Clinical and Genetic Features of Multiplex Families with Multiple System Atrophy and Parkinson's Disease.

While multiple system atrophy (MSA) has been considered a sporadic disease, there were previously reported multiplex families with MSA. Furthermore, several families with multiple patients with MSA and Parkinson's disease (PD) have been reported. As genetic risk factors for MSA, functionally impaired variants in COQ2 and Gaucher-disease-causing GBA variants have been reported. While it has been established that GBA variants are associated with PD, COQ2 may also be associated with PD. In 672 patients with MSA, we identified 12 multiplex families of patients with MSA and PD in first-degree relatives. We conducted a detailed analysis of the clinical presentations of these patients and genetic analyses of GBA and COQ2. In the multiplex families, a patient with MSA with predominant parkinsonism (MSA-P) was observed in nine families, while a patient with MSA cerebellar subtype (MSA-C) was observed in three families. Six families had siblings with MSA and PD, five families had a parent-offspring pair with MSA and PD, and in one family, a sibling and a parent of an MSA patient had PD. In genetic analyses of these patients, GBA variants were identified in one of the 12 MSA patients and two of the seven PD patients. Functionally impaired variants of COQ2 were identified in two of the 12 MSA patients and not identified in the seven PD patients. This study further emphasizes the occurrence of MSA and PD in first-degree relatives, raising the possibility that a common genetic basis underlies MSA and PD. Even though variants of COQ2 and GBA were identified in some patients in multiplex families with MSA and PD, it is necessary to further explore as yet unidentified genetic risk factors shared by MSA and PD.

Tumefactive multiple sclerosis which initially presented with brainstem encephalitis with a long-term follow-up.

Tumefactive demyelinating lesions (TDLs) are rare in multiple sclerosis (MS). We herein report a case of tumefactive MS which initially presented with brainstem encephalitis with a long-term follow-up. The patient had experienced relapse mostly in the brainstem in the first twenty years, and then in the periventricular white matter afterwards. The patient responded well to steroid treatment recovered without sequalae. However, immunodeficiency due to the long-term use of oral prednisolone made aggressive therapy during the relapse impossible, so recovery after steroid therapy is incomplete. Our case is different from classical MS in clinical course and response to treatment. Our report offers rare information on long-term outcome of tumefactive MS.

The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy.

Multiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Atypical parkinsonism caused by Pro105Leu mutation of prion protein: A broad clinical spectrum.

OBJECTIVE: To delineate molecular and clinical characteristics of 3 families with PRNP P105L mutation, a variant of Gerstmann-Sträussler-Scheinker syndrome whose main motor symptoms were parkinsonism and/or involuntary movements. METHODS: The causative mutation was first determined in the affected patients of family 1 using whole-exome sequencing, and then mutational analysis was extended to families 2 and 3. The clinical features of the patients of these 3 families were summarized. Haplotype analysis was performed using high-density single nucleotide polymorphism array. RESULTS: The whole-exome sequencing revealed that the heterozygous mutation c.314C>T (p.P105L) in PRNP was the only known pathogenic mutation shared by the 3 patients of the family with autosomal dominant parkinsonism. We further identified the same mutation in patients of the other 2 families with autosomal dominant parkinsonism and/or involuntary movements. The clinical features of our patients with PRNP P105L mutation included various motor symptoms such as parkinsonism and involuntary movements in addition to progressive dementia. The clinical features in part overlapped with those of other forms of inherited prion diseases, such as fatal familial insomnia and Huntington disease-like type 1. The patients with PRNP P105L mutation shared a haplotype spanning 7.1 Mb around PRNP, raising the possibility that the mutations in the patients originated from a common founder. CONCLUSION: Most of the patients presented with parkinsonism in addition to progressive dementia. Although spastic paraparesis has been emphasized as the main clinical feature, the clinical spectrum of patients with PRNP P105L is broader than expected.

Memory impairment following right cerebellar infarction: a case study.

We reported a patient with a right cerebellar infarction who showed anterograde amnesia. Cognitive dysfunction caused by cerebellar lesions was called cerebellar cognitive affective syndrome, and deactivation of the contralateral prefrontal cortex function due to disconnections of cerebello-cerebral fiber tracts have been hypothesized as mechanism underlying the syndrome. The episodic memory impairment, however, could not be supported by the same mechanism because the prefrontal lesions cannot cause amnesia syndrome. The feature of the impairment of our patient was similar to that of diencephalic amnesia, and a single photon emission computed tomography study showed a relative hypoperfusion in the right cerebellar hemisphere and left anterior thalamus. We considered that the memory deficit was caused by the dysfunction of the thalamus, which is a relay center of the cerebello-cerebral connectivity network.