Metabolic Diseases

  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. Image Upload 1
    Crumpled Paper tissue as seen in Gaucher Disease
  35. Image Upload 2
    Foamy Cells as seen in Neimann-Pick
  36. Image Upload 3
    Diffuse Leukodystrophy sparing the U-fibers as seen in Metachromatic Leukodystrophy or Krabbe Disease
  37. Image Upload 4
    Anigokeratoma as seen in Fabry Disease
  38. Image Upload 5
    Globoid Cells as seen in Krabbe Disease
  39. Image Upload 6
    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. Image Upload 7
    X-linked Adrenoleukodystrophy (X-ALD)
  70. Image Upload 8
    Canavan Disease
Card Set
Metabolic Diseases
Metabolic Diseases