Different clinical phenotypes in siblings with a presenilin-1 P264L mutation.

BACKGROUND: Mutations in the presenilin-1 gene (PSEN1) have been identified in autosomal dominant early-onset cases of Alzheimer's disease (AD). AIMS: To investigate different clinical phenotypes of siblings possessing the same heterozygous P264L mutation in the PSEN1 gene. METHODS: We evaluated clinical features, neuroimaging results, and neuropsychological examinations. The PSEN1 gene and other dementia-related gene mutations were screened. RESULTS: We clinically diagnosed the proband as atypical AD with frontotemporal dementia features and diagnosed the elder brother of the proband as typical AD, based on neuropsychological symptoms and a brain imaging examination including amyloid imaging data. A heterozygous P264L mutation in the PSEN1 gene was identified in both siblings. CONCLUSION: This study is one of few reports of AD siblings possessing the same mutation but exhibiting different clinical phenotypes in a Japanese family possessing a P264L mutation in the PSEN1 gene. The current results suggest that unknown modifiers, including both genetic and epigenetic factors, may alter the pathological and clinical phenotypes of a genetically predetermined disease.

Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Familial semantic dementia with P301L mutation in the Tau gene.

BACKGROUND/AIMS: Semantic dementia (SD) is a clinical subclassification of frontotemporal lobar degeneration. Patients with 'pure SD' present with semantic memory impairment preceding the frontal symptoms, and there have been no reports of familial cases. METHODS: We evaluated the clinical features of, and performed neuropsychological examinations on, the proband and two affected family members. Then we performed neuroimaging and genetic analysis of MAPT and other dementia-related genes in the proband. RESULTS: All three cases had semantic memory impairment with loss of word meanings as the primary early symptom. We diagnosed all cases as pure SD and identified a P301L mutation in the MAPT gene of the proband. CONCLUSION: Although the P301L mutation identified here has been previously described as pathogenic for frontotemporal dementia with parkinsonism-17 (FTDP-17), the proband and his two affected relatives showed different clinical symptoms from those of typical FTDP-17 cases who carry the P301L mutation. Pathologically, pure SD usually shows a TAR DNA-binding protein proteinopathy, but the molecular understanding of SD is not well established. Although our cases were clinically pure SD, the proband has a tau gene mutation, which would lead to tauopathy. These findings suggest that reconsideration of the molecular understanding of SD is warranted.

Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD.

Comprehensive analysis of the genes responsible for neuroacanthocytosis in mood disorder and schizophrenia.

Neuroacanthocytosis syndromes are mainly comprised of two diseases: chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). There is a high incidence of psychiatric disorders such as mood disorder and schizophrenia among neuroacanthocytosis patients. We hypothesized that neuroacanthocytosis-related-genes might be associated with susceptibility to these psychiatric disorders. We performed a comprehensive mutation screen of VPS13A and XK, the gene responsible for ChAc and MLS, respectively, in 85 mood disorder subjects and XK in 86 schizophrenia subjects and compared the variants to 100 or more control alleles. We also performed copy number variation (CNV) analysis in 72 mood disorder subjects and 86 schizophrenia subjects. We identified three non-synonymous, two synonymous and six intron variants in mood disorder subjects and a novel GAT triplet repeat polymorphism in VPS13A. By CNV analysis, we identified a heterozygous exon 60-61 deletion in VPS13A in one mood disorder subject. We identified one non-synonymous and one intron variant in mood disorder and schizophrenia subjects, respectively, in XK. The presence of a pathogenic mutation or a potentially functional variant in mood disorder or schizophrenia subjects suggests that neuroacanthocytosis-related-genes might be involved in the pathogenesis of these psychiatric disorders.

Mitochondrial DNA deletion mutations in patients with neuropsychiatric symptoms.

It has been suggested that mitochondrial dysfunction is important in the pathogenesis of psychiatric disorders such as depression, schizophrenia and dementia. We report herein three adult patients exhibiting such psychiatric symptoms as the core manifestation, accompanied by various degrees of myopathic symptoms. Pathological findings in biopsied skeletal muscle were compatible with mitochondrial myopathy in all cases. Maternal inheritance was not apparent in all three cases; however, two patients were born to consanguineous parents. Mutation analysis on the mitochondrial DNA (mtDNA) and seven nuclear genes, in which pathogenic mutations are known to cause mtDNA deletions, was performed. MtDNA deletion mutations were identified in skeletal muscles of all patients. Neither pathogenic mutations nor copy number variation was identified among the nuclear genes. Although further studies are needed, the molecular pathways inducing mitochondrial abnormalities may be implicated in a variety of psychiatric conditions.

[Neuroacanthocytosis update].

