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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 295
[65]
In 2011, Heeringa et al. reported a novel cause for steroid-resistant nephrotic syndrome associated with
sensorineural hearing loss due to variants in the COQ6 gene. Twenty-three patients in 16 families with
similar clinical manifestations and two mutations in the COQ6 gene have been identified to date [65-71] .
Extra-renal manifestations such as ataxia, seizures, muscle weakness, white matter changes, and optic
atrophy were less common [65,68] . The age of onset of the renal disease varied from 2 months to 6.4 years but
was most common in infancy and early childhood. The course was progressive with median age of onset of
end stage renal disease between 13 months and 19 months [65,68] . The most common histopathologic finding
was focal segmental glomerulosclerosis. Abnormal mitochondrial proliferation in the podocytes was also
[68]
noted on electron microscopy .

Coenzyme Q10 supplementation alone at 5-30 mg/kg/day was reported in a few patients. Significant
improvement in proteinuria with normal renal function was noted on follow-up of these patients [66,70,72-74] )
However, hearing loss had not improved after Coenzyme Q10 supplementation [66,72] . Hence, early
supplementation of Coenzyme Q10 seemed to help avoid development of massive proteinuria and
[72]
consequently chronic renal failure .

GFER deficiency (OMIM #613076)
Human Growth Factor ERV-1-like (GFER) (also known as augmenter of liver regeneration 1, ALR1) is
one of the sulfhydryl oxidases with a FAD-binding domain, which together with disulfide carrier Mia40
forms part of the disulfide relay system (DRS) and constitutes the mitochondrial import and assembly
(MIA) pathway. The MIA pathway plays an important role in the biogenesis of many mitochondrial
[75]
intramembrane space (IMS) proteins . GFER has two distinct isoforms: the long isoform (205 amino acids,
23 kD), which is mainly located in the IMS of the mitochondria, and the shorter isoform (125 amino acids,
15 kD), which is present in the nucleus. Mia40 functions as an import receptor of cysteine-rich substrates
in the IMS and promotes oxidative folding of these proteins. It is re-oxidized by GFER in a disulfide-
transfer reaction with electrons transferred to cytochrome c, thus connecting the DRS to the electron-
[76]
transport chain of the mitochondria and establishing its role in Complex IV activity .

[77]
In 2009, Di Fonzo et al. reported homozygous missense mutations (c.581 G > A p.R194H) in the GFER
gene in three siblings from a consanguineous Moroccan family. Subsequent functional studies using
analogous mutation (R182H) in yeast ERV1 showed altered mitochondrial morphology, mitochondrial
instability, reduced cyt C oxidase activity, weaker FAD binding, decreased thermal protein stability, and
[79]
altered protein folding [77,78] . Daithanka et al. (2010) also characterized the human GFER/ALR protein
and demonstrated that the R194H led to marked loss of protein stability by an increased rate of FAD
dissociation and enhanced proteolysis susceptibility with only minimal effect on enzymatic activity.

There are eight patients in four families reported with mutations in the GFER gene [77,80,81] , to date. The age
range of the patients was 3 to 21 years with one deceased at 21 years of age. The predominant features were
neuromuscular including hypotonia and psychomotor retardation of variable severity, muscle hypotrophy,
progressive muscle weakness requiring ventilatory support, and, additionally, cataracts and lactic acidosis.
[81]
Other clinical features included movement disorder, dysautonomia, cachexia and orthopedic problems ,
hearing loss , and adrenal insufficiency . MRI of the brain showed normal findings (4/6), cerebellar and
[77]
[80]
moderate cortical atrophy (1/6), and thin corpus callosum (1/6). Histopathologic muscle findings included
abnormal mitochondrial morphology, ragged red fibers, COX negative, and atrophic fibers. Enzymatic
testing revealed isolated Complex IV deficiency or combined deficiencies of Complexes I-IV. The missense
mutation (c.581 G > A; p.R194H) was identified in six out of the eight patients.

Riboflavin supplementation was not reported in these patients. Experiments have indicated that the FAD
[78]
cofactor is detached from Erv1 R182H during the catalytic reaction and inactivated the protein . The