Mitochondrial diseases are a group of rare genetic disorders that affect the mitochondria, which are the energy-producing organelles within our cells. These disorders can have diverse and often debilitating effects on various organ systems, including the brain and nervous system. One specific mitochondrial disorder is mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Verbal auditory agnosia, a condition where individuals struggle to recognize speech sounds, is rarely associated with MELAS syndrome. Metformin, a commonly prescribed medication for diabetes, has been linked to lactic acidosis and has potential connections to mitochondrial dysfunction, which can exacerbate the clinical features of mitochondrial diseases.
Case Presentation1,2
A 43-year-old man arrived at the emergency department with a sudden and alarming set of symptoms. He experienced an abrupt fever, accompanied by a severe headache and a striking impairment in his ability to understand spoken language. While he could still communicate effectively through handwritten notes, the spoken word was incomprehensible to him. Two months earlier, he was diagnosed with diabetes mellitus, and his treatment regimen included vildagliptin and metformin to manage his blood glucose levels.
Upon conducting laboratory tests, medical professionals discovered elevated lactate levels in the patient’s bloodstream and cerebrospinal fluid. Further investigation using brain MRI scans unveiled lesions in the temporal lobes of his brain. Initially, the medical team diagnosed the patient with acute encephalitis and administered acyclovir as the treatment. However, subsequent MRI scans following the acyclovir treatment demonstrated a worsening of the previously observed temporal lobe lesions. A mitochondrial DNA point mutation at position 3,243 (m.3243A > G) with 25% heteroplasmy was discovered only through a comprehensive analysis of the patient’s mitochondrial genome. This genetic mutation is consistent with MELAS syndrome.
Remarkably, the patient’s clinical symptoms and elevated serum lactate levels began to improve significantly after discontinuing the use of metformin.
FIGURE 1. Initial and follow-up MRI after 14 days of acyclovir treatment. (A) initial ADC, (B) initial DWI, (C) initial T2 corona, (D) initial T2 FLAIR, (E) follow-up ADC, (F) follow-up DWI, (G) follow-up T2 corona, (H) follow-up T2 FLAIR, and (I) follow-up MRS. ADC, Apparent diffusion coefficient; DWI, Diffusion-weighted image; FLAIR, Fluid attenuated inversion recovery; MRS, Magnetic resonance spectroscopy.
Discussion3
This case represents a captivating example of late-onset MELAS syndrome with a presentation characterized by acute verbal auditory agnosia. In this condition, the patient can hear sounds but can’t comprehend speech. This unique case provides critical insights into the diverse clinical manifestations of mitochondrial diseases and underscores the potential impact of metformin on mitochondrial function.
Mitochondrial diseases are a group of rare genetic disorders that affect the mitochondria, which are responsible for generating energy within our cells. These disorders can lead to a wide range of health problems, including neurological issues. MELAS syndrome, in particular, is a rare mitochondrial disorder that can manifest with symptoms such as myopathy, exercise intolerance, stroke-like episodes, seizures, elevated lactate levels, sensorineural hearing loss, and diabetes mellitus.
Verbal auditory agnosia is a rare condition where individuals can hear sounds but struggle to recognize speech sounds. This impairment is usually associated with strokes but, in rare instances, can be linked to conditions like MELAS syndrome. Typically, lesions associated with this condition are found in the bilateral superior temporal cortex of the brain.
Conclusion4
In this case, the initial diagnosis of acute encephalitis was prompted by the patient’s fever, headache, and auditory agnosia, along with the presence of temporal lobe lesions on brain imaging. However, the persistence of elevated lactate levels in both blood and cerebrospinal fluid led to the consideration of a mitochondrial cause. In MELAS syndrome, dysfunctional mitochondria can’t produce enough energy, resulting in the accumulation of pyruvate and subsequent lactate production. Metformin, a medication used to manage diabetes, is known to interfere with mitochondrial function, potentially worsening the symptoms of mitochondrial disorders. While the relationship between metformin and MELAS syndrome remains uncertain, some experts caution against its use in individuals with this condition.
In conclusion, this case illustrates the importance of considering mitochondrial diseases as potential causes of diabetes mellitus and highlights the need for caution when prescribing metformin. It also emphasizes the importance of raising awareness among healthcare providers regarding the varied clinical presentations of mitochondrial disorders, including late-onset MELAS syndrome. Further research is needed to understand better the potential interactions between metformin and mitochondrial dysfunction in patients with these complex conditions.
References
- Smith K, Chiu S, Hunt C, Chandregowda A, Babovic-Vuksanovic D, Keegan BM. Late-onset mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes presenting with auditory agnosia. The neurologist. (2019) 24:90–2.
- Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol. (2003) 63:844–8.
- Ng YS, Bindoff LA, Gorman GS, Klopstock T, Kornblum C, Mancuso M, et al. Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol. (2021) 20:573–84.
- Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, et al. Melas: an original case and clinical criteria for diagnosis. Neuromusc Disord. (1992) 2:125–35.
