Enzyme Deficiencies Flashcards
Most IEMs, genetics wise are …
autosomal recessive or X linked recessive
groups of inborn errors of metabolism
- metabolites
- metabolic pathway
- Function of enzyme
- function of organelle
IEMs of amino acid metabolism
PKU
Oculocutaneous albinism
branched chain aa metabolism - maple syrup urine disease
IEMs of Carbohydrate metabolism
G6PDD
monosaccharide metabolism - galactosemia, hereditary fructose intolerance
glycogen storage disorders - von gierke, cori, anderson, pompe, Mcardle syndromes; hepatic phosphorylase deficiency
IEMs of steroid metabolism
congenital adrenal hyperplasia
androgen insensitivity syndrome
IEM of Lipid metabolism
familial hypercholesterolemia
Lysosomal storage disorders
mucopolysaccharidoses
sphingolipidoses
Purine/pyrimidine metabolism
Lesch Nyhan syndrome
SCID
IEM of Porphyrin metabolism
Hepatic
Erythropoietic
Untreated PKU (phenylketonuria) leads to
severe intellectual impairments and development of seizures
Defects in branched chain AA metabolism leads to
Maple syrup urine disease
What deficiency causes PKU?
defect in the enzyme Phenylalanine hydroxylase (PAH) which converts Phenylalanine into Tyrosine, results in deficiency of Tyrosine which is required for melanin synthesis
this leads to buildup of phenylalanine which then converts to phenylpyruvic acid that is excreted through urine
Branched chain AA?
Valine
Leucine
Isoleucine
What is the prognosis for pts with Maple syrup disease?
tend to be susceptible to deterioration even with dietary restriction
tend to suffer recurrent illnesses from the catabolic protein breakdown
What defect leads to Maple syrup disease?
branched chain ketoacid decarboxylase deficiency leads to Val, Leu and Ile
Single largest metabolic disorder?
Glucose 6 Phosphate dehydrogenase
G6PDD genetically is ….
X linked recessive
What is G6PD responsible for?
oxidative step of pentose phosphate pathway
What type of cell in G6PDD pts is most affected?
Red blood cells because unlike other cells doesnt have other ways to handle oxidative stress
with G6PDD, there is a defect in ….
the ability to handle oxidative damage because there is reduced ability to produce NADPH, this is a potent reducer to protect against oxidative damage
G6PDD Pt suffers acute oxidative damage from exposure to moth balls, what could occur?
Hemolytic anemia - presents as jaundice (see in newborns with G6PDD), paleness, dark urine, fatigue, shortness of breath/rapid heart rate, splenomegaly
Galactosemia pts are deficient in …
galactose 1-phosphate uridyl transferase
Galactosemic newborn presents with
vomiting, lethargy, failure to thrive and jaundice within the second week of life
Untreated galactosemia leads to
mental retardation
cataracts
liver cirrhosis
Hereditary Fructose intolerance is caused by?
deficiency in fructose-1-phosphate aldolase (Aldolase B)
leads to build up of Fructose in liver
Glycogen stores are largest in
liver and muscles
Congenital Adrenal Hyperplasia caused by
deficiency in 21-hydroxylase -90%
MCC of ambiguous genitalia in FEMALE newborns
salt losing form - presents 2-3 wks of life with circulatory collapse, hyponatremia, hyperkalemia
Androgen insensitivity syndrome
Receptor defective leaving pt unresponsive to testosterone leading to external female characteristics
Familial Hypercholesterolemia
Autosomal dominant single gene disorder
High morbidity and mortality rates via premature coronary artery disease
Familial Hypercholesterolemia is characterized by
problems with the LDL receptor which leads to increased endogenous synthesis of cholesterol
What issues can there be with receptors in FH?
reduced/defective biosynthesis
reduced/defective transport
abnormal binding of LDL by the receptor
abnormal internalization of the receptor
Mucopolysaccharidoses are characterized by
skeletal, vascular or CNS along with coarsening of facial features
What is Mucopolysaccharidoses due to?
progressive accumulation of sulfated polysaccharides
Sanfilippo syndrome
Most common MPS
due to deficiency in any one of four enzymes involved in degradation of heparin sulfate
Most common Sphingolipidoses?
