SURF1 deficiency: a multi-centre natural history study

To identify previously published cases a systematic literature search was conducted in PubMed in January 2013 using the search terms “SURF1”, “SURF-1”, “Leigh syndrome”, “cytochrome c oxidase deficiency”, “complex IV deficiency”, and “Cox deficiency”. The search was limited to studies in humans published after 1.1.1998 (the year SURF1 deficiency was first described). There were no language restrictions. Of 2135 identified records, 1969 were excluded based on review of titles, 110 were excluded on the basis of abstracts, and 56 full-text records were retrieved. Of these, 43 records describing 129 cases with SURF1 deficiency were reviewed. Bibliographies were searched manually for additional records. The cases were used to ascertain previously identified phenotypes and genotypes, to draw phenotype and genotype comparisons between our cohort and previously published cases and for Kaplan- Meier survival analysis. These cases were not included in our natural history analysis, as data was incomplete and the chronological onset of symptoms was not available in many of the published cases. Authors were contacted and raw data was obtained for survival rates of LRPPRC-deficient LS patients [8] and nuclear-encoded complex I-deficient LS patients [9].

We identified 57 patients with SURF1 disease born between 1976 and 2010, diagnosed at ten centres in the UK (n = 52) and two centres in Australia (n = 5). Genotypes were established in 54 patients and 3 deceased patients were assumed to have the same genotype as their affected sibling with SURF1 deficiency since they had a similar disease course. Detailed clinical data were available in 45 patients. It was not possible to trace clinical records and/or the responsible clinician in the remaining 12 cases. One patient from a consanguineous pedigree was found to have genetically confirmed Zellweger syndrome in addition to SURF1 disease (homozygous c.799_800delCT) and was excluded from further analyses. The study group consisted of 44 patients (24 males, 55%) from 37 pedigrees, with 10 (23%) patients from consanguineous families. Of these, 4 cases (cases 1b, 30, 35 and 36 in Table 1) have been published [3, 10, 11]. White Europeans formed the largest ethnic group (n = 20, 45%) followed by Bangladesh Bengali (n = 5, 11%), Indian Gujarati (n = 5, 11%) and Pakistani (n = 4, 9%). Other ethnicities included Turkish Cypriot (n = 2), Chinese (n = 1), Sri Lankan (n = 1) and six cases where the ethnicity was not specified.

The median age for the onset of first symptoms was 9.5 months (range 0–60 months) and the majority of the patients presented in the first year (32/44, 73%). The most frequently noted initial symptoms were poor feeding/vomiting (frequently attributed to gastro-oesophageal reflux) and poor weight gain (Table 2). The neonatal period was uneventful in the majority of patients (41/44, 93%) except in two patients with feeding problems and one patient with hypotonia. Developmental regression, defined as a loss of cognitive or motor skills, was the initial symptom in 3/44 (7%) patients. Most patients (26/44, 59%) presented with a combination of gastro-intestinal symptoms, poor weight gain and hypotonia. Three patients who underwent a general anaesthetic in the first two months experienced significant problems during the recovery period. One patient (case 30), who had surgery for transposition of the great arteries on day 9, developed persistent vomiting and required enteral feeding. The second patient (case 26) became hypotonic following surgery for pyloric stenosis at 8 weeks. The third patient (case 4) developed a movement disorder after an upper gastro-intestinal endoscopy.

Review of 44 cases with SURF1 deficiency revealed that 32 patients met the criteria for Leigh syndrome [3] and 12 patients were classified as “Leigh-like” due to atypical or normal radiological features or where neuroimaging was not available. The development of clinical features over time is demonstrated in Figure 1. Poor weight gain and hypotonia were the most prevalent symptoms, and tended to be preceded by gastro-intestinal symptoms such as poor feeding/vomiting (Figure 1). Long term enteral feeding was required in 21/44 (48%). Developmental regression (median age-of-onset 19 months) was noted in 27/38 (71%) cases and was precipitated by an intercurrent viral infection in 12 patients.

