Metabolic Disorders Screened Overseas but not Screened in Australia Condition Features Inherited Diagnosis Treatment Newborn Screen

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1 Metabolic Disorders ed Overseas but not ed in Australia Biotinidase Deficiency Severe form causes seizures & delay Biotin can prevent complications NZ, USA Tyrosinaemia Type I Coma & death before age 10 Medication & low protein diet >90% survival USA Sensitivity >95% Specificity > 99% Ornithine Transcarbamylase (OTC) Deficiency Post-neonatal form forms causes coma in infants and children X-linked Medication & low protein diet & liver transplant USA Sensitivity 65-90% Hartnup Disease Rashes, coordination problem, depression or psychosis High protein diet, avoidance of certain medications & sunlight Immunological Disorders ed Overseas but not ed in Australia Canada X-linked Severe Combied Immunodeficiecy (SCID) Recurrent infections 3-6 X-linked Bone marrow transplant < 3 94% survival NZ, USA

2 Adenosine Deaminase Deficiency Recurrent infections 6-12 Bone marrow transplant < 3 94% survival NZ, USA Interleukin 7 Receptor Alpha Deficiency (IL7- SCID) Recurrent infections 3-6 Bone marrow transplant < 3 94% survival NZ, USA Lysosomal Storage Disorders with Treatment ed Overseas but not in Australia Gaucher Disease Bone, spleen, liver lung, heart and nervous system Early diagnosis can avoid bone marrow biopsy Enzyme replacement therapy effective for some subtypes (not neurological features) USA Mucopolysaccharid osis type I (MPS I) delay, heart & lung disease age by 18 Bone marrow transplant can improve survival when done before complications arise USA Mucopolysaccharid osis type II (MPS II) delay, heart & lung disease age at 18 X-linked Enzyme replacement therapy effective for some types (not neurological features) USA

3 Pompe Disease Muscle and heart disease enzyme replacement therapy prolongs survival when started before 6 USA, Austria, Taiwan Krabbe Disease 85-90% of children have delay before 6 Stem cell transplant improves lifespan and functional ability USA Fabry Disease Rashes, painful hand and feet & kidney disease in childhood or adolescence X-linked similarlity with juvenile arthritis Enzyme replacement therapy (uncertain benefit for cardiac and renal and neurologic disease which occurs later) USA, Italy, Austria and Taiwan Other Conditions with Treatment ed Overseas but not in Australia X-Linked Adrenoleukodystro phy (X-ALD) delay and underactive adrenal glands at 4-8 years X-linked Stem cell transplant in boys with early stage cerebral disease improves survival and steroid replacement therapy can be lifesaving. USA

4 Difficult to Diagnose Lysosomal Storage Disorders ed Overseas but not in Australia Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type A & B) delay and lung disease onset at 3 Supportive not curative treatment, avoiding contact sport that could cause trauma to enlarged liver/spleen USA Metabolic Conditions ed Overseas and but not all Australian States Arginase Deficiency problems by age 3 Medication and low protein diet NSW but not Victoria Galactoseaemia type I problems, can be fatal Lactose free diet can prevent complications NSW but not Victoria Galactoseaemia Type II Cataracts galactose free diet can prevent cataracts NSW but not Victoria

5 Treatable Metabolic Conditions not ed Overseas or in Australia Familial Hypercholesterola emia (FH) Narrowing of heart arteries can begin in childhood, cause heart attack in young adults Dominant Sign of the disease don t show until an adult Low fat diet, medication Newborn screening considered but current MS/MS technology can t detect Sensitivity 30-70% (20-40% do not have a genetic cause for FH) Hereditary Fructose Intolerance Seizures, coma in Fructose free diet Considered in UK Wilson Disease Liver failure, problems& psychiatric problems between age 6 and 45, often presents with irreversible complications Medication Suggested but current screening technology can t detect. Pilot study in Korea Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) delay, seizures in Medication Suggested for screening but current technology can t detect, Pilot study in NSW Sensitivity >95% (5% don t have a genetic cause)

6 Treatable Endocrine Conditions not ed Overseas or in Australia X-Linked Adrenal Hypoplasia Congenita Life threatening vomiting and dehydration at 3 weeks X-linked Normally diagnosed when infant presents severely unwell Medication Not screened Sensitivity >58% (40% don t have a genetic cause) Specificity >99% MODY Type 2 (Maturiy Onset Diabets in the Young Type 2) Mildly elevated blood glucose in teenager or adult Dominant Often misdiagnosed and commenced unnecessarilyon Insulin diet, oral hypoglycaemic agents Not screened Permanent Neonatal Diabets Mellitus Glucokinase- Congenital hyperinsulinism (GCK-CHI) Severe diabetes presenting in newborn Low blood glucose in Blood glucose level Insulin Not screened Low sensitivity (uncommon cause of PNDM), specificity > 99% Dominant Blood glucose level diet, diazoxide drugs Not screened Low sensitivity (6 genes cause CHI) Specificty >99% Treatable Liver & Kidney Condition not ed Overseas or in Australia Autosomal Polycystic Kidney Disease Kidney failure and high blood pressure in Kidney or liver transplant can prolong life Not screened Sensitivity >75% (25% don t have a genetic cause) Specificity >99%

