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Metabolic 5 5-2013

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metabolic medicine part 2 bu dr.azad haleem al-mezori

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Metabolic 5 5-2013

  1. 1. Metabolic Medicine Part two Hevi Pediatric Teaching Hospital 5-5-2013
  2. 2. • Disorders of Amino Acid Metabolism (tyrosinemia, homocystinuria, NKH, MSUD, and PKU) • Urea Cycle Defects • Disorders of Organic Acid Metabolism ( propionic acidemia, isovaleric acidemia, methylmalonic aciduria, and glutaric aciduria) • Disorders of Fatty Acid Metabolism (MCAD) • Disorders of Carbohydrate Metabolism (hereditary fructose intolerance, galactosemia, and GSDs) • PEROXISOMAL DISORDERS (Zellweger syndrome, X- linked adrenoleukodystrophy) • MUCOPOLYSACCHARIDOSES (MPS) (Hurler syndrome) • SPHINGOLIPIDOSES (Gaucher disease, Niemann-Pick disease)
  3. 3. Disorders of Amino Acid Metabolism • Disorders of amino acid metabolism include • tyrosinemia, • homocystinuria, • NKH, • MSUD, and • PKU.
  4. 4. Phenylketonuria • PKU is inherited in an autosomal recessive • Classic PKU results from a deficiency of the PAH enzyme, which is responsible for converting phenylalanine into tyrosine. • Other forms of PKU can be caused by deficiencies in the synthesis of biopterin, which is cofactor for the PAH enzyme.
  5. 5. • Clinical Manifestations of Untreated PKU • Eczema. • Hypopigmentation. • Seizures. • Limb spasticity. • Mousy odor. • Severe mental retardation.
  6. 6. • Women of childbearing age with PKU must maintain strict adherence to their diet because of the teratogenic effects of elevated phenylalanine. • Infants born to mothers with uncontrolled PKU can have microcephaly, growth retardation, developmental delay, and congenital heart disease.
  7. 7. • Treatment • Phenylalanine-restricted diet in infancy, ideally continued throughout lifetime. • More recently, a synthetic form of biopterin has become clinically available and allows further liberalization of diet in some patients.
  8. 8. Tyrosinemia • There are five known inherited disorders of tyrosine metabolism. • We will address tyrosinemia types I .
  9. 9. Tyrosinaemia (type 1) • Tyrosinaemia type 1 results from a block in the catabolism of tyrosine, producing byproducts which damage the liver and kidney. • Clinical features of tyrosinaemia • Early onset (severe) liver disease with coagulopathy, proximal renal tubulopathy • Late onset: Faltering growth and rickets (secondary to renal Fanconi) • Development of hepatocellular carcinoma in late childhood/adolescence
  10. 10. • Diagnosis • Tyrosine is raised in the plasma and the presence of succinylacetone in urine is pathognomonic. • Confirm by liver enzymology (fumarylacetoacetase).
  11. 11. • Treatment • Dietary restriction of tyrosine and phenylalanine with or without liver transplantation; • however, the drug Nitisinone (NTBC)is now used in some patients to create a block upstream of the pathway of tyrosine metabolism, leading to accumulation of less toxic metabolites.
  12. 12. Maple Syrup Urine Disease (MSUD) • MSUD results from deficient activity of the BCKD (branched-chain keto acid dehydrogenase ) • occurs in approximately 1 in 200,000 births. • It derives its name from the sweet smelling urine of affected patients. • Deficiency of this enzyme leads to accumulation of the BCAAs including leucine, isoleucine, and valine. • Much of the toxicity is related to the elevated level of leucine, which is neurotoxic.
  13. 13. Clinical Manifestations (Vary According to Level of Functional Enzyme Present) • Severe forms present in infancy with lethargy, vomiting, hypotonia, seizures, and/or death.
  14. 14. • Patients with intermediate levels of enzyme can present during childhood or adulthood with episodic neurologic decompensation, often during an intercurrent illness. • Chronic progressive forms of MSUD exist and can present with gradual neurologic problems including seizures and developmental delay.
