| Summary: | Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis, progressive degeneration of the basal ganglia and neuromuscular features with characteristic persistent hyperCKemia. The main NA syndromes include autosomal recessive chorea-acanthocytosis (ChAc) and X-linked McLeod syndrome (MLS). A series of Italian patients selected through a multicenter study for these specific neurological phenotypes underwent DNA sequencing of the <i>VPS13A</i> and <i>XK</i> genes to search for causative mutations. Where it has been possible, muscle biopsies were obtained and thoroughly investigated with histochemical assays. A total of nine patients from five different families were diagnosed with ChAC and had mostly biallelic changes in the <i>VPS13A</i> gene (three nonsense, two frameshift, three splicing), while three patients from a single X-linked family were diagnosed with McLeod syndrome and had a deletion in the <i>XK</i> gene. Despite a very low incidence (only one thousand cases of ChAc and a few hundred MLS cases reported worldwide), none of the 8 <i>VPS13A</i> variants identified in our patients is shared by two families, suggesting the high genetic variability of ChAc in the Italian population. In our series, in line with epidemiological data, McLeod syndrome occurs less frequently than ChAc, although it can be easily suspected because of its X-linked mode of inheritance. Finally, histochemical studies strongly suggest that muscle pathology is not simply secondary to the axonal neuropathy, frequently seen in these patients, but primary myopathic alterations can be detected in both NA syndromes.
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