Acute onset of diabetes and rapid cognitive decline in a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome

Background

Mitochondrial diseases are a group of rare diseases caused by dysfunction of the mitochondrial respiratory chain, which occurs due to mutations in the mitochondrial or nuclear genomes. One of the most common mutations recognized till date is the m.3243A>G point mutation in the mitochondrial tRNA leucine 1 gene. Mitochondrial diseases affect multiple organs with unpredictable time of onset and severity, resulting in various clinical syndromes. The mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome associated with the m.3243A>G mutation has a reported prevalence of 0.18/100,000 in Japan (1). Diabetes is a common manifestation in patients with MELAS syndrome, presenting with a type 1- or type 2-like phenotype (2). In a cohort of patients with MELAS syndrome, diabetes was associated with latent progression of cognitive decline (2). Severe hyperglycemic crisis could be life threatening (3, 4), but the impacts on cognitive decline have not been reported. Herein, we report a case of rapid cognitive decline in a patient with MELAS syndrome who was hospitalized due to severe hyperglycemic crisis.

Case presentation

The patient was a 36-year-old woman with no history of hearing loss, visual impairment, muscle weakness, or epilepsy. Her family history was positive for diabetes (Fig. 1).

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Family pedigree. The index patient developed mitochondrial diabetes at the age of 36 years. Her mother, aunt, and uncle started taking oral antidiabetic drugs in mid-adulthood. Her sister and cousin required insulin therapy in their twenties.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0416

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She was initially hospitalized at the age of 27, in 2013, due to disturbance of consciousness and seizures, but was discharged with unconfirmed diagnosis. Five years later, in 2018, she was hospitalized again with the same symptoms; however, following that hospitalization, she started experiencing progressive dementia and hearing loss.

In 2020, at the age of 34, she presented to our hospital due to vomiting and headaches. At that time, her blood glucose and plasma lactate levels were 4.5 mmol/L and 3 mmol/L, respectively. Genetic testing was performed, which confirmed the presence of the m.3243A>G mutation, and she was diagnosed with MELAS syndrome. She was prescribed coenzyme Q-10, thiamine, folic acid, and acetyl L-carnitine as symptomatic treatment.

In March 2022, the patient was admitted to the hospital due to seizures and coma. On admission, dehydration and deep breathing were observed. The patient’s blood pressure was 95/60 mmHg, and her BMI was 16.9 kg/m2 (150 cm height, 38 kg weight). It was reported that she had started to complain of frequent urination, weight loss, and frequent consumption of sweetened beverages approximately 1 month before the admission.

Investigation

Blood tests revealed severe hyperglycemia (33.8 mmol/L, HbA1c: 10.4%), increased lactate level (10.2 mmol/L), and mild metabolic acidosis (pH: 7.35, HCO₃⁻: 16 mmol/L), without significant ketosis (beta-hydroxybutyric acid: 0.93 mmol/L). The decreased estimated glomerular filtration rate suggested acute kidney injury due to hypovolemia (Table 1). Brain MRI showed hyperintense edema in the left frontal region (Fig. 2A) in addition to old lesions.

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MRI findings. Fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) scans, and apparent diffusion coefficient (ADC) maps obtained A) on admission (March 2022) and B) after 1 month (April 2022). The initial FLAIR image shows only hyperintense edema in the left frontal lobe, while the follow-up scan also shows a left occipital lobe lesion (yellow arrows), with old lesions visible in the right occipital lobe on both scans (green arrow). DWI scans show cortical areas of restricted diffusion that are hyperintense on DWI and hypointense on ADC maps (yellow arrows), as well as subcortical vasogenic edema indicated by ADC hyperintense areas (red arrows). The two hemisphere lesions observed on the 2013, 2018, and 2020 scans became old lesions with partial encephalomalacia.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2023, 2; 10.1530/EDM-22-0416

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Treatment

The metabolic disturbances were normalized within 2 days with insulin infusion and fluid replacement therapy. The lactate level decreased from 10.2 mmol/L to 2.5 mmol/L. During the hospital stay, the patient was mostly on nasogastric feeding and parenteral nutrition due to unconsciousness and unpredictable seizures. On day 7 from admission, she regained consciousness and the seizures were controlled. She was discharged on day 10. Insulin was added to her therapy, including 18 units of glargine and 6 units of glulisine before each of the three main meals.