Hypertrichosis was reported in 18/44 (41%) patients. There was no significant correlation between the presence of hypertrichosis and lactic acidosis. Nystagmus and ophthalmoplegia were found in 25/42 (60%) and 22/42 (52%) patients, respectively, and occurred later (median age-of-onset 29 months). Movement disorder was noted in 22/42 (52%) patients (median age-of-onset 2 years) with an isolated intention tremor in 13 patients, choreoathetoid movements in 3, and dystonia in 2, while 4 patients demonstrated a combination of these abnormal movements. Only 6/44 (14%) patients reported seizures (generalised tonic clonic 5, myoclonic 1) and 4 of these patients were from Australia. Other less frequent clinical features included optic atrophy in 10/44 (23%), encephalopathy in 9/44 (20%) and hypertrophic cardiomyopathy in 1/44 (2%). None of the patients were reported to have pigmentary retinopathy or sensorineural deafness.

CSF lactate was elevated in all subjects who had this measured (mean 4.3, range 2.5-8.6 mmol/L, normal <2 mmol/L). Metabolic acidosis was present in 21/33 (64%) patients (mean bicarbonate level 14.7, range 10–17 mmol/L). 31/38 (81%) patients had elevated blood lactate (mean 4.4, range 2.3-7.3 mmol/L) (Table 3). Fibroblast COX activity was found to be low in all subjects who were tested (25/25, 100%) and ranged from levels below the detection limit of the assay, to 57% of the lower limit of the reference range (reference range 30–90 nmol/mg protein/min).

We analysed the histology and RCE findings of all patients where a muscle biopsy was performed (n = 33). Lipid content was increased in 15/33 (46%) of biopsies and type 1 fibre predominance was noted in 8 biopsies. COX histochemistry demonstrated absent COX in 9 (27%) biopsies and reduced COX staining in 14 (42%) biopsies. Ten (30%) of the biopsies were reported to have normal COX histochemistry with uniform staining of all fibres. RCE activities were measured in 28 biopsies. Two post-mortem biopsies were excluded since post-mortem delay may have resulted in artefactual loss of RCE activities. An isolated decrease of COX activity was found in all except one biopsy where the COX activity was at the lower end of the reference range (COX activity/citrate synthase ratio was 0.016 (reference range 0.014-0.034).

Magnetic resonance imaging (MRI) and Computerised tomography scan (CT) information was available for 39 subjects (33 MRI and 6 CT scans). The patterns of involvement are shown in Table 3. Most MRIs showed findings characteristic of Leigh syndrome (28/33, 85%), with symmetrical hyperintense lesions on T2-weighted imaging in the brainstem and/or basal ganglia (Table 3). Two patients had normal MRI scans which were performed at 1 year of age and follow up imaging was not available. Two patients (one already published, [10]) had leukoencephalopathy (defined as a disorder that predominantly or exclusively affects the white matter of the brain [12]), while one patient had cerebellar atrophy and involvement of the dentate nucleus. Six patients had CT scans of which 3 were found to be normal and three had bilateral symmetric hypodensities in the basal ganglia.

Sixteen patients had nerve conduction studies performed. Abnormal peripheral nerve conduction was noted in 13/16 (81%) with most (7) demonstrating a demyelinating neuropathy compared to an axonal neuropathy in 2 subjects. The type of neuropathy was unspecified in 4 subjects. Many (9/13, 69%) subjects showed a mixed sensori-motor involvement whereas 2 subjects had a pure sensory neuropathy.

