COMMON INHERITED METABOLIC CONDITIONS IN SOUTH AFRICA DIAGNOSING RARE DISEASE IN GENETICALLY UNIQUE AND UNDERSTUDIED POPULATION GROUPS

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1 COMMON INHERITED METABOLIC CONDITIONS IN SOUTH AFRICA DIAGNOSING RARE DISEASE IN GENETICALLY UNIQUE AND UNDERSTUDIED POPULATION GROUPS S MELDAU, G VAN DER WATT INHERITED METABOLIC DISEASES GROUP UCT / NHLS

2 NHLS/UCT INHERITED METABOLIC DISEASES GROUP Clinical diagnosis Clinicians Biochemistry - amino acids, organic acids, carnitines, VLCFAs etc Red Cross Hospital - Chemistry Tissue Culture + specific enzyme assay Metabolic lab UCT Genetic analysis IMD molecular lab - GSH

3 OBJECTIVES TO PRESENT COMBINED RARE DISEASE DATA FROM THE NATIONAL HEALTH LABORATORY SERVICES (NHLS) INHERITED METABOLIC DISEASE (IMD) LABORATORIES AT RXH AND GSH OVER THE PAST 0 YEARS METHODS DATA FROM IMD CASES WITH CONFIRMED DIAGNOSES WERE RETRIEVED FROM EXISTING DATABASES AT THE TWO REFERRAL CENTRES. ALL IDENTIFIABLE PATIENT INFO HAVE BEEN REMOVED.

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5 GALACTOSAEMIA (N=45) 5 38 p.s35l/p.s35l p.q88r/p.s35l p.s35l/?

6 GLUTARIC ACIDURIA TYPE (N=38) 4 9 GCDH: p.a93t/p.a93t GCDH: p.a93t/? GCDH: p.a93t/p.his96pro(vus) GCDH: p.a93t/p.r40w GCDH: p.glu59pro/p.glu59pro GCDH: p.r355c/p.r383c

7 CYSTINOSIS (N=~3) 9 CTNS:c.97-G>A/c.97-G>A CTNS:c.97-G>A/c.809C>T CTNS:c.97-G>A/c.8_delGACT CTNS:c.97-G>A/c.4C>T

8 MPV7 NEUROHEPATOPATHY (See Poster #P3) 5 MPV7:p.Q36X/p.Q36X

9 Beta-ketothiolase (MAT) Biotinidase deficiency CAH-OHase deficiency CPT II Crigler Najjar syndrome Cystinosis Cystinuria Dihydropteridine reductase deficiency Dihydrolipoyl DH (E3) Formiminoglutamatetransferase Galactosaemia (GALT) Glutaric aciduria type (GA) Glutathione-synthase deficiency Glycogen Storage Disease - all Hepatorenal Tyrosinosis type I Histidinaemia L--hydroxyglutaric aciduria Hypophosphatasia HMG-CoA Lyase Deficiency Hyperoxaluria type (AGXT) Holocarboxylase Synthase (HCSD) Isovaleric Acidaemia (IVA) Lesh Nyhan Syndrome Alkaptonuria Lysosomal Storage Disease (LSD) Methylmalonic Acidaemia (MMA) Maple Syrup Urine Disease Mitochondrial cytopathy Molybdenum Cofactor defic MPV7 Neurohepatopathy (African) MTHFR defic Multiple Acyl Dehydrogenase (MADD) Myoadenylate Deaminase Non Ketotic Hyperglycinaemia (NKH) Ornithine Amino Transferase defic Peroxisomal Acyl-CoA Oxidase Prolidase Propionic Acidaemia PKU Pyruvate dehydrogenase Pyridoxine Dependent Epilepsy VLCADD LCHADD SCOT Urea Cycle Defects X linked Ichthyosis X-ALD Zellweger spectrum At time of abstract submission

