Leigh syndrome in individuals bearing m.9185T>C MTATP6 variant. Is hyperventilation a factor which starts its development?

Abstract

Leigh syndrome (LS), subacute necrotizing encephalomyelopathy is caused by various genetic defects, including m.9185T>C MTATP6 variant. Mechanism of LS development remains unknown. We report on the acid-base status of three patients with m.9185T>C related LS. At the onset, it showed respiratory alkalosis, reflecting excessive respiration effort (hyperventilation with low pCO2). In patient 1, the deterioration occurred in temporal relation to passive oxygen therapy. To the contrary, on the recovery, she demonstrated a relatively low respiratory drive, suggesting that a “hypoventilation” might be beneficial for m.9185T>C carriers. As long as circumstances of the development of LS have not been fully explained, we recommend to counteract hyperventilation and carefully dose oxygen in patients with m.9185T>C related LS.Electronic supplementary materialThe online version of this article (10.1007/s11011-017-0122-1) contains supplementary material, which is available to authorized users.

A Chinese Family With Adult-Onset Leigh-Like Syndrome Caused by the Heteroplasmic m.10191T>C Mutation in the Mitochondrial MTND3 Gene

“…Considering all patients with the T10191C mutation, particularly patients with high-ratio mutation (30–32, 43), we speculate that earlier onset and more severe phenotype are well correlated with both higher mutational load and lower residual activity of CI, which is in line with Malfatti et al's study (33). However, Nesbitt et al thought the mutation loads measured in muscle and blood did not correlate with symptoms (26).…”

“…In addition to the above neurological manifestations, non-neurological abnormalities can also be present. In this case series, the most common symptoms were respiratory problems (7/26, excluding patient 1 and 9), which were very prominent in LS: 2 patients showed bradypnea (28, 32), 5 patients showed apnea or dyspnea or respiratory distress (26, 31, 32, 42, 43), 2 patients exhibited respiratory acidosis (30, 32), and the prominent initial symptom of patient 19 was pneumorrhagia. Other common non-neurological symptoms were gastrointestinal (5/26, excluding patient 1 and 9), consisting of vomiting and poor feeding (26, 28, 31, 32, 35).…”

“…Patients 17, 18, and 19 showed autonomic nervous disorders, mainly hypothermia, fever or bradycardia. In addition, a few patients appeared lethargic or even comatose in the late stages of the disease (26, 30, 32, 43). In addition to the above neurological manifestations, non-neurological abnormalities can also be present.…”

Leigh Syndrome: A Tale of Two Genomes

“…Similar to the m.8993 mutations, lymphoblast studies did not show abnormality in ATP synthesis. The reason for the onset of LS in individuals carrying this mutation is unknown; however, disease onset and exacerbation in m.9185T > C cases correspond to febrile viral-like illness or infection ( Saneto and Singh, 2010 ; Piekutowska-Abramczuk et al, 2018b ). In one case, hypoxia treatment reversed LS in a patient carrying this disorder while the brother of this patient with 100% mutated mtDNA for m.9185T > C mutation did not present with NARP/MILS ( Piekutowska-Abramczuk et al, 2018b ).…”

Quantifying Mitochondrial Dynamics in Patient Fibroblasts with Multiple Developmental Defects and Mitochondrial Disorders

“…Two of the patient cell lines have mtDNA mutations affecting the MTND3 (SBG4: m.10158T>C) and MTND5 (SBG5: m.12706T>C) subunits of complex I of the electron transport chain. These mutations affecting complex I and V have been implicated in Leigh syndrome (LS) [18,[20][21][22][23]. LS is a classic mitochondrial disorder that affects mental and motor activity, where disease severity and developmental defects are tied to specific mutations and mutant load [18,24,25].…”