Phenotypic variation of TTC19‐deficient mitochondrial complex III deficiency: A case report and literature review

Abstract

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.

TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III

“…Loss-of-function mutations in TTC19 have been found in patients with cIII 2 deficiency associated with heterogeneous neurological syndromes (Ardissone et al, 2015;Atwal, 2014;Ghezzi et al, 2011;Kunii et al, 2015;Melchionda et al, 2014;Mordaunt et al, 2015;Morino et al, 2014;Nogueira et al, 2013). TTC19 ablation in D. melanogaster causes cIII 2 deficiency associated with a neurological phenotype in adult flies (Ghezzi et al, 2011).…”

“…Pathogenic mutations have been found in some of cIII 2 -related ancillary factors, including BCS1L (de Lonlay et al, 2001;Fellman, 2002;Fernandez-Vizarra et al, 2007;Hinson et al, 2007;Morá n et al, 2010;Ramos-Arroyo et al, 2009), TTC19 (Ardissone et al, 2015;Atwal, 2014;Ghezzi et al, 2011;Kunii et al, 2015;Melchionda et al, 2014;Mordaunt et al, 2015;Morino et al, 2014;Nogueira et al, 2013), LYRM7 (Dallabona et al, 2016;Invernizzi et al, 2013), UQCC2 (Tucker et al, 2013), and UQCC3 (Wanschers et al, 2014). In particular, mutations in TTC19 have been identified in patients with heterogeneous, but invariably severe, phenotypes, including early-onset, slowly progressive encephalomyopathy; adult-onset, rapidly progressive multisystem neurological failure; adult-onset spinocerebellar ataxia; and childhood or juvenile spinocerebellar ataxia with psychosis (OMIM: 613814).…”

Mitochondrial complex III Rieske Fe-S protein processing and assembly

“…Since the first TTC19 mutations were published in 2011 [30], a significant number of cases have been subsequently reported [44,45]. The biochemical profile of these patients, showing isolated cIII deficiency, underscores the importance of TTC19 for a correct biogenesis of this complex.…”

Management of Leigh syndrome: Current status and new insights

“…Mutations in TTC19 are usually nonsense whereas in BCS1L they are missense although either can lead to a range of neurological symptoms. In particular, as well as the common findings of abnormal magnetic resonance imaging (MRI) in TTC19 , bilateral retinal cherry red spots are a unique manifestation . In complex IV (CIV; also known as COX) subunit mutations, SURF1 and LRPPRC are remarkable.…”

“…In particular, as well as the common findings of abnormal magnetic resonance imaging (MRI) in TTC19, bilateral retinal cherry red spots are a unique manifestation. 15 In complex IV (CIV; also known as COX) subunit mutations, SURF1 and LRPPRC are remarkable. The former is involved in COX biogenesis and is the most common cause of LS with nearly onethird of cases affected.…”