  15. 15. • Diagnosis: • Elevated branch-chain amino acids plus alloisoleucine • Elevated branch-chain oxo-acids on urinary organic acids • Enzymology on fibroblasts • Ammonia, lactate, and bicarbonate are often normal. • Treatment • Restriction of intake of the BCAAs. • The enzyme cofactor thiamine is given in the hope of improving residual enzyme activity.
  16. 16. Homocystinuria • Homocystinuria is an autosomal recessive condition. • classically caused by cystathionine beta- synthase deficiency. This enzyme is responsible for metabolizing homocysteine to cystathionine. • Pyridoxine is a cofactor for this enzyme.
  17. 17. • Clinical Manifestations • Mental retardation. • Eye lens dislocation(classically downward) • Marfanoid body habits(span greater than height)high arched palate, arachnodactyly • Restricted joints movement. • Osteoporosis. • Acute vascular thrombosis.
  18. 18. • Treatment • 50% of patients will respond to pyridoxine supplementation. • Folate should also be supplemented as depletion affects response. • Other treatment modalities include methionine-restricted, cystine-supplemented diet. • Betaine is effective at lowering homocysteine .
  19. 19. Nonketotic Hyperglycinemia • NKH results from defects in the glycine cleavage system. • Glycine is a neurotransmitter; excitatory centrally and inhibitory peripherally.
  20. 20. • Clinical features • Increased fetal movements (inutero seizures) • Hiccups and hypotonia. • Progressive apnea/encephalopathy. • Seizures. • Developmental delay. • EEG shows a burst suppression pattern;
  21. 21. • Diagnosis: • elevated glycine on urinary or plasma amino acids. • CSF glycine to plasma glycine ratio greater than 0.08 is diagnostic of NKH. • Ketosis and acidosis are not seen. • Enzymology ;is traditionally assessed in the liver, but a new assay using lymphocytes is now available.
  22. 22. • Treatment • Sodium benzoate and dextromethorphan may help to reduce seizure activity and increase arousal in some patients. • Sodium-Valproic Acid (Depakene) should be avoided since it can raise CSF glycine levels.
  23. 23. Urea Cycle Defects (Disorders of Protein/Nitrogen Metabolism) • In normal individuals, excess nitrogen is converted into urea, which is excreted in the urine by a process known as the urea cycle. • A defect in this cycle will lead to abnormal nitrogen metabolism, and an elevation in ammonia, which at high levels is neurotoxic. • Excess nitrogen is also stored as glutamine and glycine, which are also elevated in these disorders. • All disorders of the urea cycle are inherited in an autosomal recessive manner, except OTC deficiency, which is inherited in an X-linked manner.
  24. 24. Clinical features of Urea cycle defects: • Vomiting (may be a cause of cylical vomiting) • Encephalopathy. (intoxication following symptom free period in neonate) . • Tachypnoea (ammonia stimulate respiratory center) • Progressive spastic diplegia and developmental delay (arginase deficiency) • Milder forms can present during childhood with episodic encephalopathy triggered by intercurrent metabolic stress.
  25. 25. • Diagnosis • The specific deficient enzyme in a patient with a suspected urea cycle defect can be identified by examining the patterns of urine organic acids and plasma amino acids. • Final confirmation of the diagnosis requires enzymology.
  26. 26. Characteristics of urea cycle defects
  27. 27. • Treatment • Acute treatment during crisis periods is centered around reducing the levels of ammonia by • dialysis and IV medications designed to provide alternative mechanisms of nitrogen excretion, such as sodium benzoate and phenylbutyrate.
  28. 28. Disorders of Organic Acid Metabolism • Defects in the catabolism of amino acids result in the accumulation of organic acids which are detected in urine. • Disorders of organic acid metabolism include • propionic acidemia, isovaleric acidemia, methylmalonic aciduria, and glutaric aciduria.
  29. 29. • Propionic acidaemia (PA) and methylmalonic aciduria (MMA) result from blocks in branched-chain amino acid degradation, • isovaleric acidaemia (IVA) is the result of a block in leucine catabolism. • glutaric aciduria type 1 (GA-1) results from a block in lysine and tryptophan metabolism.
