Contemporary Neurobiological Studies of Neuroacanthocytosis

The heterogeneous group of NA disorders can now be clearly classified on the basis of molecular genetic studies. The principal NA syndromes are autosomal recessive ChAc and X-linked McLeod syndrome, but now Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration can be included. All of these diseases share common neurological manifestations with involuntary movements, progressive deterioration of the higher cortical function, and can be diagnosed by clinical, laboratory and imaging techniques as well as by detecting gene mutations.

A number of highly significant advances in autosomal recessive ChAc have recently been reported from Japan. The disease has been linked in most families to chromosome 9q21, where Ueno and colleagues found a mutation in the gene encoding a large (3100 amino acids) protein designated "chorein" in 2001 [39]. A deletion was found in the coding region of the cDNA leading to a frame shift, resulting in the production of a truncated protein in both alleles of the patients and single alleles of the obligate carriers. This protein is thought to be an evolutionarily conserved protein that is probably involved in the cellular protein sorting and trafficking [25]. We have also reported a family with apparent autosomal dominant inheritance. From this family, our group found a novel single heterozygous frame shift mutation in the last nucleotide of exon 57 of the ChAc gene in 2003 [26]. In order to rule out Huntington's disease-like 2, in which autosomal dominant inheritance is seen, expansion of the CTG/CAG repeat within junctophilin-3 gene was excluded [27]. Our findings confirm that clinical features in patients with ChAc with apparent autosomal dominant inheritance does not differ from those in a recessive form. It remains unclear why one mutation in the ChAc gene causes recessive inheritance in one family and another mutation within the same gene causes an apparent autosomal dominant inheritance of ChAc.

Tomemori and colleagues produced a gene-targeted mouse model for ChAc in 2005 [37]. They identified the mouse ChAc cDNA sequence and the exon-intron structures of the gene, and produced a ChAc model mouse by introducing a deletion of 60-61 exons, using a gene-targeting technique. Hematological study of this model revealed typical acanthocytes in the peripheral blood with a marked increase of the osmotic fragility of red blood cells. Motor evaluation of these animals during late adult stages showed statistically significant changes with a shorter stride length, poorly coordinated balance in the Rotarod test, and decreased locomotor activity as compared to control animals. No involuntary movements were observed in this mouse model. Histopathological study also confirmed striatal degeneration with gliosis, consistent with the findings in humans with ChAc.

As a number of important neuroscientific advances in ChAc have come from Japan in recent years, we anticipate that this is a most promising arena for further developments in the study of NA syndromes, in particular ChAc.

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