SURF1 deficiency: a multi-centre natural history study
1 Mitochondrial Research Group, UCL Institute of Child Health, London, UK
2 Department of Biochemistry, University of Oxford, Oxford, UK
3 Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle-upon-Tyne, UK
4 Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Australia
5 Central Manchester University Hospital, Manchester, UK
6 Evelina Children’s Hospital, London, UK
7 Bristol Royal Hospital for Children, Bristol, UK
8 St George’s Hospital NHS Trust, London, UK
9 Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK
10 Southampton University Hospitals NHS Foundation Trust, Southampton, UK
11 Yorkshire Regional Genetics Service, Leeds, UK
12 Birmingham Children’s Hospital, Birmingham, UK
13 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
14 Women’s & Children’s Hospital, Adelaide, Australia
15 Royal Belfast Hospital for Sick Children, Belfast, Ireland
16 Metabolic Unit, Great Ormond Street Hospital, London, UK
Orphanet Journal of Rare Diseases 2013, 8:96 doi:10.1186/1750-1172-8-96Published: 5 July 2013
SURF1 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.
We 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.
The 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.
SURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis.