Beyond the case for NBS in South Africa Chris Vorster 28/05/2016
The case for NBS in SA Economic justification Cost Utility analysis = Cost/QALY GDP/Capita Immediate implementation (WHO) Political justification Genetic and congenital conditions become important once the Infant Mortality Rate < 50/1000 Human rights SA constitution Ch 2 Section 28(c) UN Convention on the Rights of the Child Art 24(1) & 24(2) Laboratory and Clinical capability Medical Aids and Public Health Expected clinical experience
Why beyond the case for NBS in SA 400 Screens per month Reimbursed by Discovery Health LIMS implementation and interfacing Aggressive marketing by Next Biosciences First advisory panel meeting Publication in the SAMJ to follow Personal feedback from paediatricians
Next Biosciences initiative Role of Next in NBS Permission from practising paediatricians Market the service to expecting parents Arrange for collection in collaboration with Ampath Manage all correspondence and recollections Only involve paediatrician when required Initiatives (since mid February) 127 paediatricians 379 Gynaecologists 53 antenatal classes
Primary screening disorders 2016 Rationale What can we screen for? What does the rest of the world screen for? We should modify it over time. Amino Acid Disorders 1 Citrullinemia, Type I 2 Classic Phenylketonuria 3 Homocystinuria 4 Maple Syrup Urine Disease 5 Tyrosinemia, Type I Organic acid disorders 6 3-Hydroxy-3-Methyglutaric Aciduria 7 3-Methylcrotonyl-CoA Carboxylase Deficiency 8 Glutaric Acidemia Type I 9 Holocarboxylase Synthase Deficiency 10 Isovaleric Acidemia 11 Methylmalonic Acidemia (Cobalamin disorders) 12 Methylmalonic Acidemia (methylmalonyl-coa mutase) 13 Propionic Acidemia 14 ß-Ketothiolase Deficiency Disorders of fatty acid oxidation 15 Carnitine Uptake Defect/Carnitine Transport Defect 16 Medium-chain Acyl-CoA Dehydrogenase Deficiency 17 Very Long-chain Acyl-CoA Dehydrogenase Deficiency Disorders of carbohydrate metabolism 18 Classic Galactosemia Endocrine disorders 19 Congenital adrenal hyperplasia 20 Primary Congenital Hypothyroidism 21 Biotinidase Deficiency 22 Cystic Fibrosis Other Disorders
Primary conditions Secondary conditions Primary Amino Acid Disorders screening disorders 2016 Phe Classic phenylketonuria BH4 biosynthesis or regeneration Cit Citrullinemia type I Citrullinemia type II, Argininosuccunic aciduria, Pyrovate carboxylase deficiency Methyladenosyltrasferase deficiency, Glycine N-methyltransferase deficiency, AdoHcy Met Homocystinuria (CBS deficiency) From an analyte perspective Hydrolase deficiency Tyr Tyrosinemia type I Tyrosinemia Type II, Tyrosinemia Type III Xle Maple syrup urine disease Hydroxyproline (Benign hydroxyprolinemia) Organic Acid Disorders C3 Methylmalonic acidemia (mutase deficiency), Methylmalonic acidemia (Cobalamin disorders), Propionic acidemia Succinyl-CoA synthase deficiency, Cblc, CblD, CblF, TC-II deficiency C5 Isovaleric acidemia Short/Branched chain Acyl-CoA dehydrogenase deficiency C5DC Glutaric acidemia type I Holocarboxylase Synthase Deficiency, 3-Methylcrotonyl-CoA Carboxylase Deficiency, 2-Methyl-3-OH-Butyric acidemia C5OH 3-Hydroxy-3-Methyglutaric Aciduria, ß-Ketothiolase Deficiency, Biotinidase Deficiency 3-Methylglutaconic aciduria type 1 Disorder of Fatty Acid Oxidation LCFA C16, C16OH, C14, Very long-chain Acyl-CoA dehydrogenase deficiency, (Trifunctional protein deficiency), Carnitiene:Acylcarnitine translocase deficiency C14:1 (Long chain 3-OH-Acyl-CoA dehydrogenase deficiency) Carnitine palmitoyltransferase I & II deficiency MCFA C10, C10:1, C8, C6 Medium-chain Acyl-CoA dehydrogenase deficiency 2,4-Dienoyl-CoA reductase deficiency Other FA Carnitine uptake disorder Glutaric acidemia Type II, Medium/Short-chain 3-OH-Acyl-CoA dhydrogenase deficiency Medium-chain ketoacyl_coa dehydrogenase deficiency, Short-chain Acyl-CoA dehydrogenase deficiency Disorders of Carbohydrate Metabolism Gal-1-P Classic Galactosemia Endocrine Disorders TSH Congenital Hypothyroidism 17-OH-P Congenital Adrnal Hyperplasia Other Disorders Biotinidase enzyme activity Biotinidase deficiency IRT Cystic Fibrosis Congential heart disease, Hepatic and gastrointestinal disease, Prematurity, Trisomy, CDG disorder, Etc.
