Inborn Errors of Metabolism

Board Review 11/27/2012 Inborn Errors of Metabolism

Test Question What topic should we do for December Board Review? • Poisonings and Environmental Exposures • Substance Abuse

Approach to Metabolic Disorders…

Inborn Errors of Metabolism • Acute Presentation • Metabolic crisis • Sudden onset of lethargy, vomiting, irritability, respiratory compromise, seizures, encephalopathy • Typically due to hyperammonemia, acidosis, ketosis, hypoglycemia • Chronic Presentation • Indolent course • Can affect multiple organ systems • CNS • Liver • Heart • Kidney • Muscle • Eye • Dysmorphic features

Acute Presentation

Typical Acute Metabolic Crisis… • Appear normal at birth • Metabolic intermediate responsible for symptoms is removed by maternal placenta • Within days-months (rarely years) will develop a septic/shock-like picture • Acute onset: lethargy, vomiting, tachypnea (or apnea), irritability, seizures • Encephalopathic • Workup for infection/sepsis yields normal results

Question #1 An infant who presented with vomiting is now lethargic and progressing to a comatose state. Mom says she just found out the newborn screen was abnormal. Which two tests are most important EMERGENTLY so that interventions may be started? • Potassium and brain MRI • WBC and ketones • Lactate and platelets • Glucose and ammonia • Cardiac stress test and glucose tolerance test

Lab Workup • Acidosis • pH <7.3, pCO2<30,bicarb <15 • Can suggest: • Metabolic disorder • Infection • Dehydration • Intoxication • Anoxia • Elevated lactate • Measured on blood gas • Can suggest: hypoxia or poor perfusion (dehydration) • Metabolic disorders: • Glycogen storage disease • Pyruvate defect • Fructose 1,6 biphosphonate deficiency • Mitochondrial disease

Lab work up (continued) • Ketosis • Ketones are a normal part of physiology, but not when they generate acidosis • Organic acidemias • Hyperammonemia • Urea cycle defects • Organic acidemias • Fatty acid oxidation defects • Hypoglycemia • Hyperinsulinism • Liver failure • Glycogen storage disease, tyrosinemia, galactosemia, Niemann-Pick • Organic acidemias • Fatty acid oxidation defect

Additional Work-up

Question #2 A 3 day old infant was initially vigorous at birth but now has poor feeding, tachypnea, and lethargy. Septic work-up is negative. Serum electrolytes, glucose, and lactate are normal. An ABG shows: pH 7.53, pCO2 20, HCO3 25. Serum ammonia level is 465mcmol/L (elevated). Urine ketones are negative. What is the most likely diagnosis? • Fatty acid oxidation defect • Urea cycle defect • Organic acidemia • Glycogen Storage Disease Type I • Renal tubular acidosis

Specific Disorders • Urea Cycle Defects • Organic Acidemias • Amino Acid Disorders • Carbohydrate Disorders • Fatty Acid Oxidation Defects

Urea Cycle Defects

Urea Cycle Defects • Classic presentation: • First few days of life: poor feeding, vomiting, tachypnea, lethargy  coma • Late onset: • Partial enzyme deficiencies • Recurrent vomiting, developmental delay, learning difficulties, seizures, brittle hair, protein intolerance • Failure to thrive • Precipitating cause for acute hyperammonemic encephalopathy • Infection, trauma, fasting, medications (glucocorticoids)

Urea Cycle Defects • Hyperammonemia WITHOUT acidosis • Usually have respiratory ALKALOSIS • No ketones • No hepatomegaly • Types: • Ornithinetranscarbamylase deficiency (X-linked) • Carbamoyl phosphate synthase deficiency (AR) • Citrullinemia (AR) • Argininosuccinicacidemia (AR) • Argininemia (AR) (arginase deficiency) • Does not present with hyperammonemia • Neurologic manifestations

Urea Cycle Defects • Diagnosis: plasma amino acid concentrations • Urine orotic acid value can help distinguish types • Enzyme analysis of tissue samples • Treatment: • Reduce ammonia! (more on this later) • Reduce protein intake • Avoid catabolism • Arginine supplements can be helpful

Question #3 A 2 day old newborn presents with feeding difficulties and lethargy. Septic work-up is negative and urine organic acid values suggest an organic acidemia. The following are lab values which could be seen on initial presentation EXCEPT: • Low pH • Hyperammonemia • Hyperglycemia • Elevated lactate • Ketones in the urine

Organic Acidemias • Organic acids are the intermediates in the catabolism (break down) of amino acids, lipids and other compounds • Products go to Krebs cycle  ATP • Specific enzyme deficiencies lead to characteristic urine organic acid profiles

