Pakistan Society Of Chemical Pathologists Distance Learning Programme In Chemical Pathology Lesson No 20 Inborn Errors of Metabolism (Short Name: IEM) By Surg Commodore Aamir Ijaz MCPS, FCPS, FRCP (Edin) Professor Of Pathology / Consultant Chemical Pathologist Bahria University Medical & Dental College / PNS SHIFA Karachi

Options Fatty acid oxidation disorder Galactosemia Glycogen Storage Disease Type I Maple Syrup Urine Disease Mucopolysaccharidosis Nonketotic hyperglycinaemia Organic Aciduria Persistent Hypinsulinaemic Hypoglycaemia of Infant Phenylketonuria Pyruvate Dehydrogenase Complex Deficiency Urea cycle disorder

Q 1. A newborn of 5 days refuses to take feed, has vomiting, and lethargy. He develops hepatomegaly, jaundice, oedema, ascites and sepsis. Important biochemical findings are: • Hypoglycaemia on breast-feeding • Urine for reducing substance: +++ • Urine by Glucose Strip: + • Putting the baby on lactose free milk reversed the reducing substance test to negative. • Albumin in urine: + What is the most probable diagnosis? b. Galactosemia 07/04/2019 04:58

Q 2. An infant presents with progressive neurological impairment with mental retardation (IQ not improving with age). He also has mousy odour, skin pigmentation and abnormal physical growth. His biochemical findings are: • Acidosis: Negative • Ferric Chloride Test: ++++ • Ketones : + • Ammonia (NH3): Normal • Lactate: Normal • Glucose: Normal • Calcium: Normal • Gutherie`s Test Positive What is the most probable diagnosis? + i. Phenylketonuria 07/04/2019 04:58

j. Pyruvate Dehydrogenase Complex Deficiency Q 3. A male newborn has severe neurological deterioration with neuroradiological abnormalities i.e. corpus callosum agenesis, dilated ventricles and abnormal basal ganglia. His biochemical findings are : • Acidosis: +++ • Ketones : + • NH3: + • Lactate: +++ • CSF Lactate: ++++ • Glucose: Normal • Calcium: Normal • Gutherie`s Test Negative What is the most probable diagnosis? + j. Pyruvate Dehydrogenase Complex Deficiency 07/04/2019 04:58

c. Glycogen Storage Disease Type I Q 4. A 10 months child presents with protruded abdomen, truncal obesity, short stature, hepatomegaly, and growth delay. His biochemical findings are : • Attack of hypoglycaemia on brief fast • Ketones : + • NH3: Normal • Lactate: +++ • Triglycerides: Increased • Insulin: Normal What is the most probable diagnosis? + c. Glycogen Storage Disease Type I 07/04/2019 04:58

Q 5. A newborn with neurological deterioration of intoxication type with moderate hepatocellular disturbance, hypotonia, seizures and coma. His biochemical findings are : • Alkalosis: + • Ketones : + • NH3: ++++ • Lactate: Normal • Glucose: Normal • Calcium: Normal • Gutherie`s Test Negative What is the most probable diagnosis? + k. Urea cycle disorder 07/04/2019 04:58

e. Mucopolysaccharidosis Q 6. A 14 month child has repeated upper airway obstruction and frequent ear, nose and throat infections. She has short stature, hepatosplenomegaly, increasing facial dysmorphism, cardiac disease, progressive learning difficulties and corneal clouding. Her biochemical findings are : • Urine heparan sulfate : Increased • Urine keratan sulphate: Increased What is the most probable diagnosis? + 07/04/2019 04:58

f. Nonketotic hyperglycinaemia Q 7. A newonate appeared normal at birth but within the first few hours developed a progressive encephalopathy characterized by lethargy, axial and limb hypotonia. Respiration became increasingly irregular culminating in apneic attacks leading to deep coma. He also started fitting. His biochemical findings are : • pH: Normal • Ketones : Negative • NH3: Normal • Lactate: Normal • Glucose: Normal • Calcium: Normal • Increased Glycine was detected in CSF by Thin Layer Chromatography What is the most probable diagnosis? + 07/04/2019 04:58

h. Persistent Hyperinsulinaemic Hypoglycaemia of Infant Q 8. A newborn with hepatomegaly with recurrent hypoglycaemic attacks. His biochemical findings are : • Fasting Glucose: Low • Lactate: Normal • Acidosis: + • NH3: Normal • Ketones : Negative • ALT Raised • Fasting Insulin: Markedly increased What is the most probable diagnosis? 07/04/2019 04:58

