ChAc is an autosomal recessive neurodegenerative disorder, with an incidence of 3 in 10 million people, higher in men or those aged 20–30 years [7]. Because of its insidious onset, low incidence and unspecific symptoms, ChAc is easy to be misdiagnosed and missed. Here, we detailed the clinical symptoms, laboratory indexes, imaging features, genetic variations in one ChAC case, which may provide more reference for the diagnosis and treatment.
The patient suffered from lingual dystonia, tongue and lip biting, dysarthria, progressive chorea, elevated serum muscle enzymes, peripheral neuropathy, and psychiatric symptoms, all suggesting multisystemic involvement of ChAc disease. ChAc is typically manifested by early limb chorea and tongue dystonia[8], Tongue dystonia is occasionally reported in Tardive dyskinesia, McLeod syndrome, and pantothate myoase-dependent neurodegenerative disease (PKAN), but all these diseases develop without lip autophagy or biting[9]. Therefore,lip autophagy or biting may distinguish these diseases from ChAc.
Elevated serum creatine kinase is also an important diagnostic index.Whether muscle and peripheral neuropathy are the primary or secondary cause of ChAc is still controversial[10] .Peripheral neuropathy is an important features that distinguishes ChAc from other chorea[11, 12]. Psychiatric symptoms are also the clinical symptoms of ChAc, with depression and OCD symptoms being the most common [13]. ChAc develops with striatal degeneration, especially caudate degeneration[14]. Neuropathological examination also suggests that neuronal loss and gliosis are more obvious in the caudate nucleus[15]. Therefore, ChAc often shows expansion of bilateral lateral ventricles and caudate atrophy on imaging MRI[16], which also appeared on the MRI in the present case. In addition, we performed electronic microscopy of peripheral red blood cells, finding that “spinous red blood cells accounted for 1%”. In general, the proportion of spine erythrocytes in the normal peripheral blood smear does not exceed 3%, but may rise to 5–50% in ChAc patients[17]. However, many ChAc patients present negative spine erythrocytes, which may be explained by the difference in experimental equipment and methodology. Some patients develop spine erythrocytes only in the late stage of the disease[18]. It is also possible that the spine-erythrocyte-associated signaling pathway is not activated[19]. Therefore, peripheral blood cell smear analysis is useful for the diagnosis of ChAc, but even if the result is negative or less than 3%, the possibility of ChAc diagnosis cannot be excluded.
Although an initial diagnosis of ChAc can be established based on the patient's clinical manifestations, imaging, muscle enzymes, electromyography, and peripheral blood smear results, a "genetic diagnosis" is always needed. The VPS13A on chromosome 9q21 has been recognized as a causative gene, including 72 exons and encoding the chorein protein [20]. VPS13A mutations dysregulate chorein protein to promote actin polymerization, thus leading to cell membrane rupture and echinocytosis[21]. VPS13A mutations may involve frameshift mutations, large deletions/repeats, small insertions/deletions, splice site mutations, nonsense mutations, or missense mutations, all increasing the complexity of ChAc diagnosis[22, 23].
In the present case, two heterozygous mutations in the VPS13A gene were detected: (1) c.4242 + 1G > T (NM_033305; exon36) resulting from amino acid splicing; (2) c.9270_9274dupCAGAC (exon69, NM_033305) resulting from a frameshift in the amino acid R3092Pfs * 8, which is located in the last 10% of the coding region. Both mutations lead to the dysfunction of VPS13A. We also performed genetic testing on the parents and two sons of the proband. The father had no abnormal mutation, and but the mother and both sons each contained one VPS13A heterozygous mutation c.4242 + 1G > T, suggesting that the heterozygous mutation of VPS13A (c.4242 + 1G > T) is inheritable in the proband's family. The heterozygous mutation of VPS13A (c.9270_9274dupCAGAC) is a spontaneous mutation. Its pathogenicity remains unknown according to the ACMG guidelines, and has never been reported in the literature database. However, the present case proves that this mutation may also serve as main cause of neurological symptoms.
This patient was treated with oral tablets of sulphide hydrochloride (100 mg, 3 times daily), olanazapine (5 mg once a night), benzhexol (2 mg once daily), escitalopram (5 mg once daily), aripiprazole (5 mg once daily). During the hospital stay, the symptoms showed no significant improvement. During a follow-up of 3 months, the patient had one episode of GTCS. EEG in the community hospital found epileptic discharge. No further diagnosis and treatment were made, not antiepileptic drugs were given. At present, the symptoms of ChAc can only be alleviated by drugs and surgery. Non-autonomous motor symptoms can be treated with dopamine antagonists or consumptive drugs, such as thiazoline and clozapine. Levodopa relieves dystonia, and focal botulinum toxin injection improves oratoid dystonia in ChAc patients[24, 25]. Deep brain stimulation is increasingly adopted as a new treatment for ChAc[26].
In conclusion, a female was diagnosed with ChAc according to clinical, imaging, muscle enzyme, electromyography, peripheral blood smear, genetic test results. The whole-exome sequencing of the proband and her family members showed two new pathogenic mutation sites of VPS13A gene in the proband. This case report can provide new information about the symptoms and genetic factors of ChAc.