Neuroacanthocytosis syndromes are all exceedingly rare with an estimate prevalence of less than 1 to 5 per 1,000,000 for each disorder worldwide [2]. Currently, 43 pathogenic variants of XK gene have been included in the Human Gene Mutation Database (HGMD, v2019.4), including 13 missense/ nonsense variants, 6 splicing variants, 12 small deletion/ insertion/ indels and 12 gross deletions. In the Chinese population, there were 6 pathogenic variants of XK gene have been reported (Table 3), two of which were included in HGMD. Combined with three novel variants in the current study, there are 9 pathogenic XK variants including five nonsense variants, two small deletions and two gross deletions. ChAc are relatively more common than MLS. There are 126 pathogenic variants of VPS13A in HGMD, including 41 missense/ nonsense variants, 25 splicing variants, 48 small deletion/ insertion/ indels and 12 gross deletion/ insertion/ complex rearrangements. Combined with three novel variants in our study, there are 10 pathogenic VPS13A variants in the Chinese population (Table 1 and Table 3), including 7 missense/ nonsense variants, one splicing variant and two small insertion/ deletions. These 19 pathogenic variants were all from single families and we did not find any hotspot variant in the Chinese population.
Table 3
Reported Chinese patients with neuroacanthocytosis
Index no. | Gene | Nucleotide change (Amino acid change) | Exon | Variant type | HGMD | AAO | Main clinical symptoms | CK (U/L) | Language |
1 | XK | c.856_860del (p.L286Yfs*16) | 3 | Hemi | DM | 40 + Y | Wasting of limb muscles, chorea of feet | 2148 | English [4] |
2 | XK | c.154C > T (p.Q52*) | 1 | Hemi | DM | 62Y | Myalgia, muscle fatigue, chorea of toes | 602–3328 | English [5] |
3 | XK | Gross deletion: entire gene + CYBB + ex.1–44 DMD | 1–3 | Hemi | NA | 4Y1M | Chronic granulomatous disease, unexpected discovery | 7149 | Chinese [6] |
4 | XK | Gross deletion: entire gene + CYBB + ex.1–2 DMD | 1–3 | Hemi | NA | 1Y9M | Chronic granulomatous disease, unexpected discovery | 2837 | Chinese [6] |
5 | XK | c.89C > A (p.S30*) | 1 | Hemi | NA | 10M | Fever, seizure, unexpected discovery | 14889 | English [7] |
6 | XK | c.1004G > A (p.W335*) | 3 | Hemi | NA | 40 + Y | Chorea of limbs, orolingual dystonia | 928–1280 | Chinese [8] |
7 | VPS13A | c.7280_7284del (p.Y2427Sfs*6) c.8278C > T (p.Q2760*) | 52 60 | Het Het | DM DM | 30Y | Chorea of limbs, orolingual dystonia, tongue and lip biting, seizure | 1122 | English [9] |
8 | VPS13A | c.8282C > G (p.S2761*) c.9276-1G > A | 60 70 | Het Het | DM DM? | 45Y | Orolingual dystonia, tongue and lip biting | 137 | English [9] |
9 | VPS13A | c.486T > G (p.Y162*) | 6 | Hom | NA | 28Y | Chorea of limbs, orolingual dystonia, tongue and lip biting, seizure | 404 | Chinese [10] |
10 | VPS13A | c.8823C > G (p.Y2941*) | 65 | Hom | DM | 26Y | Chorea of limbs, orolingual dystonia, tongue and lip biting, seizure | NA | English [11] |
11 | VPS13A | c.80dup (p.S28Lfs*17) | 1 | Het | NA | 26Y | Chorea of limbs, orolingual dystonia, tongue and lip biting | 453 | English [12] |
XK: NM_021083.3; VPS13A: NM_033305.2; Het: heterozygote; Hemi: hemizygous; Hom: homozygous; Het: heterozygous; HGMD: Human Gene Mutation Database (v2019.4); DM: disease causing; NA: not available; AAO: age at onset; Y: years old; M: months; CK: creatine kinase. |
MLS and ChAc share a number of similar features [17] and there is a striking phenotypic overlap in these two disorders, including age at onset, chorea, dysarthria, orofacial dyskinesia, seizures, psychiatric symptoms and brain MRI, but some clues may help to differentiate them. First, in genetics, MLS is inherited in an X-link way and ChAc in an autosomal recessive manner. Therefore, the family history and the gender can give important clues to help diagnosis. Besides, the gross deletion in XK gene often involves adjacent genes such as DMD, CYBB, RPGR and OTC, and leads to concomitant disorders such as dystrophinopathy, chronic granulomatous disease, retinitis pigmentosa and ornithine transcarbamylase deficiency [18]. Although our patients did not have gross deletions, which have been reported in two Chinese patients with chronic granulomatous, whose DMD genes were also involved [6]. It is important to screen MLS phenotype in males with chronic granulomatous disease for complication monitoring and management. In clinical manifestations, the orolingual dystonia is more frequently presented in ChAc. In our study and previous reports in the Chinese population, all ChAc patients had orolingual dystonia, but less than half MLS had the condition. In addition, the severity often disproportionate to other involuntary movements in ChAc. For example, self-mutilating tongue and lip biting, which present in 40% of Caucasians [19] and 85% (6/7) of reported Chinese ChAc patients, are very rare in MLS patients [17].
In the other hand, MLS patients seemed to have higher CK levels than ChAc in the Chinese population. About 78% of MLS patients (7/9) had CK above 1000 U/L, whereas only one of six ChAc patient reached this level. Moreover, MLS patients can have muscle complaints with mild involuntary movements, which often lead to a confusion with myopathy [4, 5]. However, the EMG usually show axonal neuropathy, so sometimes these patients can be misdiagnosed with Kennedy’s disease, which is also an X-link disorder manifests with proximal weakness, hyperCKemia, and axonal neuropathy-mimic EMG [20]. Therefore, it is important to pay attention to mild involuntary movement and differentiate MLS in males with both hyperCKemia and a neuropathic EMG. The acanthocyte rate in peripheral blood can usually fall 5–50% in ChAc and 8–30% in MLS [2], which is consistent with our results. However, the presence of acanthocytes may vary over time and can be absent in some cases [21–24], thus cannot be used to distinguish different NA syndromes.