Mitochondrial diseases are a heterogenous group of multisystemic disorders caused by genetic mutations affecting mitochondrial oxidation function. Brain involvement is commonly found in most cases but rarely as the unique clinical manifestation. Since the knowledge of its clinical manifestation combined with genetic testing is important for preventing misdiagnosis and delay in treatment, we report here how we diagnosed and managed a very unusual case of mitochondrial encephalopathy.

We report a 52-year-old woman with recurrent stroke-like episodes carrying the m.10158T>C mutation in the MT-ND3 gene, which is also responsible for fatal infant-onset Leigh syndrome. Despite the common mutation, the present case featured a distinct clinical and neuroimaging manifestation from Leigh syndrome. This patient presented with sudden onset of right-sided hemiparesis and hemilateral sensory disturbance accompanied by a left temporal cluster-like headache and later developed epilepsy during hospitalization, with no other signs suggestive of myopathy, lactate acidosis, or other systemic symptoms. Brain magnetic resonance imaging revealed variable lesions involving multiple cortical and subcortical regions. Furthermore, a negative genetic test obtained from peripheral blood delayed the diagnosis of mitochondrial disease, which was eventually established through second-generation DNA sequencing using biopsied muscle.

Based on this report, we suggest that clinicians pursue proper genetic testing for patients when the clinical phenotype is suggestive of mitochondrial diseases.

Diagnosis of mitochondrial disease is challenging. Symptoms such as a stroke-like episode, lactic acidosis, deafness, diabetes mellitus, short stature, and myopathy, often with a family history showing maternal inheritance, are the most common chara-cteristics of a mitochondrial disease. Additionally, a stroke-like episode often occurs in childhood or adolescence. Nonetheless, a diagnosis of mitochondrial diseases in patients with adult onset is often delayed due to a lack of family history, atypical manifestations, and limited resources for functional, pathologic, and/or genetic testing in routine clinical practice[1]. We report an adult-onset patient with mitochondrial encephalopathy carrying the m.10158T >C mutation in the MT-ND3 gene. The encephalopathy manifested as isolated recurrent stroke-like episodes without clinical myopathy or other organ dysfunction. In this paper, we focus on how we diagnosed this case and the distinct feature of the brain magnetic resonance imaging (MRI), which is important for preventing misdiagnosis and delay in treatment. Additionally, we summarize the clinical implications of such cases with this mutation.

The diagnosis was MELAS syndrome harboring the m.10158T>C mutation.

We administered levetiracetam (1000 mg/d) and oxcarbazepine (400 mg/d) to control epilepsy. Q10 and L-arginine were also administered.

Over the next 6 mo, the present patient did not manifest any further stroke-like episodes.

We herein report a case of adult-onset mitochondrial encephalopathy, whereby the patient was admitted three times for similar stroke-like episodes before the definitive diagnosis was confirmed. Despite highly suggestive MRI features of MELAS syndrome, the diagnosis of mitochondrial encephalopathy was delayed due to the following reasons: (1) Lack of family history showing maternal inheritance; (2) Isolated symptoms of CNS impairment, without myopathy, lactic acidosis, or other systemic disorders; and (3) Negative mitochondrial genetic testing using peripheral blood. Although muscle biopsy revealed no abnormality, genetic testing using the biopsied muscle demonstrated a 69.6% heterozygous T10158C mutation in the MT-ND3 gene.

Although MELAS is not uncommon in clinical practice, its diagnosis may be challenging because the clinical symptoms are highly variable and genetic findings may be absent. Our patient presented with a headache, seizure, and acute focal lesion observed by MRI, which fit the diagnostic criteria of supportive MELAS by Yatsuga et al[2]. Although her level of lactic acid in blood was normal, the presence of an inverted lactate peak was detected in the temporal cortex by MRS, which is a useful tool to detect metabolic dysfunction in the brain[3]. Additionally, despite no obvious myopathy, the biopsied muscle showed a 69.6% heteroplasmic mutation, T10158C, in the MT-ND3 gene.

The MT-ND3 protein is a structural component of multimeric enzyme complex I of the mitochondrial respiratory chain, which drives ATP generation in mitochondria[4]. The MT-ND3 T10158C mutation, which is located in the coding region of the loop domain of the ND3 subunit protein, has been identified in infants and pediatric patients with Leigh syndrome or Leigh-like disease[5]. However, the manifestation of late-onset stroke-like encephalopathy similar to MELAS in our patient harboring the MT-ND3 T10158C mutation highlights the complicated genotype-phenotype relationship in mitochondrial diseases. In a literature review, we found four similar cases of MT-ND3 T10158C mutation (in muscle)[6,7], and all of these patients presented with adult-onset, isolated involvement of the central nervous system. Moreover, MRI revealed similar features among these five patients, with lesions predominately in the posterior cortex of the supratentorial region; in contrast, MRI typically shows involvement of the basal ganglia, brainstem, and cerebellum in Leigh syndrome. Thus, adult-onset patients harboring the MT-ND3 T10158C mutation may exhibit unique clinical features. Although no myopathy symptoms were observed in any of these cases and genetic testing using peripheral blood was negative, muscle specimens should be obtained to establish a definitive diagnosis. This may be explained by heteroplasmic mtDNA mutations in various tissues, in which case, the mutation load in muscles is higher than that in blood[8].

Adult-onset mitochondrial encephalopathy in the presence of the MT-ND3 T10158C mutation shows unique clinical characteristics. Despite a lack of lactic acidosis, myopathy, or other clinical implications, the diagnosis of MELAS needs to be con-sidered for adult-onset patients with a stroke-like episode of encephalopathy. Due to the heteroplasmic mutation load, a negative genetic test obtained when using peripheral blood does not necessarily exclude the diagnosis of mitochondrial disease, and next-generation DNA sequencing using biopsied muscle should be considered.