Complex II deficiency—A case report and review of the literature

Abstract

Complex II deficiency is a rare cause of mitochondrial respiratory chain defects with a prevalence of 2-23%. It is exclusively nuclear encoded and functions in the citric acid cycle by oxidizing succinate to fumarate and in the mitochondrial electron transport chain (ETC) by transferring electrons to ubiquinone. Of the four subunits, SDHA and SDHB are catalytic and SDHC and SDHD are anchoring. Mutations in SDHA and SDHAF1 (assembly factor) have been found in patients with CII deficiency and a mitochondrial phenotype. We present a patient with CII deficiency with a previously undescribed phenotype of dilated cardiomyopathy, left ventricular noncompaction, failure to thrive, hypotonia, and developmental delay. Also, a comprehensive review of 36 cases published in the literature was undertaken. The results show that CII deficiency has a variable phenotype with no correlation with residual complex activity in muscle although the phenotype and enzyme activities are comparable within a family. For some, the condition was fatal in infancy, others had multisystem involvement and some had onset in adulthood with mild symptoms and normal cognition. Neurological involvement is most commonly observed and brain imaging commonly shows leukoencephalopathy, Leigh syndrome, or cerebellar atrophy. Mutations in SDHAF1 are associated with leukoencephalopathy. Other organ systems like heart, muscle, and eyes are only involved in about 50% of the cases but cardiomyopathy is associated with high mortality and morbidity. In some patients, riboflavin has provided clinical improvement.

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

“…Clinically, the phenotypic presentation of both SDHB patients in this report lies well within the phenotypic spectrum of complex II deficiency (Jain-Ghai et al 2013) as well as of SDHB deficiency (Alston et al 2012;Helman et al 2015). Onset at age 6-12 months, progressive neurological involvement with spasticity, truncal hypotonia, and pathological brain imaging as in patient 1 and 2 are typically described for the more severely affected patients, and cardiomyopathy as found in patient 2 is likewise reported in about 25% of 37 complex II deficient patients reviewed by Jain-Ghai et al (2013). Time of death at age 25 months (patient 1) and 12 months (patient 2) is relatively early compared to mortality in the complex II deficient cohort where only 5 of 37 patients reportedly deceased before the age of 2.5 years.…”

“…Of the six patients with SDHB deficiency, one patient died at age 1 year, whereas the remaining five patients are alive, with current ages from 19 months to 9 years (Alston et al 2012;Helman et al 2015). The ophthalmological features of patient 1 including optic atrophy, decreased vision, and nystagmus are in line with the expected phenotype of mitochondrial encephalomyopathy including previously reviewed patients with complex II deficiency (Jain-Ghai et al 2013). No specific eye manifestations have been described in previous reports of complex II-related leukoencephalopathy (Alston et al 2012;Jain-Ghai et al 2013;Helman et al 2015).…”

“…Complex II has a dual role in mitochondrial metabolism: it functions in the citric acid cycle as well as in the RC, transferring electrons to ubiquinone (Jain-Ghai et al 2013). Two subunits, SDHA and SDHB, have a catalytic function, while SDHC and SDHD are considered anchoring proteins.…”

“…Two subunits, SDHA and SDHB, have a catalytic function, while SDHC and SDHD are considered anchoring proteins. In addition, a number of proteins, including SDHAF1, SDHAF2 (SDH5), SDHAF3, and SDHAF4, are required for correct assembly and functioning of the protein complex (Jain-Ghai et al 2013). Overall, complex II deficiency is a rare cause of RC deficiency and was primarily identified in cases with biallelic SDHA and SDHAF1 mutations, while heterozygous mutations of SDHA, SDHB, SDHC, SDHD, and SDHAF2 were found to cause familial paraganglioma/pheochromocytoma (Ghezzi et al 2009;Rutter et al 2010;Jain-Ghai et al 2013).…”

“…In addition, a number of proteins, including SDHAF1, SDHAF2 (SDH5), SDHAF3, and SDHAF4, are required for correct assembly and functioning of the protein complex (Jain-Ghai et al 2013). Overall, complex II deficiency is a rare cause of RC deficiency and was primarily identified in cases with biallelic SDHA and SDHAF1 mutations, while heterozygous mutations of SDHA, SDHB, SDHC, SDHD, and SDHAF2 were found to cause familial paraganglioma/pheochromocytoma (Ghezzi et al 2009;Rutter et al 2010;Jain-Ghai et al 2013). Familial paraganglioma/pheochromocytoma is a hereditary tumor susceptibility disorder with development of paraganglioma and pheochromocytoma with high penetrance, and with an increased risk for malignancy and renal cell carcinoma in the case of SDHB mutations (Ricketts et al 2010).…”