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We describe clinical characteristics of 10 patients (five families) with familial hemifacial spasm, with reviews of 13 patients hitherto reported in the literature. There is no clear difference in clinical manifestations between sporadic and familial hemifacial spasms. There is no definite inheritance pattern, but may be autosomal dominant with low penetrance. The ages of onset of familial hemifacial spasm are variable, but occasionally can occur at early years of life. There is a left-side predominance with respect to the affected side of cases with familial hemifacial spasm. Similar to sporadic hemifacial spasm, vascular decompression was effective, suggesting that vascular compression is involved in generating hemifacial spasm even in the familial cases. Familial hemifacial spasm may not be a rare disorder, but may possibly be overlooked. Clarifying the role of genetic susceptibility in pathophysiological mechanisms underlying hemifacial spasm is an important approach toward better understanding of the pathogenesis of cranial rhizopathies.

We report 14 patients with idiopathic recurrent cranial neuropathy, in whom multiple cranial nerves were involved recurrently, either at the same or different times, and appeared bilaterally. Oculomotor nerve involvement was most frequent, while the abducens and facial nerves were the next most frequent. Clinical courses were benign and not progressive, and the symptoms responded well to corticosteroids. Ten patients developed Tolosa-Hunt syndrome during the course of their illness. Laboratory findings and CSF were normal. MRI and CT studies were unremarkable, except for an asymmetric appearance of the cavernous sinus in some patients. One patient showed focal hypertrophic pachymeningitis in the posterior fossa in MRI. We discuss the relationship of the idiopathic recurrent cranial neuropathy with disorders characterized by inflammation of the dura mater, such as Tolosa-Hunt syndrome and cranial pachymeningitis.

1,2,3,4-Tetrahydroisoquinoline (TIQ), which is structurally similar to MPTP, has been found in human brain and has been reported to inhibit the mitochondrial respiration as does 1-methyl-4-phenylpyridinium ion (MPP + ). However, the potency of inhibition by TIQ is less than that of MPP + . In this study, we report the effects of N -methyl-1,2,3,4-tetrahydroisoquinoline ( N -Me-TIQ) and N -methylisoquinolinium ion ( N -Me-IQ + ) on the mitochondrial electron transport system using mitochondria prepared from mouse brains. Five mM N -Me-TIQ and 500 μ M N -Me-IQ + inhibited complex I activity to 54% and 63% of the control, respectively. The IC 50 of N -Me-TIQ and N -Me-IQ + were approximately 6.5 mM and 650 μM, respectively. Neither substance inhibited complex II, III and IV activities. Kinetic analyses of N -Me-IQ + on complex I activity revealed uncompetitive inhibition against NADH and non-competitive inhibition against ubiquinone. These inhibitory characteristics were the same to those of MPP + and the inhibitory potency of N -Me-IQ + on complex I activity was stronger than that of MPP + .

Total biopterin (T-BP) levels in the ventricular cerebrospinal fluid (CSF) and clinical features of 19 patients with juvenile parkinsonism (JP: Parkinson's disease manifesting below the age of 40) were evaluated and compared with 61 patients with classical Parkinson's disease (classical PD: symptoms developing at the age of 40 or above). The JP patients were divided into two subgroups: JP-I; those with good response to levodopa followed by marked motor fluctuations and dopa-induced dyskinesias (DID), JP-II; those with milder response than JP-I with less fluctuations and DID being more similar to classical PD. Both of the mean ventricular CSF T-BP concentrations in the JP and classical PD patients were significantly lower than that in neurological controls. Moreover, the mean T-BP level in the JP-I was markedly lower than that in the JP-II or classical PD. Total biopterin levels revealed a gaussian distribution in the classical PD. However, a bimodal distribution was noted in the JP, with the lower peak consisting of only JP-I patients. These results seem to indicate that JP-II represents early-onset classical PD, while JP-I represents a distinct subgroup having a different physiopathology from classical PD.

Parkinson's disease (PD) is a common degenerative disease, but its etiology is still unknown. However, since the discovery of MPTP, many investigators have been interested in the mitochondrial function in PD. We investigated mitochondrial functions in PD patients using the methods which have successfully been applied to mitochondrial myopathies (MM), i.e. assay of lactate and pyruvate, measurement of muscle mitochondrial respiratory enzyme activities and Southern blot analysis of muscle mitochondrial DNA. Parkinson's disease patients did not differ from controls in the mean blood and CSF (cerebrospinal fluid) lactate and pyruvate levels at the basal resting state or during an aerobic exercise. But mitochondrial complex I activity of the skeletal muscle was significantly decreased in PD. In the Southern blot analysis, we could not find major deletions or insertions of mitochondrial DNA in PD. Our studies disclosed a differential mitochondrial impairment between PD and MM. We discuss the implication of our observation.

