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Inborn errors of metabolism

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Inborn errors of metabolism

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Inborn errors of metabolism

  1. 1. Inborn errors of metabolism Aseem Jain Resident of pathology JNMC
  2. 2. • Many childhood conditions are caused by single gene mutations that encode specific proteins. • These mutations can result in alteration of primary protein structure or the amount of protein synthesized. • The function of protein, whether it is an enzyme, receptor, transport vehicle, membrane component or structural element may be compromised or abolished. • These hereditary biochemical disorders are termed as inborn errors of metabolism. • This term was coined by ‘Garrod’.
  3. 3. Classification Disorders Examples Disorders of Amino acid metabolism Phenylketonuria, Alkaptonuria, Homocyteinuria, Disorders of Carbohydrate metabolism Galactosemia, Glycogen storage diseases Disorders of Porphyrin metabolism Acute intermittent porphyrias Disorders of Purine / Pyrimidine metabolism Lesch-Nyhan syndrome Disorders of Steroid metabolism Congenital adrenal hyperplasia Disorders of Mitochondrial function Kearns-Sayre syndrome Disorders of Peroxisomal function Zellweger syndrome Disorders of Lysosomes Lysosomal storage diseases
  4. 4. Phenylalanine & Tyrosine
  5. 5. • Hyperphenylalaninemia depends on the degree of enzyme deficiency and may vary from very high plasma concentrations (>20mg/dl) to mildly elevated levels (2-10mg/dl). • Classic Phenylketonuria(PKU) - >20mg/dl plasma concentration of phenylalanine ; Autosomal recessive ; M=F ; 1 in 11000 births. • Hyperphenylalaninemia – 2-10mg/dl plasma concentrations of phenylalanine. Hyperphenylalaninemia
  6. 6. • Clinical features – 1. Affected infant is normal at birth. 2. Severe mental retardation by 6 months. 3. Only 2-5% have normal IQ. 4. The infants are lighter in complexion than their siblings. 5. Seborrhoeic or eczematoid rash. 6. Urine/Sweat – musty or mousy odor. 7. Neurologic signs. 8. Microcephaly. 9. Widely spaced teeth. 10. Growth retardation.
  7. 7. • Diagnosis – 1. Plasma phenylalanine is elevated. 2. Urine - Typical musty/mousey odor. - Phenistix reagent strips are available. - At 30 seconds following immersion into urine, the color of the test area is noted and compared with the chart provided. - Gray to Gray green color indicates positive test. - This test detects 5-10mg/dl phenylalanine. • Maternal PKU
  8. 8. Alkaptonuria • Rare autosomal recessive disorder. • Incidence – 1 in 250,000 births. • First human inborn error of metabolism to be discovered. • Discovered by Garrod. • Caused by deficiency of Homogentisate oxidase. • The gene encoding this enzyme is mapped to chromosome 3q13.3.
  9. 9. • Clinical features – 1. Onchronosis – most evident in ear, nose and cheek. 2. Arthritis – involves large joints (spine, hip & knee). 3. Blackening of urine on standing. 4. High incidence of heart disease. Homogentisic Benzoquinone Alkapton acid acetate Oxidation Polyphenol oxidase Polymerization
  10. 10. • Diagnosis – • Urine – Ferric chloride & Nitric acid tests. • 2ml Urine + 2 drops 10%FeCl3 = Dark blue color. (Ferric chloride test). • 4ml 3% silver nitrite + 0.5ml Urine + mix + Few drops of Ammonium hydroxide = Black color. (Silver nitrite test). • Other disorders of tyrosine metabolism – 1. Tyrosinemia type I / Hepatorenal tyrosinemia 2. Tyrosinemia type II / Occulocutaneous tyrosinemia 3. Tyrosinemia type III
  11. 11. Homocystinuria
  12. 12. • Clinical features – 1. FTT & developmental delay. 2. Subluxation of ocular lens (ectopia lentis). 3. Astigmatism, glaucoma, cataract, optic atrophy may occur. 4. Progressive intellectual disability. 5. Normal IQ. 6. Psychiatric and behavioral disturbances(50%). 7. Convulsions(20%). 8. Skeletal abnormalities. 9. Fair complexion, blue eyes and malar flush. 10. Thromboembolic episodes.
