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Multicenter Study
. 2020 Jul;43(4):819-826.
doi: 10.1002/jimd.12218. Epub 2020 Feb 10.

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

Erika Ogawa  1   2 , Takuya Fushimi  1 , Minako Ogawa-Tominaga  1 , Masaru Shimura  1 , Makiko Tajika  1 , Keiko Ichimoto  1 , Ayako Matsunaga  1 , Tomoko Tsuruoka  1 , Mika Ishige  2 , Tatsuo Fuchigami  2 , Taro Yamazaki  3 , Yoshihito Kishita  4 , Masakazu Kohda  4 , Atsuko Imai-Okazaki  4 , Yasushi Okazaki  4 , Ichiro Morioka  2 , Akira Ohtake  3   5 , Kei Murayama  1   4
Affiliations
Multicenter Study

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

Erika Ogawa et al. J Inherit Metab Dis. 2020 Jul.

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.

Keywords: Japanese patients; Leigh syndrome; early onset; genetic diagnosis; mortality.

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Conflict of interest statement

Erika Ogawa, Takuya Fushimi, Minako Ogawa‐Tominaga, Masaru Shimura, Makiko Tajika, Keiko Ichimoto, Ayako Matsunaga, Tomoko Tsuruoka, Mika Ishige, Tatsuo Fuchigami, Taro Yamazaki, Yoshihito Kishita, Masakazu Kohda, Atsuko Imai‐Okazaki, Yasushi Okazaki, Ichiro Morioka, Akira Ohtake, and Kei Murayama declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Age distribution of living patients (N = 124)
Figure 2
Figure 2
A, Distribution of age at death (N = 40). B, Length of disease course (deceased cases; N = 38)
Figure 3
Figure 3
A, Overall survival rate with number of subjects at risk. B, Survival rate by types of mutation with number of subjects at risk. In red, patients with mutations in mitochondrial DNA. In blue, patients with mutations in nuclear DNA. They showed similar mortality (P = .36). mt: mutation in mitochondrial DNA. nuc: mutation in nuclear DNA. C, Survival rate by complex deficiency with number of subjects at risk. In red, patients with defected enzyme activities. In blue, patients with no defect detected. Patients with no defect detected showed a better survival rate compared to patients with defected enzyme activities (P = .026). D, Survival rate by age of onset with number of subjects at risk. In red, patients with disease presentation before 6 months of age (early onset). In blue, patients with disease presentation in and after 6 months of age (late onset). Early onset showed significantly higher mortality (P < .0001). Tick marks show censored cases. Shaded areas show 95% confidence interval
Figure 4
Figure 4
Distribution of age at onset by genetic diagnosis
Figure 5
Figure 5
Length of disease course by genetic diagnosis and severity. There was a significant difference in onset age between NDUFAF6 deficient patients who maintained head control (N = 5) and patients either deceased or who had lost head control (N = 3; P = .004). The left end of each bar shows the median age of disease onset. The right end of each bar shows the present age or age at death. Head control (+): alive with head control (+). Head control (−): alive but head control lost or never acquired
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