Metabolic Diseases

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Metabolic Diseases
2012-09-11 09:02:56
Metabolic Diseases

Metabolic Diseases
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  1. What clinical warning signs should cause you to consider a metabolic disease?
    • Fulminant neonatal encephalopathy
    • Progressive encephalopathy
    • Symptoms that come and go with metabolic stressors
    • Chronic static encephalopathy - expecially when it is combined with disturbances in other organ systems
  2. What are the major groups of metabolic diseases?
    • Diseases involving complex molecules (e.g.lysosomal).
    • Diseases resulting in intoxication due to a metabolic block (e.g. aminoacidopathies)
    • Diseases caused by deficeicny energy metabolism (e.g. mitochondrial diseases)
  3. What are some common features of disorders of metabolism involving complex molecules?
    • Typically involve structural proteins that compose membranes present in multiple tissues
    • Accumulation of susch substances causes multiorgan system involvement
    • There is often enlargement of the viscera and coarsening of the features
    • They tend to follow a chronic and progressive disease coarse affecting both the central and peripheral nervous system
  4. What are some common features of disorders of metabolism involving intoxication?
    • These mainly include the inborn errors of metabolism
    • They will commonly present as neonatal encephalopathy but less commonly may cause symptoms that relapse and remit with metabolic stress or a chronic, static encephalopathy
  5. What are some common features of disorders of metabolism involving disorders of deficienct energy metabolism?
    • Symptoms will tend to wax and wane over time often occurring in periods of metabolic stress
    • The most commonly affect tissues include the Brain, Muscle, Eye, and Heart
  6. What are some examples of diseases involving complex molecules?
    • Lysosomal Storage Diseases
    • Peroxisomal Disoders
    • Disorders of Cholesterol Metabolism
  7. What are some examples of metabolic disorders involving the accumulation of toxic substances (i.e. intoxications)?
    • Aminoacidopathies
    • Organic Acidemias
    • Urea Cycle Disorders
    • Sugar Intolerance
  8. What are some examples of diseases in which the primary pathology is a deficiency in energy metabolism?
    • Congenital Lactic Acidemia
    • Disorders of Fatty Acid Oxidation
    • Disorders of Glycogenosis
    • Disorders of Gluconeogenesis
    • Disorders of the Kreb's Cycle
    • Respiratory chain / Mitochondrial Diseases
    • Disorders of Pyruvate and Lactic Acid Metabolism
  9. Name the major classes of lysosomal storage diseases.
    • Sphingolipidoses (e.g. cerebrosides, spingomyelins, and gangliosides)
    • Leukodystrophies (e.g. Metachromatic, Krabbe, Adrenoleukodystrophy, Pelizeus-Merzbacher)
    • Mucopolysaccharidoses (e.g. Hurler)
    • Glycoproteinoses (e.g. Alpha-mannosidoses, Sialidosis, Mucolipidoses)
  10. Name the spingolipidoses ...
    • Niemann-Pick
    • Gaucher
    • Fabry
    • Ferber
    • GM1 Gangliosidosis
    • GM2 Gangliosidosis
    • Sandhoff
  11. What are the common characteristics of the sphingolipidoses?
    • Invole membrane lipids made from spingosine
    • Three classes - cerebrosides, sphingomyelins, gangliosides
    • Most are AR (except Fabry)
    • Most have subtypes with different presentations
    • Most have childhood forms with hypotonia progressing to spastic paresis, chronic / progressive encephalopathy, and early death
    • Cherry Red Spot is common
    • Most care is supportive but ERT is available for some forms
  12. Neimann-Pick ...
    • Lysosomal storage disease
    • AR
    • Deficiency - spingomyelinase (Foam Cells)
    • Four subtypes (A - D)
    • Type A - infantile, FTT, H>SM, hypotonic --> spastic paresis, decreased DTR's, death by 2, Cherry Red Spot
    • Type B - H>SM, hypercholesterolemia, less neurologic involvement
  13. Gaucher Disease ...
    • Spingolipidosis
    • AR (most frequent lysosomal storage disease)
    • Deficiency in Glucocerebrosidase ("crumpled tissue")
    • Three subtypes (1 - 3)
