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Phenotypic variation of TTC19 ‐deficient mitochondrial complex III deficiency: A case report and literature review
Author(s) -
Mordaunt Dylan A.,
Jolley Alexandra,
Balasubramaniam Shanti,
Thorburn David R.,
Mountford Hayley S.,
Compton Alison G.,
Nicholl Jillian,
Manton Nicholas,
Clark Damian,
Bratkovic Drago,
Friend Kathryn,
Yu Sui
Publication year - 2015
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36968
Subject(s) - failure to thrive , nonsense mutation , genetics , biology , respiratory chain , nonsense , phenotype , mitochondrial disease , mutation , compound heterozygosity , mitochondrial dna , disease gene identification , exome sequencing , gene , mitochondrion , missense mutation
Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT‐CYB , the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7 , and UQCC3. BCS1L, TTC19 , UQCC2, LYRM7 , and UQCC3 are complex III assembly factors. We report on an 8‐year‐old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh‐like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities. © 2015 Wiley Periodicals, Inc.