Inborn error of metabolism

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Approach to Inborn Error of Metabolism in a Neonate : 

Approach to Inborn Error of Metabolism in a Neonate Dr.Somashekhar chikkanna

Slide 2: 

IEM was coined by a British physician, Archibald Garrod(1857-1936), in the early 20th century (1908) Definition- IEM are disorders in which there is a block at some point in the normal metabolic pathway caused by a genetic defect of specific enzyme

Objectives : 

Objectives To recognize IEM in a neonate with non-specific signs and symptoms To make use of simple lab tests in the diagnosis of IEM To know the initial management of life threatening conditions associated with IEM To consider specific examples

Metabolic disorders : 

Metabolic disorders Collective incidence one in 1,500 persons Individual inborn or congenital errors of metabolism are very rare More than 1400 IEM have been described Many are potentially treatable via diet and/or drug therapy

Slide 5: 

Rapid accurate diagnosis is essential to prevent death & permanent neurologic sequelae Diagnosis is important for treatment & prognostication & also for genetic counselling & antenatal diagnosis in subsequent pregnancies IEM can be complex,diverse & rare and this can make treatment problematic

Slide 6: 

IEM should be considered a differential diagnosis: Child with unexplained,overwhelming, or progressive disease particularly after a normal pregnancy or birth, but deteriorates after feeding Child with acute encephalopathy, particularly preceded by vomiting,fever or fasting Child with symptoms and signs of acidosis or hypoglycemia

Slide 7: 

Parental consanguinity Family history of neonatal deaths Peculiar odor Acute fatty liver or HELLP during pregnancy

Slide 8: 

Clinical features symptoms Respiratory distress Hypotonia Poor sucking reflex Rapidly progressive encephalopathy Severe metabolic acidosis Peculiar odour Apnea or tachypnea

Slide 9: 

Persistent Vomiting, diarrhoea, dehydration Lethargy Intractable Seizures These can be easily & falsely attributed to other causes such as infection Babies show deterioration after a normal initial period of hours to weeks

Other symptoms : 

Other symptoms Failure to thrive CNS symptoms -development delay, movement or psychiatric disorders or cerebral palsy Sudden infant death syndrome (SIDS) Episodic illness – anorexia, vomiting, lethargy, coma Cardiomyopathy Muscular – hypotonic, weakness, cramps

Slide 11: 

GI – anorexia, vomiting, diarrhoea, malabsorption Liver disease- jaundice, ascites, coagulopathy neonatal cholestasis Ophthalmic abnormalities Reye’s syndrome–like illness Dysmorphic features Metabolism – acidosis, hypoglycaemia

FEATURES : 

FEATURES

Slide 13: 

signs coarse facies -lysosomal disorders cataract -galactosemia, zellweger syndrome r p - mitochondrial disorders cherry red spot -lipidosis hepatomegaly -storage disorders, urea cycle defects

Slide 14: 

renal enlargement – zellweger syndrome eczema/alopecia – biotinidase deficiency abnormal kinky hair – menkes disease decreased pigmentation – phenylketonuria

Coarse facies : 

Coarse facies

cherry red spot : 

cherry red spot

cataract : 

cataract

cataract : 

cataract

Retinitis pigmentosa : 

Retinitis pigmentosa

Metabolic pathways : 

Metabolic pathways The major metabolic pathways for protein, carbohydrates and lipids are closely integrated with key molecules such as acetyl co-enzyme A via complex mechanisms

Categories of IEM : 

Categories of IEM Disorders of: Amino acids Carbohydrates Fatty acid Lysosomal and peroxisomal function Mitochondrial Organic acids

Slide 22: 

Amino acid metabolism Phenylketonuria Maple syrup urine disease Tyrosenemia Alkaptonuria Homocystinuria Non ketotic hyperglycinemia Hartnup disease

Slide 23: 

Carbohydrate metabolism Galactosemia Glycogen storage disease

Slide 24: 

Fatty acid oxidation Medium-chain acyl-CoA dehydrogenase deficiency Niemann-Pick disease Farber’s disease Gangliosidoses Krabbé disease Metachromatic leukodystrophy

Slide 25: 

Lysosomal storage Gaucher’s disease Fabry’s disease Hurler’s syndrome Disorders of the steroid pathway Congenital adrenal hyperplasia Smith Lemli Opitz syndrome

Slide 26: 

Organic aciduria Methylmalonicaciduria Propionic aciduria Peroxisomes Zellweger syndrome Adrenoleukodystrophy Urea cycle Ornithine transcarbamylase deficiency Arginosuccinate deficiency

Slide 27: 

