Identification of m.3243A>G mitochondrial DNA mutation in patients with cerebellar ataxia.

BACKGROUND: The mitochondrial DNA m.3243A>G mutation can affect mitochondrial function and lead to a wide phenotypic spectrum, including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, diabetes mellitus, hearing impairment, cardiac involvement, epilepsy, migraine, myopathy, and cerebellar ataxia. However, m.3243A>G has been rarely reported in patients with cerebellar ataxia as their predominant manifestation. The aim of this study is to investigate the prevalence and clinical features of m.3243A>G in a Taiwanese cohort of cerebellar ataxia with unknown genetic diagnosis. METHODS: This retrospective cohort study conducted the mutation analysis of m.3243A>G by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) in 232 unrelated Han Chinese patients with genetically-undetermined cerebellar ataxia. The clinical presentation and neuroimaging features of patients with m.3243A>G mutation-related cerebellar ataxia were characterized. RESULTS: We identified two patients harboring m.3243A>G mutation. These patients have suffered from apparently sporadic and slowly progressive cerebellar ataxia since age 52 and 35 years, respectively. Both patients had diabetes mellitus and/or hearing impairment. The neuroimaging studies revealed generalized brain atrophy with predominantly cerebellar involvement in both individuals and bilateral basal ganglia calcifications in one of the patients. CONCLUSION: Mitochondrial m.3243A>G mutation accounted for 0.9% (2/232) of genetically-undetermined cerebellar ataxia in the Han Chinese cohort in Taiwan. These findings highlight the importance of investigating m.3243A>G in patients with genetically-undetermined cerebellar ataxia.

Transient Postictal Hyperglycemia as a Diagnostic Clue of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes.

PURPOSE: To propose that transient postictal hyperglycemia as a diagnostic clue of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). CASE REPORT: We reported two non-diabetic patients presenting with generalized seizure and transient postictal hyperglycemia. At the acute stage, both patients had hyperglycemia with serum glucose levels more than 400 mg/dl, normal glycated hemoglobin (HbA1C) levels, normal ketone body levels, and absence of infection signs. Within three days of the seizure event, both patients were euglycemic and did not require any diabetes treatment. Brain MRI examination revealed gyriform restricted diffusion at bilateral superior temporal gyrus in one patient, and diffuse cerebral and cerebellar atrophy without restricted diffusion lesions in another patient. Polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis confirmed that both patients harbored the m.3243A more than G mutation. CONCLUSION: Seizure-induced stress hyperglycemia is uncommon in normal individuals, but such kind of energy crisis may be pronounced in patients with mitochondrial dysfunction. Early diagnosis of mitochondrial diseases-related epilepsy and hyperglycemia is crucial since certain antiepileptic drugs (ex. Valproic acid) and antihyperglycemic agents (ex. Metformin) are contraindicated in patients with mitochondrial diseases. Our findings support that transient postictal hyperglycemia may be a red flag to consider the diagnosis of MELAS.

Mitochondrial DNA m.3243A>G mutation rarely causes CADASIL-like phenotype.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are 2 monogenic cerebral small vessel diseases sharing several common clinical features including young stroke, migraine, and cognitive dysfunction. The aim of this study was to understand the role of MELAS in patients with CADASIL-like manifestations. We screened 429 unrelated patients with genetically unassigned CADASIL-like syndrome for mitochondrial DNA m.3243A>G mutation. None of them were found to have the mutation. Our finding suggests that m.3243A>G rarely causes CADASIL-like phenotype. It may be not necessary to consider MELAS as a differential diagnosis of CADASIL. Screening m.3243A>G in patients with CADASIL-like phenotype is of limited value.