AN APPROACH TO INBORN ERRORS OF METABOLISM final.pptx

inborn errors of metabolism in pediatrics

1. AN APPROACH TO INBORN ERRORS OF METABOLISM

2. Ranges in severity of presentation and time of onset Severe metabolic disorders present in the newborn period Milder forms → childhood or even late adulthood Even though individually rare, incidence is approximately 1 in 1000 Low specificity of symptoms and Low prevalence of disorders → DIFFICULT TO DIAGNOSE

3. consider these disorders in patients with (1) recurrent attacks of encephalopathy, vomiting, ataxia, and metabolic acidosis, especially when the attacks appear to be triggered by illness or changes in diet (since both catabolism and increased protein intake can provoke metabolic deterioration); (2) progressive or chronic symptoms of failure to thrive, weakness, or developmental delay; or (3) unusual organ dysfunction such as cardiomyopathy, hepatomegaly, skeletal findings, or lens dislocation.

4. CLASSIFICATION Disorders of intermediary metabolism affecting small molecules Disorders involving primarily energy metabolism Disorders involving complex molecules

5. Disorders of intermediary metabolism affecting small molecules Very large group Acute or progressive intoxication due to accumulation of normal or unusual compounds proximal to the metabolic block

6. Eg: Classical IEMs of amino acid metabolism ( PKU, MSUD, Tyrosinemia, Homocystinuria) Organic acidemias ( Methylmalonic, Propyl, Isovaleric, Multiple carboxylase deficiency) Urea cycle disorders ( CPS-1 deficiency, HHH syndrome ) Galactose and Fructose metabolism disorders Porphyrias

7. Except for arginase deficiency , the other urea cycle defects have similar clinical presentations in the neonatal period: infants may be asymptomatic in the first 24 to 48 hours and then develop progressive lethargy, poor feeding, vomiting, hypothermia, seizures, and hyperventilation. Arginase deficiency has classically been thought to present with amore slowly progressive course, resulting in spastic quadriparesis, intellectual disability, and less abnormal hyperammonemia .

8. Later-onset urea cycle defects may present with episodic ataxia, progressive cognitive and physical disabilities, or fulminant progressive encephalopathy Ornithine transcarbamoylase deficiency - High urine orotic acid , Low citrulline Most common urea cycle defects; X-linked; often lethal in boys, girls who present in the neonatal period may do poorly as well both men and women may present later in life with an episodic ataxia or encephalopathy, often associated with illness, high protein load, or steroid-triggered catabolism

9. 2) Disorders involving primarily energy metabolism Conditions with deficient energy production/ utilization Mitochondrial disorders, Disorders of glycolysis, Glycogen metabolism and gluconeogenesis Failure to thrive, hypoglycemia with high lactate, hepatomegaly, hypotonia, cardiomyopathy, myopathy, neurological symptoms

10. 3) Disorders of complex molecules Lysosomal storage disorders, peroxisomal disorders, congenital disorders of glycosylation Progresive and permanent symptoms with no precipitating factors Multisystem involvement Developmental delay, Organomegaly, Coarse facies, Arthropathy

11. NEONATES → Unexpected deterioration after normal initial period Non specific, “sepsis-like”, hypotonia, apnea, bradycardia and hypothermia CHILDREN → Sudden and rapid illness precipitated by fever, infection or fasting Acute encephalopathy, recurrent episodes Developmental regression Facial dysmorphism, Structural anomalies Peculiar odour Persistent or recurrent hypoglycemia, intractable metabolic acidosis, hyperammonemia Reye like syndrome E.coli sepsis

12. TYPES OF PRESENTATIONS Encephalopathy with or without metabolic acidosis Acute liver disease Hypoglycemia Dysmorphic features Cardiac disease Hydrops

13. Encephalopathy with or without metabolic acidosis Encephalopathy, seizures, and tone abnormalities → organic acidemias , urea cycle defects and congenital lactic acidosis Intractable seizures → pyridoxine dependency, nonketotic hyperglycinemia , molybdenum cofactor defect and folinic-acid responsive seizures

14. Acute liver disease Jaundice → Gilbert syndrome, Crigler -Najjar syndrome Hepatic failure (jaundice, ascites, hypoglycemia , coagulopathy) → Tyrosinemia, galactosemia,neonatal hemochromatosis, glycogen storage disease type IV Neonatal cholestasis → Alpha-1 antitrypsin deficiency, Niemann-Pick disease type C