  14. Fabry Disease ...
    • Sphingolipidosis
    • X-linked (some female carriers)
    • Deficiency in alpha galactosidase
    • Storage of lipids in blood vessles of the heart, cornea, peripheral nerves and kidneys
    • Pain crises (acroparesthesias)
    • Cardiomyopathy, Stroke, Aneurysms
    • Angiokeratomas
  15. Farber's Disease ...
    • Sphingolipidosis
    • AR deficiency in ceramidase
    • Infantile onset
    • Hoarse cry, hyperasthesia, SQ nodules, joint swelling / contractures
  16. GM 1 Gangliosidosis
    • Spingolipidosis
    • AR
    • Deficiency in beta-galactosidase
    • Three subtypes (Infantile, Juvenile, and Adult) with variable presentations
  17. GM 2 Gangliosidosis ...
    • Spingolipidosis
    • AR
    • Deficiency in Heoxaminidase A
    • Three subsets (Infantile, Juvenile, and Adult)
    • Infantile form is Tay-Sachs disease - starts at 6 monthswith regression, startle, impaired vision, cherry red spot, hypotonia --> spasticity, seizures, macrocephaly
  18. Sandhoff Disease ...
    • Spingolipidosis
    • AR
    • Deficiency in Hexosaminidae A and B
    • Features similar to Tay-Sachs but patients also have HSM
  19. Metachromatic Leukodystrophy ...
    • Spingolipidosis
    • AR
    • Deficiency in Arylsulfatase A
    • Causes deposition of sulfatides in central and peripheral white matter
    • MRI - demyelination sparing the U-fibers
    • DX: Urine Sulfatides
    • Three subtypes: infantile, juvenile, and adult
    • TX: mainly supportive with BMT for later onset
  20. Krabbe Disease ...
    • Spingolipidosis
    • AR
    • Deficiency in Galactocerebroside beta-galactosidase
    • Causes central and peripheral demyelination
    • Three substypes (Infantile, Juvenile, and Adult)
    • Infantile "krabby baby" with tonic spasms
    • DX: Globoid cells in cerebral white matter
  21. Cerebrotendinous Xanthomatosis ...
    • Spingolipidosis
    • AR
    • CNS accumulation of Cholestanol
    • Causes tendinous xanthomas, cerebellar demyelination, progressive ataxia, dementia, cataracts
  22. Multiple Sulfatase Deficiency ...
    • Spingolipidosis
    • AR
    • Deficiency in Arylsulfatase A/B/C, Mucopolysaccahride Sulfatase, and Steroid Sulfatase
    • Clinical picture is a cross between Metachromatic and the Mucopolysaccharidoses
  23. Name the Mucopolysaccharidoses ...
    • Type 1h - Hurler
    • Type 1h/s - Hurler-Scheie
    • Type 1s - Scheie
    • Type 2 - Hunter
    • Type 3 - Sanfilipo
    • Type 4 - Morquio
    • Type 6 - Maroteaux-Lamy
    • Type 7 - Sly
    • Type 8 - Natowicz
  24. What are some of the common features of the Mucopolysaccharidoses?
    • Group of disorders caused by a deficiency in lysosomal enzymes required for the degradation of glycosaminoglycans
    • Lead to accumulation of Dermatin, Heparin, Keratan, or Chondroitin Sulfate
    • Common features include: Coarse facial features, Skeletal deformities, Cervical cord compression, Obstructive Hydrocephalus, HSM
    • Most cause MR (except Scheie, Morquio, Maroteaux-Lamy)
    • Mianly treated by ERT or BMT
  25. Hurler Disease ...
    • MPS Type 1
    • AR
    • Deficiency in alpha-L-iduronidase
    • Three subtypes:
    • Hurlers - severe, neuroologic and systemic
    • Hurler-Scheie - milder phenotype
    • Scheie - mlder neurologic symptoms
    • TX - recombinant alpha-L-iduronidase or BMT
  26. Hunter's Disease ...
    • MPS Type 2
    • X-linked
    • Deficiency in Iduronate-2-sulfatase
    • Phenotype is similar to Hurler's but milder with no corneal clouding
    • TX - iduronate-2-sulfatase