We identified SURF1 mutations in 57 patients; 16/57(28%) had the homozygous c.312_320del10insAT insertion/deletion, 15/57(26%) were compound heterozygotes, 12/57(21%) had homozygous splice site mutations, 10/57(18%) had homozygous deletions, 2/57 (4%) had homozygous insertions, 1/57 (2%) had homozygous missense mutations and 1/57(2%) had homozygous nonsense mutations. The most frequently occurring mutation in our cohort was c.312_321del10insAT (p.Leu105X) (16 homozygous and 11 compound heterozygous). The next most common mutations were c.792_793delAG which occurred exclusively in Bangladesh Bengali subjects (n = 5, 3 pedigrees) and the splice mutation c.240+1G>T which was observed in 5 individuals, all of white European origin. The c.792_793delAG mutation has previously only been described in a patient of Japanese origin [13]. Individuals of Pakistani origin had the novel c.799_800delCT mutation or the c.324-11T>G mutation. The c.516-2A>G mutation segregated in two different Indian Gujarati pedigrees and has previously only been described in one subject of unspecified mixed Caucasian Asian parenthood [7]. The c.324-11T>G genotype was observed in 4 individuals from 2 different Pakistani pedigrees and one individual of Indian Gujarati origin. All five patients from the Australian cohort had at least one c.312_321del10insAT (p.Leu105X) mutation. No specific genotype phenotype correlation was observed. The patients surviving >10 years had varied SURF1 genotypes: one was homozygous for the c.312_321del10insAT mutation, two were compound heterozygotes, two had homozygous insertions and one had a splice site mutation.

In our cohort we identified 19 SURF1 mutations (Figure 2) in 57 patients including 5 novel pathogenic mutations (c.468_469delTC, c.799_800delCT, c.575G>A (p.Arg192Gln), c.751+5G>A. and c.752-2A>G).

Of the novel mutations identified, the homozygous c.799_800delCT was found in a Pakistani family where the patient (case 29) presented with early onset disease from birth and died at 2 years. The novel splice site c.751+5G>A mutation, generating an aberrant transcript with incorporation of 31 base pairs of intron 7 into a proportion of mature mRNAs, was found in one subject (case 3) who was a compound heterozygote (c.312_321del10insAT, c.751+5G>A). She had an atypical milder clinical course with longer survival. Her first concerning symptoms were at 16 months when she was noted to have mild motor delay and ataxia but in retrospect mild hypotonia was present from birth. She subsequently developed nystagmus and external ophthalmoplegia. She is currently studying business studies at 19 years of age. The novel missense mutation (c.575G>A, p.Arg192Gln) was found in a 12 year old female (case 2) with ataxia and a 4 year old male (case 22) with developmental delay, ataxia and hypertrophic cardiomyopathy. This was the only patient in the cohort with cardiomyopathy. The female patient subsequently developed nystagmus with ophthalmoplegia but she is currently able to ride a bicycle and play the violin. The splice site mutation c.752-2A>G was found in a patient (case 37) of Australian origin who presented with irritability and poor feeding since birth. Unfortunately clinical information was unavailable for the patient with the homozygous c.468_469delTC mutation.

Among the 44 patients with detailed clinical data, five were alive at the time of writing (age range 2–19 years) while in three patients the current vital status was not known. Of the 36 deceased patients with known cause of death, the cause was central respiratory failure in 29/36 (80%). Seven patients survived beyond 10 years of age (cases 2, 3, 8a, 17, 20, 25a, 25b in Table 1). Of these, 6 presented with neurological symptoms such as ataxia and motor developmental delay; of note, gastro-intestinal symptoms were not the prominent presenting feature in these cases. Furthermore, these six patients also did not experience developmental regression.

Literature searches identified 98 SURF1-deficient cases with available survival data, which we pooled together with the data from our 44 cases. In a Kaplan-Meier analysis (Figure 3), we compared the survival experience of these 142 SURF1-deficient cases to two other groups with LS due to nuclear gene mutations. We compared the survival of SURF1 deficiency to 56 patients with LRPPRC deficiency [8] and 63 patients with nuclear-encoded complex I-deficient LS/“Leigh- like” disease [9] Median survival length was longer in patients with SURF1 deficiency (median 5.4, 25th centile 3.0, 75th centile 10 years) than in patients with LRPPRC deficiency (median 1.8, 25th centile 1.0, 75th centile 4 years), and nuclear-encoded complex I-deficient LS (median 1.6, 25th centile 1.0, 75th centile 10 years) (p < 0.001 for difference across groups; logrank test).

A systematic review of the literature revealed published clinical data on 129 SURF1-deficient patients and mutation data in a further 28 cases. The findings are summarised in Additional file 1: Table S1. Features which were found in these patients but not present in our cohort included unspecified hepatic involvement (3 cases), renal tubulopathy (4 cases) and facial dysmorphism (5 patients) [7, 14‐19].