Hot Cross Bun Sign in Progressive Ataxia with <scp>ELOVL4</scp> Mutation—Case Report

Spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders that encompass progressive ataxia along with abnormal eye movements, fine motor movement difficulties, gait abnormalities, peripheral neuropathy, and autonomic dysfunction.1 There are currently approximately 50 different SCAs described that are distinguished either by their gene mutation or chromosomal location of the mutation if an exact gene is not known.2 Few neuroimaging findings may point to a particular subtype and its subsequent mutation. SCA 34 or ataxia (ATX)-ELOVL4 has been reported in seven families as well as another single patient.3 Its prevalence is noted to be 0.2% of patients with ataxia in the Japanese population.4 The mutation associated to this SCA subtype is in elongation of very long-chain fatty acids-like 4 (ELOVL4) whose function we discuss below.3 Pontocerebellar degeneration may lead to the typical “hot-cross bun” sign, which is commonly associated with multiple system atrophy- cerebellar subtype and some other SCA syndromes, but has been described in other SCA34 cases as well.1, 3, 5, 6 A 65-year-old Caucasian woman presented to the clinic for difficulties with her gait and speech. Her earliest symptoms included difficulty with riding a bike at 30 years of age. In her mid-50s, she developed problems with speech, swallowing, double vision, and required a cane for ambulation. At age 60, she transitioned to a walker. At the time of her clinical presentation, she had developed autonomic dysfunction including, bowel, and bladder incontinence. On further investigation, she had family history of similar issues in her daughter, mother, maternal aunt, maternal grandmother, and maternal great aunt. Her exam demonstrated end gaze nystagmus and square wave jerks. She had reduced optokinetic response in vertical and horizontal directions. There was significant dysmetria on finger to nose testing as well as past pointing on finger chase exam (see Video 1 ). Patient demonstrated trace bradykinesia on finger tap and hand movements. Her gait was ataxic requiring a walker to ambulate. She was diffusely hyperreflexic. Overall, her exam was asymmetric with worsened findings on the left side. There were no skin lesions on examination. Magnetic resonance imaging (MRI) of her brain revealed cerebellar and brainstem atrophy with hot cross bun sign (Fig. 1). Whole exome sequencing revealed heterozygous missense variant in ELOVL4, coding DNA: c.736 T > G, p.W246G. Patient was treated with amantadine (100 mg) twice a day dose, but did not perceive any benefit. Physical and speech therapy were also recommended. ELOVL4 is a protein that belongs to the ELOVL family of fatty acid elongases that are responsible for catalyzing formation of long chain fatty acids.7 This protein catalyzes both very long chain saturated fatty acids (VLC-SFA) and very long chain polyunsaturated fatty acids (VLC-PUFA), which in the central nervous system (CNS) are thought to be important for synaptic signaling (regulating presynaptic neurotransmitter vesicle release) and neuronal survival (found at higher levels compared to other cells).7 Mutations of this gene cause a variety of conditions including Stargardt-like macular dystrophy, spinocerebellar ataxia 34 (SCA34), or neuro-ichthyotic syndrome (infantile onset of seizures, spasticity, intellectual disability, ichthyosis, and premature death).7 To our knowledge, there have been 5 different ELOVL4 mutations described for SCA34: c.539A > C, p.Q180P; c.504G > C, p.L168F; c.736 T > G, p.W246G; c.698C > T, p.T233M, and c.512 T > C,p.I171T.5, 8 They have been identified in patients from Iran, Canada (French), Canada (English), Japan, Brazil, and the United States.3 Phenotypically neurological symptom onset ranges from teenage years to early 50s and is typically described as a slowly progressive condition with ataxia, oculomotor signs (like abnormal saccades, nystagmus, ophthalmoplegia, and square wave jerks), pyramidal signs (increased deep tendon reflexes [DTRs]) or decreased DTRs, different degrees of cerebellar and pontine atrophy.3 Hot cross bun sign, a radiological feature usually described in multiple system atrophy—cerebellar subtype (MSA-C), has been described in (ATX)-ELOVL4 before with the mutations c.539A > C, p.Q180P (4), c.698C > T, p.T233M,5 c.504G > C, p.L168F,5 and like our patient in c.736 T > G, p.W246G.1 Additional skin findings including erythrokeratodermia have also been reported.4 The mutation found on our patient (p.W246G) has been described in 2 Japanese families (without common ancestry).1 The patients in the two families did not demonstrate skin lesions and 67% of these patients demonstrated “hot-cross” bun sign on the MRI. This is consistent with the clinical findings in our patient. Of note, per our patient's knowledge she has no Japanese ancestry.1 This case adds to the SCA34 phenotype and its occurrence in a different racial population. It brings to light the importance of seeking this diagnosis with the given clinical presentation and radiological sign. (1) Research Project: A. Conception, B. Organization, C. execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique.M.M.E.: 1C, 2A R.T.: 1A, 1B, 2A, 2B Ethical Compliance Statement: The authors confirm patient's consent was obtained for this case report. CARE guidelines were followed with respect to this case report. 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. Funding Sources and Conflicts of Interest: The authors have no conflicts of interest and no funding sources to disclose at this time. Financial Disclosures for the Previous 12 Months: The authors have no financial disclosures.

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