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Introduction

Cerebellar ataxia is a progressive neurological disorder that is most frequently caused by inflammation or injury to the cerebellum. As the cerebellum regulates movement and muscular function, individuals with cerebellar ataxia often experience a lack of coordination and struggle to accomplish everyday chores. Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive disease. It presents early in life and its symptoms include progressive cerebellar ataxia, oculomotor apraxia, dysarthria, peripheral axonal neuropathy and hypoalbuminemia (1).

Acquired ataxias may be transient or chronic and may be triggered by environmental (trauma or toxin exposure) or medical (infection, tumors or stroke) factors. Hereditary ataxias are heterogeneous, with causal mutations documented in >50 genes and inheritance patterns ranging from classical dominant to recessive, mitochondrial to X-linked (2). Of note, four genes have been implicated in the development of AOA (3). AOA1 is prevalent in Japanese and Portuguese populations (4). Mutations in the APTX gene are primarily responsible for AOA1(5). This gene is located on chromosome 9p21. It encodes aprataxin and is involved in mitochondrial DNA repair through transcription regulation (5). Pathogenic variants of the APTX gene destabilize aprataxin and subsequently increase the effects of single-strand breaks in DNA, even when there are no apparent gross errors (6).

A total of 18 other mutations were identified as pathogenic variants of APTX; these mutations were found in 39 families (5). In the present case report, a patient with AOA1 is described, who had a novel homozygous missense mutation, His251Tyr, due to c.751 C>T substitution.

Case report

An eight-year-old female patient presented in 2021 at the pediatric neurology clinic of King Fahad Specialist Hospital Dammam (Dammam, Saudi Arabia) with progressive ataxia and an unsteady gait. The patient was the first child of healthy consanguineous parents. The patient had three healthy brothers and no family history of gait disturbances or neurological disorders. The patient's mother's pregnancy with the patient was uneventful and the patient was delivered at full term via normal vaginal delivery. The patient's birth weight was within the normal range and she was a healthy infant. The patient also achieved normal developmental milestones until the age of 14 months. The patient was able to sit without support at eight months of age and began walking at 14 months of age. The patient then began to experience imbalances during walking and recurrent falls. As the patient grew older, the patient's family noticed that the patient's ataxic gait was progressively worsening. The patient also subsequently presented with dysarthria and ataxic handwriting. A brief mental examination revealed that the patient performed normally at school and that the patient's cognitive function was normal. Prior to presentation, the patient was a healthy child with an unremarkable medical and surgical history. The patient had no history of recent infection, abnormal movements, visual or hearing difficulties, or developmental regression.

General examination revealed mild telangiectasia. The patient's growth parameters were within normal ranges, apart from the patient's head circumference, which was 50 cm below the 25th percentile. Motor examination revealed normal muscle bulk, tone and power bilaterally. The patient's deep tendon reflexes were +1 bilaterally in both the upper and lower extremities. Furthermore, the patient's Babinski reflex was bilaterally normal. Sensory examination results were also normal. An ocular examination revealed oculomotor apraxia. The patient had no nystagmus and the rest of the cranial nerves were unremarkable. A cerebellar examination revealed wide-based ataxic gait, head titubation, dysarthria, scanning speech, intention tremor, dysmetria and dysdiadochokinesia.

Brain magnetic resonance imaging (MRI) indicated diffused cerebellar atrophy (Fig. 1). No other brain parenchymal abnormalities were detected. Otherwise, the patient's MRI was unremarkable.

Figure 1 MRI images of the patient. (A) Axial MRI displaying cerebellar volume measurement; the red zone indicates the brain area. (B) Normal brain MRI of a sagittal view demonstrates normal vermis structures. (C) axial view and (D) coronal view demonstrate diffused cerebellar atrophy and vermian hypoplasia. Primary fissures (thick arrow) and pre-pyramidal fissures (thin arrow) are visible in the fastigium. (E) fastigium.

