Dear Editor, A 26-year-old Indian male, born to non-consanguineous parents with a normal birth and perinatal period, presented with progressive gait imbalance since 16 years of age. He noticed limb tremulousness beginning at 20 years of age, along with occasional sudden jerks that caused him to drop items from his hands. He has no history of seizures, bladder or bowel problems, or vision or hearing difficulties. His family history is notable for epilepsy and ataxia in his mother, although no records are available Figure 1. On examination, he had normal ocular movements and normal muscle strength in all limbs, except for mild weakness and atrophy of the intrinsic muscles of the feet. He had impaired proprioceptive sensation in both lower limbs up to the knees, with a positive Romberg’s sign. Tendon reflexes were absent in the lower limbs and diminished in the upper limbs. He also exhibited dysarthria, axial and appendicular ataxia, and asymmetric postural tremor (right > left) with action myoclonus Video 1. Routine blood biochemistry, including copper studies, serum creatine kinase, plasma lactate, and ammonia, was normal. Magnetic resonance imaging (MRI) of the brain showed generalized cortical volume loss Figure 2 and 3. Nerve conduction studies revealed length-dependent sensory-motor axonopathy, with electromyogram results showing polyphasic motor unit action potentials and reduced recruitment, suggesting a neurogenic origin. The electroencephalogram demonstrated generalized background slowing, but no epileptiform discharges. Direct ophthalmoscopy revealed no diagnostic ocular pathology. Whole-exome sequencing identified a heterozygous variant of uncertain significance in the CCDC88C gene, c. 4777G>A, suggestive of spinocerebellar ataxia type 40. However, according to existing literature, SCA 40 is a spastic ataxic syndrome with ocular dysmetria, vertical gaze palsy, and olivopontocerebellar atrophy on MRI, features that did not match the patient’s phenotype. 1 Given the patient’s multiaxial involvement and maternal history of seizures and ataxia, mitochondrial disorders were considered. Mitochondrial exome analysis showed a pathogenic heteroplasmic mutation in the MT-TK gene (m. 8344A>G), consistent with myoclonic epilepsy with ragged red fibers (MERRF). He was managed by a multidisciplinary team of neurologists and gait and rehabilitation specialists. Pharmacological interventions included levetiracetam (1 g/day), clonazepam (1 mg/day) for myoclonus, and a mitochondrial cocktail. Figure 1: Pedigree of the proband "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": "1₅xddmk8y", "pub-id-type": "other", "content-type": "media-source", "id": "Kaltura"} Figure 2: MRI T2 axial image of the proband showing generalised cortical volume lossFigure 3: MRI T2 sagittal and coronal images showing mild cerebellar and cerebral atrophyMERRF is a rare mitochondrial syndrome characterized by myoclonus, seizures, ataxia, and ragged red fibers on muscle biopsy using Gomori’s trichrome stain. It is also known as Fukuhara disease or myoencephalopathy with ragged-red fibers. The m. 8344A>G mutation is the most prevalent worldwide and causes a codon change in the mitochondrial transfer RNA for lysine. In addition, the m. 8356T>C and m. 8363G>A point mutations can also cause MERRF or a MERRF/MELAS overlap phenotype. These mutations affect the assembly of respiratory chain complexes, particularly the cytochrome-c-oxidase complex (complex IV), causing “energy failure” at the cellular level; consequently, cells with high energy demands are more vulnerable. Dysfunction of myocyte cell bodies causes myopathy, damage to neurons in peripheral nerves causes neuropathy, dysfunction of cortical inhibitory interneurons causes myoclonus, and impairment of inner ear hair cells leads to sensorineural deafness. 2 Due to heteroplasmy—the coexistence of mutant and wild-type mitochondrial DNA—a certain threshold of mutant DNA must be present in the tissue for clinical manifestations to occur. Expression of mutant mitochondrial Deoxyribonucleic acid (mtDNA) in offspring depends on the stochastic distribution of mitochondria during oogenesis. 3 Hetaroplasmic distribution of mutant mitochondrial DNA can also explain asymmetric clinical manifestations, especially in the context of myopathy. 4 Common clinical manifestations include myopathy, neuropathy, hearing loss, dementia, short stature, and optic atrophy. Less common features include cardiomyopathy, pigmentary retinopathy, pyramidal signs, ophthalmoparesis, multiple lipomas, and diabetes mellitus. 5 Usually, myoclonus is more closely associated with ataxia than with seizures. Both hypokinetic and hyperkinetic movement disorders are common in mitochondrial disorders. Dystonia (Leigh’s disease) is the most common movement disorder (MD) in the pediatric age group, whereas parkinsonism is the main movement disorder in adults. Ataxia (Polymerase gamma (POLG), neuropathy, ataxia, retinitis pigmentosa (NARP), Coenzyme Q10 deficiency), myoclonus (MERRF), and chorea (Leigh disease) are also common manifestations of the respective mutations. 6 Muscle and brain MRI typically show cerebral and cerebellar atrophy and, in rare cases, white matter hyperintensities. There is no curative treatment; empirical therapy with vitamins and cofactors, including coenzyme Q and L-carnitine, is often tried. Valproic acid inhibits carnitine uptake and produces potentially lethal intermediate metabolites, so it must be used with caution Figures 1–3. An important clinical takeaway from this case is that it is always advisable to correlate the clinical phenotype with the genotype, and if there is a discrepancy, it is prudent to revisit the history, perform reverse phenotyping, and reconsider the choice of genetic testing. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient (s) has/have given his/her/their consent for his/ her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Acknowledgment The authors thank the patient and his family members for their active contribution to this study. The authors also thank the reviewers for their comments and suggestions. Author contribution A. Research project: 1. Conception: Jacky Ganguly, Hrishikesh Kumar 2. Organization: Debayan Dutta, Jacky Ganguly, Soumava 3. Execution: Debayan Dutta B. Statistical analysis: 1. Design: Purba Basu 2. Execution: Debayan Dutta, Purba Basu 3. Review and Critique: Jacky Ganguly, Soumava Mukherjee, Hrishikesh Kumar C. Manuscript preparation: 1. Writing of the first draft: Debayan Dutta 2. Review and Critique: Jacky Ganguly, Soumava Mukherjee, Hrishikesh Kumar Ethical compliance statement The authors confirm that approval from an institutional review board/patient consent was not required for this work. The patient provided informed written consent for the publication of his videos. 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.
Dutta et al. (Thu,) studied this question.