7 Treatable Immunological Condition not ed Overseas or in Australia Familial Hemophagocytic Lymphohistiocytosi s Life threatening activation of immune system in Difficult, presents with prolonged fever Bone marrow transplant Not screened Sensitivity 56-80% (30% don t have a genetic cause) Treatable Neurological Conditions not ed Overseas or in Australia g SCN1A- seizure disorders Febrile seizures or severe intractable seizures Dominant Diagnosed after a seizure occurs Parental education & avoid specific anti epileptics, triggers & swimming alone etc Not screened Sensitivity > 80% (10-20% duplications or deletions) Treatable Lysosomal Storage Conditions not ed Overseas or in Australia Niemann-Pick Disease Type C1 Liver and lung disease during Medication (miglustat) may prevent problems Not screened Sensitivity 80-90% Cystinosis Kidney impairment & poor growth in Cystine-depleting agents Not screened

8 Mucopolysaccharid osis type IVA (Morquio Syndrome Type A) Arthritis and poor growth at age 1-3 Enzyme replacement therapy can improve quality of life Not screened Mucopolysaccharid osis type VI (Maroteaux Lamy syndrome) Fequent respiratory infection, heart failure) Enzyme replacement therapy can improve quality of life Not screened Arylsulfatase A deficiency (Metachromatic Leukodystrophy) problems at age 1-2 Bone marrow transplant may be effective if done before symptoms appear Not screened Conditions Associated with SIDS and Sudden Unexplained Death in the Young (SUDY) Long QT syndrome (& very rarely Short QT syndrome) Syncope (fainting spells), SIDS, SUDY Dominant Normally diagnosed after syncope occurs or after SUDY in the family Medication and avoiding QT prolonging medications ECG screening thought to be cost effective in literature Sensitivity >70% (not all genes tested) Specificity 95% (VUS in asians 8%) Brugada syndrome Syncope (fainting spells), SIDS, SUDY Dominant Normally diagnosed after syncope occurs or after SUDY in the family Avoiding certain drugs can prevent cardiac arrest, implantable defibrillator ECG screening thought to be cost effective in literature Sensitivity % (not all genes tested) Specificity > 95%

9 Familial WPW (& very rarely hypertrophic cardiomyopathy) Palitpations, Syncope (fainting spells) Dominant Normally diagnosed after syncope or palpitations occur medication, ablation therapy, some medication absolutely contraindicated Not ed Sensitivity > 70% Specificity > 95% Treatable Metabolic Conditions, Onset Early Adulthood not ed Overseas or in Australia Type 1 Hereditary Haemochromatosis Iron overload causing liver failure, normally at age 40-60, often presents with irreversible complications venesection, avoid alcohol Whole population screening not recommende d due to low penetrance Difficult to Diagnose Lysosomal Storage Disorders not ed Overseas or in Australia Hexosaminidase A Deficiency (Tay- Sachs disease) Progressive delay onset 3-6 Supportive not curative Not screened Hexosaminidase A and B Deficiency (Sandhoff Disease) Progressive delay onset 3-6 Supportive not curative Not screened

10 Mucopolysaccharid osis type IIIA (Sanfilippo syndrome type A) delay & behavioural problems in childhood Difficult, presents similar to autism Supportive not curative Not screened Mucopolysaccharid osis type IIIB (Sanfilippo syndrome type B) delay & behavioural problems in childhood Difficult, presents similar to autism Supportive not curative Not screened Mucopolysaccharid osis Type IVB (Morquio syndrome type B) Poor growth, onset between 1-3 years Experimental not curative Not screened GM1 gangliosidosis (betagalactosidase-1 deficiency) delay beginning in Experimental not curative Not screened Neuronal Ceroid Lipofuscinoses: CLN1, 2 & 3 (Batten Disease) delay, seizures beginning in Supportive, avoid certain medications Other Disorders Difficult to Diagnose and not ed Overseas or in Australia Mucolipidosis II (Inclusion Cell Disease) Arthritis, poor growth, heart failure in Not screened Supportive not curative Not screened

11 Mucolipidosis III alpha/beta (pseudo-hurler polydystrophy) Slowly progressive arthritis, poor growth, heart failure in childhood Supportive not curative Not screened Dicarboxylic Aminoaciduria Can cause delay Difficult to diagnose Low protein diet, no evidence ed in Australia but offers higher sensitivity and/or specificity not screened Condition Features Inherited Treatment Newborn ing Classical Homocystinuria Can cause delay Diet and vitamin supplementation Current screening may not identify vitamin responsive forms Cystic Fibrosis Recurrent lung infections cause Not curative but can prolong life current screening has lower sensitivity Systemic Primary Carnitine Deficiency Coma or heart failure age 3-2 years, adult onset form occurs Vitamin supplment and avoid fasting False positives may occur with affected mothers with unaffected newborns MCAD deficiency (Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency) Can result is seizures and coma age 3-2 years, adult ones presentation occurs Low fat diet, avoid fasting False-negatives from screening occur when the baby is already ill and carnitine-depleted at the time of the test

12 Holocarboxylase Synthetase Deficiency (Infantile Multiple Carboxylase Deficiency) Can cause delay commencing at 3 Vitamin supplementation Currently screened Isovaleric Acidaemia delay can appear inc childhood Diet and vitmin supplmentation Currently screened Glutaric Acidaemia Type I can cause delay commencing in, can have onset in adulthood Low protein diet and vitamin supplementation Rare patients excreting normal or only minimally elevated levels of glutaric acid might have normal levels of glutarylcarnitine in blood spots and might be missed Citrullinaemia Type I Seizures and coma at age 4 days, adult onset form Low protein diet, liver transplant is curative Currently screened LCHAD deficiency(longchain 3 hydroxyacyl-coa dehydrogenase deficiency) Can cause coma in Diet and vitamin supplementation Currently screened Maple syrup urine disease Can cause coma in Diet and vitamin supplementation, liver transplant Newborn screening does not reliably detect intermediate forms

13 Phenylketonuria (PKU) Can cause delay Diet Does not differentiate between PAH deficiency and biopterin defects