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Ataxia with oculomotor apraxia type 1 (AOA1, MIM 208920) is an autosomal recessive disorder characterized by early-onset cerebellar ataxia, polyneuropathy, oculomotor apraxia, hypoalbuminemia, and hypercholesterolemia.1 It is caused by pathogenic variants of APTX, which encodes the aprataxin protein that is involved in DNA strand-break repair.1
We recruited a consanguineous family (coded as RDHM-02) with individuals affected by an undiagnosed movement disorder (Fig. 1A). The proband (VI:11, aged 40 years) was identified by personal contact. He had dysarthria and weakness of lower limb muscles. The disease onset reportedly occurred at ages of 2–6 years. The family history was obtained, and the affected individuals underwent standardized videotaping. The videos were evaluated by movement-disorders experts (C.K. and N.B.) after exome sequencing results were obtained. The proband and the other affected individuals in family RDHM-02 had cerebellar ataxia with severe gait impairment. Individual VI:11 exhibited severe polyneuropathy and a complete loss of ambulation by the age of 7 years, while individuals VI:13, VII:1, and VII:6 had ocular apraxia. Mild upper limb and moderate lower limb dystonia were observed in all affected family members except individual VI:11. Individual VII:6 exhibited a distinct high-frequency dystonic hand tremor and mild distal chorea of the upper limbs. The serum cholesterol level (234 mg/dL) was elevated in the oldest affected individual (who was aged 40 years), while the albumin levels were normal (Supplementary Table 1 in the online-only Data Supplement).
Genomic DNA was extracted from blood samples.2 Whole-exome sequencing was performed for two individuals (VI:11 and VI:12), and the variants were prioritized.3 Sanger sequencing confirmed the segregation of a novel homozygous nonsense mutation [c.388C>T (p.Gln130Ter)] in APTX (NM_175073.2) associated with the phenotype (Fig. 1A and B). The variant was absent from public databases and the DNA of 100 controls (200 chromosomes were analyzed).
APTX (Fig. 1C) encodes aprataxin, which is composed of three main domains: FHA (an N-terminal forkhead-associated domain), HIT (a histidine triad domain), and Znf (a C-terminal Cys2His2 zinc finger domain) (Fig. 1D). Relatively few variants of APTX result in complete deletion of the HIT and Znf domains.1 The mutation c.388C>T (p.Gln130Ter) in affected members of family RDHM-02 introduced a stop codon into the APTX open reading frame (Fig. 1D). This is probably a null allele due to invoking either nonsense-mediated decay of the mRNA4 or degradation of the truncated protein. Western-blot analysis of lymphoblastoid cell lines derived from AOA1 patients homozygous for different nonsense mutations (Fig. 1C) has revealed undetectable levels of aprataxin,1 which supports the present hypothesis.
Frame-shift, splice-site, and nonsense mutations of APTX are believed to cause early onset and more-severe phenotypes compared to those caused by the missense mutations.5 This is supported by the patients in family RDHM-02 having severe features of AOA1 with an early disease onset. Oculomotor apraxia and chorea have been observed in 85% and 80% of cases, respectively,5 and the latter manifestations were present in some of the patients in family RDHM-02 (Supplementary Table 1 in the online-only Data Supplement). Polyneuropathy and a complete loss of ambulation have been reported in AOA1 patients at 7–10 years after the disease onset.5 However, these phenotypes were clinically observed only in individual VI:11 in the present study, with the limitation that none of the affected individuals were evaluated by electrophysiological testing since this was not available. Hypercholesterolemia (75%) and hypoalbuminemia (83%) are variable features in AOA1 and appear at 10–15 years after disease onset.5 The oldest present patient (individual VI:11) had elevated cholesterol but a normal albumin level (Supplementary Table 1 in the online-only Data Supplement). The phenotypic variability among the patients in family RDHM-02 carrying an identical mutation underlines the difficulty of establishing genotype-phenotype correlations in autosomal recessive AOA1.
The current research has identified a new variant of APTX and highlights the utility of whole-exome sequencing in diagnosing a rare Mendelian disorder that could only have been diagnosed at a highly specialized movement-disorder center based on clinical findings. These findings have major implications for the family and their counseling, which can now be facilitated by utilizing whole-exome sequencing data.
We express our gratitude to all members of the family RDHM-02. Work reported here was supported by a career development award from the Hermann and Lilly Schilling Foundation (CK), Germany, research award from Chinese Academy of Sciences (SQ), China and award #2877 from Higher Education Commission (SN), Pakistan.
Conflicts of Interest: The authors have no financial conflicts of interest.
The online-only Data Supplement is available with this article at https://doi.org/10.3988/jcn.2017.13.3.303.
Clinical features of family RDHM-02