Laboratory analyses were performed to measure ammonia, lactate, albumin, lipid profile, immunoglobulins, alpha-fetoprotein, peripheral smear, serum vitamin E, serum and urine amino acids, serum and urine acylcarnitine, urine organic acids and fatty acids; all were normal and so were the patient's liver and renal function. The patient's audiological and ophthalmological examinations were also unremarkable.

Next-generation sequencing of 214 genes was performed using genomic DNA extracted from a blood sample using Human All Exon V6 (SureSelectXT Target Enrichment System for Illumina Paired-End Sequencing Library, version 1.3.1) (7). A variant of uncertain significance was identified; c.751C>T p.(His251Tyr) was detected with probable homozygosity in the APTX gene (chromosome 9). This variant of the APTX gene may be responsible for early-onset ataxia with oculomotor apraxia and hypoalbuminemia.

Discussion

Pathogenic variants of the APTX gene have been associated with early-onset ataxia. The present study reported on a rare case of an APTX gene mutation in an eight-year-old female patient. The patient was diagnosed with hereditary progressive ataxia. The identified variant, c.751C>T p.(His251Tyr) with probable homozygosity in the APTX gene (chromosome 9), was of uncertain significance. It is located in a highly conserved residue. This variant was detected with high confidence according to best practice guidelines (8,9). The following discussion explores the previously published literature on autosomal recessive cerebellar ataxias, with an emphasis on the APTX gene.

Autosomal recessive cerebellar ataxia (ARCA) is a set of disorders. ARCA subtypes related to AOA have recently been identified and classified into two major types: AOA1 and AOA2(10). Mutations in the APTX gene may lead to ataxia, with oculomotor apraxia and hypoalbuminemia (11,12). Aprataxin, a member of the histidine triad family, is encoded by the APTX gene (10). It has been identified as the causal gene in ataxia-oculomotor apraxia syndrome in a different group of individuals with autosomal recessive inheritance.

Individuals of various ethnicities may have mutations in the APTX gene (4,10,13,14) (Table I). The most prevalent ARCA mutation in Japan is c.689 690insT; in Portugal, it is c.837G>A (15,16). Shimazaki et al (15) performed a sequencing analysis of the APTX gene in six patients from four Japanese families. Except for one patient with a sporadic mutation, all other patients had inherited the condition in an autosomal recessive manner. Furthermore, two patients had a novel homozygous missense mutation (c.80A>G). In one case, a missense compound heterozygous c.95C>T mutation led to the replacement of proline with leucine at amino acid position 32. Tranchant et al (16) found two variants of the APTX gene in three non-Portuguese and non-Japanese individuals. One of these patients had a nonsense W279X mutation; the other two patients were French siblings who carried a missense K197Q mutation and a compound heterozygous nonsense W279X mutation. Sekijima et al (11) reported 689 insT in the APTX gene in a 14-year-old female with severe generalized dystonia. Another study reported 14 patients with APTX gene mutations in nine families, including five novel variants in exons 5 and 6 (A198V, D267G, W279R and IVS5+1) (13). To screen for APTX mutations, Habeck et al (17) tested 165 patients with early-onset ataxia in Germany. Another genetic study of 13 patients from three unrelated Tunisian families with AOA1 identified mutations in the APTX gene (18). APTX exon 7 deletions were detected in a family with normal clinical presentation of AOA1 and no severe phenotypes. With AOA1, it is difficult to establish an association between genotype and phenotype, as symptoms vary among different families with the same mutation (18).

Table I Comparative studies including clinical characteristics of previously reported cases.

Table I

Comparative studies including clinical characteristics of previously reported cases.

