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.