  13. 13. • Diagnosis – • Elevation of both methionine and homocystine in body fluids are diagnostic. • Assay of enzyme in liver biopsy specimen • DNA analysis
  14. 14. Glycogen storage diseases
  15. 15. Type (GSD) Defect Clinical features Lab findings Genetics Ia (Von Gierke disease) Glucose 6 phosphatase . Gene on chromosom e 17q21 Doll like face Thin extremities, short stature, protuberant abdomen, skin xanthomas, retinal changes, hepatomegaly 1. Hypoglycemia, 2. lactic acidosis, 3. hyperuricemia, 4. Dyslipidemia, 5. Normal liver transaminase Diagnosis – Liver biopsy Autosomal recessive IIIa (Cori’s/ Forbes disease/ Limit dextrino sis) Debranching enzyme. Gene on chromosom e 1p21. Hepatomegaly, Growth retardation, Muscle weakness, Cardiomyopathy 1. Dyslipidemia, 2. hypoglycemia, 3. ↑ hepatic transaminases, 4. fasting ketosis, 5. Normal lactate and uric acid 6. EMG shows myopathy Diagnosis- abnormal glycogen and abnormal enzyme activity on liver and muscle biopsy Autosomal recessive
  16. 16. Type (GSD) Defect Clinical features Lab findings Genetics IV (also called Anderson’s disease, amylopectinosis) Glycoge n branchi ng Enzyme. Gene on chromos ome 3p21. Hepatospleno megaly, failure to thrive, liver cirrhosis, portal hypertension, ascites, esophageal varices, fatal by 5 years of age 1. Tissue deposition of amylopectin like material 2. Deficiency of branching enzyme in liver Autosomal Recessive VI (also called Hers disease) Glycoge n phospho rylase (in liver) Hepatomegal y, growth retardation in early childhood 1. Mild hypoglycemia, 2. Dyslipidemia, 3. ketosis 4. Normal uric acid and lactic acid Diagnosis: Abnormal enzyme activity in biopsy of affected tissues Autosomal recessive
  17. 17. Type (GSD) Defect Clinical features Lab findings Genetics IXa Phosphorylase kinase (in liver) Hepatomegaly, protuberant abdomen, growth retardation, delay in motor development Mild dyslipidemia, mildly elevated liver transaminases, fasting ketosis, mild hypoglycemia Diagnosis: Abnormal enzyme activity in biopsy of affected tissues X linked
  18. 18. Type (GSD) Defect Clinical features Lab findings V (McArdle disease) Muscle phosphoryl ase Exercise intolerance, muscle Cramps, Dark red urine after intense exercise, Usually presents in 2nd or 3rd Decade Myoglobinuria, ↑ creatinine kinase at rest and increases after exercise, ↑ ammonia and ↑ uric acid with exercise Diagnosis - enzymatic evaluation of muscle VII (Tarui disease) Phosphofru ctokinase Same as in type V + Severe exercise intolerance or myopathy in childhood, compensated hemolytic anemia, more hyperuricemia than type V ↑ Creatine kinase ↑ bilirubin, reticulocytosis, Hyperuricemia Diagnosis - biochemical or histochemical demonstration of enzyme defect II/Pompe disease Lysosomal acid alpha glucosidase (GAA) (acid maltase) Muscle weakness, feeding problem, macroglossia, hepatomegaly, Cardiomyopathies, swallowing difficulties ↑ Creatine kinase, ↑ aspartate Transaminase. • Diagnosis - decreased or absent acid alpha-glucosidase (GAA) activity in muscle
  19. 19. Galactosemia
  20. 20. • Inability to metabolize galactose occurs in the galactosemias, which may be caused by inherited defects of galactokinase, uridyl transferase, or 4- epimerase though deficiency of uridyl transferase is best known. • It has an autosomal recessive mode of inheritance. • The most common mutation of the GALT gene is the Q188R mutation on chromosome 9. • 1 in 60,000 live births. • Typically presents by second half of 1st week of life.
  21. 21. • Clinical features – 1. Hypoglycemia, 2. Vomiting, 3. Diarhhoea, 4. Irritability, 5. Feeding difficulties, 6. Failure to thrive, 7. Jaundice, 8. Hepatomegaly, 9. Easy bruisibility, 10. Increased risk of developing cerebral edema, 11. Viterous hemorrhage 12. E.coli sepsis
  22. 22. • Diagnosis – 1. Hyperbilirubinemia, 2. Elevated liver transaminases, 3. Metabolic acidosis, 4. Galactosuria, 5. Glycosuria, 6. Hypoglycemia, 7. Abnormal clotting measurements, 8. Liver biopsy, 9. Thin layer chromatography, 10. Microbiological and fluorometric assays are used in the screening of the newborn to detect galactosemia.
  23. 23. Mucopolysaccharoidoses • Hereditary, progressive diseases caused by mutations of genes encoding for lysosomal enzymes needed to degrade glycosaminoglycans (GAGs). • The enzymes involved in the degradation of these molecules cleave terminal sugars from polysaccharide chains. • When there is a block in the removal of a terminal sugar, the remainder of the polysaccharide chain is not further degraded and these chains accumulate within the lysosomes in various tissues and organs.
  24. 24. MPS Type Name Enzyme defect Gene/chro mosome Accum ulated GAGs Clinical features I-H Hurler disease Alpha-L- iduronidase IDUA/ 4p16.3 HS,DS Mental retardation, Corneal clouding,URTI, Large tongue, prominent forehead, joint stiffness, short stature II Hunter disease Iduronate sulfate sulfatase IDS/ Xq27.3-28 HS,DS Features same as Hurler syndrome but are less severe IIIA,B ,C,D Sanfillipo A,B,C,D •HSS •NAADG •AGNAT •NAG6S SGSH/17q NAGLU/17q HGSNAT/8p GNS/12q HS Behavioral problems, sleeping disorder, aggression, progressive dementia, coarse hair, clear cornea IV A,B Morquio A,B N acetyl glucosamin e 6 sulfatase Beta galactosidas e GALNS/16q GLB/3p KS Short trunk dwarfism, fine corneal opacities, bone dysplasia, height below 125cm
  25. 25. • MPS type VI (Maroteaux lamy disease) • MPS type VII (Sly disease) • MPS type IX (Hyaluronidase deficiency) • The accumulated mucopolysaccarides are generally found in mononuclear phagocytic cells, endothelial cells, smooth muscle cells and fibroblasts. • Common sites – Spleen, liver, bone marrow, lymph nodes, blood vessels and heart. • Hepatosplenomegaly, skeletal deformities, valvular lesions & subendothelial arterial deposits & lesions in brain are common threads that run through all MPS.