    Remeber - a hunter hits the target X
  27. Salfilippo Disease
    • MPS Type 3
    • AR
    • Deficiency in enzymes degrading Heparin Sulfate
    • Severe MR with little other features
  28. Morquio Disease ...
    • MPS Type 4
    • AR
    • Deficciency in enzymes degrading Keratan Sulfate
    • Low IQ with neurologic symptoms from bony compression and corneal clouding
  29. Maroteaux-Lamy ...
    • MPS Type 6
    • AR
    • Deficienc in enzymes degrading Dermatan Sulfatse
    • Like Hurler but no MR
  30. The Oligosidoses include ...
    • alpha-Mannosidosis
    • Sialidosis
    • Mucolipidosis II (I-cell disease)
    • Galactosialidosis
  31. What are some of the defining characteristics of the Peroxisomal Disorders ?
    • Dysmosphisms
    • Congenital malformations of cerebrogenesis
    • Hepato-intestinal Dysfunction
    • DX - plasma very long chain fatty acids (VLCFA) and Phytanic Acid levels
  32. Name some of the most common Peroxisomal Disorders.
    • X-linked Adrenoleukodystrophy (X-ALD)
    • Refsum Disease (classic)
    • Zellweger Syndrom
  33. Features of X-linked Adrenoleukodystrophy (X-ALD) include ...
    • It is the most common peroxisomal disorder
    • Defect in ABCD1 gene (peroxisomal membrane transport protein)
    • Causes impaired beta-oxidation
    • Three forms - Childhood, Adolescent, Adult
    • Child (4-8, behavior --> spastic paraparesis, visual loss)
    • Adult (dementia, seizures, psychiatric, parapresis)
    • Adrenomyeloneuropathy (slow rogressive parapresis and impaired vibratory sensation and Addison's Disease)
  34. Crumpled Paper tissue as seen in Gaucher Disease
  35. Foamy Cells as seen in Neimann-Pick
  36. Diffuse Leukodystrophy sparing the U-fibers as seen in Metachromatic Leukodystrophy or Krabbe Disease
  37. Anigokeratoma as seen in Fabry Disease
  38. Globoid Cells as seen in Krabbe Disease
  39. Posterior predominant Leukodystrophy as seen in X-linked Adrenoleukodystrophy (X-ALD)
  40. What are the features of Refum Disease ...
    • AR
    • d/f phytanoyl-CoA hydroxylase
    • Onset shool-age to adolescence
    • Retintis pigmentosa, polyneuropathy, ichthyosis, deafness, anosmia, arrhythmias
    • DX: fatty acids and elevated CSF protein
    • TX: diet low in phytanic acid or PLEX
  41. What are the featueres of Zellweger Syndrome ...
    • AR
    • Absence of all peroxisomes leading to high levels of Cu/Fe
    • Present in infancy c/ dysmorphisms, hypotonia, seizures, hearing loss, ocular abnormalities, FTT
    • TX: supportive
    • PX: death in a year
  42. What are examples of disorder that cause intoxication?
    • Aminoacidopathis
    • Organic Acidemias
    • Urea Cycle Defects
    • Sugar Intlerances
  43. Name some of the aminoacidopathies ...
    • Phenylketonuria
    • Homocysteineuria
    • Molybdenum Cofactor Deficiency
    • NKH
  44. What are the classic features of PKU ...
    • AR
    • d/f phenylalaine hydroxylase
    • Onset infancy
    • Musty odor, MR, spass, microcephaly, light pigmentation, hypertonia, tremors
    • DX: Phe level on the newborn screen or Urine
    • TX: low PHE diet
  45. What are the clinical features of homocystinuria?
    • AR
    • d/f in cytathionine-beta-synthase
    • Downward lens dyslocation, skeletal long-born abnormalities, stroke, seizres, MR
    • DX: Urine homocysteine and methionine
    • TX: low MET diet supplemented with pyridoxine, folate, cystine, betaine, and antithrombotic treatmed
  46. What are the characteristics features of Molybdenum cofactor deficiency?
    • AR
    • d/f in the last step of metabolism in Met to sulfate
    • May be caused by a d/f in the Mb cofactor or the enzyme
    • Early refractory seizures, severe MR, FTT, microcephaly, hypotonia --> hypertonia, lens dislocation, early death