Neuroacanthocytosis is an inclusive term for a genetically heterogeneous group of disorders characterized by the association of neurological abnormalities with red cell acanthocytosis. In the late 1960s, Levine et al. reported a family with a syndrome of neurological deficits such as choreiform involuntary movements, epileptic seizures, intellectual impairment, and paranoid ideation along with acanthocytosis without any disturbance in either alpha- or beta-lipoproteins nor retinitis pigmentosa. Critchley et al. also reported familial cases with acanthocytosis and neurological disorders without beta-lipoproteinemia. These cases have been classified as the Levine-Critchley syndrome of neuroacanthocytosis. Cases of neuroacanthocytosis have been classified into 2 groups depending on the presence or absence of movement disorders such as chorea. One group comprises the core neuroacanthocytosis syndromes in which neurodegeneration occurs primarily in the basal ganglia, specifically the striatum, causing movement disorders. The core neuroacanthocytosis syndromes mainly comprise of the two diseases, chorea-acanthocytosis and the McLeod syndrome. Huntington's disease-like 2, and pantothenate kinase-associated neurodegeneration (PKAN) are very rare but these diseases can also be included in this group of syndromes. Advances in molecular genetics have enabled us to distinguish between these diseases. Recently, the hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa and pallidal degeneration syndrome (HARP syndrome) has been genetically shown to be an allelic form of PKAN. The second group of neuroacanthocytosis syndromes includes abetalipoproteinemia (Bassen-Kornzweig disease) and hypobetalipoproteinemia that are characterized by the abnormal decay of lipoprotein with the intestinal malabsorption of fat leading to neurological abnormalities and acanthocytosis. In this type of neuroacanthocytosis shows a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa are observed, but movement disorders are not seen.

Clinical and molecular genetic assessment of a chorea-acanthocytosis pedigree.

BACKGROUND: Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. There are only few reports that studied clinical status of the obligate carriers of ChAc. Clinical courses with follow-up neuroradiological and neuropsychological evaluations in individuals with ChAc have been rarely reported. METHODS: We followed an index patient with ChAc and evaluated the clinical features of the pedigree members. Genetic analyses of VPS13A and genes responsible for other neuroacanthocytotic and neurodegenerative diseases were performed. CONCLUSIONS: The index patient was homozygous for a 3889C>T nonsense mutation in the VPS13A gene and presented with a typical ChAc phenotype. Neuropsychological evaluation with brain imaging in the patient over 3 years revealed atrophy and a decrease in blood flow at the basal ganglia and frontal lobe, and impairment in cognitive function reflecting frontal lobe dysfunction in progressive manners. Four out of five heterozygous mutation carriers in the pedigree showed signs or symptoms potentially attributable to a heterozygous VPS13A mutation.

Brain-specific transcript variants of 5' and 3' ends of mouse VPS13A and VPS13C.

Mutations in vacuolar protein sorting 13A (VPS13A) gene are responsible for chorea-acanthocytosis (ChAc). We previously determined the full-length sequence and exon-intron structure of mouse VPS13A and generated a ChAc model mouse by using the gene targeting technique. In the process, we found diverse 5' and 3' transcript variants. Since ChAc is a rare neurodegenerative disorder, the mouse model should be useful for investigation of ChAc molecular pathogenesis, and the model's brain specific variants of VPS13A will be indispensable in these investigations. In the present study, we investigated mouse VPS13A transcript variants. We found brain-specific variants of mouse VPS13A, which may be involved in the brain-specific pathology of ChAc. In addition, we identified for the first time mouse VPS13C cDNA sequences and brain-specific variants of VPS13C.

In vivo distribution and localization of chorein.

Chorea-acanthocytosis (ChAc) is a hereditary neurodegenerative disorder caused by loss of function mutations in the VPS13A gene encoding chorein. In this study, we produced an antibody against chorein and examined its protein-level expression and localization in mouse. Immunoblot analysis revealed that chorein was expressed in a gene dose-dependent manner in the VPS13A deletion-mice that we recently developed, which confirms the sensitivity of the antibody. Chorein was highly expressed in testis, kidney, spleen, and brain, and was expressed ubiquitously in various brain regions. Subcellular analysis of the brain showed high levels of chorein in microsomal and synaptosomal fractions. Immunohistochemically, chorein-like immunoreactivity was ubiquitously observed in the brain in the neuronal perinuclear region, cytoplasm and fibers. In testis and kidney, clear cell-specific patterns of chorein-like immunoreactivity were detected. Our findings provide basic information on chorein in vivo and may contribute to taking the first step toward understanding molecular pathogenesis of ChAc.

Chorein deficiency leads to upregulation of gephyrin and GABA(A) receptor.

Chorea-acanthocytosis (ChAc) is a hereditary neurodegenerative disorder caused by loss of function mutations in the VPS13A gene encoding chorein. Recently, using a gene-targeting technique to delete exons 60-61, we produced a ChAc-model mouse that corresponds to a human disease mutation. In this study, a comparative microarray analysis of gene expression in the striatum revealed an increased level of gephyrin gene expression in the ChAc-model mice compared with wild type mice. Since gephyrin is known as a GABA(A) receptor-anchoring protein, we compared the protein-level expression and localization of gephyrin and the GABA(A) receptor alpha1 (GABRA1) and gamma2 (GABRG2) subunits. Gephyrin and GABRG2 immunoreactivities in the striatum and hippocampus of the ChAc-model mice were significantly higher than those in the wild types. Our results suggest that chorein functional loss may lead to a compensatory upregulation of gephyrin and GABRG2 in the pathologic condition in ChAc.

A gene-targeted mouse model for chorea-acanthocytosis.

Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene and produced a CHAC model mouse introducing no. 60-61 exon deletion corresponding to a human disease mutation by a gene-targeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.