Supplementary Material Complex I deficiency: clinical features, biochemistry and molecular genetics Elisa Fassone 1 and Shamima Rahman 1,2,3* 1 Mitochondrial Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London WC1N 1EH, UK 2 Metabolic Unit, Great Ormond Street Hospital, London WC1N 3JH, UK 3 MRC Centre for Neuromuscular Diseases, National Hospital for Neurology, Queen Square, London WC1N 3BG, UK * Author for correspondence Address for correspondence: Clinical and Molecular Genetics Unit UCL Institute of Child Health 30 Guilford Street London WC1N 1EH UK Tel: +44(0)207 905 2608 Fax: +44(0)207 404 6191 Email: [email protected] Supplementary Table 1 Complex I deficiency Numbe (% Gene Lactate r of Age at Age at Clinical residual Gene Protein (Complex I (normal <2.0 References patient Onset Death phenotype actvity change(s) change(s) subunits) mM) s compared to mean control) cpd het 5 14 and 17 myoclonic CSF M and Fb R59X + 2 c.175C>T + months months epilepsy elevated low T423M c.1268C>T Schuelke M et al. Nat Genet. (macrocystic) 1999 Mar [1] 6 CSF M and Fb homozygous 1 10 years leuko- A341V months elevated low c.1022 C>T encephalopathy E214K + cpd het exon 8 M low (Fb c.640G>A + 1 1 year 3 years LS* B 2.6 mM skipping -> normal) A>C intron 8 unstable splice site mRNA A432P + Bénit P et al. cpd het premature Am J Hum 6 M low (Fb 1 18 months LS B 4 mM c.1294G>C + stop codon -> Genet. 2001 Jun months normal) c.989–990del2 unstable [2] mRNA cpd het 5 alive at 3 M low (Fb Y204C + 1 LS B 4.7 mM c.611A>G + months years normal) C206G c.616T>G NDUFV1 Bugiani M et al First not CSF M 36% (Fb homozygous Biochim Biophys 1 leukodystrophy A341V months reported elevated normal) c.1022C>T Acta. 2004 Dec [3] B 3.7- 8.0 cpd het Laugel V et al 7 alive at 7 M 32%‡ Y204C + 1 LS mM; CSF 4.8 c.611A>G + Pediatr Neurol. months years (Fb normal) C206G mM c.616T>G 2007 Jan [4] Zafeiriou DI et cpd het 9 alive at 16 (cystic) leuko- M 30%‡; R257Q + al. 1 B 1.8 mM c.770G>A + months months encephalopathy Fb 31%‡ A211V Neuropediatrics. c.632T>C 2008 Jun [5] CSF 55 + 44 Breningstall GN 6 and 11 alive at 32 leuko- mg/dL homozygous et al. Semin 2 M 38% R386C months months encephalopathy (normal ≤ c.1156C>T Pediatr Neurol. 20) 2008 Dec [6] B 21.6 mM; Calvo SE et al. M 11%; Fb homozygous 1 2 weeks 4 months FILA CSF 18.1 E377K Nat Genet. 2010 20% c.1129G>A mM Oct [7] B 1.7 + 5.2 Vilain C et al. 3.5 M low (liver homozygous 2 4.5 months LS mM; CSF 2.3 R386H Clin Genet. months normal) c.1156G>A + 2.8 mM 2011 Jun [8] homozygous B 4bp deletion of Bénit P et al skipping of NDUFV2 3 5 days 3 months HCM persistently M 40-50% intron 2 Hum Mutat. exon 2 >5 mM IVS2+5+8delGT 2003 Jun [9] TA homozygous Pagniez- 4bp deletion of Mammeri H et not not skipping of 1 HCM not reported F 15%‡ intron 2 al. Mol Genet NDUFV2 reported reported exon 2 IVS2+5+8delGT Metab. 2009 Apr TA [10] 4 and 9 B 32 mg/dl M 20%‡; hemizygous 2 14 months LS G8R months (normal <20) Fb 17%‡ c.22G>C Fernandez- Moreira D et al cerebellar ataxia Ann Neurol. 6 alive at 10 M 30%‡; hemizygous 1 and myoclonic B normal R37S 2007 Jan [11] months years Fb 70%‡ c.251G>C epilepsy cerebellar ataxia alive at 35 B and CSF hemizygous 1 4 years and neuro- M 5–10% G32R years normal c.94G>C NDUFA1 degeneration Potluri P et al Mol Genet Metab. 2009 Apr cerebellar ataxia alive at 30 B 3 mM: hemizygous [12] 1 5 years and neuro- M 5–10% G32R years CSF 2 mM c.94G>C degeneration Mayr A et al. lactic acidosis 11 alive at 5 hemizygous Mol Genet 1 (recurrent B 3–4 mM M 20% G32R months years c.94G>C Metab. 2011 episodes) May [13] impaired exon 2 splicing -> Hoefs SJ et al M 20%‡; homozygous frameshift -> Am J Hum NDUFA2 1 5 days 11 months HCM and LS not reported Fb 36%‡ c.208+5G >A unstable Genet. 2008 Jun truncated [14] protein -> degraded van den Bosch soon M 29%; F homozygous BJ et al J Med NDUFA9 1 after 1 month LS B 10 mM R321P 11% c.962G>C Genet. 