First author, year	Number of patients	Region	Age of onset	Clinical features	Genes	(Refs.)
Moreira, 2001	15 families	Portugal and Japan	2-5 years	Early-onset ataxia, cerebellar atrophy, ocula-motor apraxia and hypoalbuminemia	Exon 5: c.617C>T; c.689dupT (689insT), (689-690insT); Exon 6: c.837G>A	(4)
Date, 2001	7 families	Japan	First or second decade of life	Progressive ataxia, areflexia, sensory loss and hypoalbuminemia	Exon 5: c.617C>T; c.689dupT (689insT), (689-690insT);Exon 6: c.788T>G; c.841delT	(10)
Castellotti, 2011	13	Italy	3-7 years	Ataxia, dysarthria, nystagmus, areflexia, sensory neuropathy	Exon 3: c.477delC Exon 4: c.C541T Exon 7: c.C916T	(14)
Shimazaki, 2002	5	Japan	3-12 years	Cerebellar ataxia, peripheral neuropathy, oculomotor apraxia, external ophthalmoplegia, choreiform movements, facial grimacing, mental deterioration, cerebellar atrophy, hypoalbuminemia, hypercholesterolemia	Exon 5: c.602A>G; c.617C>T; c.689dupT (689insT), (689-690insT)	(15)
Tranchant, 2003	3	France and Italy	2 years and 15-22 years	1st Italian patient: Progressive ataxia, areflexia, oculomotor apraxia, hypoalbuminemia and hypercholesterolemia; 2 French siblings: Later onset of ataxia, areflexia, dysarthria and dystonia	Exon 5: c.589A>C Exon 6: c.837G>A	(16)
Le Ber, 2003	14	France (7 families), Italy (1 family) and Algeria (1 family)	2-18 years	Gait ataxia, chorea, dystonia, dysarthria, areflexia, axonal sensorimotor neuropathy	Exon 5: c.593C>T; c.770+1G>A Exon 6: c.835T>C; c.837G>A	(13)
Habeck, 2004	3	Germany	4-6 years	Cerebellar ataxia, dysarthria, oculomotor apraxia, areflexia and hypotonia	Exon 6: c.837G>A	(17)
Amouri, 2004	3 unrelated families	Tunisia	Mean of 5 years	Cerebellar ataxia, dysarthria, ocular apraxia, distal axonal neuropathy, cerebellar atrophy, hypoalbuminemia, hypercholesterolemia	Exon 7: c.875-1G>A; total deletion of gene	(18)

Recently, the APTX mutation c.484-2A>T was reported for the first time in a patient with Charcot-Marie-Tooth disease (19). Pedroso et al (20) described the case of a female patient with slow progressive gait impairment. Neurological tests revealed ocular motor apraxia and myoclonic jerks. AOA1 was verified by a homozygous mutation in the APTX gene (c.[837G>A];[837G>A]). In 2020, Ababneh et al (21) discovered a recurrent homozygous nonsense mutation (c.837G>A, p.W279*) in the APTX gene in three patients with AOA1. In a study of Palestinian and Israeli Arab families, WES identified a homozygous mutation, c.837G>A: p.(Trp279*), in a patient with speech and oculomotor apraxias and cerebellar ataxia (22).

Renaud et al (23) identified a p.Trp279 mutation in 53 patients with AOA1. In a consanguineous Iranian family with hereditary AOA1 (five affected and six unaffected individuals), WES revealed a novel homozygous stop-gain APTX gene mutation (c.739A>T; p.Lys247*) (3). Hirano et al (24) identified a homozygous two-base deletion in the middle of exon 3 of the APTX gene. Karimzadeh et al (25) reported a homozygous frameshift mutation, c.418_418 del, in the APTX gene. Complete homozygous deletion of APTX (62 kb) has also been reported in a patient with AOA1(26). Deletion of exon 6 of APTX in an 18-year-old female was reported by Paucar et al (27). A new homozygous deletion in c.643 and an A>T single nucleotide polymorphism in c.641 in exon 6 were discovered in a seven-year-old pediatric patient (28). Another study described a patient with a homozygous deletion of APTX and behavioral abnormalities (29). Castellotti et al (14) screened a large cohort and found variants of the APTX gene in 13 ataxic individuals (6%), 11 of whom were homozygous for the mutations p.W279X, p.W279R and p.P206L. They also observed three new mutations: c.477delC, c.C541T and c.C916T. A unique homozygous missense variant of APTX was discovered in a 34-year-old female patient born to consanguineous parents (30).