We report two families (Family S and Family N) with early-onset parkinsonism in two generations. The mode of inheritance appeared to be autosomal dominant, however, haplotye analysis suggested linkage to chromosome 6q25.2-27, the PARK2 locus, and all affected members were homozygotes in their haplotypes. In Family S, the affected father was married to unaffected mother, who carried one disease-linked haplotype at chromosome 6q25.2-27. In Family N, the unaffected mother carried one disease-linked haplotype. Quantitative PCR amplification analysis revealed exon 3 deletion in Family S and exon 5 deletion in Family N. The age of onset was from 18 to 22 years in Family S and 25 to 42 years in Family N. In both of their hometowns, most people lived in the same districts for many generations and consanguineous marriages had been common. Thus, the carrier state of the parkin gene might have been high in those communities, and marriage of a patient and a carrier is expected to result in autosomal dominant like inheritance. We conclude that PARK2 cannot be excluded even if the mode of inheritance appears as autosomal dominant, when the affected patients are young.

The involvement of the central nervous system (CNS) in Sweet's syndrome (acute febrile neutrophilic dermatosis) is rare. We report a 47-year-old woman who presented with acute encephalitis and was subsequently diagnosed as having Sweet's syndrome. She developed altered consciousness following fever and erythematous skin plaques in the extremities. Cerebrospinal fluid (CSF) examination disclosed neutrophilic pleocytosis without decreased glucose level. Brain magnetic resonance imaging (MRI) showed abnormal signal intensity lesions in the basal ganglia and the hippocampus. Skin biopsy revealed a dense dermal infiltration of neutrophils, which is compatible with Sweet's syndrome. Treatment with acyclovir and antibiotics failed, but the subsequent corticosteroid therapy was effective. Awareness of neurological complication in Sweet's syndrome may avoid unnecessary empiric therapy for meningoencephalitis and will lead to a successful treatment with corticosteroids.

We report an immunohistochemical study on manganese superoxide dismutase (Mn SOD) in Parkinson's disease (PD) patients and age-matched control subjects. Overall appearance of immunostaining intensity of nigral neurons did not differ significantly between the PD patients and the control subjects. However, when the immunostaining intensity of each neuron was semiquantitatively analyzed, both very intensely stained (more than normal) neurons as well as neurons stained only weakly were more frequently detected in the lateral part than in the medial and the central parts of the substantia nigra in PD patients. As a result, the proportion of normally stained neurons was significantly smaller in the lateral part of the substantia nigra in PD patients; however, the overall distribution of the neurons among the three rating grades for immunostaining did not differ significantly. The immunostaining intensity of the neuropils in the medial and the central part of the substantia nigra tended to be more intense in PD patients than in the control subjects. Our results suggest up-regulation of Mn SOD mainly in the dendritic processes of the less involved nigral neurons.

Apoptosis may be an important mechanism of cell death in some experimental disease models as well as in human neurodegenerative disorders. We report evidence to indicate apoptosis in the substantia nigra of Parkinson's disease patients. We studied the midbrains of 7 patients with late onset PD, 4 patients with young onset PD and 6 control subjects using the nick-end labeling method. Intense nuclear staining indicating apoptotic process was observed in 8 out of 11 parkinsonian patients studied. Apoptosis may be a contributor to the nigral neuronal death in Parkinson's disease (PD).

We have sequenced all mitochondrial tRNA genes from 9 Japanese patients with chronic progressive external ophthalmoplegia (CPEO) who had no detectable large mtDNA deletions nor mutations previously reported, and identified 6 different base substitutions in 6 patients. Since 5 of the 6 substitutions were homoplasmic in distribution and recognizable in some normal controls, they were thought to be polymorphisms in normal individuals. One mutation at nucleotide (nt) 12311 in the tRNA Leu( cun ) gene was not present in 90 normal controls nor in 103 patients with other mitochondrial myopathies. This mutation was in a heteroplasmic state, and the mutated site was conserved among other species during evolution, suggesting a disease-related mutation. However, the significance of this mutation has to be studied further. In Japanese CPEO patients without large deletions, a point mutation in the mitochondrial tRNA gene is not likely to be a frequent cause.

