Card Set Information
What clinical warning signs should cause you to consider a metabolic disease?
Fulminant neonatal 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
Disorders of Cholesterol Metabolism
What are some examples of metabolic disorders involving the accumulation of toxic substances (i.e. intoxications)?
Urea Cycle Disorders
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 ...
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
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
: Urine Sulfatides
: infantile, juvenile, and adult
: 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
: 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
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
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)
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
: fatty acids and elevated CSF protein
: 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
: death in a year
What are examples of disorder that cause intoxication?
Urea Cycle Defects
Name some of the aminoacidopathies ...
Molybdenum Cofactor Deficiency
What are the classic features of PKU ...
d/f phenylalaine hydroxylase
Musty odor, MR, spass, microcephaly, light pigmentation, hypertonia, tremors
: Phe level on the newborn screen or Urine
: 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
: Urine homocysteine and methionine
: 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
: Urine sulfite and low uric acid
What are the characteristic features of Non-ketotic Hyperglycinemia?
AR d/f in glycine cleavage
Rapid and progressive hypotonis, seizures, apnea, coma, hiccup
: EEG --> burst syppression, CSF:Plasma GLY level
: 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
: 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
: 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
: 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
: acquired macrocephaly, dystonia, chorea, motor delay, hypotonia, enlarged subdural spaces, SDH, retinal hemorrhage
: Urine OA --> elevated glutaric acid
: 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
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
: Urine-OA, Serum-AA, Hyperammonemia
: 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 -->
: enzyme activity in cultured fibroblasts / muscle, DNA analysis, ischemic exercise test
: 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
: DD, hypotonia, seizures, ataxia
: enzyme activity in fibroblasts, muscle BX, genetic
: 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
: Vomiting, Lethargy, Hypoketotic Hypoglycemia Coma, SIDS, Cardiomyopathy, Weakness
: Urine-OA, Urine-Ketonase, and Acylcarnitine Profile
: 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?
Progressive disorders affecting the GM > WM caused by the accumulation of lipopigmented storage material
Multiple subtypes (Infantile, Late Infantile, Juvenile, Adult)
: Inclusions bodies noted on BX of conjunctiva, sweat glands, rectum, genetic testing, enzymology from blood
What are the characteristic features of Pantothate Kinase deficiency (PKAN - aka Hallervorden-Spatz)?
Deposition of Iron in the GP / SN
: Childhood onset extrapyramidal symptoms, spasticity, optic atrophy, retinitis pigmentosa, seizures
: MRI showed "eye of the tiger"
What are the characteristic features of Menkes Kinky Hair Syndrome?
d/f in Copper Transporter (ATP7A)
: Motor and Mental Retardation, Seizures, Torturous Cerebral Vessels, "kinky" hair, hypothermia
: Low Serum Cu and Ceruloplasm
: 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
: elevated serum and urine uric acid
What are the characteristic features of Canavan Disease?
d/f Aspartoacylase --> accumulation of NAA
: 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%
: macrocephaly, spasticity, dysconjugate gaze, mental / motor retardation
: 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
: MRI --> dys/hypo myelination, PLP gene sequencing
Name the metabolic disorders with X-linked inheritance ...
Fabry (alpha-galactosidase A d/f)
X-linked Adrenoleukodystrophy (X-ALD)
Ornithine Transcarbamylase Deficiency (OTC)
Pyruvate Dehydrogenase Comple Deficiency (PDHC)
X-linked Adrenoleukodystrophy (X-ALD)