  30. 30. Clinical features of organic acidaemias • Acute neonatal encephalopathy (intoxication), or chronic intermittent forms • Dehydration · • Marked acidosis (↑anion gap), ketosis . • Neutropenia +/- thrombocytopenia (acute marrow suppression) • Progressive extra pyramidal syndrome (MMA, PA) basal ganglia necrosis • Renal insufficiency (MMA) • Pancreatitis . • Cardiomyopathy (PA, MMA) • Patients with isovaleric acidemia are often described as having a peculiar body odor (sweaty feet)
  31. 31. • Diagnosis • Both the acylcarnitine profile and urine organic acid profile are essential in making a diagnosis.
  32. 32. • Treatment • Protein restriction. • Carnitine supplementation (provides alternate methods of propionic acid and methylmalonic acid secretion). • There are B12 responsive forms of methylmalonic aciduria. • Propionate is partly produced by gut organisms, therefore decompensation in PA and MMA may be precipitated by constipation. • Metronidazole is used in MMA and PA to alter the gut flora to reduce propionate production and help avoid constipation.
  33. 33. Glutaric Aciduria Type 1 • Glutaric aciduria type 1 is due to a deficiency in glutaryl- CoA . • Clinical Manifestations: • Macrocephaly • Normal development before catastrophic decompensation (usually <1 year) • Choreoathetosis and dystonia (basal ganglia involvement) • Magnetic resonance imaging features: bifrontotemporal atrophy, subdural haematomas, basal ganglia decreased signal
  34. 34. • Diagnosis • Elevated levels of glutaric acid in the urine or CSF. • Abnormal acylcarnitine profile. • Patients do not generally have hypoglycemia, acidosis, or hyperammonemia. • Treatment • Lysine and tryptophan restricted diet. • Carnitine supplementation. • Support during intercurrent illnesses.
  35. 35. Disorders of Fatty Acid Metabolism • The fat oxidation defects commonly present with hepatic, cardiac or muscle symptoms. • Fatty acids are a major fuel source in the fasted state • Fatty acids are oxidized by most tissues except the brain, which is reliant on hepatic fatty acid for ketone production. • Fatty acids are the preferred substrate for cardiac muscle. • during prolonged exercise they are a vital energy source for skeletal muscle.
  36. 36. • Long-chain free fatty acids are esterified in the cell cytosol and then enter the mitochondria as fatty acylcarnitines. • Medium- and short-chain fatty acids are able to enter the mitochondria directly. • They then undergo beta oxidation until they become acetyl-CoA, which is then used to make ketone bodies. • These disorders are all inherited in an autosomal recessive manner.
  37. 37. Medium-chain acyl-CoA. dehydrogenase (MCAD) deficiency • MCAD deficiency is the commonest fat oxidation disorder. • Clinical features of MCAD deficiency • Hypoketotic hypoglycaemia(During prolonged fasting) • Encephalopathy • Reye-like syndrome: hepatomegaly, deranged liver function • Mean age at presentation 15 months, commonest precipitant is diarrhoea • Sudden infant death (consider in older infant> 6 months)
  38. 38. • Diagnosis • Detection requires a strong clinical suspicion . • The presence or absence of ketosis should be sought in all cases of hypoglycaemia. • Plasma-free fatty acids are raised, while ketone formation is impaired. • Urinary organic acids reveal a characteristic dicarboxylic aciduria in the acute state. • Acylcarnitines are elevated .
  39. 39. • Management • Prevention is better than cure. • Once the diagnosis is known, further decompensations can be avoided by employing an emergency regimen of glucose polymer drinks during intercurrent illnesses or admission for a 10% dextrose infusion if the drinks are not tolerated.
  40. 40. Disorders of Carbohydrate Metabolism • Disorders of carbohydrate metabolism include: • hereditary fructose intolerance, • galactosemia, • and the GSDs (Glycogen storage disease)
  41. 41. Galactosemia • Galactosemia is a result of deficient (galactose-1- phosphate uridyl transferase) • Most patients present in the first or second week of life with hepatomegaly, jaundice, vomiting, hypoglycemia, hypotonia, and cataracts (oil droplet cataract) • Neonates also present with Escherichia coli sepsis.
