SURF1 deficiency: a multi-centre natural history study

Orphanet Journal of Rare Diseases

Shamima Rahman⁹  Garry K Brown^1,16  Anupam Chakrapani⁵  Donncha Hanrahan^1,14  David Ketteridge²  Erlend T Aasheim⁸  Louise Simmons⁵  Angus Dobbie^1,15  Katharine Forrest³  John M Land¹  Robert W Taylor^1,11  David R Thorburn^1,10  Antonia Clarke⁴  Phillip E Jardine⁶  Mike Champion⁷  Andrew A M Morris^1,12  Joy Yaplito-Lee^1,10  Robert McFarland^1,11  Ruth M Brown^1,16  Yehani Wedatilake^1,13 

[1] Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK;Women’s & Children’s Hospital, Adelaide, Australia;Southampton University Hospitals NHS Foundation Trust, Southampton, UK;St George’s Hospital NHS Trust, London, UK;Birmingham Children’s Hospital, Birmingham, UK;Bristol Royal Hospital for Children, Bristol, UK;Evelina Children’s Hospital, London, UK;MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK;Metabolic Unit, Great Ormond Street Hospital, London, UK;Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Australia;Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle-upon-Tyne, UK;Central Manchester University Hospital, Manchester, UK;Mitochondrial Research Group, UCL Institute of Child Health, London, UK;Royal Belfast Hospital for Sick Children, Belfast, Ireland;Yorkshire Regional Genetics Service, Leeds, UK;Department of Biochemistry, University of Oxford, Oxford, UK

关键词: Mitochondrial disease;    Complex IV;    Cytochrome c oxidase;    Leigh syndrome;    SURF1;   

Others  :  863681
DOI  :  10.1186/1750-1172-8-96

 received in 2013-05-03, accepted in 2013-06-20,  发布年份 2013

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusions

SURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis.

【 授权许可】

   
2013 Wedatilake et al.; licensee BioMed Central Ltd.

【 图 表 】

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