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Balasubramaniam et al. J Transl Genet Genom 2020;4:285-306 I http://dx.doi.org/10.20517/jtgg.2020.34 Page 297

involved in electron transfer. It is also one of the subunits comprising the electron input (N) functional
[87]
module of Complex I .

Phenotypic variability is observed in patients with Complex I deficiency due to mutations in the NDUFV2
[111]
gene. Bénit et al. 2003 reported three affected siblings in a consanguineous family presenting with early
onset hypertrophic cardiomyopathy, truncal hypotonia, feeding difficulties, growth retardation, and early
death within the first year of life. Another patient also presented with hypertrophic cardiomyopathy and
[112]
encephalopathy . However, a separate family with three affected siblings presented with Leigh syndrome
[113]
[113]
without cardiac involvement . These patients reported by Cameron et al. had seizures by 10 months of
age, progressive clinical course, and two died at 19 months and 10 years. One of these patients was started
on riboflavin plus other supplements. One sibling is still alive at 32 years despite a vegetative state by three
years of age. All these patients were homozygous for a 4-bp deletion in intron 2 (IVS2 + 5_ + 8delGTAA)
of the NDUFV2 gene [113] . Studies using human disease cell model showed that this deletion caused a
[114]
significant reduction in the mitochondrial targeting ability of the NDUFV2 protein .

In a cohort of 37 children with cavitating leukoencephalopathies, three (3/37, 8.1%) were compound
heterozygotes for pathogenic mutations in the NDUFV2 gene [109] . The age of onset of symptoms was
4-46 months with stable/improved clinical course and frontal predominant and deep white matter patterns
[109]
on brain MRI .
Succinic dehydrogenase subunit A deficiency (OMIM #252011)
Succinic dehydrogenase subunit A (SDHA), a flavoprotein with FAD as cofactor, is a nuclear encoded and
catalytic subunit of Complex II (succinate dehydrogenase) which oxidizes succinate to fumarate in the
Kreb’s cycle and transfers electrons to ubiquinone in the mitochondrial electron transport chain [115] .

Mutations in SDHA gene result in both a mitochondrial disease causing Complex II deficiency and
tumor susceptibility. A large proportion (47%) of germline mutations in SDHA has been reported in
gastrointestinal stromal tumors [116] . Other tumors such as paraganglioma/pheochromocytoma, pituitary
adenoma, and renal carcinoma have also demonstrated SDHA germline mutations [117-121] .

Complex II deficiency due to mutations in SDHA presents with variable clinical presentations and age
of onset from prenatal to adulthood. The first report of a nuclear gene mutation causing a mitochondrial
respiratory chain deficiency in humans was identified in two sisters presenting with developmental
regression at 10 months of age, pyramidal tract signs, leukodystrophy with early demise, Complex II
deficiency, and homozygous mutations (R554W) in the SDHA gene [122,123] . Further reports of patients with
SDHA mutations have since been described [124-131] . Leigh or Leigh-like syndrome was a common phenotype.
Slower progression with survival up to 11 years of age has been observed [126,127,130] , and, in one patient, there
was no apparent cognitive impairment at 10 years of age [130] . Isolated cardiomyopathy presenting from
32 weeks in utero to 10 years of age was associated with high mortality in two large Bedouin families with
homozygous G555E mutations in the SDHA gene [132] .

Adult presentation has been reported in two sisters (62 and 56 years) with normal cognition, late-onset
(mid-40s), and slowly progressive cerebellar ataxia, visual impairment, optic atrophy, proximal weakness,
and partial Complex II deficiency in skeletal muscle [133] . Riboflavin supplementation did not prevent
neurological progression in these two patients. These patients were found to be heterozygous for a missense
mutation (R408C) in a highly conserved region of the mature SDHA protein, suggesting an autosomal
dominant inheritance pattern [134] . Another family with three affected members who presented with optic
atrophy, dilated cardiomyopathy, ataxia, and isolated Complex II deficiency in fibroblast were also found
to be heterozygous for a R451C missense mutation. This family serves as the second report supporting an
autosomal dominant inheritance [135] .