Outcome and follow-up

Patient adherence and response to insulin therapy were achieved. The insulin dose was gradually reduced during the follow-up, and the basal-bolus regimen was switched to a basal regimen with 12 units of glargine and a dipeptidyl peptidase 4 inhibitor. She gained 2 Kg, and the fasting blood glucose level was normalized to approximately 6−7 mmol/L.

However, in the first two months after discharge, the patient was rehospitalized twice (in April and May 2022) due to unconsciousness and seizures. In April, before being unconscious and hospitalized, she complained about multiple episodes of transient vision loss for two days. At this admission, her blood glucose was 5.6 mmol/L, and Na level was 142 mmol/L. Brain MRI showed a new lesion in the left occipital lobe (Fig. 2B). One month later, she was admitted again due to sudden unconsciousness and seizures; blood glucose and Na level were 8.3 mmol/L and 138 mmol/L, respectively. The seizures were controlled, and the patient regained consciousness the next day. We noted neither focal limb weakness nor pyramidal signs. Other laboratory tests were unremarkable.

Her cognition, communication, visual acuity, and hearing capacity seems markedly decreased after the onset of diabetes, despite the later improvement in glycemic control (HbA1c: 7.6%). Since July 2022, she was no longer able to perform daily activities and became dependent on family support.

Discussion

Mitochondrial diseases are multi-organ disorders with clinical, biochemical, and genetic heterogeneity caused by mitochondrial dysfunction. Mitochondria are the primary organelles providing energy in the form of ATP. Decrease in ATP levels can cause dysfunction of cells and organs, with the brain, muscles, heart, kidneys, and liver being the most vulnerable target organs due to their high energy requirement.

The m.3243A>G point mutation is one of the most common mitochondrial DNA (mDNA) mutations. Unlike that of nuclear DNA, mDNA inheritance is via non-Mendelian maternal inheritance. This point mutation is responsible for the heterogeneity of clinical phenotypes: MELAS, maternally inherited diabetes and deafness, oligosymptomatic patients, and healthy carriers (5).

The diagnosis of MELAS syndrome was first introduced in 1992 (6). Later on, the MELAS Study Committee of Japan published new diagnostic criteria, based on which definitive diagnosis is established when patients meet two of the criteria for clinical findings of stroke-like episodes (headache with vomiting, seizures, hemiplegia, cortical blindness, and acute focal lesions on neuroimaging) and two of the criteria for evidence of mitochondrial dysfunction (high plasma or cerebrospinal fluid lactate levels, mitochondrial abnormalities in muscle biopsy, and MELAS syndrome-related gene mutation) (1).

In patients with MELAS syndrome with m.3243A>G mutation, other symptoms of mitochondrial dysfunction have been observed, for example hearing impairment, deafness, short stature, and in particular, diabetes. Murakami et al. found that adult patients with MELAS syndrome with m.3243A>G mutation had a high prevalence of diabetes of up to 92.9% (13 of 14 cases) (2). Our patient met the definitive diagnosis criteria of the MELAS Study Committee of Japan based on the clinical findings (headache with vomiting, seizures, and focal lesions on neuroimaging) and evidence of mitochondrial dysfunction (high plasma lactate level and presence of m.3243A>G mutation). The onset of diabetes in our patient occurred at the age of 36, about 9 years after the first symptoms and 2 years after the diagnosis of MELAS syndrome. In the study by Maassen et al., the average age at onset of diabetes in patients with m.3243A>G mutation was 38 years (7).

Mitochondrial diabetes can manifest with a type 1- or type 2-like phenotype depending on the severity of insulin resistance or decreased beta-cell function (7). In patients with type 2-like phenotype of diabetes, blood glucose levels can be initially controlled by diet and/or with oral antidiabetic agents (7, 8). Metformin is contraindicated due to the risk for lactate acidosis (8). Nonetheless, most patients develop an insulin requirement several years after the onset of diabetes (7). In our patient, the initial presentation of diabetes was with type 1-like phenotype, with a high initial insulin requirement of approximately 0.9 units/kg total daily dose. However, her insulin requirement decreased after resolution of the glucose toxicity due to acute severe hyperglycemia. Acute onset of diabetes in patients with MELAS syndrome has been previously reported, even with life-threating ketoacidosis (3, 9).