Although the above-mentioned studies provide valuable information about the likely function of APTX mutations in early-onset ataxia, genotype-phenotype correlations have not yet been clearly confirmed (18,31). In essence, while further research is required to establish the effect on the protein, a homozygous missense mutation, His251Tyr, caused by a c.751 C>T substitution in APTX, is probably deleterious for AOA1 in an autosomal recessive manner (32,33). Yokoseki et al (34) provided a comprehensive overview of this issue, finding that patients with the p.Pro206Leu or p.Val263Gly mutations had less gait disruption than those with the c.689 690insT mutations and that patients with the p.Pro206Leu or p.Val263Gly mutations had less gait disruption than those with the c.689 690insT mutations. In that study, patients with the c.689 690insT mutation exhibited a higher cumulative rate of inability to walk without assistance than those with the other mutations. Patients with p.Pro206Leu or p.Val263Gly mutations were found to have reduced ocular motor apraxia and no cognitive impairment, whereas patients with early-onset ataxia and hypoalbuminemia and the c.689 690insT mutation had more severe phenotypes. Those with the p.Pro206Leu or p.Val263Gly mutations presented with less ocular motor apraxia and no cognitive impairment, whereas patients with the c.689 690insT mutation had more severe symptoms, including early-onset ataxia and hypoalbuminemia (34).

Before drawing broad conclusions from the present study, it is necessary to recognize its limitations. The fact that the present study is a case study on a single patient means that various features of genotype-phenotype association may arise in other contexts. In addition, the present analysis is based on only exome sequencing data, which has constraints on its own. Future research should extend this area by using other methods for copy number variation detection, such as XHMM, CANOES and CLAMMS (35,36). Utilizing Sanger sequencing to validate the existence and homozygous condition of the variation will further reaffirm the conclusion of this report. In addition, it was not assessed whether the mutation was inherited, since no genetic testing was performed on any of the other family members because the parents refused further testing.

In conclusion, the present study reported on the identification of a variant of uncertain significance, c.751C>T p.(His251Tyr), in an eight-year-old female patient with hereditary progressive ataxia. Based on a detailed review of the literature, it was concluded that in patients with autosomal recessive or solitary instances of cerebellar ataxia that worsen over time, after Friedreich's ataxia has been ruled out, genetic testing should be used to check for APTX mutations. At first, there are usually no signs of oculomotor apraxia or other functional problems. However, choreic movements are likely caused by AOA1. As the AOA1 phenotype initially appears similar to other types of choreic disorders, early-onset choreic patients who do not have significant mutations in the IT15 or JPH3 genes should also be checked for APTX mutations. Early detection of hyperkinetic movement disorders in patients with AOA1 is important to ensure the right treatment is provided. Finally, patients with early-onset ataxia and mixed-movement disorders should be genetically tested for a number of diseases, including AOA1.

With breakthroughs in genetic testing, the identification of children with this disease will become easier in the future. Current treatments for AOA1 focus on rehabilitation therapy; there is currently no specific treatment for AOA1. Although the present results are encouraging, more research is required to establish the etiology of AOA1 in terms of causative mutations.

Acknowledgements

Not applicable.

Funding

Funding: No funding was received.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

RA, AA and SB designed the study. AA, GA and BA collected the clinical data. AA, GA, BA and RA analysed and interpreted the data. RA, AA, GA, BA and SB drafted the manuscript. RA and SB confirmed the authenticity of the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The study was carried out in accordance with the code of international and local Ethics (Declaration of Helsinki). This study was reviewed and approved by the local ethics committee of the King Fahad Specialist Hospital Dammam (Dammam, Saudi Arabia).

Patient consent for publication

The parents of the patient provided written informed consent for publication.

Competing interests

The authors declare that they have no competing interests.

References