  42. 42. • Diagnosis • Diagnosis is based on the clinical picture, the presence of reducing substances in the urine • Enzymology : by measuring the level of galactose 1 phosphate uridyltransferase (Gal 1-Put) in red cells. • Galactosaemia should be considered in all cases of severe early-onset jaundice.
  43. 43. • Treatment includes a lactose-free diet throughout life. • Long-term complications, in spite of good control, thought to be due to endogenous production of galactose from glucose. • Includes: developmental delay, particularly involving speech, feeding problems and infertility in girls.
  44. 44. Hereditary Fructose Intolerance • It is result from a defect of fructose 1,6-bisphosphate aldolase. • When patients are exposed to fructose, they can have gastrointestinal symptoms with nausea and vomiting, seizures, and coma. • Liver failure and proximal renal tubule defects can be seen. • Exacerbations may occur following exposure to fructose contained in medicines • A chronic form can also develop leading to growth failure and chronic renal and liver damage. • Treatment :Lifelong avoidance of fructose.
  45. 45. Glycogen Storage Disorders • Glucose is stored in the liver and muscles as glycogen. • The glycogen storages disorders are a large class of disorders that cause defects in glycogen production or utilization. • They primarily present with either muscle or liver abnormalities or both. • Hepatic forms present with hepatomegaly and hypoglycaemia, • the muscle forms present with weakness and fatigue.
  46. 46. GSD Ia (von Gierke disease) • Enzyme :Glucose-6-phosphatase • Major Organ Involvement: Liver, kidney
  47. 47. • Clinical Features : • Hypoglycemia ; Fasting tolerance is limited, usually 1 -4 h. • Massive hepatomegaly in the absence of splenomegaly is strongly suggestive of a hepatic GSD because glycogen is not stored in the spleen. • Nephromegaly is common. • Abnormal fat distribution results in 'doll-like' faces and thin limbs. • Long-term complications include renal insufficiency, liver adenomas with potential for malignant change, gout, osteopenia and polycystic ovaries.
  48. 48. • Investigations: show raised plasma lactate levels, hyperuricaemia and hyperlipidaemia. • Treatment consists of frequent feeds during the day with continuous feed overnight. • From age 2, uncooked corn starch is introduced as a slow-release form of glucose, prolonging the gap between feeds. • Allopurinol controls the uric acid level in the blood. • Liver transplantation is reserved for patients with malignant change in an adenoma or failure to respond to dietary treatment.
  49. 49. GSD II (Pompe disease) • Enzyme :Lysosomal alpha-glucosidase , acid maltase deficiency • Major Organ Involvement: Muscle, • Clinical Features : generalized Myopathy, cardiomyopathy, hypotonia, weakness, hyporeflexia and large tongue. • ECG reveals giant QRS complexes. • Vacuolated lymphocytes are seen on the blood film. • Confirmatory enzymology is performed on fibroblasts. • ERT (enzyme replacement therapy )recently available, which extends life expectancy.
  50. 50. • GSD III Debrancher (Cori disease): affects liver and muscle. • GSDIV Brancher (Andersen disease), GSD VI (Hers disease) and GSD IX: affects liver. • GSD V (McArdle disease) and GSD VII(Tarui disease): affects Muscles.
  51. 51. PEROXISOMAL DISORDERS • Peroxisomes harbour many vital cellular functions, including • the synthesis of plasmalogens, (essential constituents of cell walls), cholesterol and bile acids, and • the oxidation of very long- chain fatty acids and breakdown of phytanic acid (vitamin A) and glyoxylate.
  52. 52. • Disorders are biochemically characterized by the number of functions impaired. • Multiple enzymes affected (peroxisomal biogenesis defects) - Zellweger syndrome (ZS) • Several enzymes involved- rhizomelic chondrodysplasia punctata (RCDP) • Single enzyme block- X-linked adrenoleukodystrophy (XALD), Refsum disease, hyperoxaluria
  53. 53. • Inheritance is autosomal recessive with the exception of the XALD. • The first-line investigation is very-long-chain fatty acids which are elevated in ZS and XALD. • Further investigation requires fibroblast studies.
  54. 54. Zellweger syndrome • ZS is the classic peroxisomal biogenesis disorder with distinctive dysmorphic features. • prominent forehead, hypertelorism, large fontanelle.
