bims-symami 2023-04-23 papers

Issue of 2023–04–23
five papers selected by
The Lily Foundation

Elife. 2023 Apr 19. pii: e87194. [Epub ahead of print]12

Are some mutations more equal than others?

Auden Cote-L'Heureux, Yogesh N K Maithania, Melissa Franco, Konstantin Khrapko.

A large-scale study of mutations in mitochondrial DNA has revealed a subset that do not accumulate with age.

Keywords: aging; duplex sequencing; genetics; genomics; mitochondrial DNA; mouse; somatic mutations

DOI: https://doi.org/10.7554/eLife.87194

Endocrinol Diabetes Metab Case Rep. 2023 Apr 01. pii: 22-0416. [Epub ahead of print]2023(2):

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

Nam Quang Tran, Chien Cong Phan, Tran Bao Vuong, Thang Viet Tran, Phat Tung Ma.

Summary: Mitochondrial diseases are a group of rare diseases presenting with heterogeneous clinical, biochemical, and genetic disorders caused by mutations in the mitochondrial or nuclear genome. Multiple organs can be affected, particularly those with high energy demand. Diabetes is a common endocrine manifestation of mitochondrial diseases. The onset of mitochondrial diabetes can be latent or acute, and the presenting phenotype can be type 1- or type 2-like. Studies show that diabetes ais associated with latent progression of cognitive decline in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Herein, we report a case of rapid cognitive decline after the acute onset of diabetes in a patient with MELAS syndrome. The patient was a 36-year-old woman who was hospitalized due to hyperglycemic crisis and seizures. She was diagnosed with MELAS syndrome two years previously, and had gradually progressing dementia and hearing loss. However, following the acute onset of diabetes, she developed rapid cognitive decline and loss of ability to perform daily activities. In conclusion, the acute onset of diabetes could be an associated risk factor for rapid cognitive decline in patients with MELAS syndrome. Thus, these patients as well as healthy carriers with related genetic mutations should undergo diabetes education and screening tests. Moreover, clinicians should be aware of the possibility for acute onset of hyperglycemic crisis, particularly in the presence of triggering factors.
Learning points: Diabetes is a common endocrine manifestation of mitochondrial diseases, presenting with a type 1- or type 2-like phenotype depending on the level of insulinopenia. Metformin should be avoided in patients with mitochondrial diseases to prevent metformin-induced lactic acidosis. Mitochondrial diabetes can manifest before or after the onset of MELAS syndrome. In patients with MELAS syndrome, diabetes can initially manifest with a life-threatening severe hyperglycemic crisis and can cause rapid cognitive decline. Diabetes screening tests (e.g. hemoglobin A1c, oral glucose tolerance test, or random blood glucose level measurement) should be performed either systematically or in the presence of symptoms, particularly after triggering events. Genetic testing and counseling should be provided to patients and their families for the purpose of better understanding the inheritance, progression, and possible outcomes of the disease.

DOI: https://doi.org/10.1530/EDM-22-0416

Clin Neurol Neurosurg. 2023 Apr 07. pii: S0303-8467(23)00128-2. [Epub ahead of print]229 107712

A very early onset MNGIE-like syndrome with POLG1 mutation and accompanying leukoencephalopathy.

Cansu Altuntaş, Tugce Aksu Uzunhan, Biray Ertürk, Mey Talip Petmezci, Nafiye Emel Çakar, Bilge Noyan, Ali İhsan Dokucu, Hasan Önal.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a well-known mitochondrial depletion syndrome. Since Van Goethem et al. described MNGIE syndrome with pathogenic POLG1 mutations in 2003, POLG1 gene became a target for MNGIE patients. Cases with POLG1 mutations strikingly differ from classic MNGIE patients due to a lack of leukoencephalopathy. Here we present a female patient with very early onset disease and leukoencephalopathy compatible with classic MNGIE disease who turned out to have homozygous POLG1 mutation compatible with MNGIE-like syndrome, mitochondrial depletion syndrome type 4b.

Keywords: Gastroparesis; Inherited peripheral neuropathy; Leukoencephalopathy; MNGIE syndrome; Mitochondrial DNA Depletion Syndrome

DOI: https://doi.org/10.1016/j.clineuro.2023.107712

Cerebellum. 2023 Apr 22.

POLG2-Linked Mitochondrial Disease: Functional Insights from New Mutation Carriers and Review of the Literature.

Max Borsche, Marija Dulovic-Mahlow, Hauke Baumann, Sinem Tunc, Theresa Lüth, Susen Schaake, Selin Özcakir, Ana Westenberger, Alexander Münchau, Evelyn Knappe, Joanne Trinh, Norbert Brüggemann, Katja Lohmann.

Different pathogenic variants in the DNA polymerase-gamma2 (POLG2) gene cause a rare, clinically heterogeneous mitochondrial disease. We detected a novel POLG2 variant (c.1270 T > C, p.Ser424Pro) in a family with adult-onset cerebellar ataxia and progressive ophthalmoplegia. We demonstrated altered mitochondrial integrity in patients' fibroblast cultures but no changes of the mitochondrial DNA were found when compared to controls. We consider this novel, segregating POLG2 variant as disease-causing in this family. Moreover, we systematically screened the literature for POLG2-linked phenotypes and re-evaluated all mutations published to date for pathogenicity according to current knowledge. Thereby, we identified twelve published, likely disease-causing variants in 19 patients only. The core features included progressive ophthalmoplegia and cerebellar ataxia; parkinsonism, neuropathy, cognitive decline, and seizures were also repeatedly found in adult-onset heterozygous POLG2-related disease. A severe phenotype relates to biallelic pathogenic variants in POLG2, i.e., newborn-onset liver failure, referred to as mitochondrial depletion syndrome. Our work underlines the broad clinical spectrum of POLG2-related disease and highlights the importance of functional characterization of variants of uncertain significance to enable meaningful genetic counseling.

Keywords: Adult-onset ataxia; Mitochondrial dysfunction; POLG2

DOI: https://doi.org/10.1007/s12311-023-01557-x

Sci Rep. 2023 Apr 20. 13(1): 6445

Watching the human retina breath in real time and the slowing of mitochondrial respiration with age.

Pardis Kaynezhad, Ilias Tachtsidis, Sobha Sivaprasad, Glen Jeffery.

The retina has the greatest metabolic demand in the body particularly in dark adaptation when its sensitivity is enhanced. This requires elevated level of perfusion to sustain mitochondrial activity. However, mitochondrial performance declines with age leading to reduced adaptive ability. We assessed human retina metabolism in vivo using broad band near-infrared spectroscopy (bNIRS), which records colour changes in mitochondria and blood as retinal metabolism shifts in response to changes in environmental luminance. We demonstrate a significant sustained rise in mitochondrial oxidative metabolism in the first 3 min of darkness in subjects under 50 years old. This was not seen in those over 50 years. Choroidal oxygenation declines in < 50 s as mitochondrial metabolism increases, but gradually rises in the > 50 s. Significant group differences in blood oxygenation are apparent in the first 6 min, consistent with mitochondrial demand leading hemodynamic changes. A greater coupling between mitochondrial oxidative metabolism with hemodynamics is revealed in subjects older than 50, possibly due to reduced capacity in the older retina. Rapid in vivo assessment of retinal metabolism with bNIRS provides a route to understanding fundamental physiology and early identification of retinal disease before pathology is established.

DOI: https://doi.org/10.1038/s41598-023-32897-7