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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
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)
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
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
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
What are some examples of diseases involving complex molecules?
- Lysosomal Storage Diseases
- Peroxisomal Disoders
- Disorders of Cholesterol Metabolism
What are some examples of metabolic disorders involving the accumulation of toxic substances (i.e. intoxications)?
- Organic Acidemias
- Urea Cycle Disorders
- Sugar Intolerance
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
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)
Name the spingolipidoses ...
- GM1 Gangliosidosis
- GM2 Gangliosidosis
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
- Lysosomal storage disease
- 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
Gaucher Disease ...
- AR (most frequent lysosomal storage disease)
- Deficiency in Glucocerebrosidase ("crumpled tissue")
- Three subtypes (1 - 3)
Fabry Disease ...
- 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
Farber's Disease ...
- AR deficiency in ceramidase
- Infantile onset
- Hoarse cry, hyperasthesia, SQ nodules, joint swelling / contractures
GM 1 Gangliosidosis
- Deficiency in beta-galactosidase
- Three subtypes (Infantile, Juvenile, and Adult) with variable presentations
GM 2 Gangliosidosis ...
- 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
Sandhoff Disease ...
- Deficiency in Hexosaminidae A and B
- Features similar to Tay-Sachs but patients also have HSM
Metachromatic Leukodystrophy ...
- 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
Krabbe Disease ...
- 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
Cerebrotendinous Xanthomatosis ...
- CNS accumulation of Cholestanol
- Causes tendinous xanthomas, cerebellar demyelination, progressive ataxia, dementia, cataracts
Multiple Sulfatase Deficiency ...
- Deficiency in Arylsulfatase A/B/C, Mucopolysaccahride Sulfatase, and Steroid Sulfatase
- Clinical picture is a cross between Metachromatic and the Mucopolysaccharidoses
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
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
Hurler Disease ...
- MPS Type 1
- 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
Hunter's Disease ...
- MPS Type 2
- 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
- MPS Type 3
- Deficiency in enzymes degrading Heparin Sulfate
- Severe MR with little other features
Morquio Disease ...
- MPS Type 4
- Deficciency in enzymes degrading Keratan Sulfate
- Low IQ with neurologic symptoms from bony compression and corneal clouding
- MPS Type 6
- Deficienc in enzymes degrading Dermatan Sulfatse
- Like Hurler but no MR
The Oligosidoses include ...
- Mucolipidosis II (I-cell disease)
What are some of the defining characteristics of the Peroxisomal Disorders ?
- Congenital malformations of cerebrogenesis
- Hepato-intestinal Dysfunction
- DX - plasma very long chain fatty acids (VLCFA) and Phytanic Acid levels
Name some of the most common Peroxisomal Disorders.
- X-linked Adrenoleukodystrophy (X-ALD)
- Refsum Disease (classic)
- Zellweger Syndrom
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)
Crumpled Paper tissue as seen in Gaucher Disease
Foamy Cells as seen in Neimann-Pick
Diffuse Leukodystrophy sparing the U-fibers as seen in Metachromatic Leukodystrophy or Krabbe Disease
Anigokeratoma as seen in Fabry Disease
Globoid Cells as seen in Krabbe Disease
Posterior predominant Leukodystrophy as seen in X-linked Adrenoleukodystrophy (X-ALD)
What are the features of Refum Disease ...
- 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
What are the featueres of Zellweger Syndrome ...
- 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
What are examples of disorder that cause intoxication?
- Organic Acidemias
- Urea Cycle Defects
- Sugar Intlerances
Name some of the aminoacidopathies ...
- Molybdenum Cofactor Deficiency
What are the classic features of PKU ...
- 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
What are the clinical features of homocystinuria?
- 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
What are the characteristics features of Molybdenum cofactor deficiency?
- 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
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
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
What are the clinical features of Maple Syrup Urine Disease?
- 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
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
What are the clinical features of Glutaric Aciduria Type 1 (aka glutaric acidemia)?
- 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
Name the Urea cycle Defects ...
- Carbamyl Phosphate Synthetase deficiency
- Ornitine transcarbamoylase deficiency
- Arginosuccinic Synthetase deficiency
- Arginosuccinic Lysase deficiceny
- Arginase deficiency
- N-acetylglutamate synthetase deficiency
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
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
What are the clinical features of Glycogen Storage Diseases?
- 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
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)
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
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
What are the clinical features of Fatty Acid Oxidation Disorders?
- 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)
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)
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)
- DX: Inclusions bodies noted on BX of conjunctiva, sweat glands, rectum, genetic testing, enzymology from blood
- TX: supportive
What are the characteristic features of Pantothate Kinase deficiency (PKAN - aka Hallervorden-Spatz)?
- 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"
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
What are the characteristic features of Lesch-Nyhan Disease?
- 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
What are the characteristic features of Canavan Disease?
- d/f Aspartoacylase --> accumulation of NAA
- DX: MRI --> diffuse abnormality in cerebral white matter, Urine shows NAA, MRS, genetic testing
What are the characteristic features of Alexander Disease?
- 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
What are the characteristic features of Pelizaeus-Merzbacher Disease?
- d/f in proteolipid protein expression
- - Infantile --> slow, progressive nystagmus, head tremor MR, spasticity, dystonia, optic atrophy, seizures
- - Adult --> spastic paraplegia
- DX: MRI --> dys/hypo myelination, PLP gene sequencing
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)
X-linked Adrenoleukodystrophy (X-ALD)
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