Disorders of metal metabolism Wilson disease Hemochromatosis Menkes disease Others Hypothyroidism Hemoglobinopathies MELAS

Mode of inheritance : 

Mode of inheritance AR inheritance PKU Maple syrup urine disease Glycogen storage disease Galactosemia Organic acidurias MCAD Zellweger syndrome

Slide 29: 

X-linked recessive (XLR) inheritance Ornithine carbamylase deficiency Fabry disease Pyruvate dehydrogenase deficiency

Slide 30: 

AD inheritance Marfan syndrome Acute intermittent porphyria Familial hypercholesterolemia Mitochondrial inheritance Kearns-Sayre syndrome Leigh syndrome

Investigations : 

Investigations First line investigations Complete blood count:neutropenia& thrombocytopenia Arterial blood gas analysis and electrolytes Blood glucose Plasma ammonia( 0.5-1.6 mmol/L) Blood arterial lactate(0.5-1.6 mmol/L)

Slide 32: 

Liver function tests Urine ketones Urine reducing substances Serum uric acid

Slide 33: 

Second line investigations Gas chromatography & mass spectrometry (GCMS) of urine for organic acidemias Plasma amino acids & acyl carnitine profile-by tandom mass spectrometry – organic acidemias, urea cycle defects, aminoacidopathies, fatty acid oxidation defects

Slide 34: 

High performance liquid chromatography – organic acidemias & aminoacidopathies Lactate/pyruvate ratio – lactate acidosis Urinary orotic acid – hyperammonia/urea cycle defect Enzyme assay- Biotinidase assay-biotinidase deficiency GALT(galactose-1-phosphate uridyl transferase) -galactosemia

Slide 35: 

M R I- Zellweger syndrome – diffuse cortical migration & sulcation abnormalities Menke`s disease,NKH PDD - agenesis of corpus collosum MSUD -brain stem & cerebellar edema

Slide 36: 

Propionic acid& methyl malonic acid derivatives - basal ganglia signal change Glutaric aciduria -frontotemporal atrophy,subdural hematomas

Slide 37: 

Magnetic resonance spectroscopy- MSUD,mitochondrial disorders EEG - comb like rhythm,burst like suppression in NKH CSF analysis -glycine levels elevated in NKH Plasma very long chain fatty acids – -peroxixomal disorders Mutation analysis

Precautions to be observed while collecting samples : 

Precautions to be observed while collecting samples Should be collected before specific treatment is started or feeds are stopped, as may be falsely normal if the child is off feeds Detailed history including drug details should be provided to the lab (sodium valproate therapy may increase ammonia levels)

Slide 39: 

Samples for blood ammonia and lactate should be transported in ice and immediately tested. Lactate sample should be arterial and collected after 2 hrs fasting in a preheparinized syringe Ammonia sample is to be collected approximately after 2 hours of fasting in EDTA vacutainer. Avoid air mixing. Sample should be free flowing.

Samples to be obtained in infant with suspected IEM when diagnosis is uncertain and death seems inevitable : 

Samples to be obtained in infant with suspected IEM when diagnosis is uncertain and death seems inevitable Blood: 5-10 ml; frozen at -20c; both heparinized (for chromosomal studies) and EDTA (for DNA studies) samples to be taken Urine: frozen at –20c CSF: store at –20c

Slide 41: 

Skin biopsy: including dermis in culture medium or saline with glucose. Store at 4-80C. Do not freeze Liver, muscle, kidney and heart biopsy: as indicated Clinical photograph (in dysmorphism) Infantogram (in skeletal abnormalities)

Presentation : 

Presentation Metabolic acidosis Hyperammonemia Hypoglycemia

Metabolic acidosis : 

Metabolic acidosis pH <7.35 Excess H+ HCO3 deficit Calculate anion gap Na – (Cl + HCO3) Normal is 8-16meq/l

Metabolic Acidosis : 

Metabolic Acidosis If Chloride is increased- HCO3 wasting - GI or renal disorders If Chloride is Normal and Anion gap is > = 16--- excess acid production

Metabolic acidosis : 

Metabolic acidosis Approach is to give Na HCO3 If unresponsive to HCO3-- IEM

Hyperammonemia : 

Hyperammonemia Normal ammonia level- < 50 umol/l > 200 -- IEM If within 24 hours of life; preterm, RDTHAN After 24 hours- IEM

Hypoglycemia : 

Hypoglycemia Glucose level helps in the differential diagnosis

STEPS: : 

STEPS: 1. Determine if there is metabolic acidosis 2. Is anion gap >16? 3. Is there hypoglycemia? 4. Is there hyperammonemia? Within 24 HOL? After 24 HOL?