a. Fatty acid oxidation disorder Q 9. An infant has been brought in a Paediatric Clinic with history of attacks of hypoglycemic featured by lethargy, nausea, and vomiting which rapidly progresses to coma within 1–2 h. Seizures also occur. His biochemical findings during the attacks are usually like following: • Hypoglycaemia precipitated by fasting • Acidosis: + • Ketone bodies: Inappropriately Low • Lactate: + • Fasting Insulin: Normal • Postprandial total acylcarnitine levels: <25-50% of normal What is the most probable diagnosis? 07/04/2019 04:58

g. Organic Aciduria Q 10. An 8 months old baby is admitted in a hospital as he is failing to thrive. Urine Amino Acids By Ion Exchange HPLC Analysis shows:  Urine Homocystine/Creat ratio: 9 µmol/mmol (0 - 5) Urine Organic Acids By GC/MS shows:  Urine Ketones: Negative by Multistix  Urine *MMA/Creatinine ratio: 1413 µmol/mmol (0 - 30)  Urine Methylcitrate/Creat ratio: 50 µmol/mmol (0 - 25)  Urine Creatinine : 1.3 mmol/L *MMA: Methyl Malonic Acid What is the most probable diagnosis? 07/04/2019 04:58

BCQs

e. IEM which give rise to intoxication Q 11: Maple syrup urine disease (MSUD) is a disorder of branched chain amino acids. MSUD belongs to which categories of Inborn Errors of Metabolism (IEM): a. IEM involving complex molecules b. IEM involving energy metabolism. c. IEM of cytoplasmic defects d. IEM of mitochondrial defects e. IEM which give rise to intoxication e. IEM which give rise to intoxication

Q 12: Dietary restriction is most helpful in which of the following disorders: a. Methyl malonic acidaemia b. Ornithine aminotransferase deficiency c. Phenylketonuria d. Propionic acidaemia e. Pyruvate dehydrogenase complex deficiency c. Phenylketonuria

Q 13:. Which of the following is a part of NBS: a Q 13: Which of the following is a part of NBS: a. Amniotic fluid bilirubin b. Genetic testing of siblings c. Maternal anomaly scan d. Maternal β-HCG estimation e. Newborn hearing test e. Newborn hearing test

Q 14: Most common samples used for NBS are: a. Neonatal heel prick b Q 14: Most common samples used for NBS are: a. Neonatal heel prick b. Neonatal Stool c. Neonatal Urine d. Neonatal venous plasma e. Umbilical Cord Blood a. Neonatal heel prick

e. Tandem Mass Spectrometry Q 15: Which of the following techniques is said to have revolutionized the NBS programmes: a. Atomic absorption photometry b. Chemiluminescence c. GC-MS d. HPLC e. Tandem Mass Spectrometry e. Tandem Mass Spectrometry

Q 16: All of the following disorders are screened in NBS EXCEPT: a Q 16: All of the following disorders are screened in NBS EXCEPT: a. Biotinidase deficiency b. Congenital adrenal hyperplasia c. Gilbert syndrome d. Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency. e. Sickle cell disease c. Gilbert syndrome

Q 17: Phenylketonuria (PKU) is due to a deficiency of the enzyme Phenylalanine Hydroxylase required for conversion of phenylalanine to tyrosine. Deficiency of enzyme leads to high phenylalanine and its metabolites. Which of the following substances is most commonly tested in the dried blood spots for NBS of PKU: a. Tyrosine b. Phenylalanine hydroxylase c. Phenylacetate d. Phenylalanine e. Phenylpyruvate d. Phenylalanine

d. Immunoreactive trypsin estimation Q 18: NBS for Cystic Fibrosis is mostly done by : a. Cholecystokinin-secretinin test b. Faecal chymotrypsin estimation c. Faecal elastase-1 estimation d. Immunoreactive trypsin estimation e. Sweat chloride test d. Immunoreactive trypsin estimation

Q 19: For NBS of organic acidurias which of the following substances is tested: a. Acylcarnitines b. Isovaleric acid c. Methylmalonic acid d. Propionic acid e. Urinary organic acids a. Acylcarnitines

Q 20: Genetic mutations are used for NBS of which of the following congenital defects: a. Congenital Hypothyroidism b. Cystic fibrosis c. MSUD d. Phenylketonuria e. Tyrosinaemia b. Cystic fibrosis

Thank You and Best Of Luck