    • DX: Urine sulfite and low uric acid
    • TX: supportive
  47. What are the characteristic features of Non-ketotic Hyperglycinemia?
    • AR d/f in glycine cleavage
    • Nenatal onset
    • Rapid and progressive hypotonis, seizures, apnea, coma, hiccup
    • DX: EEG --> burst syppression, CSF:Plasma GLY level
    • TX: Supportive, Dextromethorphan, Sodium Benzoate
  48. Name some of the Organic Acidurias and their clinical features ...
    • These are defects in the metabolism of LEU, ISO, VAL
    • Classically present in the neonatal period with encephalopathy (poor PO, lethargy, comoa, cerebral edema)
    • Less commonly present in infancy with chronic / progressive FTT
    • DX: Serum AA's, Urine OA's, Acylcarnitine Profile
  49. What are the clinical features of Maple Syrup Urine Disease?
    • AR
    • D/f in branched chain ketoacid hydrogenase which also impairs metabolism of LEU / ISO / VAL
    • Sweet urine odor, Ataxia, Cerebral Edema
    • TX: Low BCAA diet, Thiamine, and avoid catabolism
  50. What are the clinical features of later of the later branched chain organic acidurias
    • Isovaleric / Propionic and Methymalonic Aciduria
    • Dehydration, HSM, Hyperammonemia, lactic acidosis
    • TX: BCAA resricted diet, avoid metabolis, carnitive
    • IVA --> also gets glycine
    • MMA --> also gets B12
  51. What are the clinical features of Glutaric Aciduria Type 1 (aka glutaric acidemia)?
    • AR
    • d/f glutayl-CoA dehydrogenase --> abnl metabolism of TRP and LYS
    • SX: acquired macrocephaly, dystonia, chorea, motor delay, hypotonia, enlarged subdural spaces, SDH, retinal hemorrhage
    • DX: Urine OA --> elevated glutaric acid
    • TX: Low LYS, + carnitine, riboflavin, baclofen, benzos, avoid catabolism
  52. Name the Urea cycle Defects ...
    • Carbamyl Phosphate Synthetase deficiency
    • Ornitine transcarbamoylase deficiency
    • Arginosuccinic Synthetase deficiency
    • Arginosuccinic Lysase deficiceny
    • Arginase deficiency
    • N-acetylglutamate synthetase deficiency
  53. What are some of of the common features of the Urea Cycle Defets?
    • d/f in the elimination of N from ALA, GLU, GLN, ASP, GLY
    • All AR (except OTC d/f which is X-linked)
    • Lethargy, Vomitting, FTT, Coma, Cerebral Edema
    • DX: Urine-OA, Serum-AA, Hyperammonemia
    • TX: Avoid catabolism, protein restricted diet, avoid VPA, IV steroids.
    • In crisis --> give dextrose, sodium benzoate (for GLY), sodium phenylbutyrate (for GLU), arginine, and Dialysis to remove ammonia
  54. Name some of the disorders of Energy Metabolism ...
    • Glycogen Storage Diseases
    • Congenital Lactic Acidemias
    • Fatty Acid Oxidation Disorders
    • Kreb's Cycle Disorders
    • Mitochondrial Respiratory Chain Disorders
  55. What are the clinical features of Glycogen Storage Diseases?
    • AR
    • Caused by enzyme defects in glycogen:
    • - Liver --> HSM and hypoglycemia
    • - Muscle --> cramps, weakness, myopathy
    • - General -->
    • DX: enzyme activity in cultured fibroblasts / muscle, DNA analysis, ischemic exercise test
    • TX: Prevent hypoglycemia and in some cases (e.g. Pompe) enzyme supplementation
  56. Name some of the Glycogen Storage Diseases ...
    • GSD1a - von Gierke's (glu-6-phosphate d/f)
    • GSDII - Pompe (lysosomal acid alpha-glucosidase aka acid maltase d/f)
    • GSDV - McArdle's (myophosphorylase d/f)
    • GSDVII - Tarui (phosphofructokinase d/f)
  57. What are the clinical features ofthe Congenital Lactic Acidemias?
    • Caused by defects in the mitochondrial enzymes that mtabolize pyruvate
    • Include Pyruvate Carboxylase d/f, Phosphoenolpyruvate carboxykinase d/f, and Pyruvate Dehydrogenase Complex d/f