Slide 49: 

Copyright ©1998 American Academy of Pediatrics

Management : 

Management Aims Induce activity – as in vitamin-responsive disorders Counteract the biochemical disturbances and prevent acute intercurrent decompensation Prevent chronic and progressive deterioration by diet and/or therapy

Slide 52: 

Approximately 12% of inborn errors can be controlled by therapy A further 55% treatment is beneficial But in 33% treatment has little effect

Approach : 

Approach

Emergency management : 

Emergency management Focused on supportive care and when diagnosed directed to suppression of production of toxic metabolites and stimulation of their elimination Supportive care Ventilation and circulatory support (particularly in very ill babies) Correction of electrolyte imbalance

Slide 55: 

Rehydration and maintain hydration to counter poor feeding,increased renal fluid loss and to ensure efficient diuresis of toxic metabolites Correction of acidosis, though mild acidosis can be protective against hyperammonemia in urea cycle defects

Hyperammonia : 

Hyperammonia Discontinue all feeds- Provide adequate calories by intravenous glucose and lipids Maintain glucose infusion rate 8-10mg/kg/min Start intravenous lipid 0.5g/kg/day (up to 3g/kg/day) After stabilization gradually add protein 0.25g/kg till 1.5 g/kg/day

Slide 57: 

Dialysis is the only means for rapid removal of ammonia Hemodialysis is more effective and faster than peritoneal dialysis Peritoneal dialysis may be more widely available and feasible Exchange transfusion is not useful

Slide 58: 

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 (IV N.A in India) Sodium phenylbutyrate (N.A in India)-loading dose 250 mg/kg followed by 250-500 mg/kg/day L-arginine (oral or IV)- 300 mg/kg/day (IV N.A in India) L-carnitine (oral or IV)- 200 mg/kg/day

Metabolic acidosis : 

Metabolic acidosis Supportive care: hydration, treatment of sepsis, seizures, ventilation Treat acidosis: sodium bicarbonate 0.35- 0.5mEq/kg/hr (max 1-2mEq/kg/hr) Thiamine: up to 300 mg/day in 4 divided doses Avoid sodium valproate

Slide 60: 

Riboflavin: 100 mg/day in 4 divided doses Add co-enzyme Q: 5-15 mg/kg/day L-carnitine: 50-100 mg/kg orally

Refractory seizures with no obvious etiology : 

Refractory seizures with no obvious etiology Seizures persist despite 2 or 3 antiepileptic drugs in adequate doses Consider trial of pyridoxine 100 mg i.v Oral pyridoxine 15 mg/kg/day(if i.v N.A)

Slide 62: 

persist despite pyridoxine Consider trial of biotin10 mg/day & folinic acid 15 mg/day Rule out glucose transporter defect: measure CSF and blood glucose In G.T.D CSF glucose = or < 1/3rd of the blood glucose level G.T.D responds to the ketogenic diet

Asymptomatic newborn with a history of sibling death with suspected IEM: : 

Asymptomatic newborn with a history of sibling death with suspected IEM: Do baseline metabolic screen Start oral dextrose feeds (10% dextrose) After 24 hours- repeat screen If normal-start breast feeds Monitor sugar, blood gases , urine ketones, blood ammonia 6 hourly

Slide 64: 

Some authorities recommend MCT(MCT oil) before breast feeds Some don`t because of unpalatibility of MCT oil After 48 hours-repeat metabolic screen Obtain samples for TMS and urine organic acid tests Child needs careful observation & follow-up for first few months as IEM may present in different age groups in members of the same family

Specific measures : 

Specific measures Restrict diet PKU -Phenylalanine restriction MSUD -Branch chain amino acid restriction Galactosemia -Galactose restriction

Slide 66: 

Supplement deficient product Congenital hypothyroidism -Synthroid Glycogen storage disease -Cornstarch Urea cycle disorders -Arginine

Slide 67: 

Stimulate alternate pathway Urea cycle disorders -Sodium phenylbutyrate -Carglumic acid Organic acidemias -Carnitine Isovaleric acidemia -Glycine Wilson disease -Penicillamine

Slide 68: 

Supply vitamin cofactor Multiple carboxylase -Biotin deficiency Homocystinuria -Pyridoxine Methylmalonic acidemia -vitamin B12 MSUD -Thiamine Propionic aciduria -Biotin

Slide 69: 

Replace enzyme Severe combined immunodeficiency –PEG-ADA Gaucher’s disease -Cerezyme - Agalsidase alfa and beta

Slide 70: 

Transplant organ Metachromatic leukodystrophy -Bone marrow Ornithine transcarbamylase -Liver deficiency Tyrosinemia -Liver Glycogen storage disease -Liver

