A RARE CASE OF MITOCHONDRIAL ENCEPHALOMYOPATHY WITH LACTIC ACIDOSIS AND STROKE-LIKE EPISODES SYNDROME

. Plasma amino acids and urine organic acids are shown in Table 2, and Table 3 shows the dried blood spot and mutational analysis for this patient.


Introduction
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder inherited maternally.The estimated prevalence is 11.5 in 100,000 people [1].The rarity and complexity of its manifestations can make it challenging to diagnose, often requiring a high index of suspicion.

Case presentation
A 7-year-old boy presented with a jerky movement of his right upper and lower limbs during sleep, associated with up-rolling eyeballs and no drooling of saliva.This episode occurred less than one minute and aborted spontaneously.Postictally, the patient had vomiting followed by two episodes of fitting with similar characteristics and duration.Blood pressure and heart rate were stable with slightly elevated temperature.Lung and abdominal examinations were unremarkable with no dysmorphism observed clinically.During his admission, he was treated for meningoencephalitis and right ureterocoele.He was given anti-epileptic and broad-spectrum antibiotics to cover for possible sepsis.He had multiple series of admissions due to a similar presentation.The antenatal and perinatal history was uneventful, and he was the youngest of three siblings.There was no significant medical illness in the family history and his parents were non-consanguineous.Initial developmental milestone was up to age, but he was later found to have learning difficulties.Initial blood investigations showed normal urea and creatinine levels with mild hyponatremia and low normal chloride that were suggestive of fluid loss, especially during vomiting, as stated in the history.Mild to moderate hypercalcaemia and hyperphosphatemia were likely due to acute metabolic changes post-seizure.Notably, the patient exhibited a consistently elevated lactate level, which was also observed during previous admissions.Liver function test was normal while full blood count showed slightly elevated white blood cells possibly due to mild infection or inflammation (Table 1).Plasma amino acids and urine organic acids are shown in Table 2, and Table 3 shows the dried blood spot and mutational analysis for this patient.His inborn error of metabolism screening revealed a non-specific pattern.In view of his recurrent encephalopathy episodes and abnormal basal ganglia findings, the primary team decided to proceed with genetic testing for mitochondrial disorder.The genetic testing yielded a positive result, identifying a heteroplasmic pathogenic m.3243A>G variant in the MT-TL1 gene.This pathogenic variant is consistent with MELAS syndrome.Similar findings were noted in patient's asymptomatic mother and sister's genetic screening.IV arginine was administered for prevention of further stroke-like episode during admission [2].He was subsequently discharged well with antiepileptic medication and further follow-up.

Discussions
MELAS syndrome is a rare, inherited mitochondrial disorder, typically presenting from childhood to adolescence.It is a multi-organ disease with symptoms including stroke-like episodes, dementia, epilepsy, lactic acidosis, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature.It is characterized by a buildup of lactic acid in the body and temporary muscle weakness [3].It is one of the most common maternally inherited mitochondrial disorders.
The pathogenesis of MELAS syndrome is complex and not fully understood [4].It involves impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide deficiency.About 80% of MELAS syndrome patients have a specific mutation in the transfer RNA gene [5].The cause of stroke-like episodes in MELAS is unclear but may be due to transient dysfunction in oxidative phosphorylation within the brain.Mitochondrial angiopathy of small vessels could be responsible for contrast enhancement of affected regions.The multisystem dysfunction in MELAS syndrome may be due to parenchymal and vascular oxidative phosphorylation defects.Mutations disrupt mitochondrial transfer RNA (tRNA) function, affecting intramitochondrial protein synthesis.This could decrease respiratory chain activity by reducing the translation of specific genes [6].
MELAS syndrome, typically starting between ages 2 and 15, is characterized by recurring stroke-like episodes, possibly due to nitric oxide deficiency in the brain's small blood vessels [7].These episodes differ from typical strokes in their MRI findings and progression.
Encephalopathy, or mental deterioration, often accompanies these episodes and progresses slowly from childhood (Table 4).Other symptoms can include cardiac disorders, diabetes, and chronic fatigue.[8].Plasma amino acid analysis may show higher plasma alanine and branched-chain amino acids (BCAA), with lower plasma arginine and citrulline [9].This could be due to increased arginine clearance and decreased de novo arginine synthesis rate, likely secondary to lower citrulline availability.A higher plasma alanine level is expected due to lactic acidaemia.The metabolism of BCAA occurs in mitochondria, leading to elevated BCAA concentration in MELAS syndrome due to mitochondrial dysfunction [10].
MELAS syndrome diagnosis involves neuroimaging, muscle biopsy, and genetic analysis.CT scans have limited value, but MRI is helpful.Mitochondrial myopathies present as exercise intolerance and weakness, common in varied myopathy; hence, muscle biopsy is advised.Muscle biopsy of a subject with MELAS syndrome stained with succinate dehydrogenase will appear like ragged red fibres.Genetic analysis confirms the diagnosis.most common mutation (bp3243) has a variable phenotype, also found in patients with progressive external ophthalmoparesis, myopathy alone, diabetes, and deafness.Approximately 80% of MELAS syndrome cases are caused by mutation m.3243A>G of the MT-TL1 gene, and the rest of MELAS syndrome patients have the 3271T>C mutation [11,12].MELAS syndrome presents with varied clinical phenotypes, often leading to misdiagnosis.A stepwise approach can facilitate diagnosis.Mitochondrial diseases such as MELAS are maternally inherited due to mutations in mitochondrial DNA.Each offspring receives both wild type and mutated mitochondrial DNA (mtDNA) copies from their mother and the severity of the disease depends on the proportion of mutated mtDNA in their cells, known as the mutation load.

Conclusion
MELAS syndrome is a progressive, neurodegenerative disorder linked to maternally inherited mtDNA mutations.Diagnosis involves recognising clinical manifestations, laboratory findings from blood and CSF biochemistry, neuroimaging, muscle biopsy, and genetic testing.High CSF and plasma lactate levels, with suggestive clinical history, raise suspicion of MELAS syndrome until proven otherwise.

Table 2 .
Plasma amino acids and urine organic acid profile

Table 3 .
Dried blood spot and mutation analysis result The unexplained developmental delay, recurrent episodes of encephalopathy, with further history of short stature and failure to thrive, episodes of muscle cramps and easy fatiguability raised the suspicion of mitochondrial disease.Magnetic Resonance Imaging (MRI) brain showed left parieto-occipital focal cerebritis and basal ganglia calcification.In addition to that, karyotyping was sent which came back