The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

Age-related changes in blood pressure and heart rates of patients with Parkinson's disease.

This study evaluated yearly changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rates (HR) for patients with Parkinson's disease (PD). Data were collected for the last 10 years from medical records of 28 PD patients and 30 non-PD patients with other neurological disorders. Age-related changes in each group were analyzed by year using mean values of SBP, DBP, and HR obtained at their bi-monthly visits. In results, PD patients had a gradual decrease in SBP with longer disease duration, and mean SBP significantly decreased from Year 7-11 compared to the mean values for Year 1 (p < .001 or p < .01). In non-PD patients, mean SBP significantly increased from Year 4-11 compared to the mean values for Year 1 (p < .001 or p < .01). This is the first study to report age-related changes of BP in individual patients with PD over 10 years.

A patient with ossification of the yellow ligament and ventriculomegaly with 22q11.2 deletion syndrome undiagnosed until adulthood.

A 44-year-old female developed mild gait disturbance. She had a history of a ventricular septum defect, deafness, epilepsy, schizophrenia and cataracts. Magnetic resonance imaging showed ventriculomegaly of the brain and lower thoracic spinal stenosis due to ossification of the yellow ligament (OYL). She was diagnosed as having 22q11.2 deletion syndrome (22q11.2DS) by chromosome analysis, and OYL was suspected to be a secondary symptom due to hypoparathyroidism. This is the first report of 22q11.2DS with OYL and ventriculomegaly. Since the present patient was not diagnosed until adulthood, we emphasize that we should keep this common but heterogeneous congenital disease in mind.

RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.

Recently, the expansion of an intronic AAGGG repeat in the replication factor C subunit 1 (RFC1) gene was reported to cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In Europeans, the expansion accounted for 22% of sporadic patients with late-onset ataxia. We genotyped 37 Japanese patients comprising 25 familial (autosomal recessive or undecided transmission) and 12 sporadic ones with late-onset ataxia. We found intronic repeat expansions in RFC1 in three (12%) of the familial patients and one (8.5%) of the sporadic ones. Although our cohort study was small, the disease frequency in Japanese patients with CANVAS might be lower than that in European ones. In addition, we found biallelic ACAGG repeat expansion in one patient, indicating ACAGG repeat expansion might cause CANVAS. Clinically, we found one patient with sleep apnea syndrome, which has not been reported previously. Thus, this study might expand the clinical and genetic spectrum of CANVAS.

A Japanese SPG4 Patient with a Confirmed De Novo Mutation of the SPAST Gene.

Spastic paraplegia type 4 (SPG4) is caused by mutations of the SPAST gene and is the most common form of autosomal-dominantly inherited pure hereditary spastic paraplegia (HSP). We herein report a Japanese patient with SPG4 with a confirmed de novo mutation of SPAST. On exome sequencing and Sanger sequencing, we identified the heterozygous missense mutation p.R460L in the SPAST gene. This mutation was absent in the parents, and the paternity and maternity of the parents were both confirmed. The patient showed a pure SPG4 phenotype with an infantile onset. This study may expand the clinical and genetic findings for SPG4.

Variants in saposin D domain of prosaposin gene linked to Parkinson's disease.

Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson's disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson's disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson's disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson's disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson's disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson's disease.

Sympathetic outflow to skin predicts central autonomic dysfunction in multiple system atrophy.

BACKGROUND: To find out the physiological method for evaluating the severity of central autonomic dysfunction, we performed detailed evaluation of cutaneous vasomotor neural function in a comparatively large sample of multiple system atrophy (MSA). METHODS: We evaluated cutaneous vasomotor neural function in 24 MSA patients. Skin sympathetic nerve activity (SSNA) and sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex [SVR]) were recorded at rest, as well as reflex changes after electrical stimulation. The parameters investigated were SSNA frequency at rest, reflex latency and amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and spontaneous SVR and SSR frequency. RESULTS: There were negative correlations between resting SSNA and disease duration or the SCOPA-AUT score, but these were not significant. SSNA reflex latency displayed significant positive correlations with disease duration and SCOPA-AUT score (p < 0.001 and p < 0.01, respectively). In all five patients who underwent the same examination twice, SSNA reflex latency was significantly longer at the second examination than at the first examination (p < 0.005). A significant positive correlation was identified between recovery time of skin blood flow and SCOPA-AUT score or reflex latency (p < 0.05). Significant correlations were not observed between SCOPA-AUT score or disease duration and other parameters. CONCLUSIONS: These results suggest that some MSA patients with a comparatively short duration of disease potentially have impaired thermoregulatory function. Measurement of sympathetic outflow to the skin is potentially a useful tool for predicting the severity of central autonomic dysfunction in MSA.

VPS13D-related disorders presenting as a pure and complicated form of hereditary spastic paraplegia.

BACKGROUND: Alterations of vacuolar protein sorting-associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D-related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia. METHODS: We applied whole-exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan. RESULTS: We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy. CONCLUSION: In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D-related disorders.

UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.

We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium (JASPAC). Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.

Pathological findings in a patient with non-dystrophic myotonia with a mutation of the SCN4A gene; a case report.

