement of abnormal pyruvate metabolism and cardiac conduction defect with coenzyme Ql0 in Kearns‐Sayre syndrome

In a patient with Kearns-Sayre syndrome, concentration of coenzyme Ql0, a component of the mito-chondrial electron transport system, was decreased in serum and in the mitochondrial fraction of skeletal muscle. Serum concentrations of lactate and pyruvate were abnormally high, especially after exercise or oral glucose loading. Levels of folic acid in plasma and CSF were decreased. ECG showed a first-degree atrioventricular block. After administration of coenzyme Ql0 60 to 120 mg daily for 3 months, serum levels of lactate and pyruvate became normal, with improvement of atrioventricular block and ocular movements.

Marked reduction in CSF lactate and pyruvate levels after CoQ therapy in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS)

Many CoQ trials for mitochondrial encephalomyopathy are reported, however, the action of CoQ in the central nervous system is unknown. We administered CoQ to a patient with MELAS, and decreasing CSF lactate and pyruvate levels were revealed. This reduction in CSF lactate and pyruvate may be evidence that CoQ acts directly on the CNS. There have been no other descriptions of evidence of CoQ effective action in the central nervous system, a finding unique to this report.

Involvement of the central nervous system in myotonic dystrophy

To investigate the etiological factors responsible for intellectual impairment and mood changes in patients with myotonic dystrophy (DM), we evaluated 14 patients with DM by means of neuropsychological evaluation and magnetic resonance images (MRI). There were significant differences between patients and controls in regard to the Barthel index, Zungs depression scale, attention, verbal fluency and digit span. All patients had ventricular enlargement and white matter abnormalities on MRI. However, the severity was variable and there was no difference in neuropsychological testing between patients with mild ventricular dilatation and those with severe dilatation. On the other hand, significant differences were present between patients with mild white matter lesions and those with severe white matter abnormalities in regard to verbal fluency and attention. Neuropathologic examination of an autopsied brain showed an increase in the interfascicular space of the white matter which produced pallor on myelin staining. The present findings suggested that the white matter abnormalities were the cause of cognitive impairment among patients with DM.

Two novel variants of transthyretin identified in Japanese cases with familial amyloidotic polyneuropathy : transthyretin (Glu42 to Gly) and transthyretin (Ser50 to Arg)

Two mutant genes coding for two different variants of transthyretin were identified in two independent kindreds with familial amyloidotic polyneuropathy. A single base change from A to G was identified in exon 2 of transthyretin gene in two brothers from the first kindred. This base change led to replacement of glutamate by glycine at position 42 of 127-residue molecule. In a patient from the second kindred, T to G transversion in exon 3 of transthyretin gene led to replacement of Ser by Arg at position 50. The two mutants were discovered by randomly sequencing recombinant clones containing the entire length of each one of the four exons selectively amplified by polymerase chain reaction. The base change produced a new restriction site for Hae III and Cfr 13 I in the exon 2 and for Mva I in the exon 3, respectively. Restriction fragment length polymorphisms and allele-specific oligonucleotide hybridizations confirmed the base changes. The accurate detection of the new mutant genes is hereafter possible by these procedures.

Dopamine metabolism in the central nervous system after discontinuation of l-dopa therapy in patients with Parkinson disease

The dopamine turnover rate in the central nervous system (CNS) of parkinsonian patients was studied by means of the intravenous probenecid test during drug holiday (DH) and alternate day L-dopa therapy (ADDT). After L-dopa therapy was stopped, the dopamine turnover rate decreased more rapidly in patients with the marked wearing-off phenomenon than that in patients without fluctuation of symptoms. The lumbar CSF concentrations of L-dopa and 3-O-methyldopa of patients with and without wearing-off phenomenon were similar during L-dopa therapy. DH improved the effect of L-dopa on parkinsonian symptoms; it did not affect, however, the metabolism of exogenous L-dopa. The dopamine turnover rate in the CNS before L-dopa therapy or on on-days did not differ between patients tolerating and those not tolerating ADDT. However, it was significantly lower on off-days in patients not tolerating ADDT than in those tolerating ADDT. The relationship between dopamine storage in the CNS and the response to L-dopa therapy is discussed.

A novel variant of transthyretin (Tyr114 to Cys) deduced from the nucleotide sequences of gene fragments from familial amyloidotic polyneuropathy in Japanese sibling cases

A to G transversion was identified in exon 4 of transthyretin gene in familial amyloidotic polyneuropathy in two sibling cases living in Osaka. This transversion led to the replacement of tyrosine by cysteine residue at codon 114 of 127 residue molecule. This identification was achieved by randomly sequencing recombinant clones containing the entire length of each one of the four exons selectively amplified by polymerase chain reaction. Dot blot analysis with allele-specific oligonucleotides indicated the linkage of this mutation with the disease and confirmed the single base change.