Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis

Abstract

Leigh syndrome is a major phenotype of mitochondrial diseases in children. With new therapeutic options being proposed, assessing the mortality and clinical condition of Leigh syndrome patients is crucial for evaluating therapeutics. As data are scarce in Japan, we analysed the mortality rate and clinical condition of Japanese Leigh syndrome patients that we diagnosed since 2007. Data from 166 Japanese patients diagnosed with Leigh syndrome from 2007 to 2017 were reviewed. Patients' present status, method of ventilation and feeding, and degree of disability as of April 2018 was analysed. Overall, 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow‐up. Median age of living patients was 8 years (1‐39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate of patients with onset before 6 months of age was significantly higher than that of onset after 6 months. All patients with neonatal onset were either deceased or bedridden. MT‐ATP6 deficiency caused by m.8993T>G mutation and MT‐ND5 deficiency induced a severe form of Leigh syndrome. Patients with NDUFAF6 , ECHS1 , and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across the genetic diagnoses. The clinical condition of many patients was poor; however, few did not require mechanical ventilation or tube‐feeding and were not physically dependent. Early disease onset and genetic diagnosis may have prognostic value.

Leigh Syndrome: A Tale of Two Genomes

“…This makes its challenging to fully identify the most predominant symptoms in patients with LS. In recent years, however, efforts have been made to compile clinical information from various centers across Europe, Asia, the United States, and Australia ( Sofou et al, 2014 , 2018 ; Ganetzky et al, 2019 ; Hayhurst et al, 2019 ; Hong et al, 2020 ; Ogawa et al, 2020 ; Stendel et al, 2020 ). These have allowed for metadata analysis and systemic retrospective studies to find unifying symptoms for LS.…”

“…To date, the most common clinical features associated with LS are (see Figure 2 for more details): ataxia, hypotonia, developmental delay, seizures, poor feeding/feeding difficulties associated with dysphagia, failure to thrive, persistent vomiting, elevated serum or cerebrospinal fluid lactate levels, and abnormal ocular disturbances ( Gerards et al, 2016 ; Lee S. et al, 2019 ; Chang et al, 2020 ; Hong et al, 2020 ; Ogawa et al, 2020 ; Stendel et al, 2020 ). Aside from the neuromuscular and ocular abnormalities, abnormalities in other organ systems have also been reported in some cases ( Figure 2 ).…”

“…Furthermore, findings such as RRF are associated with another mitochondrial disorder: myoclonus epilepsy with ragged red fibers (MERRF). Finally, biochemical findings highlighting deficiencies in respiratory chain complexes, while important in LS diagnosis have also been inconsistent ( Ganetzky et al, 2019 ; Ogawa et al, 2020 ). As stated earlier, these observations highlight the need to combine findings from various diagnostic tools including genetic findings for proper diagnosis of LS.…”

Successful recovery from severe hypertension in a patient with Leigh syndrome

“…In the majority of cases, dysfunction of the mitochondrial respiratory chain is responsible for the disease and LS is caused by either mitochondrial or nuclear gene mutations with large genetic heterogeneity [ 3 ]. Usually, patients with SURF-1 deficiency have reduced activity in complex IV and relatively mild symptoms and better survival [ 4 , 5 ]. Hypertension is rarely associated with this condition, but based on previous reports, usually indicates the terminal phase of the illness [ [6] , [7] , [8] , [9] ].…”

Focal Segmental Glomerulosclerosis with a Mutation in the Mitochondrially Encoded NADH Dehydrogenase 5 Gene: A Case Report

“…The enzyme NADH dehydrogenase (ubiquinone) is known as Complex I, which belongs to the MRC complex. Therefore, MT-ND5 gene mutations cause mitochondrial OXPHOS disorder, which results in the occurrence of mitochondrial diseases, such as MELAS (28-30), Leigh's syndrome(29)(30)(31)(32), and Leber's hereditary optic neuropathy…”