Consolidating biallelic SDHD variants as a cause of mitochondrial complex II deficiency

Abstract

Isolated mitochondrial complex II deficiency is a rare cause of mitochondrial respiratory chain disease. To date biallelic variants in three genes encoding mitochondrial complex II molecular components have been unequivocally associated with mitochondrial disease (SDHA/SDHB/SDHAF1). Additionally, variants in one further complex II component (SDHD) have been identified as a candidate cause of isolated mitochondrial complex II deficiency in just two unrelated affected individuals with clinical features consistent with mitochondrial disease, including progressive encephalomyopathy and lethal infantile cardiomyopathy. We present clinical and genomic investigations in four individuals from an extended Palestinian family with clinical features consistent with an autosomal recessive mitochondrial complex II deficiency, in which our genomic studies identified a homozygous NM_003002.3:c.[205 G > A];[205 G > A];p.[(Glu69Lys)];[(Glu69Lys)] SDHD variant as the likely cause. Reviewing previously published cases, these findings consolidate disruption of SDHD function as a cause of mitochondrial complex II deficiency and further define the phenotypic spectrum associated with SDHD gene variants.

Mitochondrial protein dysfunction in pathogenesis of neurological diseases

“…Except for LS, multiple point mutations in SDHB are reported in patients with leukoencephalopathy (Alston et al, 2012 ; Ardissone et al, 2015 ; Helman et al, 2016 ; Kaur et al, 2020 ). In patients with early progressive encephalomyopathy, a homozygous or compound heterozygous mutations in SDHD p.E69K and p.*164Lext*3 (a mutation that extends the SDHD C-terminus by the three extra amino acids Leu, Pro, and Phe) was identified (Jackson et al, 2014 ; Lin et al, 2021 ). Moreover, although CI and CIII are the main sources of mitochondrial ROS, growing studies indeed reveal that CII also serves as a source and modulator of ROS (Yankovskaya et al, 2003 ; Hadrava Vanova et al, 2020 ).…”