10 Beta-ketothiolase (MAT) Biotinidase deficiency CAH-OHase deficiency CPT II Crigler Najjar syndrome Cystinosis Cystinuria Dihydropteridine reductase deficiency Dihydrolipoyl DH (E3) Formiminoglutamatetransferase Galactosaemia (GALT) Glutaric aciduria type (GA) Glutathione-synthase deficiency Glycogen Storage Disease - all Hepatorenal Tyrosinosis type I Histidinaemia L--hydroxyglutaric aciduria Hypophosphatasia HMG-CoA Lyase Deficiency Hyperoxaluria type (AGXT) Holocarboxylase Synthase (HCSD) Isovaleric Acidaemia (IVA) Lesh Nyhan Syndrome Alkaptonuria Lysosomal Storage Disease (LSD) Methylmalonic Acidaemia (MMA) Maple Syrup Urine Disease Mitochondrial cytopathy Molybdenum Cofactor defic MPV7 Neurohepatopathy (African) MTHFR defic Multiple Acyl Dehydrogenase (MADD) Myoadenylate Deaminase Non Ketotic Hyperglycinaemia (NKH) Ornithine Amino Transferase defic Peroxisomal Acyl-CoA Oxidase Prolidase Propionic Acidaemia PKU Pyruvate dehydrogenase Pyridoxine Dependent Epilepsy VLCADD LCHADD SCOT Urea Cycle Defects X linked Ichthyosis X-ALD Zellweger spectrum This week

11 PRIMARY HYPEROXALURIA (N=0) 8 AGXT p.ad/p.ad AGXT:p.AD/p.S58L AGXT c.445delg/c.445delg

12 MTDNA CYTOPATHIES (N=46) (See Poster #P4) mtdna mutations LHON mutations m.778g>a m.4484t>c m.3460g>a m.3635g>a MILS mutations LHON MILS MELAS:m.343A>G NARP/Leigh:m.8993T>C/G Multiple deletions MERRF:m.8344 Large mtdna deletions m.4459a>g m.3094t>c

13 OTC (N=) OTC: Exdel OTC: p.pro347leu OTC:p.Leu95Ser OTC: p.asp96thr OTC:p.Pro5Leu/- OTC: del ex5-0 OTC:p.Arg4Gly OTC:p.c.867+G>T

14 X-LINKED ADRENOLEUKODYSTROPHY (N=0) 3 ABCD:p.R58Q ABCD p.r58qw ABCD: p.r660p ABCD: p.g5s ABCD: p.s08l ABCD:p.P543L ABCD: p.y74c

15 -OH DEFICIENCY CAH (N=) CYPA: 5` convers (incl ex )/compl gene del CYPA: 5` convers (incl ex )(?Homozyg) CYPA: p.arg357trp/conv ex 4-0 CYPA: c.90-3c>g homoz CYPA: c.90-3c>g/cypa*0k CYPA:p.Ile73Asn/p.Ile73Asn CYPA: p.gln38x/exon 6 cluster CYPA: conv exon 3 / conv exon 7-8 CYPA: p.r479l/?

16 CONCLUSIONS Most commonly diagnosed IMDs (excl. CHT and CF): GA Cystinosis Galactosaemia MPV7 PH MtDNA cytopathies: MELAS LHON Urea cycle defects (mainly OTC) Propionic Acidaemia CAH XALD

17 CONCLUSIONS Most commonly diagnosed IMDs (excl. CHT and CF): GA Cystinosis Significantly amenable to treatment if diagnosed early Galactosaemia MPV7 PH MtDNA cytopathies: MELAS LHON Urea cycle defects (mainly OTC) Propionic Acidaemia CAH XALD

18 CONCLUSIONS Most commonly diagnosed IMDs (excl. CHT and CF): GA [] p.a93t :36 ; /5 84 newborns Cystinosis [] c.97-g>a :50 ; /0 000 newborns Significantly amenable to treatment if diagnosed early Galactosaemia [3] p.s35l :60 ; /4 400 newborns MPV7 [4] p.q36x :68 ; /8 496 newborns PH p.ad?? MtDNA cytopathies: MELAS LHON Urea cycle defects (mainly OTC) Propionic Acidaemia CAH XALD Genetics With exception of mtdna, X-linked disorders (OTC and XALD) and CAH, all have underlying mutations that are unique to South African populations [] Van der Watt et al, 00; [] Owen et al, 05; [3] Henderson et al, 00; [4] Meldau et al (currently under review)

19 TAKE HOME MESSAGE We should be careful in SA of using IMD incidence data from other countries or anecdotal evidence to direct how we employ limited resources in the field of rare diseases. These data increasingly support our opinion that founder mutations and not consanguinity are responsible for the large proportion of recessive IMDs that we diagnose.