Hiroaki Nozaki

Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families

Background: Spinocerebellar ataxia type 15 (SCA15) is a progressive neurodegenerative disorder characterized by pure cerebellar ataxia, very slow progression, and distinct cerebellar atrophy. The locus for SCA15 was first mapped to 3p24.2-3pter in an Australian family. We have subsequently mapped two Japanese families presenting with ataxia and postural tremor of the head, arm, or trunk to the SCA15 locus. Recently, partial deletions involving both the type 1 inositol 1,4,5-triphosphate receptor (ITPR1) and sulfatase modifying factor 1 (SUMF1) genes have been identified in Australian and British families with SCA15. Methods: We conducted fine haplotype analysis on the region including ITPR1. To identify the deletion, we conducted gene dosage analysis and array-based comparative genomic hybridization (aCGH) analysis. Gene expression analysis was performed using quantitative real-time reverse transcription PCR. Mutational analyses of ITPR1 and SUMF1 were also performed. Results: We have identified a 414-kb deletion including the entire ITPR1 and exon 1 of SUMF1 in patients in family A. The expression levels of ITPR1 and SUMF1 mRNAs of the patient were half those of the normal control. Furthermore, in family B, we have identified a C-to-T substitution at position 8581 of ITPR1, resulting in the amino acid substitution of leucine for proline at codon 1059, which is highly conserved among species. Conclusions: Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor.

A novel mutation in the Htra1 gene causes carasil without alopecia

Y. Nishimoto, MD, PhD M. Shibata, MD, PhD M. Nihonmatsu, MMed H. Nozaki, MD, PhD A. Shiga, MD, PhD A. Shirata, MD, PhD K. Yamane, MD, PhD A. Kosakai, MD, PhD K. Takahashi, MD, PhD M. Nishizawa, MD, PhD O. Onodera, MD, PhD N. Suzuki, MD, PhD A NOVEL MUTATION IN THE HTRA1 GENE CAUSES CARASIL WITHOUT ALOPECIA Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by a mutation in the high-temperature requirement A serine peptidase 1 (HTRA1) gene.1 Alopecia, spondylosis, and cognitive impairment are the clinical triad. Alopecia does not necessarily appear in all patients with CARASIL, but this feature contributes to an early diagnosis.1,2 We present the case of a patient with CARASIL who had a novel mutation in the HTRA1 gene and did not show alopecia even 10 years after onset.

A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions

Recent studies have demonstrated that hypothalamic lesions associated with brain tumor, head trauma, and encephalopathy can cause symptomatic hypersomnia with a reduced orexin (hypocretin) level in the cerebrospinal fluid (CSF). Aquaporin 4 (AQP4), a member of the AQP superfamily, is strongly expressed in the hypothalamus in which orexin (hypocretin)-containing neurons are primarily concentrated. We report the case of a patient with a serum anti-AQP4 antibody who presented with recurrent hypersomnia, symmetrical hypothalamic lesions with long spinal cord lesions on MRI, and a reduced CSF orexin (hypocretin) level, all of which were improved simultaneously by steroid therapy. Further studies should be performed to determine the roles of anti-AQP4 antibody positivity in patients with hypersomnia associated with orexin (hypocretin) deficiency and hypothalamic lesions.

Clinical and genetic characterizations of 16q-linked autosomal dominant spinocerebellar ataxia (AD-SCA) and frequency analysis of AD-SCA in the Japanese population

Autosomal dominant spinocerebellar ataxias (AD‐SCAs) form a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, a single nucleotide substitution in the 5′‐untranslated region of the puratrophin‐1 gene was found to be associated with one type of AD‐SCA linked to chromosome 16q (16q‐SCA). To obtain further insight into the contribution of the C‐to‐T substitution in the puratrophin‐1 gene to the clinical and genetic characteristics of patients with 16q‐SCA, we analyzed 686 families with 719 individuals diagnosed with progressive ataxia. We found C‐to‐T substitution in the puratrophin‐1 gene in 57 unrelated families with 65 affected individuals. The mean age at onset in the patients with 16q‐SCA was 59.1 (range, 46–77). Ataxia is the most common initial symptom. The elderly patients over 65 occasionally showed other accompanying clinical features including abnormalities in tendon reflexes, involuntary movements, and reduced vibration sense. We also examined the frequency of the AD‐SCA subtype, considering the effects of age at onset. In the 686 AD‐SCA families, SCA6 and Machado‐Joseph disease/SCA3 are frequent subtypes, followed by dentatorubral‐pallidoluysian atrophy and 16q‐SCA. 16q‐SCA is not a rare subtype of Japanese AD‐SCA, particularly in patients with ages at onset over 60.

Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation

The clinical characteristics of colony stimulating factor 1 receptor (CSF1R) related adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) have been only partially elucidated.

Functional characterization of the P1059L mutation in the inositol 1,4,5-trisphosphate receptor type 1 identified in a Japanese SCA15 family.