Organic Acids Defects Isoleucine Valine Methionine Cholesterol Odd chain fatty acids propionicacidemia methylmalonicacidemia biotin B12 Propionyl CoA Methylmalonyl CoA Succinyl CoA Krebs Cycle isovalericacidemia leucine Isovaleryl CoA 3MCC HMG CoA Acetyl CoA ETS Even chain fatty acids glutaricacidemia ATP Lysine Tryptophan Acetyl CoA Glutaryl CoA Crotonyl CoA

Organic Acidemias • Important features • High anion gap metabolic acidosis • Ketosis • Elevated lactate • +/- hypoglycemia • +/- hyperammonemia • Typically presents in first few days of life with introduction of protein into diet • Irritable, poor feeding, lethargy  coma

Organic Acidemias • Diagnosis: urine organic acids • Plasma acylcarnitine profile can help distinguish between types • Types (multiple!!) • Isovalericacidemia • Seizures, high incidence of infection, odor of sweaty feet • Propionicacidemia • Methlymalonicacidemia • May respond to vitamin B12

Urea Cycle Defects vs Organic Acidemias UCD OA

Amino Acid Disorders • Other disorders of amino acid catabolism • Similar clinical manifestations to organic acidemias • Diagnosed differently • Plasma amino acids (vs urine organic acids )

Phenylketonuria (PKU) • Deficiency of enzyme that converts phenylalanine to tyrosine • Not typically seen due to newborn screening • Asymptomatic for a few months, then… • Severe vomiting, irritability, eczema, mousy odor of urine • Blond hair, blue eyes • Late signs: profound intellectual disability** • Pregnant woman not treated adequately: • Fetal risks: miscarriage, SGA, microcephaly, cardiac defects • Treatment: low phenylalanine diet (lifelong!**), frequent monitoring, dietary counseling, adequate tyrosine intake

Maple Syrup Urine Disease • Deficiency of enzyme used to breakdown branched-chain amino acids • leucine, isoleucine, valine • Clinical signs: • First week of life: poor feeding, tachypnea with shallow breathing, profound lethargy, hypertonicity • Maple syrup smelling urine • Hypoglycemia, acidosis

Tyrosinemia • Multiple subtypes • Type I: liver failure, kidney involvement, nerve problems • Type II: oculocutaneous • Corneal ulcerations leading to clouding, skin thickening on palms/soles • Treatment: low tyrosine and phenylalaine diet

Homocystinuria • Cystathioninesynthase deficiency  elevated methionine levels • 2 subtypes: Pyridoxine (B6) responsive and B6 resistant • Better IQ prognosis in responsive type • Clinical manifestations: • Ectopialentis (posterior), skeletal abnormalities (marfanoid), cognitive deficits, thromboembolic events • Light-colored skin, hair, eyes • Diagnosis: homocysteine in urine • Treatment: pyridoxine • If no response: diet high in cystine and low in methionine

Galactosemia • Deficiency of galactose-1-phosphate uridyltransferase • Appear normal until first meal • Develop poor feeding, failure to thrive, vomiting, lethargy, jaundice, abdominal distension, hepatomegaly • Labs: • Hypoglycemia • +Reducing substances in urine (non-glucose)

Galactose Metabolism glucose (cataracts) Breast milk, cow’s milk galactokinase Galactose Lactose Gal-1-P (galactose-glucose) galactose-1-P uridyltransferase (classical) Glucose-1-P Glucose-6-P glycolysis pyruvate

Question #4 A 6 day old female who is breast fed is brought to the emergency room due to poor feeding, vomiting, hepatomegaly, and jaundice. You suspect galactosemia. Which of the following would support this diagnosis? • Blood culture positive for E. coli • Diabetic mother • Serum ammonia > 600 mcmol/L • Cherry red spot on retina • Microcephaly

Galactosemia • Diagnosis: enzyme assay on RBCs • Complications: Liver disease (cirrhosis with portal hypertension/ascites), Gram-negative (E. coli) sepsis, cataracts, MR, speech delay, ovarian failure • Cataracts are reversible with diet change • Developmental and speech delays are common despite good dietary control** • Treatment: galactose free diet, ophthalmology and developmental follow-up

Question #5 A 9 year old male is brought to the emergency room due to vomiting and lethargy shortly after a birthday party. PMHx is significant for FTT in late infancy which resolved without determination of a diagnosis. He had had several bouts of vomiting in the past, usually after consuming candy or soft drinks. Labs reveal elevated AST and ALT. What is the most likely diagnosis? A. Hereditary fructose intolerance B. Glycogen storage disease Type II C. Fatty acid oxidation defect D. Fabry disease E. Zellweger syndrome

