JASPAC: Japan Spastic Paraplegia Research Consortium

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by weakness and spasticity of the lower extremities. HSPs are heterogeneous disorders that involve over 80 causative genes. The frequency of HSPs is estimated to be 10–100/1,000,000. With this background, the Japanese research group “Japan Spastic Paraplegia Research Consortium: JASPAC” was organized in 2006 to elucidate the molecular epidemiologies of HSPs in Japan and the molecular pathologies of HSPs. To date, the JASPAC has collected 714 HSP families and analyzed 488 index patients. We found 279 pathogenic variants or probable pathogenic variants of causative genes in the 488 HSP patients. According to our results, we found 178 families with autosomal dominant patients (65%), and 101 with autosomal recessive and sporadic patients (48%). We found 119 patients with SPG4, 17 with SPG3A, 15 with SPG31, 13 with SPG11, and 11 with SPG10. Other HSP genes were the cause in less than five patients. On the other hand, we could not find causative genes in 35% of the autosomal dominant patients, or 52% of the autosomal recessive and sporadic patients. We are now trying to find new causative genes and elucidate the molecular mechanisms underlying HSPs

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. Keywords: Neuronal intranuclear inclusion disease, Non-convulsive status epilepticus, Generalized periodic discharges, Autonomic neuropathy, Skin biops

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

Abstract 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

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

Abstract 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

SPTLC2 variants are associated with early‐onset ALS and FTD due to aberrant sphingolipid synthesis

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early‐onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. Methods Our research commenced with an in‐depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early‐onset ALS (onset age of <40 years). This involved whole‐exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early‐onset ALS and further included 440 patients with adult‐onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. Results We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early‐onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early‐onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. Interpretation Our study revealed novel SPTLC2 variants in patients with early‐onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development