BACKGROUND: Non-dystrophic myotonias (NDMs) are skeletal muscle disorders involving myotonia distinct from myotonic dystrophy. It has been reported that the muscle pathology is usually normal or comprises mild myopathic changes in NDMs. We describe various pathological findings mimicking those of myotonic dystrophy (DM) in biopsied muscle specimens from a patient with NDMs with a long disease duration. CASE PRESENTATION: A 66-year-old Japanease man presented eye closure myotonia, percussion myotonia and grip myotonia together with the warm-up phenomenon and cold aggravation from early childhood. On genetic analysis, a heterozygous mutation of the SCN4A gene (c.2065 C > T, p.L689F), with no mutation of the CLCN1, DMPK, or ZNF9/CNBP gene, was detected. He was diagnosed as having NDMs. A biopsy of the biceps brachii muscle showed increasing fiber size variation, internal nuclei, chained nuclei, necrotic fibers, fiber splitting, endomysial fibrosis, pyknotic nuclear clumps and disorganized intermyofibrillar networks. Sarcoplasmic masses, tubular aggregates and ragged-red fibers were absent. CONCLUSION: It is noteworthy that the present study revealed various pathological findings resembling those seen in DM, although the pathology is usually normal or mild in NDMs. The pathological similarities may be due to muscular modification with long-standing myotonia or excessive muscle contraction based on abnormal channel activity.

Clinical and Genetic Study of the First Japanese FTDP-17 Patient with a Mutation of +3 in Intron 10 in the MAPT Gene.

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with mutations in the MAPT gene is a hereditary neurodegenerative tauopathy with various clinical phenotypes. We herein report the first Japanese patient with FTDP-17 caused by an IVS10+3G>A mutation in the MAPT gene, which is linked to an H1M haplotype. The present study suggests that the IVS10+3G>A mutation in the MAPT gene can have originated from a non-Caucasian population. In the disease course, myoclonus and respiratory failure can be observed. This study may expand on the clinical and genetic findings for FTDP-17 with mutations in the MAPT gene.

Non-convulsive status epilepticus associated with neuronal intranuclear inclusion disease: A case report and literature review.

We report a case of neuronal intranuclear inclusion disease (NIID) confirmed by detection of intranuclear inclusions in a skin biopsy specimen. Brain magnetic resonance imaging showed mild cerebral atrophy and linear hyperintensities at the corticomedullary junction on diffusion-weighted images. This patient developed nonconvulsive status epilepticus with generalized periodic discharges on electroencephalography after recurrent symptoms of paroxysmal nausea and slowly progressive cognitive decline. There have been no previous reports of NIID with nonconvulsive status epilepticus to our knowledge. Since adult patients with NIID display a wide variety of clinical manifestations, skin biopsy should be considered in patients who have leukoencephalopathy of unknown origin.

Spinocerebellar ataxia type 31 associated with REM sleep behavior disorder: a case report.

BACKGROUND: Spinocerebellar ataxia type 31 (SCA 31) is a slowly progressive neurodegenerative disorder characterized by pure cerebellar ataxia. Unlike other CAG repeat diseases, sleep-related problems have not been reported in patients with SCA 31 so far. CASE PRESENTATION: A 67-year-old woman was admitted to our hospital with dysarthria and gait disturbance after onset age of 62 years. Neurological examination revealed pure cerebellar ataxia. Genetic analysis detected expansion of a TGGAA repeat in the coding region of the BEAN/TK2 gene on chromosome 16p22.1, confirming the diagnosis of SCA 31. One year later, her husband noticed the patient talking loudly during sleep once or twice a week. Overnight polysomnography showed rapid eye movement sleep without atonia. Cardiac scintigraphy with iodine-123-labeled meta-iodobenzylguanidine revealed a low heart/mediastinum ratio, indicating reduced uptake, and a high washout rate. CONCLUSION: To our knowledge, this is the first report of a patient with SCA 31 associated with rapid eye movement sleep behavior disorder (RBD). In the future, evaluation of autonomic function, assessment of the frequency of RBD, and performance of cardiac iodine-123-labeled meta-iodobenzylguanidine scintigraphy in a larger number of SCA 31 patients could be useful to resolve important issues regarding the mechanism of RBD.

Exome Sequencing Reveals a Novel Homozygous Frameshift Mutation in the CYP7B1 Gene in a Japanese Patient with SPG5.

SPG5 is a rare subtype of autosomal recessive hereditary spastic paraplegia caused by a homozygous mutation in the oxysterol 7α-hydroxylase gene, CYP7B1. We describe the first Japanese patient with SPG5 with a novel mutation in the CYP7B1 gene. On exome sequencing, we identified a homozygous frameshift mutation, c.741delA, p.K247fs, in exon 3 of the CYP7B1 gene. The patient showed spastic paraparesis with white matter hyperintensities in the bilateral corona radiata and periventricular and subcortical regions on brain magnetic resonance imaging. The present study expands the mutation spectrum of CYP7B1 and provides an opportunity to study the genotype-phenotype correlation in SPG5.

Novel GARS mutation presenting as autosomal dominant intermediate Charcot-Marie-Tooth disease.

We report the first family with a glycyl-tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot-Marie-Tooth disease (DI-CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI-CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.