Tay Sachs - high incidence among Ashkenazi jews
Gaucher
Tay Sachs is due to…
deficiency in subunit of beta-hexosaminidase, this results in accumulation of sphingolipid GM2 ganglioside
What is a diagnostic clue for Tay Sachs?
presentation of characteristic cherry red spot in the center of the macula fundus
Gaucher is due to ….
glucosylceramide beta glucosidase
Lesch Nyhan syndrome
Hypoxanthine guanine phophoribosyltransferase (HGPRT)
leads to increased amounts of purines - see 200x higher levels - likely due to increased amounts of PRPP
Symptoms of Lesch Nyhan syndrome
uric acid crystals uncontrolled movements spasticity mental retardation compulsive self mutilation
Adenosine Deaminase Deficiency
inherited immunodeficiency
defect in adenosine deaminase - responsible for 15% of SCID - bubble boy disease
Adenosine deaminase is responsible for …
conversion of AMP to IMP in purine salvage pathway
pts are severely deficient in both T and B cells, leaving them without functional immune system
Porphyrins are …
ringed structures which can chelate metal ions
What are the two main phorphyrin functions?
liver - cytochromes in ETC and detox of substances
Erythrocytes - hemoglobin
Acute Intermittent Porphyria
due to deficiency uroporphyrinogen I synthase which leads to increased excretion of precursors porphobilinogen and S-aminolevulinic acid in urine
Congenital Erythropoietic Porphyria characterized by
extreme photosensitivity
hemolytic anemia - most require multiple blood transfusions and splenectomy
Red/brown discoloration of teeth which fluoresce red under UV light
Congenital Erythropoietic porphyria due to
deficiency in uroporphyrinogen III synthase
see build up of reticulocytes since body in need of RBCs
is there an effective treatment for PKU?
supplementation with PAH prove ineffective
infant and child pts with PKU keep to strict diet low in phenylalanine
after normal neural development can relax dietary restrictions
Oculocutaneous albinism results from . . . .
a deficiency of tyrosinase which converts Tyrosine to Melanin
Phenotype of Oculocutaneous albinism?
no melanin production leads to lack of pigment in hair, skin, iris, and ocular fundus of patients
What results from the lack of pigment seen in OCA?
leads to poor visual acuity, nystagmus (pendular eye movements) and underdevelopment of fovea
What characterizes OCA type 1?
mutation within tyrosinase gene on chromosome 11q
classic albinism - no measurable tyrosinase activity
What characterizes OCA type 2?
due to mutation in P gene (mouse homolog called pink eye) on chromosome 15q
Newborns with Maple syrup urine disease present with?
first week of life with vomiting, alternating tone
if left untreated, then leads to death within a few weeks
treatment involves dietary restriction of intake of V, I and L
What are some sources of oxidative damage?
infection - colds and flu
Drugs - NSAIDS, quinolones, sulfa drugs, tylenol, drugs metabolized through liver, naphtalene (moth balls) and artifical food coloring
Foods - fava beans and other legumes, sulfites, menthol-containing foods
Acute oxidative damage in pt with G6PDD can lead to …
hemolytic anemia which presents with paleness, jaundice, dark urine, fatique, shortness of breath/rapid heart rate, splenomegaly
G6PDD is genetically …
very diverse - more than 100 different mutations identified
symptoms of Hereditary fructose intolerance
presentation age varies depends on when foods with fructose are introduced into diet
minimal to severe - failure to thrive, vomiting, jaundice, seizures
Von Gierke disease
glucose 6 phosphatase
Cori disease
amylo-1,6 glucosidase ( debrancher enzyme)
Anderson disease
glycogen brancher enzyme (synthesis enzyme)
impairs ability to build storage
Hepatic phosphorylase deficiency
multimeric enzyme complex with subunits coded for by autosomal and X linked genes
How does Von Gierke disease present?
hepatomegaly (seen when glycogen stores cannot be broken down)
hypoglycemia in infants presents as sweating, fast heart rate
How does Cori disease present?
hepatomegaly
muscle weakness
How does Anderson disease present?
hypotonia, abnormal liver function within first year of life, progresses to liver failure quickly
How does Hepatic phosphorylase deficiency present?
hepatomegaly
hypoglycemia
failure to thrive
Which glycogen storage disease affects the liver and has no effective treatment?
Anderson disease
Pompe disease
glycogen storage disease that affects muscle
due to deficiency in lysosomal enzyme alpha 1,4 glucosidase which is necessary for glycogen breakdown
McArdle Disease
due to deficiency in muscle phosphorylase
necessary for breakdown of muscle glycogen during exercise
symptoms of Pompe disease
presents in infancy with hypotonia, delay in gross motor milestones, due to muscle weakness,
eventually leads to enlarged heart and death from cardiac failure within first 2 years
no current treatment
symptoms of McArdle
presents in adolescence with muscle cramps during exercise
no effective treatmetn