Patients with m.3243A>G mutation are at a high risk for diabetes; therefore, diabetes screening is recommended in patients with mitochondrial diseases (8, 10). The new Mitochondrial Disease Guidelines recommend measurement of glycated hemoglobin (HbA1c) levels at the time of diagnosis and at an interval of 12 months for all asymptomatic patients, as well as random blood glucose and HbA1c level measurements in symptomatic patients (8). Due to the high prevalence of impaired glucose tolerance in patients with m.3243A>G mutation, periodic oral glucose tolerance testing has also been recommended (10). Our patient had a random blood glucose level of 4.5 mmol/L in 2020. No other diabetes screening tests were performed until the onset of severe hyperglycemia.

In a retrospective study including 25 patients with MELAS syndrome, four patients developed diabetes mellitus. Among them, three patients presented with hyperglycemic crisis as the first manifestation of the disease. Triggering events were surgery, infection, and status epilepticus (4). Despite normal previous screening blood tests, severe hyperglycemia seemed to be unavoidable in certain individuals. Preventing hyperglycemic events should be prioritized in patients with MELAS syndrome as these complications could be fatal (3, 4). Thus, in addition to undergoing annual screening tests, patients with m.3243A>G mutation should avoid triggering factors, and their diabetes status should be reassessed after severe events. Our patient was not well-informed about the risk for diabetes. She consumed sweetened beverages to quench her thirst, thus further increasing her blood glucose level. Therefore, patients and their families should be educated regarding the risk for diabetes, screening planning, and symptoms suggestive of hyperglycemia.

After the onset of diabetes, our patient experienced increased seizure activity and rapid decline in consciousness, hearing capacity, and visual acuity, which made her dependent on others. Murakami et al. highlighted the impact of diabetes on cognitive decline in Japanese patients with MELAS syndrome (2). Notably, the prevalence of cognitive decline was higher among patients with a prior diagnosis of diabetes than among those without a prior diagnosis of diabetes. Due to the rapid cognitive decline after the hyperglycemic crisis, we speculate that the onset of diabetes may have been an aggravating factor in our patient. Furthermore, mitochondrial dysfunction can be hyperglycemia-induced (11). Therefore, diabetes could have a negative impact on the progression of cognitive decline in patients with MELAS syndrome, and an acute onset of diabetes with severe hyperglycemic crisis could cause rapid cognitive decline in these patients. The mechanisms underlying the cognitive decline were thought to be mitochondrial respiratory failure, oxidative stress promoting the production of reactive oxygen species, and amyloid accumulation (12).

At present, there is no international consensus on the treatment of mitochondrial diseases. Treatment focuses mainly on symptoms and associated complications. Genetic testing, used for diagnosis of mitochondrial diseases, can also guide treatment decisions, particularly in avoiding the use of metformin. Therefore, genetic testing for the m.3243A>G mutation should be performed in family members, as some of them may have diabetes with different phenotypes (Fig. 1). Genetic counseling should be provided to help patients, carriers, and their families understand the disease progression and inheritance, enabling reproductive planning (13).

In summary, diabetes is a common endocrine manifestation of mitochondrial diseases. In patients with MELAS syndrome, diabetes is likely to be an associated risk factor for cognitive decline. Diabetes education and screening tests should be provided to patients with MELAS syndrome or healthy carriers with related genetic mutations. Moreover, clinicians should be aware of the possibility for acute onset of hyperglycemic crisis, particularly in the presence of triggering factors. Due to the multiorgan systemic nature and heterogeneous manifestations of mitochondrial diseases, a multidisciplinary approach is required for timely diagnosis and management of mitochondrial diseases.

Declaration of interest

The authors declare that they have no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Patient consent

Written informed consent was obtained from the patient and her family for the publication of this article and accompanying images.

Author contribution statement

T B Vuong and T V Tran treated the patient. C C Phan interpreted the brain MRI results. N Q Tran and M T Phat wrote the manuscript. All authors have read and approved the final version of the manuscript.