  58. What are the clinical features of Pyruvate Dehydrogenase Complex Deficiency (PDHC)?
    • Most common of the congenital lactic acidoses
    • X-lined > AR
    • Elevated plasma / csf lactate / pyruvate / ALA after carbohydrate load
    • SX: DD, hypotonia, seizures, ataxia
    • DX: enzyme activity in fibroblasts, muscle BX, genetic
    • TX: KGD, Thiamine, Carnitine
  59. What are the clinical features of Fatty Acid Oxidation Disorders?
    • AR
    • Caused by defcts in the Carnitine Cycle which bring Acyl-CoA into the mitochondria
    • SX: Vomiting, Lethargy, Hypoketotic Hypoglycemia Coma, SIDS, Cardiomyopathy, Weakness
    • DX: Urine-OA, Urine-Ketonase, and Acylcarnitine Profile
    • TX: Avoid fasting, IV Dextrose, Carnitine (avoid ketosis)
  60. Name some of the disorders that cause abnormalities in fatty acid metabolism ...
    • Carnitine Transporter d/f
    • Carnitine Palmitoyl-transferase-1 (CPT-1 - neonate)
    • Carnitine Palmitoyl-transferase-2 (CPT-2 - adult)
    • Medium Chain Acyl-CoA Dehydrogenase (MCAD)
    • Very Long Chain Acyl-CoA Dehydrogenase (VLCAD)
    • Short Chain Acyl-CoA Dehydrogenase (SCAD)
  61. What are the characteristic features of the Neuronal Ceroid Lipofuscinoses?
    • Mostly AR
    • Progressive disorders affecting the GM > WM caused by the accumulation of lipopigmented storage material
    • Multiple subtypes (Infantile, Late Infantile, Juvenile, Adult)
    • SX:
    • DX: Inclusions bodies noted on BX of conjunctiva, sweat glands, rectum, genetic testing, enzymology from blood
    • TX: supportive
  62. What are the characteristic features of Pantothate Kinase deficiency (PKAN - aka Hallervorden-Spatz)?
    • AR
    • Deposition of Iron in the GP / SN
    • SX: Childhood onset extrapyramidal symptoms, spasticity, optic atrophy, retinitis pigmentosa, seizures
    • DX: MRI showed "eye of the tiger"
  63. What are the characteristic features of Menkes Kinky Hair Syndrome?
    • X-linked Dominant
    • d/f in Copper Transporter (ATP7A)
    • SX: Motor and Mental Retardation, Seizures, Torturous Cerebral Vessels, "kinky" hair, hypothermia
    • DX: Low Serum Cu and Ceruloplasm
    • TX: Cu supplements and symptomatic
  64. What are the characteristic features of Lesch-Nyhan Disease?
    • X-linked
    • Disorder of purine metabolism (hypoxanthine-guanine phosphoribosyl transferase)
    • SX:progressive motor and mental retardation, seizures, dystonia, chorea, spasticity, self-injurious behaviors, gout, renal failure
    • DX: elevated serum and urine uric acid
  65. What are the characteristic features of Canavan Disease?
    • AR
    • d/f Aspartoacylase --> accumulation of NAA
    • DX: MRI --> diffuse abnormality in cerebral white matter, Urine shows NAA, MRS, genetic testing
  66. What are the characteristic features of Alexander Disease?
    • AR
    • d/f in GFAP (glial fibrillary acidic protein) in 90%
    • SX: macrocephaly, spasticity, dysconjugate gaze, mental / motor retardation
    • DX: MRI --> frontal predominant demyelination, Brain Bx showed Rosenthal Fibers
  67. What are the characteristic features of Pelizaeus-Merzbacher Disease?
    • X-linked
    • d/f in proteolipid protein expression
    • SX:
    • - Infantile --> slow, progressive nystagmus, head tremor MR, spasticity, dystonia, optic atrophy, seizures
    • - Adult --> spastic paraplegia
    • DX: MRI --> dys/hypo myelination, PLP gene sequencing
  68. Name the metabolic disorders with X-linked inheritance ...
    • Fabry (alpha-galactosidase A d/f)
    • Hunter (MPS-II)
    • X-linked Adrenoleukodystrophy (X-ALD)
    • Ornithine Transcarbamylase Deficiency (OTC)
    • Pyruvate Dehydrogenase Comple Deficiency (PDHC)
  69. X-linked Adrenoleukodystrophy (X-ALD)
  70. Canavan Disease