Broadening the Phenotype of m.5703G>A Mutation in Mitochondrial tRNAAsn Gene from Mitochondrial Myopathy to Myoclonic Epilepsy with Ragged Red Fibers Syndrome

Broadening the Phenotype of m.5703G>A Mutation in Mitochondrial tRNAAsn Gene from Mitochondrial Myopathy to Myoclonic Epilepsy with Ragged Red Fibers Syndrome

Mitochondrial diseases are a group of disorders caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA, leading to impaired cellular energy production and multisystem involvement. These diseases exhibit a wide range of clinical phenotypes due to the heterogeneous nature of the mutations and the varying degrees of tissue involvement. One such condition is Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome, a mitochondrial disorder characterized by myoclonus, generalized epilepsy, cerebellar ataxia, and mitochondrial myopathy with ragged red fibers (RRFs). Additional features may include hearing impairment, psychiatric disorders, and dysarthria. Over 20 heteroplasmic point mutations have been identified as causative of MERRF, with the m.8344A>G mutation in the mitochondrial tRNALys (MT-TK) gene being the most common, accounting for approximately 80% of cases. However, up to 10% of MERRF patients have no identifiable mutations, highlighting the genetic complexity of mitochondrial diseases.

The m.5703G>A mutation in the mitochondrial tRNAAsn (MT-TN) gene has previously been associated with mitochondrial myopathy (MM). However, no prior reports have linked this mutation to MERRF syndrome. This case report describes a patient with typical MERRF syndrome who carries the heteroplasmic m.5703G>A mutation, thereby expanding both the genotypic spectrum of MERRF and the phenotypic spectrum of the m.5703G>A mutation.

The patient was a 34-year-old Chinese man who initially presented with generalized tonic-clonic seizures at the age of 18, occurring once a year for 10 years. At 23 years old, he developed prominent myoclonic seizures in his limbs, body, or head, occurring several times daily. Despite combination therapy with valproic acid and levetiracetam, the frequency of seizures was not well controlled. By the age of 31, he exhibited muscle weakness and atrophy in all four limbs, accompanied by fatigue and exercise intolerance. He also developed bilateral eye fixation, mild right ptosis, weakness and atrophy in the masticatory and facial muscles, and mild dysarthria and dysphagia. At 32 years old, he experienced distal numbness in the lower limbs, which progressed to the thighs, along with a slightly unsteady gait and mild hearing loss. There was no evidence of a positive family history.

Physical examination revealed the patient was underweight (height: 176 cm; weight: 42 kg) with normal intelligence and mild dysarthria. Ophthalmoplegia was observed with bilateral eye fixation and right ptosis. The masticatory and facial muscles were weak and atrophic. Muscle strength was graded 4/5 (Medical Research Council Score, grades 0–5) in all distal and proximal limbs, with muscle atrophy. Ataxia was noted based on positive heel-to-shin, tandem gait, and Romberg tests. Vibration sensation was decreased in the distal lower limbs, while pinprick and touch sensation remained normal. Tendon reflexes were absent in all four limbs.

Laboratory tests showed slightly elevated serum creatine kinase (CK: 613 U/L; reference range: 50–310 U/L). Resting venous lactate, blood glucose, and thyroid hormone levels were within normal ranges. Electrocardiogram and echocardiogram results were unremarkable. An audiogram revealed sensorineural hearing loss, particularly in the right ear. Fundoscopy showed no retinal pigment degeneration, but visual evoked potential monitoring indicated abnormalities in the visual pathway. Electroencephalography (EEG) performed at age 25 revealed generalized spike-and-wave complexes. Electromyography (EMG) indicated myogenic damage, and nerve conduction velocity studies demonstrated sensory axonal polyneuropathy. Brain magnetic resonance imaging (MRI) revealed mild global cerebral atrophy, while muscle MRI showed fatty infiltration predominantly in the posterior compartment of the thigh and calf muscles.

Muscle biopsy findings supported the diagnosis of mitochondrial disease. Hematoxylin and eosin staining showed moderate variation in fiber size and mild endomysial fibrosis. Modified Gomori trichrome staining revealed scattered ragged red fibers (RRFs). Succinate dehydrogenase staining identified some ragged blue fibers without strongly succinate dehydrogenase-reactive vessels. Cytochrome c oxidase (COX) staining demonstrated scattered COX-deficient fibers.

Next-generation sequencing (NGS) of the entire mitochondrial genome, as well as 681 muscular-disease-related genes and 1029 epilepsy-related nuclear genes, was performed after obtaining informed consent. The m.5703G>A mutation in the MT-TN gene was identified in the patient’s blood and muscle tissues, with mutational ratios of 61% and 77%, respectively. This mutation was not detected in the blood of his mother. No other mitochondrial or nuclear DNA variants were identified.

The patient’s clinical features, including myoclonus, generalized epilepsy, ataxia, and mitochondrial myopathy with RRFs, align with the canonical features of MERRF syndrome. The initial symptom of generalized tonic-clonic seizures, followed by myoclonus confirmed by EEG, led to a delayed diagnosis. Valproic acid, which is not recommended for myoclonic seizures in mitochondrial diseases, was discontinued, and the patient was treated with a combination of levetiracetam and clonazepam, resulting in reduced myoclonic seizures after one month.

The m.5703G>A mutation in the MT-TN gene had previously been reported in two patients with mitochondrial myopathy, characterized by early disease onset and prominent extraocular muscle involvement. The mutational ratios in these patients were 4% (blood) and 69% (muscle) in the first case, and 48% (blood) and 80% (muscle) in the second case. In contrast, the current patient exhibited multisystem involvement, including chronic progressive external ophthalmoplegia (CPEO), limb-girdle mitochondrial myopathy, encephalopathy, and peripheral neuropathy. The higher mutational ratio in the blood (61%) compared to previous cases may correlate with the more complex phenotype.

To date, at least eight disease-related mutations in the MT-TN gene have been reported, with CPEO or limb-girdle mitochondrial myopathy being the most common phenotypes. Encephalomyopathy is rare, making this case the first report of MERRF syndrome associated with the m.5703G>A mutation. This finding expands the clinical spectrum of MT-TN gene mutations.

MERRF syndrome is genetically heterogeneous, with over 20 identified mutations, most of which are located in mitochondrial tRNA genes. While the m.8344A>G mutation in the MT-TK gene is the most common, novel mutations continue to be identified. The m.5703G>A mutation in the MT-TN gene, reported in this case, is the first of its kind associated with MERRF, further emphasizing the importance of next-generation sequencing in diagnosing mitochondrial disorders.

In conclusion, this case report highlights the association of the m.5703G>A mutation in the MT-TN gene with MERRF syndrome, broadening both the genotypic spectrum of MERRF and the phenotypic spectrum of the m.5703G>A mutation. The patient’s complex clinical presentation underscores the need for comprehensive genetic testing in mitochondrial diseases to ensure accurate diagnosis and appropriate management.

doi.org/10.1097/CM9.0000000000000151

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