Enzyme Deficiencies Flashcards
What is the causative enzyme for PKU (phenylketonuria)?
phenylalanine hydroxylase (PAH)
Which metabolic pathway does Phenylalanine hydroxylase act in?
Amino Acid metabolism
- responsible for converting phenylalanine to tyrosine
What is an inborn error of metabolism?
general term for diseases caused by mutations to genes involved with metabolic pathways
What precursor builds up in PKU?
phenylalanine which then turns to phenylpyruvic acid
How do you treat PKU?
keep on a strict diet low in phenylalanine
What enzyme is deficient in Oculocutaneous Albinism?
tyrosinase - necessary for formation of melanin
Because of the deficiency of tyrosine in PKU pateints, how to they tend look?
blond hair
blue eyes due to deficiency of melanin
Lack of pigment in Oculocutaneous Albinism, leads to what clinical symptoms?
- poor visual acuity
- nystagmus (pendular eye movement)
- underdeveloped fovea
What enzyme is deficient in Maple Syrup Urine Disease?
branched-chain ketoacid decarboxylase
Maple trees have branches.
What is the result of Maple Syrup Urine Disease?
Valine (val), leucine (leu) and isoleucine (ile) are excreted in the urine
What symptoms are present in the first week if newborns have Maple Syrup Urine Disease?
vomiting, alternating tone
What is the treatment for Maple Syrup Urine Disease?
dietary restriction of val, leu and ile
still susceptible to deterioration
What is the most common carbohydrate metabolism disorder?
Glucose-6-phosphate dehydrogenase deficiency
The glucose-6-phosphate dehydrogenase is responsible for what? pathway?
oxidative steps of the pentose phosphate pathway
What inheritance pattern is Glucose-6-phosphate dehydrogenase deficiency?
x-linked recessive
Glucose-6-phosphate dehydrogenase deficiency leads to reduced ability to produce _________?
NADPH (potent reducer used by cells to protect against oxidative damage)
-pentose phosphate pathway
Which cell type is most affected by Glucose-6-phosphate dehydrogenase deficiency? Why?
RBC no nucleus to provide other reducing sources
susceptible to oxidative damage
-results in anemias
What populations are more likely to be affected by Glucose-6-phosphate dehydrogenase deficiency?
African
Asian
Middle Eastern
Mediterranean
What are the three main sources for oxidative assaults that would cause symptoms of Glucose-6-phosphate dehydrogenase deficiency?
INFECTION - cold, flu, sinus infections
DRUGS - NSAIDs, quinolones, sulfa drugs, Tylenol, naphthalene, artificial food coloring
FOOD - fava beans and other legumes, sulfites, menthol-containing foods (toothpaste, mouthwash)
Acute oxidative damage from Glucose-6-phosphate dehydrogenase deficiency can lead to hemolytic anemia which presents with?
paleness jaundice dark urine fatigue shortness of breath/rapid heart rate splenomegaly
What treatments are available for Glucose-6-phosphate dehydrogenase deficiency?
dietary restriction
drug restriction
Galactosemia is due to a deficiency is what enzyme?
galactose-1-phosphate uridyl transferase
involved with breakdown of dietary sugar galactose
What are the symptoms of galactosemia?
newborns present with vomiting, lethargy, failure to thrive, and jaundice within 2 weeks
If untreated, galactosemia can lead to what?
mental retardation
cataracts
liver cirrhosis
What treatments are available for galactosemia?
feed formulas lacking in milk sugars (galactose and lactose)
Hereditary Fructose Intolerance results from deficiency in what enzyme?
fructose-1-phosphate aldolase (involved in breakdown of dietary fructose)
When does Hereditary Fructose Intolerance present and what are the symptoms?
presentation age varies (depends on when foods with fructose are introduced)
Symptoms: minimal to severe
Severe: failure to thrive, vomiting, jaundice and seizures
How would you treat Hereditary Fructose Intolerance?
fructose food restriction
List the 4 glycogen storage diseases affecting the liver.
Von Gierke (breakdown) Cori (breakdown) Anderson (synthesis) Hepatic phosphorylase deficiency (breakdown)
Which enzyme is deficient in Von Gierke?
glucose-6-phosphate
Which enzyme is deficient in Cori disease?
amylo-1,6-glucosidase (debrancher enzyme)
Which enzyme is deficient in Anderson disease?
glycogen brancher enzyme (synthesis of glycogen)
4,6 transferase
What is the inheritance pattern for hepatic phosphorylase deficiency?
autosomal
x-linked
How does Von Gierke present?
hepatomegaly
hypoglycemia
infants-sweating, fast HR
How does Cori disease present?
hepatomegaly
muscle weakness
How does Anderson present?
hypotonia
abnormal liver function w/i first year»_space;>liver failure
How does hepatic phosphorylase deficiency present?
hepatomegaly
hypoglycemia
failure to thrive
How would you treat Von Gierke disease?
frequent feeding to reduce hypoglycemia
avoid fasting
How would you treat Cori disease?
frequent feeding to reduce hypoglycemia
How would you treat hepatic phosphorylase deficiency?
carbohydrate supplementation
List 2 glycogen storage diseases affecting muscle.