2011 birth Nov [15] Hoefs SJ et al. M 19%; Fb <10 B 8.6 mM; cpd het c.1A>G M1? + Eur J Hum 1 23 months LS* and HCM 3% (and Fb months CSF 4.9 mM + c.425A>G Q142R Genet. 2011 CIII 34%) Mar [16] NDUFA10 Haack TB et al. >6 progressiv B and CSF M <25%; homozygous 1 LS G99E J Med Genet. months e course elevated Fb <25% c.296G>A 2012 Feb [17] leaky splicing 10 to 24 M 4--27%; homozygous 3 40 days FILA and HCM B 10–15 mM -> activation hours Fb 45% IVS1+5 G>A of cryptic splice site at Berger I et al NDUFA11 19-20bp of Ann Neurol. 18 months exon 1, ; 4 years; 2008 Mar [18] 3 to 4 HCM and B 3.2–10 M 19-39%; homozygous 3 one patient lacking the 3' months encephalopathy mM Fb 46% IVS1+5 G>A 78bp of exon alive at 6 1 months Ostergaard E et alive at 10 B 4.9 mM; M 11%; Fb homozygous NDUFA12 1 2 years LS R60X al. J Med Genet. years CSF 2.9 mM 60% c.178C>T 2011 Nov [19] M 6% (M CII+III 17% + CI V 54% Calvo SE et al. intra- - ?PM homozygous 1 4 months FILA B 5.1 mM W22R Sci Transl Med. NDUFB3 uterine artefact); c.64T>C 2012 Jan [20] Fb 12% (Fb CIII 50%) unspecified cpd het Haack TB et al. not not W22R + 1 encephalo- B elevated Fb 17% c.64T>C + J Med Genet. NDUFB3 reported reported G70X myopathy c.208G>T 2012 April [17] unspecified M >50%‡; Haack TB et al. <6 progressiv homozygous NDUFB9 1 encephalo- B elevated Fb 21- L64P J Med Genet. months e course c.191T>C myopathy 39%‡ 2012 Feb [21] cpd het 3bp in-frame 2 years; 10 months; B 4.4 mM; M and Fb deletion at codon 222 3 4 leukodystrophy 7 months CSF 3.2 mM low c.664-6 + deletion + months c.755 A>G D252G R241W + B and CSF cpd het 2 and 3 5 months; M and Fb R557X -> 2 LS persistently c.721 C>T + Bénit P et al. months 3 months low unstable high (5 mM) c.1669 C>T Am J Hum mRNA Genet. 2001 Jun [2] cpd het 2119 hemizygous A>G + de novo M707V; de shortly not B 5.3 mM; M (Fb deletion of novo deletion 1 aFbter LS reported CSF 4 mM normal) paternal of paternal birth NDUFS1 NDUFS1 allele allele Bugiani M et al 6 not M 45%; Fb homozygous Biochim Biophys 2 leukodystrophy B elevated Q522K months reported 45% c.1564C>A Acta. 2004 Dec [3] B 24 mg/dL (normal < Martín MA et al. 8.5 14 months; 20) ; CSF 30 homozygous 1 LS M 25% L231V Arch Neurol. months 8 months mg/dL c.691C>G 2005 Apr [22] (normal < 15) NDUFS1 Pagniez- cpd het Mammeri H et <6 not leuko- B 1.9 mM; V228A + 1 Fb 27% c.683T>C + al. Mol Genet months reported encephalopathy CSF 6.6 mM D252G c.755A>G Metab. 2009 Apr [10] cpd het 8 (cystic) M 63%‡; R557X + 1 12 years not reported c.1669C>T + months leukodystrophy Fb 27%‡ D619N c.1855G>A M 10%‡ (M 4 8 months; leuko- B and CSF homozygous Hoefs SJ et al 2 CIII 70%‡); R408C months 7 months encephalopathy elevated c.1222C>T Mol Genet Fb 20%‡ Metab. 2010 Jul [23] unspecified cpd het c.631– 5 211delE + 1 2 years encephalo- not reported Fb 24%‡ 633del-GAA + months V28A myopathy c.683T>C 10.5 Tuppen HA et al 4 and 2 B 3.3 mM; homozygous 2 months; 10 LL M 23% R408C Brain. 2010 Oct months CSF 4.7 mM c.1222C>T months [24] M 45% + (macrocystic) B 2.4 + 5.1 Ferreira M et al. 11 not 98%‡; Fb homozygous 2 leuko- mM (2.86 T595A Neurogenetics months reported 146% + c.1783A>G encephalopathy mM in CSF) 2011 Feb [25] 53% B cpd het 5 3 years 10 G166E + 1 leukodystrophy persistently Fb ~40%‡ c.497G>A + Danhauser et al. months months V228A elevated c.683T>C Mol Genet B cpd het Metab 2011 Jun 6 1 year 7 not V228A + 1 leukodystrophy persistently c.683T>C + [26] months months reported D252G elevated c.755A>G unspecified cpd het Haack TB et al. <6 progressiv B and CSF M <50%; V71D + 1 encephalo- c.212T>A + J Med Genet. months e course elevated Fb <50% C128X myopathy c.384T>A 2012 Feb [21] cpd het <6 progressiv B and CSF M <50%; T638NfsX14 1 leukodystrophy c.1912insA + months e course elevated Fb <50% + Y695C c.208A>G cpd het >6 progressiv M <50%; Y695H + 1 leukodystrophy B elevated c.2083T>C + NDUFS1 months e course Fb <50% Y695C c.2084A>G Invernizzi F et (macrocystic) cpd het >6 not M 14.5%; R557X + al.