Spinocerebellar ataxia type 15 (SCA15) is a group of human neurodegenerative disorders characterized by a slowly progressing pure cerebellar ataxia. The inositol 1,4,5-trisphosphate (IP(3)) receptor type 1 (IP(3)R1) is an intracellular IP(3)-induced Ca(2+) release channel that was recently identified as a causative gene for SCA15. In most case studies, a heterozygous deletion of the IP(3)R1 gene was identified. However, one Japanese SCA15 family was found to have a Pro to Leu (P1059L) substitution in IP(3)R1. To investigate the effect of the P1059L mutation, we analyzed the channel properties of the mutant human IP(3)R1 by expressing it in an IP(3)R-deficient B lymphocyte cell line. The P1059L mutant was a functional Ca(2+) release channel with a twofold higher IP(3) binding affinity compared to wild-type IP(3)R1. The cooperative dependence of the Ca(2+) release activity of the mutant on IP(3) concentration was reduced, but both wild-type and mutant receptors produced similar B cell receptor-induced Ca(2+) signals. These results demonstrate that the Ca(2+) release properties of IP(3)R1 are largely unaffected by the P1059L mutation.

Heterogeneity of cerebral TDP-43 pathology in sporadic amyotrophic lateral sclerosis: Evidence for clinico-pathologic subtypes

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are types of major TDP-43 (43-kDa TAR DNA-binding protein) proteinopathy. Cortical TDP-43 pathology has been analyzed in detail in cases of FTLD-TDP, but is still unclear in cases of ALS. We attempted to clarify the cortical and subcortical TDP-43 pathology in Japanese cases of sporadic ALS (n = 96) using an antibody specific to phosphorylated TDP-43 (pTDP-43). The cases were divided into two groups: those without pTDP-43-positive neuronal cytoplasmic inclusions in the hippocampal dentate granule cells (Type 1, n = 63), and those with such inclusions (Type 2, n = 33). Furthermore, the Type 2 cases were divided into two subgroups based on semi-quantitative estimation of pTDP-43-positive dystrophic neurites (DNs) in the temporal neocortex: Type 2a (accompanied by no or few DNs, n = 22) and Type 2b (accompanied by abundant DNs, n = 11). Clinico-pathologic analysis revealed that cognitive impairment was a feature in patients with Type 2a and Type 2b, but not in those with Type 1, and that importantly, Type 2b is a distinct subtype characterized by a poor prognosis despite the less severe loss of lower motor neurons, the unusual subcortical dendrospinal pTDP-43 pathology, and more prominent glial involvement in cortical pTDP-43 pathology than other two groups. Considering the patient survival time and severity of motor neuron loss in each group, transition from Type 1 to Type 2, or from Type 2a to Type 2b during the disease course appeared unlikely. Therefore, each of these three groups was regarded as an independent subtype.

Sacsin-related ataxia with neither retinal hypermyelination nor spasticity

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder characterized by early-onset spastic ataxia, peripheral neuropathy, and retinal hypermyelination (OMIM 270550).1 Recent reports have revealed the clinical diversity of ARSACS.2 In these patients, either spasticity or retinal hypermyelination has been observed. Here, we report a new nonsense mutation in SACS3 in Japanese siblings with neither retinal hypermyelination nor spasticity.

Long-term disability and prognosis in dentatorubral-pallidoluysian atrophy: A correlation with CAG repeat length†

Dentatorubral‐pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion. Previous studies demonstrated that the onset of DRPLA is closely associated with CAG repeat length. However, the natural history of DRPLA has not yet been evaluated. We here retrospectively investigated the factors that determine the disease milestones and prognosis in 183 Japanese patients genetically diagnosed with DRPLA. We determined the age at onset, age at which each of the subsequent clinical manifestations appeared, age at becoming wheelchair‐bound, and age at death. Kaplan‐Meier analysis revealed that the patients with CAG repeats larger than the median length of 65 repeats developed each of the clinical features of DRPLA at a younger age than those with <65 repeats. The patients became wheelchair‐bound at a median age of 33 years (n = 61; range, 3–77 years) and died at a median age of 49 years (n = 23; range, 18–80 years). The ages at becoming wheelchair‐bound and at death strongly correlated with the expanded CAG repeat length. Moreover, the patients with ≥65 CAG repeats showed a more severe long‐term disability and a poorer prognosis. In contrast, the rate of progression after the onset did not correlate with CAG repeat length. The CAG repeat length may have a considerable effect on not only the disease onset but also the disease milestones and prognosis in DRPLA patients. These effects of CAG repeat length may be relevant in designing future clinical therapeutic trials.

A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review

Objective: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. Methods: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced (“next generation”) sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. Results: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. Conclusion: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patients craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-β1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patients history, neurological exam, neuroimaging, and genetic testing are included.