Total neopterin (T-N), a by-product in the biopterin biosynthesis and an indicator of activation of the cellular immune system, and total biopterin (T-B) levels in cerebrospinal fluid (CSF), were measured in patients with various inflammatory neurological diseases and Parkinson's disease, and the following results were obtained. (1) In patients with neuro-sarcoidosis, neuro-Behcet's disease and meningitis, CSF T-N levels were markedly elevated in the exacerbation or acute stages of their neurological symptoms and remarkably decreased in the remission or chronic stages. In the neuro-sarcoidosis and neuro-Behcet's disease patients, however, CSF T-B levels showed no substantial change. (2) There was a significant positive correlation between CSF T-N levels and CSF/serum albumin ratios only in the meningitis patients. However, increases of CSF T-N levels were not associated with those of plasma T-N levels. (3) In the Parkinson's disease patients, CSF T-N levels remained normal, although CSF T-B levels significantly decreased. (4) A gradient for the CSF T-N value (lumbar greater than ventricular CSF), being reverse to the CSF T-B value, was observed. These results indicate that the significance of CSF T-N is quite different from CSF T-B, and that CSF T-N appears to be a valuable biochemical marker for evaluating the activity of inflammation within the central nervous system. Its measurement seems useful for therapeutic monitoring, especially of patients showing the chronic exacerbating-remitting course.

Glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activities were assayed in superficial pectoral muscles of hereditary dystrophic chickens, 1 week, 2 weeks, 4 weeks and 4 months after hatching. In control chickens, activities of G6PDH and 6PGDH were very low at 4 months of age; however, at 1 week of age, they were much higher than those at 4 months of age. Activities of G6PDH and 6PGDH were significantly higher in dystrophic chickens compared with those in the controls at all the stages of development studied. These findings suggest that considerable activities of G6PDH and 6PGDH are present within the pectoral muscle cells at early stages of development, at least in dystrophic chickens. GAPDH activity was significantly lower in dystrophic chickens at 2 weeks, 4 weeks and 4 months of age compared with those in control chickens. These findings together with our previous studies (Mizuno 1984a,b) in which increased activities of superoxide dismutases, catalase, glutathione peroxidase and glutathione reductase were reported in dystrophic chickens, indicate the presence of an increased capacity for the turnover of oxygen-free radicals within muscle cells in dystrophic chickens, and that oxygen-free radicals and the related activated oxygen species may be playing a role in inducing cellular damage.

Long-term effects of MPTP on striatal dopamine (DA) content and the influence of aging on the recovery were investigated in mice. Male C 57 BL 6 J mice, young (2-month-old) and mature (10-month-old), were used. Two different dosage schedules of MPTP, i.e., 4 doses subcutaneous injections of 20 mg/kg each, and 4 doses subcutaneous injections of 40 mg/kg each, were given to both young and mature mice at 12-h intervals. Assays of striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) content were performed 1 week, 1 month, 2 months, and 3 months after the last injection of MPTP. MPTP produced a marked reduction (−75% to −80%) of striatal DA content in both young and mature mice 1 week after the last injection of MPTP. In young mice, the striatal DA content showed a partial recovery in the subsequent stages studied. In contrast, no apparent recovery occurred in mature mice until as long as 3 months after the last injection. The results suggest that mice have a capacity for partial recovery of the striatal DA contents which was depleted by MPTP, and this capacity for recovery appears to be impaired in mature mice.

Effects of 1-methyl-4-phenylpyridinium ion (MPP+) on cellular respiration were studied using mitochondria prepared from mouse brains. State 3 and state 4 respiration supported by glutamate plus malate or pyruvate plus malate were significantly inhibited by 0.05 mM MPP+. On the other hand, respirations supported by succinate or alpha-glycerophosphate were not inhibited at all. Activity of mitochondrial NADH-ubiquinone oxidoreductase was significantly inhibited by MPP+. This inhibition was markedly potentiated by preincubating mitochondria with MPP+ together with glutamate plus malate. The latter observation suggested accumulation of MPP+ within the mitochondria during preincubation. When mitochondria were pretreated with an uncoupling agent such as carbonylcyanide m-chlorophenylhydrazone (CCCP) or dinitrophenol, MPP+-induced inhibition of state 3 respiration or of activity of complex I could no longer be seen. A potassium ionophore, valinomycin, showed a similar effect. Adenosine triphosphate (ATP) synthesis was also inhibited by MPP+. Among the NAD+-linked dehydrogenases in the tricarboxylic acid cycle, alpha-ketoglutarate dehydrogenase complex was significantly inhibited by MPP+. This inhibition was reversible and competitive with NAD+. Energy crisis appears to be one of the most important mechanisms of neuronal degeneration in MPTP-induced parkinsonism. Biochemical mechanisms underlying MPP+-induced inhibition of mitochondrial respiration were discussed.

A quantitative analysis of ataxia and the readiness potential were studied in four cases of ataxic hemiparesis resulting from a small infarct in the posterior limb of the internal capsule. The ataxia appeared to be the result of involvement of the corticopontine tract originating from the precentral region (areas 4 and 6) at this level. The voluntary movements of the affected limbs were characterized by slowness and irregularity similar to those seen in cerebellar ataxia. The weakness per se was not such that it could account for the ataxia. The dentato-rubro-thalamo-cortical system did not appear to be significantly involved on the basis of normal readiness potentials.