15. Hypoglycemia Persistent and severe hypoglycemia → Galactosemia Fatty acid oxidation defects Organic acidemias Glycogen storage disorders Disorders of gluconeogenesis

16. Dysmorphism Peroxisomal disorders - Zellweger - Downs like facies Pyruvate dehydrogenase deficiency → Epicanthal folds, Glutaric aciduria Type II → Macrocephaly , high forehead, rocker bottom feet Lysosomal storage diseases → Coarse facies Smith-Lemli-Opitz syndrome → Epicanthal folds, flat nasal bridge,

17. Cardiac disease Cardiomyopathy → fatty acid oxidation defects,Glycogen storage disease type II and mitochondrial electron transport chain defects

18. Non Immune Hydrops Fetalis Lysosomal storage disorders CDG

19. Newborn period Non specific Unexplained features such as poor feeding, lethargy, vomiting, hypotonia, respiratory abnormalities, apnea, bradycardia, temperature instability Unexpected deterioration after normal initial period EARLY PRESENTATION Premature neonates → TRANSIENT HYPERAMMONEMIA OF NEWBORN (THAN) Term babies → Glutaric acidemia type II, Pyruvate Carboxylase deficiency

20. Antenatal history Acute fatty liver or HELLP (hemolysis, elevated liver enzymes & low platelet counts) during pregnancy: seen in women carrying fetuses with long-chain-3-hydroxyacyl-coenzyme dehydrogenase deficiency (LCHADD) History of increased/ decreased fetal movements

21. Abnormal Body Odour MOUSY/ MUSTY ODOUR PHENYLKETONURIA BURNT SUGAR MAPLE SYRUP URINE DISEASE SWEATY FEET/ ACRID ISOVALERIC ACIDEMIA, GLUTARIC ACIDEMIA TYPE 2 CAT URINE MULTIPLE CARBOXYLASE DEFICIENCY BOILED CABBAGE TYROSINEMIA, HYPERMETHIONINEMIA ROTTEN FISH TRIMETHYLAMINURIA SULPHUROUS CYSTINURIA

22. INVESTIGATIONS Complete blood count: (neutropenia and thrombocytopenia seen in propionic and methylmalonic acidemia) Arterial blood gases and electrolytes Blood glucose Plasma ammonia Arterial blood lactate (Normal values: 0.5-1.6 mmol/L) Liver function tests Urine ketones Urine reducing substances. Serum uric acid (low in molybdenum cofactor deficiency)

23. DNPH Dinitrophenylhydrazine Test for Ketone bodies

24. SECOND LINE INVESTIGATIONS Targeted manner, based on presumptive diagnosis reached after first line investigations: 1) Gas chromatography mass spectrometry (GCMS) of urine - for diagnosis of organic acidemias. 2) Plasma amino acids and acylcarnitine profile: by tandem mass spectrometry (TMS)- for diagnosis of organic acidemias, urea cycle defects, aminoacidopathies and fatty acid oxidation defects. 3) High performance liquid chromatography (HPLC): for quantitative analysis of amino acids in blood and urine; required for diagnosis of organic acidemias and aminoacidopathies. 4) Lactate/pyruvate ratio - in cases with elevated lactate. 5) Urinary orotic acid- in cases with hyperammonemia for classification of urea cycle defect 6) Patellar stippling - Zellwegers

25. 7) Enzyme assay: Definitive diagnosis Available enzyme assays include: biotinidase assay - in cases with suspected biotinidase deficiency (intractable seizures, seborrheic rash, alopecia); and GALT (galactose 1- phosphate uridyl transferase ) assay - in cases with suspected galactosemia (hypoglycemia, cataracts, reducing sugars in urine). 8) Neuroimaging: Zellweger syndrome has diffuse cortical migration and sulcation abnormalities Agenesis of corpus callosum → Menke’s disease, pyruvate decarboxylase deficiency and nonketotic hyperglycinemia Maple syrup urine disease (MSUD): brainstem and cerebellar edema Propionic & methylmalonic acidemia: basal ganglia signal change Glutaric aciduria: frontotemporal atrophy, subdural hematomas

