Case Report of Myoclonus‐Ataxia Syndrome in an Indian Patient Due to <scp><i>SCNA1</i></scp> Gene Mutation

Myoclonus and ataxia are two movement disorders that occur frequently in several diseases. Progressive myoclonus ataxias (PMA) are the group of conditions presenting first with ataxia, with the subsequent development of myoclonus, and eventually drug-responsive epilepsy.1 As many of the PMA syndromes are of genetic origin, genetic testing is often required to confirm the diagnosis. We hereby report an interesting case of SCNA1 gene mutation manifesting as adult-onset PMA without epilepsy. A 35-year-old lady presented with insidious onset gradually progressive imbalance while walking for the last 4 years. It was associated with abnormal involuntary jerks in hands while reaching for objects. She also has jerky facial movements. There was no history of associated hearing loss, visual loss, cognitive decline, or seizures. There was no family history of similar complaints. Her higher mental function testing revealed MMSE score of 28/30 and MOCA score of 27/30. Her cranial nerve examination revealed bilateral gaze-evoked nystagmus. Her fundus was normal. The muscle tone was increased in all four limbs, and deep tendon reflexes were all exaggerated. Arhythmic jerky action-induced myoclonus was noticed on finger-nose testing in both upper limbs more prominent on the left side and was associated with dystonic posturing. She also had speech-induced oro-facial jerks. In her lower limbs, she had goal-directed irregular arhythmic jerky movements suggestive of myoclonus. The gait examination revealed broad-based ataxic gait which was also influenced by myoclonus in the lower limb (see Video 1A,B). Her complete blood counts, peripheral smear, liver function test, alfa-fetoprotein, Anti-transglutaminase, thyroid profile, and vitamin B12 levels were normal. Her MRI brain showed mild cerebellar atrophy. Her electroencephalography was normal. Her whole exome sequencing revealed a likely pathogenic heterozygous missense variant c.4676 T > C (p. Met1559Thr) in exon 28 of the SCN1A gene (chr2:g.165994322A > G; Depth: 180x) that results in the amino acid substitution of Threonine for Methionine at codon 1559 was detected. The observed variant lies in the “Ion transport protein” domain of the SCN1A protein. There is a different likely pathogenic missense variant in the same codon (as p.Met1559Lys) reported in patients affected with drug resistant epilepsy.2 The p.Met1559Thr variant has not been reported previously. The in-silico predictions of the variant are probably damaging by PolyPhen-2 and damaging by SIFT. We started her on Levetiracetam 500 mg twice daily. At three-month follow-up, she had significant improvement in her gait, suggesting that the gait was impaired more because of lower limbs myoclonus, rather than only ataxia (see Video 1C). The SCN1A gene encodes for the a-1 subunit of the neuronal voltage-gated sodium channel and is located on chromosome 2q24. Dravet syndrome (DS) is the most common presentation of SCN1A gene mutation seen in around 80% of cases.3 However, the SCN1A gene also causes other epileptic encephalopathies, such as genetic epilepsy with febrile seizures plus (GEFS+), Doose syndrome, Epilepsy of infancy with migrating focal seizures (EIMFS), West syndrome, Lennox–Gastaut syndrome (LGS), and Non-syndromic epileptic encephalopathy (NEE). Other non-epilepsy disorders caused by SCN1A mutation include hemiplegic migraine, autism spectrum disorder (ASD), sudden death, and arthrogryposis multiplex congenital.3 The functional effect of the SCN1A mutations can partially explain different phenotypes caused by the mutations in the same gene.4 Movement disorders have been reported in SCNA1 mutation but are always in association with epileptic encephalopathy and never as a sole manifestation. It is estimated that 25–30% of adults with DS have extrapyramidal features.5 Ataxia, action myoclonus, dystonia, choreoathetosis, parkinsonism, and gait disorders are known to occur in SCNA1 mutation.6-8 Different studies have shown that although seizures may decrease in older adults with DS, their motor symptoms and gait become progressively worse as they age.7 Ataxia usually appears later in life but contributes substantially to the functional impairment in patients with SCNA1 mutation. The mechanism underlying ataxia in SCNA1 mutation is linked to the loss-of-function in Nav1.1 channels, resulting in the severely impaired sodium current and action potential firing in cerebellar Purkinje neurons, which are GABAergic inhibitory neurons.9 There are two types of myoclonus described in DS: generalized massive myoclonic jerks with accompanying spike-and-wave EEG discharges and multifocal erratic myoclonic jerks rarely accompanied by EEG changes. The multifocal action myoclonus in DS resembles that seen in PME, except it does not have a severely worsening course and is not commonly associated with increased somatosensory-evoked potentials or enhanced long latency responses. It has been hypothesized that such myoclonus originates in cortical motor areas by hyper-synchronous oscillations, possibly due to sodium channel dysfunction.10 Apart from the multifocal action myoclonus unaccompanied by EEG findings, our patient also had strikingly prominent perioral dyskinetic movement. Similarly, characteristic oral dyskinesia has been recently described by Saddlier et al in patients with recurrent missense p. Thr226Met mutation in the SCNA1 gene.8 Our case has two main atypical features. First, isolated movement disorder in the form of myoclonus-ataxia without epilepsy or cognitive decline has never been reported in the literature as the presenting feature of SCNA1 mutation. Second, the age of onset in our patient's third decade is notable as a rarity in SCNA1 mutation. However, our case report has one limitation. The validation of the pathogenicity of the current genetic finding is limited by the lack of functional studies and a segregation analysis. Our case broadens the spectrum of SCN1A related disorders to include hyperkinetic movement disorder as one of the major presentations. It also further emphasizes that prominent orofacial jerks can be a clue to the SCNA1 mutation. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. A.C.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. We also confirm that the patient has given written informed consent for the publication of his video. We confirm that we have read the Journal's position on issues involved in the ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.