Ataxia without oculomotor apraxia - An unfamiliar tale of imbalance

Dear Editor, We present the case of a 33-year-old woman, who presented to our hospital with difficulty in walking and imbalance for 2 years and numbness in the feet for the past 1.5 years. She was born in a consanguineous marriage and had normal developmental milestones, no medical comorbidities, and insignificant family history. The pedigree chart is depicted in Figure 1. Extraocular movements indicated mild gaze-evoked nystagmus. Physical examination revealed no musculoskeletal deformities. Motor system examination revealed normal power, tone, and deep tendon reflexes. The patient had an ataxic gait and diminished vibration below the knees, associated with positive Romberg’s sign. She did not experience slurred speech, oculomotor apraxia (OMA), or cognitive decline [Video 1]. Her thyroid levels, vitamin B12 levels, and lipid and immunoglobulin profiles were unremarkable. Alpha-fetoprotein (AFP) was within the normal range (22.3 ng/mL; normal: 0–40 ng/mL), and creatinine phosphokinase was mildly elevated (157 U/L; normal: 10–20 mcg/L). A nerve conduction study indicated bilateral severe sensorimotor polyneuropathy in the lower limbs. Magnetic resonance imaging of the brain revealed the presence of diffuse cerebellar volume loss in both cerebellar hemispheres with atrophy of bilateral middle and inferior cerebellar peduncles [Figure 2]. Spinocerebellar ataxia (SCA) repeat expansion analysis for common types (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA12) revealed no abnormal repeat pattern. Clinical exome sequencing revealed a novel homozygous pathogenic 4-basepair deletion variant in exon-10 of the SETX gene, which results in a frameshift and premature truncation (ENST00000224140.6:c.5065_5068dup;p.Ile1690LysfsTer11). Although targeted variant testing for parents and siblings (cascade testing) was advised, the family members were not willing. The patient was diagnosed with ataxia with ocular apraxia type 2 (AOA type 2) and started on gait physiotherapy and supportive measures. She reported mild symptomatic improvement at the 6-month follow-up visit.Figure 1: Pedigree chart displaying family members {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_ecf1rzar"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Figure 2: (a) Diffuse cerebral volume loss, (b) and (c) diffuse cerebellar volume loss with prominent folia seen involving both cerebellar hemispheres, (d) atrophy of bilateral middle and inferior cerebellar peduncles (marked by arrows)Discussion Ataxia with oculomotor apraxia (AOA) is a group of inherited conditions that cause progressive problems with movement and coordination. The most common types of AOA are AOA1, 2, and 4, which are fairly comparable and result from variants in different genes. AOA1, the most commonly occurring type, is characterized by cerebellar ataxia, OMA, dysarthria, peripheral axonal neuropathy, and hypoalbuminemia.[1] It is associated with variants in the APTX gene. AOA4 typically begins in childhood. In addition to ataxia and OMA, individuals with AOA4 often develop dystonia, which can be an early symptom of the condition that diminishes over time. Patients frequently experience muscular atrophy in their hands and feet.[2] AOA4 is associated with variants in the PNKP gene. AOA2 is a rare autosomal recessive disorder characterized by sensorimotor neuropathy, progressive cerebellar ataxia, OMA, strabismus, chorea, and/or dystonia, with elevated AFP levels.[3] OMA is a sporadic feature in AOA2 and is less common than in AOA1, found in 86% of patients.[3] The frequency of OMA varies among cohorts. Anheim et al.[4] discovered OMA in 51% of the 90 individuals they studied, whereas Tazir et al.[5] found it in 32% of the 19 patients investigated. AFP levels are elevated in several autosomal recessive cerebellar ataxias (ARCAs), including ataxia telangiectasia (AT), AOA2, AOA1, and AOA4.[6] In AOA2, the AFP levels remain stable, whereas in AT, they increase progressively throughout the disease.[4] AFP level elevation is considered a ubiquitous hallmark of AOA2 (present in 99%–100% of cases), although it does not correlate with disease duration or severity.[4,5] AOA2 may manifest as ataxia and peripheral neuropathy in adulthood, occasionally without elevation of AFP levels, as observed in our patient. Clinical exome sequencing revealed the presence of a novel pathologic variant associated with the exon 10 of the SETX gene, suggestive of AOA2. The SETX gene associated with AOA2 is mapped to chromosome 9q34. It codes for senataxin, which is involved in DNA repair. To date, 125 variants of the SETX gene have been identified. Recent evidence suggests that the depletion of senataxin may impair mRNA transcription and processing.