Hereditary Fructose Intolerance • Deficiency in enzyme to break-down fructose (aldolase B) • Exposure to fructose results in vomiting, poor feeding; can see seizures in extreme cases • Continued exposure: • FTT, hepatomegaly, hypoglycemia, jaundice, renal dysfunction, liver failure, ascites • Labs: elevated liver transaminases, elevated direct bilirubin, clotting abnormalities • Diagnosis: enzyme assay from liver biopsy • Treatment: remove fructose from diet

Fructose-1,6-biphosphatase Deficiency • Enzyme converts FDP to F-6-P (part of gluconeogenesis) • Deficiency of this enzyme  when challenged with fructose, get buildup of FDP which inhibits gluconeogenesis decreased glucose production • Labs: hypoglycemia, lactic acidosis, ketosis • Hepatomegaly • Diagnosis: enzyme assay from liver biopsy • Treatment: remove fructose from diet, avoid fasting

Fatty acid oxidation defects • Multiple enzymatic reactions involved in the degradation of saturated fatty acids • Release acetyl-CoAs and ketones which are used for energy production, especially during a FASTING state • The enzymes involved in breaking down fatty acids are specific to different fatty acid lengths • Short, medium, long, and very-long acyl-CoAdehydrogenases • SCAD, MCAD, LCAD, VLCAD • Deficiency in any can lead to fatty acid oxidation defect • ALL are autosomal recessive

Fatty acid oxidation Brain ketones Fatty acids VLCAD LCAD MCAD SCAD • Medium chain acylCoAdehydrogenase deficiency(MCAD) is most common defect • 25% risk of death with first episode • SCAD is typically benign + acetyl CoA fasting Krebs cycle

Question #6 A 2 month old female becomes comatose after an upper respiratory illness. Which of the following lab findings would most suggest a disorder of fatty acid oxidation? • Hypoglycemia with metabolic alkalosis • Hypoglycemia with + ketonuria • Hyperglycemia with - ketonuria • Hyperglycemia with + ketonuria • Hypoglycemia with - ketonuria

Fatty acid oxidation defects • Key feature: Hypoketotic hypoglycemia • Reducing substances are also negative • +/- hyperammonemia • Typically presents after recent illness; period of fasting • Can be associated with hepatomegaly, liver disease, hypertrophic cardiomyopathy, arrhythmias, adult onset myopathy • Labs: glucose, electrolytes, ammonia level, LFTs, CPK, lactate, uric acid, urinalysis for myoglobinuria • Diagnosis: plasma acylcarnitine profile • +/- skin biopsy

Carnitine Transport Defects • Carnitine transports longer chain fatty acids in to the mitochondria for breakdown • Defects in the enzymes involved in this process can lead to similar symptoms of fatty acid oxidation defects • Hypoketotic hypoglycemia • Hepatomegaly, elevated transaminases, elevated ammonia • Seizures (secondary to hypoglycemia) • Can typically present in adulthood with muscle weakness, elevated CPK, myoglobinuria • Diagnosis: plasma acylcarnitine profile • +/- skin biopsy

acute crisis treatment

General Treatment Principles • Prompt recognition of possible inborn error of metabolism • Appropriate testing • Immediate interventions • Treat hypoglycemia with glucose infusions • Treat encephalopathy due to hyperammonemia • Sodium benzoate and sodium phenylacetate to remove ammonia • Emergent hemodialysis if level is > 600 • Stop all protein intake if urea cycle defect or amino acid disorder suspected • Calories supplied with dextrose and intralipids

General Treatment Principles • Can give large doses of co-factors while waiting for specific lab tests to come back • Vit B12, thiamine, biotin, riboflavin, folic acid, carnitine • Once diagnosed • Dietary counseling • Genetic counseling

Chronic Presentation

Question #7 You are seeing a new 1 year old patient for developmental delay. Based on a positive family history, you are suspecting an inborn error of metabolism as the cause. What are you MOST likely to see on exam?? • Lack of babbling but normal motor exam • Inability to sit alone or cruise but says 5-10 words • Poor babbling, inability to sit alone, no holding toys/objects in her hands • Normal development • You are worried about autism but nothing else

Clinical Manifestations • Difficult to recognize and diagnose • Onset from birth to adulthood • Neurologic abnormalities • Developmental delay that is typically global • Seizures, often resistant to medications • Movement disorders • Dystonias • Choreas • Abnormal tone • Hearing loss • Blindness • Stroke should suggest homocystinuria or the mitochondrial disorder MELAS

Clinical Manifestations

Inborn Errors of Metabolism