26. 9) Magnetic resonance spectroscopy (MRS): may be helpful in selected disorders E.g. lactate peak elevated in mitochondrial disorders, leucine peak elevated in MSUD 10) Electroencephalography (EEG): some EEG abnormalities may be suggestive of particular IEM; e.g. comb-like rhythm in MSUD, burst suppression in NKH 11) Plasma very long chain fatty acid (VLCFA) levels: elevated in peroxisomal disorders 12) Mutation analysis when available 13) CSF amino acid analysis: CSF Glycine levels elevated in NKH

27. TREATMENT 1) To reduce the formation of toxic metabolites by decreasing substrate availability (by stopping feeds and preventing endogenous catabolism) 2) To provide adequate calories 3) To enhance the excretion of toxic metabolites. 4) To institute co-factor therapy for specific disease and also empirically if diagnosis not established. 5) Supportive care- treatment of seizures (avoid sodium valproate – may increase ammonia levels), maintain euglycemia and normothermia, fluid, electrolyte & acid-base balance, treatment of infection, mechanical ventilation if required.

28. HYPERAMMONEMIA 1) Discontinue all feeds. GIR 8-10 mg/kg/min. Start intravenous lipid 0.5 g/kg/day (up to 3 g/kg/day). After stabilization gradually add protein 0.25 g/kg till 1.5 g/kg/day. 2) Dialysis 3) Alternative pathways for nitrogen excretion: • Sodium benzoate (IV or oral)- loading dose 250 mg/kg then 250-400 mg/kg/day in 4 divided doses (intravenous preparation is not available in India). • Sodium phenylbutyrate (not available in India)-loading dose 250 mg/kg followed by 250- 500 mg/kg/day. • L-arginine (oral or IV)- 300 mg/kg/day • L-carnitine (oral or IV)- 200 mg/kg/day 4) Supportive care: treatment of sepsis, seizures, ventilation. Avoid sodium valproate

29. Acute management of newborn with suspected organic acidemia 1) NPO and intravenous glucose 2) Supportive care: hydration, treatment of sepsis, seizures, ventilation. 3) Carnitine: 100 mg/kg/day IV or oral 4) Treat acidosis: Sodium bicarbonate 0.35-0.5mEq/kg/hr (max 1-2 mEq/kg/hr) 5) Start Biotin 10 mg/day orally 6) Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of methylmalonic acidemias) 7) Start Thiamine 300 mg/day (useful in Thiamine-responsive variants of MSUD) 8) Treat hyperammonemia

30. Refractory seizures with no obvious etiology (suspected metabolic etiology) 1) Trial of pyridoxine 100 mg intravenously. If intravenous preparation not available, oral pyridoxine can be given (15 mg/kg/day) 2) If seizures persist despite pyridoxine, give trial of biotin 10 mg/day and folinic acid 15 mg/day (folinic acid responsive seizures) 3) Rule out glucose transporter defect : measure CSF and blood glucose. In glucose transporter defect, CSF glucose level is equal to or less than 1/3rd of the blood glucose level. This disorder responds to the ketogenic diet.

31. LONG TERM TREATMENT DIETARY - Mainstay of treatment in phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, and glycogen storage disease Type I & III. Urea cycle disorders and organic acidurias → dietary modification → protein restriction 2) Enzyme replacement therapy (ERT) : Lysosomal storage disorders (Pompe’s disease)

32. 3) Cofactor replacement therapy : The catalytic properties of many enzymes → depend obligatory cofactors Thiamine : mitochondrial disorders, thiamine responsive variants of MSUD, PDH deficiency Riboflavin : Glutaric aciduria Type I, Type II Pyridoxine : 50% of cases of homocystinuria due to cystathionine β-synthetase deficiency, pyridoxine dependency with seizures Cobalamin : Methylmalonic acidemia (cblA, cblB), Homocystinuria Folinic acid : Hereditary orotic aciduria, Methionine synthase deficiency, Cerebral folate transporter deficiency, hereditary folate malabsorption, Biotin : Biotinidase deficiency

33. PREVENTION 1) Genetic counselling and prenatal diagnosis : Single gene defects → Autosomal recessive manner → 25% recurrence risk Prenatal diagnosis can be offered, when diagnosis confirmed Substrate or metabolite detection: phenylketonuria, peroxisomal defects Enzyme assay: useful in lysosomal storage disorders like Niemann-Pick disease, Gaucher disease. DNA based (molecular) diagnosis: Detection of mutation in proband/ carrier parents is a prerequisite