[7]Table 1 represents a compilation of all AOA cases reported in the Indian subcontinent.Table 1: Ataxia with oculomotor apraxia type 2Cerebellar ataxia with peripheral neuropathy can be caused by several underlying conditions, including genetic problems, certain infections, toxins, metabolic abnormalities, or autoimmune processes. Table 2 depicts differential diagnoses for patients presenting with cerebellar ataxia and peripheral neuropathy. Table 3 presents the common etiologies of episodic ataxia. Table 4 presents conditions with ataxias and other features predominantly associated with them. Table 5 presents the radiological features of ataxic disorders. Table 6 presents clues to treatable ataxias. Figure 3 is a flow chart showing the evaluation of patients having ataxia with peripheral neuropathy.Table 2: Diseases associated with cerebellar ataxia and peripheral neuropathyTable 3: Episodic ataxias associated with other genetic disorders[ 13 ]Table 4: Conditions with ataxias and their other predominant features[ 14-16 ]Table 5: Radiological features of ataxic disorders[ 17-19 ]Table 6: Clues to treatable ataxias[ 20 ]Figure 3: Flowchart for diagnosing patients with cerebellar ataxia with peripheral neuropathy; Anti-GAD antibody syndrome: Anti-glutamic acid decarboxylase (GAD) antibody syndrome; AOA: Ataxia with oculomotor apraxia; ARCA: Autosomal recessive cerebellar ataxia; ARSACS: Autosomal recessive spastic ataxia of Charlevoix–Saguenay; A-T: Ataxia telangiectasia; AVED: Ataxia with vitamin E deficiency; CIDP: Chronic inflammatory demyelinating polyneuropathy; CMT: Charcot–Marie–Tooth disease; CMV: Cytomegalovirus; EBV: Epstein Barr virus; FRDA: Friedreich’s ataxia; GBS: Guillain–Barré syndrome; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; HTLV: Human T-lymphotropic virus; MFS: Miller Fisher syndrome; MS: Multiple sclerosis; SCA: Spinocerebellar ataxia; SLE: Systemic lupus erythematosus; SPG7: Spastic paraplegia 7; VZV: Varicella zoster virusAtaxia can be caused by various conditions, and the approach to further investigations depends on the genetic inheritance and clinical presentation. For individuals with sporadic or autosomal recessive ataxias and a normal SCA panel, considering the clinical or whole exome panel can be beneficial for diagnosis. Confirming a genetic diagnosis can end the lengthy diagnostic process and alleviate the frustration of diagnostic uncertainty. This information can then be used to predict the future prognosis, guide decisions about having children and family planning, and potentially identify a treatable genetic cause, allowing for earlier intervention and supportive treatment. However, it is important to note that clinical or whole exome sequencing cannot identify trinucleotide expansions. Conclusions Ataxia with OMA constitutes a diverse genetic disorder and variable presentation. The investigation approach is based on inheritance patterns and clinical phenotypes, utilizing genetic tools such as the SCA panel, clinical sequencing, and whole exome sequencing to aid diagnosis. Our case underscores the importance of a comprehensive approach that utilizes inheritance patterns, disease progression, clinical symptoms, and tailored investigations such as SCA or whole exome panels. A definitive genetic diagnosis not only provides clarity but also guides prognosis and enables effective management of these complex neurological conditions. Acknowledgement None. Author contribution Research project: Conception: Organization: Execution: Statistical analysis: Design: Execution: Review and Critique: Manuscript preparation: Writing of the first draft: Review and Critique: Conceptualization, Vijayashankar Paramanandam; Methodology: Vijayashankar Paramanandam, A.N.S. Madhuri, N.Indumathi; Writing—original draft preparation: Aishwarya Mahesh Kumar; Writing—review and editing: Aishwarya Mahesh Kumar, A.N.S. Madhuri; Supervision: Vijayashankar Paramanandam,N.Indumathi. All authors have read and agreed to the published version of the manuscript. Ethical compliance statement The authors confirm that the approval of an institutional review board/ patient consent was not required for this work. We also confirm that the patient has given written informed consent for the publication of her images. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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