  55. 55. • Clinical features of Zelweger syndrome • Dysmorphic faces; • Severe neurological involvement including hypotonia, seizures and psychomotor retardation. • Sensorineural deafness. • Ocular abnormalities - retinopathy, cataracts • Hepatomegaly and liver dysfunction • Calcific stippling (especially knees and shoulders) • Faltering growth.
  56. 56. • Diagnosis • Loss of all peroxisomal functions - raised very- long-chain fatty acids, phytanate and bile acid intermediates and decreased plasmalogens. • Confirmatory enzymology on fibroblasts.
  57. 57. • Treatment • Management is supportive. • Docosahexaenoic acid supplementation has been tried.
  58. 58. X-linked adrenoleukodystrophy (XALD) • The paediatric cerebral form presents with severe neurological degeneration, usually between 5 and 10 years. • Brothers in the same family may present at different ages. • Clinical features of XAID • School failure, behaviour problems • Visual impairment • Quadreplegia • Seizures (late sign) • Adrenal insufficiency
  59. 59. • Adrenal involvement may precede or follow neurological symptoms by years. • Some only develop neurological symptoms, and others just have adrenal insufficiency. • All males developing adrenal failure should have very-long-chain fatty acid measurements taken to ensure that the diagnosis is not missed.
  60. 60. • Diagnosis • Elevated very-long-chain fatty acids, blunted synacthen response or frank hypoglycaemia. • Neuroimaging shows bilateral, predominantly posterior, white-matter invotvement. • The differential diagnosis for neurodegeneration in the school-age child includes: • Subacute sclerosing panencephalitis . • Batten disease • Wilson disease • Niemann-Pick C disease.
  61. 61. • Management • Lorenzo's oil (oleic and erucic acid) normalizes the very-long-chain fatty acids. • Bone marrow transplantation is the mainstay of therapy in patients before neurodegeneration and those diagnosed after presentation with adrenal insufficiency. • Adrenal function should be closely monitored, and steroid replacement therapy should be given once it is indicated.
  62. 62. MUCOPOLYSACCHARIDOSES (MPS) • Mucopolysaccharides (glycosaminoglycans) are structural molecules integral to connective tissues such as cartilage. • Degradation occurs within lysosomes, requiring specific enzymes. • Patients with MPS appear normal at birth and usually present with developmental delay in the first year. • The features of storage become more obvious with time.
  63. 63. Classification Type Disorder Inheritanc e Corneal clouding Skeleton Hepato- Splenomegaly MR I Hurler AR + +++ +++ +++ II Hunter XL - +++ +++ +++ III Sanfillipo AR + + + +++ IV Morquio AR + +++ + - VI Maroteaux -Lamy AR + +++ +++ - VII Sly AR + +++ +++ +++
  64. 64. • Hurler syndrome is the classical MPS with storage affecting the body and CNS. • Sanfillipo syndrome predominantly affects the CNS. • Morquio and Maroteaux-Lamy syndromes affect the body with Atlantoaxial instability often necessitating prophylactic cervical spinal fusion in the first 2-3 years. • Hunter syndrome is phenotypically similar to Hurler syndrome, however there is no corneal clouding and scapular nodules are seen.
  65. 65. Hurler syndrome • Hurler syndrome typifies the MPS group and their associated clinical problems. • The enzyme deficiency is a-iduronidase, a deficiency .
  66. 66. • Clinical features of Hurler syndrome • Coarse faces, macroglossia, hirsutism, corneal clouding • Airway/ear, nose, throat problems,secretory otitis media. • Dysostosis multiplex • Cardiomyopathy, valvular disease • Hepatosplenomegaly • Hernias- umbilical, inguinal, femoral • Stiff joints · • Developmental delay and retardation
  67. 67. • Radiographs show a characteristic skeletal dysplasia known as dysostosis multiplex • The earliest radiographic signs are thick ribs and ovoid vertebral bodies. • The lower ribs are broad and spatulate . • The skull is large, the orbits shallow and the sella turcica shoe shaped or J-shaped .