Most Common NBS conditions in SA Condition NBS Cases (confirmed) Metabolic lab SA Incidence PKU 1 4.1% 1:100 000 (Black) <1:10 000 (White) Tyrosinemia Type I 0 5.4% Incidence ref Sub-Saharan PKU patients in UK Ann Hum Genet (2008) 72,65-71 Medical Genetics in SA J Med Genet (1990) 27,760-779 Glutaric acidemia Type I 1 3.8% 1:5 000 (Black) GA-I in SA - Mol Gen Metab (2010) 178-182 Isovaleric acidemia 2 4.5% Methylmalonic acidemia 3 5.7% Propionic acidemia 2 6.3% Galactosemia 2 5.5% 1:14 000 (Black) Galactosemia in CT, SA BMC pediatrics (2002),2:7 Congenital Hypothyroidism 4 1:4 000 (White) Medical Genetics in SA J Med Genet (1990) 27,760-779 Cystic Fibrosis NA 1:2 000 (White) 1:12 000 (Mixed) 1:32 000 (black) Biotinidase deficiency 2 1.7% South Arrican Cystic Fibrosis Trust Website (MCAD) 0 1.6%
Presentation and management Condition Discipline Management Treatment Care complexity PKU Neurology Dietician Diet High High Tyrosinemia Type I Gastroenterology Gastroenterology NTBC, Liver transplant Very high High Glutaric acidemia Type I Neurology Dietician, General paediatrician Low lysine diet, Carnitine, Intermittent glucose Low-Medium Isovaleric acidemia Neurology Dietician, General paediatrician Low protein diet, Glycine, Carnitine Low Low Methylmalonic acidemia Neurology Dietician, General paediatrician Low protein diet, Vit B12, Carnitine Low Low Propionic acidemia Neurology Dietician, General paediatrician, Specialist support Care Cost Low Low protein diet, Other Medium Low Galactosemia Gastroenterology Dietician, General paediatrician Avoid galactose Low Low Congenital Hypothyroidism Endocrinology Dietician, General paediatrician Eltroxin Low Low Cystic Fibrosis Pulmonology Paediatric pulmonologist Medium High Biotinidase deficiency Neurology General paediatrician Biotin Low Low (MCAD) Neurology Dietician, General paediatrician Avoid fasting Medium Low High
Presentation and management Condition Discipline Management Treatment Care complexity PKU Neurology Dietician Diet High High Tyrosinemia Type I Gastroenterology Gastroenterology NTBC, Liver transplant Very high High Glutaric acidemia Type I Neurology Dietician, General paediatrician Low lysine diet, Carnitine, Intermittent glucose Low-Medium Isovaleric acidemia Neurology Dietician, General paediatrician Low protein diet, Glycine, Carnitine Low Low Methylmalonic acidemia Neurology Dietician, General paediatrician Low protein diet, Vit B12, Carnitine Low Low Propionic acidemia Neurology Dietician, General paediatrician, Specialist support Care Cost Low Low protein diet, Other Medium Low Galactosemia Gastroenterology Dietician, General paediatrician Avoid galactose Low Low Congenital Hypothyroidism Endocrinology Dietician, General paediatrician Eltroxin Low Low Cystic Fibrosis Pulmonology Paediatric pulmonologist Medium High Biotinidase deficiency Neurology General paediatrician Biotin Low Low (MCAD) Neurology Dietician, General paediatrician Avoid fasting Medium Low High
