Neuroacanthocytosis Syndromes in an Italian Cohort: Clinical Spectrum, High Genetic Variability and Muscle Involvement

Abstract

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 VPS13A and XK 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 VPS13A 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 XK gene. Despite a very low incidence (only one thousand cases of ChAc and a few hundred MLS cases reported worldwide), none of the 8 VPS13A 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.

Keywords: McLeod syndrome; VPS13A gene; XK gene; chorea-acanthocytosis; neuroacanthocytosis syndromes.

Figure 1

Pedigrees of the five choreo-acanthocytosis families (A–E), all with a clear recessive mode of inheritance. However, consanguineity was confirmed only for pedigree B (parents are second-degree cousins) and suspected for pedigree D (both parents carry the same VPS13A variant). Affected individuals are shaded in black. Family members that were sequenced are indicated by a dash on top of their symbol.

Figure 2

Pedigree of family F is compatible with X-linked inheritance. The molecular test of III:5 indirectly confirmed the diagnosis of McLeod syndrome for the other patients (I:1, I:2, III:4, and III:9) who had already died. Obligate carriers are indicated with a small black circle within their symbol.

Figure 3

Histological findings on muscle biopsy. The first column shows images of muscle stained with haematoxylin-eosin (H&E), the second with succinate dehydrogenase (SDH) and the third with myosinATPase at pH 9.4. (A–C) Case A-II:4 affected by ChAc: (A) moderate fiber size variability with some hypo-atrophic angulated fibers (black arrow) next to large hypertrophic fibers; (B) the great majority of type 1 fibers display multi-minicores and some poorly structured cores (white head-arrow); (C) atrophic fibers are organized in small-medium groups (type-grouping phenomena). (D–F) Case D-II:2 affected by ChAc; (D) very severe fiber size variability with numerous atrophic angulated fibers and atrophic fascicles, next to giant hypertrophic round fibers (black arrow); (E) severe myofibrillar architecture disruption with bizarre fiber shape, vortex fibers and presence of unstructured cores in most fibers (black arrow); (F) disruption of muscle architecture where fiber types are hardly distinguishable. (G–I) Case D-II:3 affected by ChAc; (G) poor fiber size variability with some hypotrophic fibers (black arrow); (H) rare structured core fibers (white arrowhead); (I) fibers grouping according to their histochemical type thus suggesting central denervation and reinnervation. (L–N) Case F-III:5 affected by McLeod syndrome; (L) fiber size variability with numerous clumps of naked nuclei (black arrow) and an infiltrate of inflammatory cells (white head-arrow); (M) numerous moth-eaten fibers (black stars); (N) some type grouping phenomena.