  68. 68. • The bones of the upper extremities become short and taper toward the ends, often with enlargement of the mid-portions. • The ends of the radius and ulna angulate toward each other. • claw hand of the patient with Hurler syndrome is pathognomonic of dysostosis multiplex. • The metacarpals are broad at their distal ends and taper at their proximal ends. • The phalanges are thickened and bullet-shaped.
  69. 69. • The clavicle is absolutely characteristic, while the lateral portion may be hypoplastic or even absent. • The vertebrae are hypoplastic, scalloped posteriorly and beaked anteriorly, especially at the thoracolumbar junction . • There is anterior vertebral wedging, with typically a hooked-shaped vertebre.
  70. 70. • Diagnosis • Urinary screen for glycosaminoglycans (raised dermatan and heparan sulphate). • Enzymology confirmed on white cells.
  71. 71. • Management • Treatment depends on early recognition to allow early bone marrow transplantation, which significantly modifies the phenotype. • Enzyme replacement clinical trials are currently underway. • Supportive care is the mainstay of untransplanted patients, with particular regard to the chest and airway requiring 3- monthly sleep studies.
  72. 72. SPHINGOLIPIDOSES • Sphingolipids are complex membrane lipids. • They are all derived from ceramide and can be divided into three groups: • cerebrosides, sphingomyelins and gangliosides. • Lysosomal hydrolases break these molecules down; • deficiencies result in progressive storage and disease. • Typical features include psychomotor retardation, neurological degeneration including epilepsy, ataxia and spasticity, with or without hepatosplenomegaly.
  73. 73. Tay-Sachs disease • Clinical features: • Developmentar regression within first year. • Macrocephcdy • Hyperacusis • Cherry-red spot. • Spastic quadriplegia
  74. 74. • Diagnosis • The presence of vacuolated lymphocytes on the blood film is a further clue. • Hexosaminidase A deficiency is confirmed on white cell enzymology. • Management • Currently, management is supportive. However, research into substrate-deprivation therapy, thereby avoiding accumulation in the first place, is under investigation.
  75. 75. Gaucher disease • Glucocerebrosidase deficiency results in the accumulation of cerebroside in the visceral organs +/- the brain depending on the type. • Clinical features of Gaucher disease • Type 1 • Non-neuronopathic (commonest) • Splenomegaly > hepatomegaly • Anaemia, bleeding tendency • Skeletal pain, deformities, osteopenia • Abdominal pain (splenic infarcts)
  76. 76. • Type 2 • Acute neuronopathic • Severe CNS involvement (especially bulbar), rapidly progressive • Convergent squinting and horizontal gaze palsy • Hepatosplenomegaly • Type 3 • Sub-acute neuronopathic • Convergent squint and horizontal gaze palsy (early sign) • Splenomegaly > hepatomegaly • Slow neurological deterioration
  77. 77. • Diagnosis • Elevated angiotensin-converting enzyme (ACE) and acid phosphatase are markers for the disease. • Bone marrow aspiration may reveal Gaucher cells • White cell enzymes for glucocerebrosidase give the definitive diagnosis. • The enzyme chitotriosidase is markedly elevated and may be used to follow disease activity.
  78. 78. • Management • Enzyme replacement therapy is effective in visceral disease in types 1 and 3. • Bone marrow transplant has been used in the past, and may have benefit for cerebral involvement in type 3. • Splenectomy has been used to correct thrombocytopenia and anaemia and relieve mechanical problems but may accelerate disease elsewhere. • There is no effective treatment for type 2.
  79. 79. Niemann-Pick disease • Niemann-Pick (sphingomyelinoses) • Types A and B are biochemically and genetically distinct from C and D.
  80. 80. Type 1 (sphingomyelinase deficiency) • Clinical features of type 1 • Type A (infantile) • Feeding difficulties • Hepatomegaly > splenomegaly • Cherry-red spot · • lung infiltrates • Neurological decline, deaf, blind, spasticity
  81. 81. • Type B (visceral involvement) • Milder course, no neurological involvement • Hepatosplenomegaly • Pulmonary infiltrates . • Ataxia • Hypercholesterolaemia
  82. 82. • Diagnosis • Bone marrow aspirate for Niemann-Pick cells. • White cell enzymes. • Genotyping may help distinguish between the two types before the onset of neurological signs. • Management • Supportive.
  83. 83. THANKS

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