Phenylalanine Key clinical findings Mental retardation Hypopigmentation Differential diagnosis Classical PKU Very high Phe, Hypertonia BH4 synthesis or regeneration Moderate Phe, Mixed hyper/hypotonia Movement disorders Non-PKU hyperphenylalaninemia Treatment principles Diet Kuvan (PKU responsive & BH4) Neurotransmitter precursors (BH4) Proposed SA Protocol Phe and Phe/Tyr ratio Repeat NBS AA analysis (± OA analysis) Initiate treatment if Phe > 360umol/L DBS biopterin and neopterin?residual hyperphenylalaninemia Blau & Duran 2014
Tyrosine Differential Diagnosis Type I Tyrosinemia Type II & III Tyrosinemia Key clinical findings Type I Liver Failure/Cirrhosis/Carcinoma Renal Tupbulopathy / Failure Type II Mental retardation Corneal erosion & Hyperkeratosis Treatment principles Diet Nitisinone / Liver transplant (Type I) Proposed SA protocol Tyrosine (umol/l) 150 250 Repeat NBS >250 / Repeat >150 Succinylacetone? Tyr > 150, SUAC negative ACMG 2009
Glutarylcarnitine Key clinical findings Macrocephaly & Hypotonia Movement disorder Reversible Irreversible Acute / Insidious Characteristic MRI ± Subdural haemorrhage Low excretors Treatment principles Diet Carnitine & Intermittent glucose Proposed SA protocol C5DC Repeat screen sac uoa (3-OH-Glutaric acid) Metabolic investigation negative White No further action Black A239T mutation Then no further action
Propionylcarnitine (C3) & Isovalerylcarnitine (C5) Key clinical findings Feeding difficulties Encephalopathic crisis AGAP Metabolic acidosis Ammonia & Ketosis Cytopenia Differential diagnosis Isovaleric acidemia (C5) Propionic acidemia (C3) Methylmalonic acidemia (C3) CblA & CblB (C3) Treatment principles Diet Ketone dipstix Carnitine IVA Glycine MMA Hydroxycobalamine responsiveness Proposed SA protocol C5 Repeat screen sac & uoa C3 sac & uoa 3-OH-PA Propionic acidemia Methylmalonic acid See next Methylmalonic acid phomocysteine Test mother for Vit B12 deficiency Methylmalonyl mutase deficiency Cobalamine synthesis (Cbl A & B) Both will have normal homocysteine Cannot distinguish without enzyme analysis, complementation studies and genetics
Galactosemia Clinical overview Jaundice (± E. coli sepsis) Liver failure/cirrhosis Cataracts Treatment principles Avoid lactose/galactose Treat hypergonadotrophic hypogonadism in females!? Breast feeding interruption!? Gal-1-P <0.6 Normal (CDC uses 0.3) 0.6 1.2 > 1.2 Follow-up NBS Breast feeding under clinical monitoring Follow-up NBS GALT enzyme analysis
Biotinidase Clinical overview Seizures, Hypotonia, Movement disorder Skin rash, Alopecia Treatment BIOT 0/- Biotin 5 20mg / day BIOT partial? Biotin 1 5mg / day Biotin (not biocytin) Tablet (not liquid) Biotinidase %activity of normal 0% BIOT 0 <10% BIOT - 10-30% BIOT partial Derived biochemical genotype Follow up sample + Mother & Father & 2 Controls Carrier 50% Partial carrier 75%
Conclusions Seamless NBS service Legal implications of not informing patients about availability Urgent need for advisory board Customized test menu including reflex testing