Slide 71: 

Gene therapy SCID - Retrovirus gene transfer

Prevention : 

Prevention 1. Genetic counselling and prenatal diagnosis Most inherited as autosomal recessive 25% recurrence risk diagnosis in index case prenatal diagnosis for subsequent pregnancies Samples required are chorionic villus tissue or amniotic fluid

Slide 73: 

Substrate or metabolite detection in 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

Slide 74: 

2. Neonatal screening Tandem mass spectrometry is widely used It is now possible to screen rapidly, simultaneously, and inexpensively for a number of very rare disorders

Slide 75: 

TMS can detect- Aminoacidopathies - phenylketonuria, MSUD, Homocystinuria, Citrullinemia, hepatorenal tyrosinemia Fatty acid oxidation defects organic acidemias -glutaric aciduria, propionic acidemia, methylmalonic acidemia, isovaleric acidemia The yield and usefulness of testing have not been clear

Slide 76: 

specific examples

Slide 77: 

Phenylketonuria (PKU) Incidence about 1 in 6000 – 10,000 unable to convert phenylalanine to tyrosine due to a recessively inherited defect in the enzyme phenylalanine hydroxylase If untreated :- Infantile spasms Significant developmental delay with disturbed behaviour, Hyperactivity and destructiveness in older children

Slide 78: 

Management By dietary restriction of phenylalanine containing foods – dietetic advice Special milks – PKU 2, 3 etc, PK aid – all amino acids but Phenylalanine Must avoid the sweetener aspartame (L- aspartyl phenylalanine)

Slide 79: 

Medium chain acyl CoA dehydrogenase deficiency (MCDA) Most common IEM of fatty acid oxidation Incidence- 1 in 10,000 Lipid metabolism is important in maintaining energy levels during fasting Lipids are oxidised for energy, firstly by lipolysis to fatty acids by the -oxidation pathway- defective in MCAD deficiency

Slide 80: 

Affected individuals appear normal until illness provoked by an excessive period of fasting, usually due to an infection First presentation is between 3 months and 2 years MCAD deficiency is the cause of 1-3% of sudden infant death syndrome

Slide 81: 

Typical signs and symptoms Recurrent hypoketotic hypoglycaemia Reye’s syndrome like illness – vomiting, lethargy, delirium, coma & convulsions Liver dysfunction

Slide 82: 

Treatment Enteral or IV glucose to correct hypoglycemia so that the body does not need to burn fat Carnitine It normally binds to medium chain CoA esters to allow these to be excreted Avoid long periods of fasting and treat signs of hypoglycaemia Attacks less frequent during childhood as fasting intolerance improves with increasing body mass

Slide 83: 

Urea cycle disorders The urea cycle detoxifies ammonia and removes surplus nitrogen from the body 80% of excreted nitrogen is in the form of urea, produced in the liver The urea cycle involved 5 enzymes and an inherited defect can occur in each & lead to hyperammonemia

Slide 84: 

No acidosis (respiratory alkalosis) No ketones (unlike organic acidemia) No hypoglycemia But with hyperammonemia

Slide 85: 

Symptoms Lethargy Hypothermia Apnoea Convulsions Onset-Any age but most likely during neonatal period, late infancy and puberty In between episodes patient usually relatively well but may have poor developmental progress

Slide 86: 

Treatment: Remove ammonia Hydration with D10 + electrolytes D/C all protein x 24 hours—calories from CHO and fat Na phenylacetate/Na benzoate Give arginine Protein restriction for life

Slide 87: 

Prognosis: guarded Even with Treatment, many will die Definitive treatment: liver transplant

Organic acidemias : 

Organic acidemias features Healthy NB rapidly ill, Ketoacidosis, poor feeding Vomiting, dehydration Hypotonia, lethargy Tachypnea, seizures Coma, unusual odors

Slide 89: 

Investigations Urine organic acids Ketonuria (in the NB)- pathognomonic of IEM Neutropenia, thrombocytopenia +/- hyperammonemia Abnormal acylcarnitine

Treatment : 

Treatment Start Biotin 10 mg/day orally Start Vitamin B12 1-2 mg/day I/M (useful in B12 responsive forms of methylmalonic acidemias) Start Thiamine 300 mg/day (useful in Thiamine- responsive variants of MSUD) If hyperammonemia is present, treat as explained above

Summary : 

Summary Metabolic acidosis + hyperammonemia Request for specific lab studies Consult metabolic specialist Initial therapy- stabilize patient! Long term treatment- based on specific IEM

Slide 92: 

Thank you