  26. 26. Gaucher disease • Multisystemic lipidoses. • Hematologic abnormalities, organomegaly, skeletal involvement. • Most common lysosomal storage diseases. • 3 types – type 1, 2, 3. • Results from deficient activity of lysosomal hydrolase, glucocerebrosidase which is encoded a gene located on chromosome 1q21-q31.
  27. 27. • The enzymatic defect results in accumulation of glucocerebroside in the cells off RE system and their progressive deposition leads to infiltration of bone marrow, hepatosplenomegaly and skeletal problems. • Clinical features – • Early childhood to late adulthood. • Bruising/ Epistaxis • Fatigue • Hepatosplenomegaly • Growth retardation • Bone pain • Pathological fractures • Reduced but detectable glucocerebrosidase activity.
  28. 28. • Gaucher type 2 disease (infantile or rapid neuronopathic form) is rare and characterized by rapid neurodegenerative course with extensive visceral involvement and death within 1st year of life. • Clinical features – • Increased tone of muscles • Failure to thrive • Strabismus • Organomegaly (liver and spleen) • Stridor • Virtually no glucocerebrosidase activity.
  29. 29. • Morphology – • Accumulation of glucocerbrosides within phagocytic cells. • The distended phagocytic cells – Gaucher cells. • Gaucher cells – often enlarged, up to 100 µm in diameter, having one or more eccentrically placed dark nuclei and fibrillary cytoplasm likened to crumbled piece of paper. • Gaucher cells are found in spleen, liver, bone marrow, lymph nodes, tonsils, thymus and Peyer patches. • PAS stain is intensely positive.
  30. 30. • Diagnosis – • Measurement of glucocerebrosidase activity in peripheral blood leukocytes or in extracts of cultured skin fibroblasts. • Chitotriosidase, an enzyme synthesized by macrophages, is markedly elevated in patients with Gaucher disease. • Biopsy.
  31. 31. Niemann Pick disease • 3 types – Type A,B,C. • Type A & B are two related disorders that are characterized by lysosomal accumulation of sphingomyelin due to inherited deficiency of sphingomyelinase enzyme. • Type A – severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin and early death within first 3 years of life.
  32. 32. • Clinical features – 1. Protuberant abdomen 2. Failure to thrive 3. Vomiting 4. Fever 5. Generalized lymphadenopathy 6. Progressive deterioration of psychomotor function. • Diagnosis – • Biochemical assays for sphingomyelinase activity in liver and bone marrow.
  33. 33. • Morphology – • Affected cells become enlarged, sometimes to 90µm in diameter, secondary to distension of lysosomes with sphingomyelin and cholesterol. • Plenty vacuoles of relatively uniform size are created imparting foaminess to the cytoplasm. • The lipid laden phagocytic foam cells are widely distributed in spleen, liver, lymph nodes, BM, tonsils, GIT and lungs. • Brain – gyri are shrunken and sulci are widened • Vacuolations and ballooning of neurons. • Retinal cherry red spot.
  34. 34. Cystic fibrosis • Also known as mucoviscidosis. • It is a widespread disorder in epithelial transport affecting fluid secretion in exocrine glands and epithelial lining of the respiratory, gastrointestinal and reproductive tracts. • In many infants, this disorder leads to abnormally viscid mucous secretions, which obstruct organ passages, leading to most of the clinical features of this disease.
  35. 35. • Clinical features –
  36. 36. • Diagnosis – • Sequencing of CFTR gene – gold standard • Persistently elevated sweat electrolyte concentrations • Measurement of nasal transepithelial potential difference in vivo •
  37. 37. Wilson’s disease • Autosomal recessive disorder • Accumulation of toxic levels of copper in many tissues & organs principally in liver, brain and eye. • Gene ATB7B (chromosome 13) encodes a 7.5kB transcript for a transmembrane copper transporting ATPase, located on the hepatocyte canalicular membrane. • Defective biliary excretion leads to copper accumulation in liver causing toxic liver injury.
  38. 38. • Clinical features – • Neuropsychiatric manifestations • Acute or chronic liver disease • Kayser-Fleischer rings • Diagnosis – • Decreased serum ceruloplasmin • Increased hepatic copper content • Increased urinary excretion of copper
  39. 39. References • Nelson textbook of pediatrics 1st south east asia edition • Robbins and cotrans basic pathology 7th edition • Henry’s clinical diagnosis and management 22nd edition • Harper illustrated biochemistry 30th edition
  40. 40. Thank You.!!

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