SURF1 deficiency: a multi-centre natural history study

Abstract

BackgroundSURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report the first natural history study of SURF1 deficiency.MethodsWe conducted a multi-centre case notes review of 44 SURF1-deficient patients from ten different UK centres and two Australian centres. Survival data for LRPPRC-deficient LS and nuclear-encoded complex I-deficient LS patients were obtained from previous publications. The survival of SURF1-deficient patients was compared with these two groups using Kaplan-Meier survival analysis and logrank test.ResultsThe majority of patients (32/44, 73%) presented in infancy (median 9.5 months). Frequent symptoms were poor weight gain (95%, median age 10 months), hypotonia (93%, median age 14 months), poor feeding/vomiting (89%, median age 10 months), developmental delay (88%, median age 14 months), developmental regression (71%, median age 19 months), movement disorder (52%, median age 24 months), oculomotor involvement (52%, median age 29 months) and central respiratory failure (78%, median age 31 months). Hypertrichosis (41%), optic atrophy (23%), encephalopathy (20%), seizures (14%) and cardiomyopathy (2%) were observed less frequently.Lactate was elevated in CSF (mean 4.3 mmol/L) in all patients (30/30) and in blood (mean 4.4 mmol/L) in 31/38 (81%). Fibroblast COX activity was universally decreased (25/25). Normal COX histochemistry was noted in 30% of biopsies, whereas muscle COX activity was reduced in 96% (25/26). Neuroimaging demonstrated lesions characteristic of LS in 28/33 (85%) and atypical findings in 3/33 (9%). Peripheral neuropathy was present in 13/16 (81%) (demyelinating 7/16, axonal 2/16). Kaplan-Meier analysis demonstrated that SURF1-deficient patients experience longer survival (median 5.4 years, p < 0.001) compared to LRPPRC deficiency (median 1.8 years) and nuclear-encoded complex I-deficient LS (median 1.6 years). Survival >10 years was observed in 7 patients, 6 of these patients did not experience neurological regression. The most frequent mutation was c.312_320del10insAT. Five novel mutations (c.468_469delTC, c.799_800delCT, c.575G>A (p.Arg192Gln), c.751+5G>A and c.752-2A>G) were identified.ConclusionsSURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis.

Leigh syndrome: One disorder, more than 75 monogenic causes

“…2,6,7 Mutations in SURF1, encoding a complex IV assembly factor, are the most common cause of complex IV deficient LS and are among the most frequently reported causes of LS, with >200 cases described to date in the literature. 35 Our recent natural history study of a SURF1 patient cohort highlighted the relatively homogenous clinical and biochemical presentation associated with SURF1 deficiency. 35 However, a minority of patients with SURF1 mutations lack the neuroradiological hallmarks of LS or show atypical features such as leukodystrophy and atrophy.…”

Leigh map: A novel computational diagnostic resource for mitochondrial disease

“…Furthermore, the efficacy of the Leigh Map is affected by the breadth of literature available for individual genes. SURF1 , one of the earliest mitochondrial disease genes to be identified and the most common nuclear genetic cause of Leigh syndrome, is the subject of numerous publications 19. Thus, SURF1 is associated with > 90 phenotypes in the Leigh Map, the largest number for any single gene.…”

Identification of a novel deletion in SURF1 gene: Heterogeneity in Leigh syndrome with COX deficiency

“…2A and C). This alteration was absent in 200 DNA samples of healthy subjects and it was not reported in any public SNP databases or in recent publications (Lee et al, 2012;Wedatilake et al, 2013). The deletion is located in a highly conserved region ( Fig.…”

“…This basic structure has been conserved during evolution, suggesting that it has a functional importance in coordinating gene expression regulation. So far, N 78 mutations were found in SURF1, and about 80% probably lead to the production of truncated proteins, mainly due to aberrant splicing, frameshift, deletions or nonsense mutations (Wedatilake et al, 2013). The majority of SURF1 mutations previously associated to LS, are located in exon 8, suggesting that this region has an important impact in the protein function or it is a hot spot for the occurrence of mutations (Lee et al, 2012).…”