Pompe
McArdle
Which enzyme is deficient in Pompe?
a-1,4-glucosidase (necessary for glycogen breakdown)
Which enzyme is deficient for McArdle?
muscle phosphorylase (necessary for breakdown of muscle glycogen during exercise)
How does Pompe present?
in infancy with hypotonia, delay in gross motor milestones
enlarged heart
cardiac failure within 2 years
What treatment is available for Pompe?
no current treatment
-experimenting with enzyme replacement therapies
How does McArdle present?
presents in ADOLESCENSE with muscle cramps during exercise
What treatment is available for McArdle?
no current treatment
List 2 steroid metabolism disorders.
Congenital Adrenal Hyperplasia (CAH)
Androgen Insensitivity Syndrome
What is the most common cause of ambiguous genitalia in female newborns?
Congenital Adrenal Hyperplasia (CAH)
In 90% of cases Congenital Adrenal Hyperplasia (CAH) is due to what enzyme deficiency?
21-Hydroxylase
25% of Congenital Adrenal Hyperplasia (CAH) cases have the salt-losing form. How does it present?
2-3 weeks of life with circulatory collapse
- hypernatremia
- hyperkalemia
What is the inheritance pattern of Congenital Adrenal Hyperplasia (CAH)?
autosomal
- seen in males
- ambiguous genitalia in females
Affected females are virilized due to accumulation of ?
adrenocorticosteroids (many have testosterone-like functions)
How are Congenital Adrenal Hyperplasia (CAH) infants treated?
replacement cortisol for life (with increases given during times of stress)
**fludrocortisone is given as well in salt-losing forms
*plastic surgery for females
Androgen insensitivity syndrome is due to defect in what?
defective testosterone receptor
normal levels of testosterone are produced but due to lack of receptors genes cannot be expressed
When is Androgen insensitivity syndrome identified?
not identified until lack of menses
in cases of “inguinal” hernia which is actually internalized testes
What is the inheritance pattern of Androgen insensitivity syndrome ?
x-linked recessive
46 XY
List a lipid metabolism disorder.
Familial Hypercholesterolemia
What is the inheritance pattern for Familial Hypercholesterolemia?
autosomal dominant single-gene
**associated with high morbidity and mortality
How can Familial Hypercholesterolemia present in childhood?
xanthomata - buildup of cholesterol under the skin
How would you treat Familial Hypercholesterolemia?
dietary restriction statin drugs (HMG-CoA reductase inhibitors)
What is the result of the mutation in Familial Hypercholesterolemia?
problems with the LDL receptor
What are the 4 main classes of problems with the receptor?
- Reduced/defective biosynthesis
- Reduced/defective transport
- Abnormal binding of LDL by the receptor
- Abnormal internalization of the receptor
What are the two lysosomal storage disorders?
Mucopolysaccharidosis
Sphingolipidosis
What is the most common Mucopolysaccharidosis?
Sanfilippo syndrome
How does Sanfilippo Syndrome (Mucopolysaccharidosis) present?
2nd year of life - coarsening of features, skeletal changed, progressive intellectual loss, seizures and death in early adult life
What enzyme is deficient in Mucopolysaccharidosis?
any one of four enzymes involved in degradation of heparin sulfate
What is the treatment for Mucopolysaccharidosis?
no standard treatment
What are the two most common Sphingolipidosis disorders?
Tay-Sachs
Gaucher
How is Sphingolipidosis characterized?
inability to degrade sphingolipids
What is the result of inability to degrade spingolipids?
accumulation of lipids or glycolipids, especially in brain, liver and spleen
If the CNS is involved in Sphingolipidosis, what is the progression of the disease?
mental deterioration
seizures
death in childhood
What enzyme is deficient in Tay Sachs?
B-hexosaminidase
results in accumulation of sphingolipid GM, ganglioside
What population has a high incidence of Tay-Sachs?
Ashkenazi Jews
How does Tay-Sachs present?
at 6 months with poor feeding, lethargy, eventual developmental regression and feeding difficulties
Death usually occurs by 3 due to respiratory infections
(less severe forms are reported)
How is diagnosis of Tay-Sachs aided?
cherry red spot in center of macula fundus
What is the treatment for Tay-Sachs?
no current treatment
What enzyme is deficient in Gaucher?
glucosylceramide B-glucosidase
What population has a high incidence of Gaucher?
Ashkenazi Jews
What is the most common Sphingolipidosis?
Gaucher
Describe Type 1 Gaucher.
adult onset (most common form) pain in limbs, joints and/or trunk tendency to bone fractures hepatomegaly mild anemia some changes in vertebrae CNS is spared
Describe Type 2 Gaucher.
presents between 3-6 months CNS involvement Failure to thrive hepatosplenomegaly developmental regression neurological deterioration **seizures Death by age 2 due to repeated respiratory infections
Describe Type 3 Gaucher.
presents in childhood with intermediate symptoms
How would you treat Gaucher?
Type 1/3
analgesics for pain management
Splenectomy in some cases
Cerezyme (enzyme replacement therapies)
Type 2
no known treatment
List two nucleic acid disorders.
Lesch Nyhan Syndrome
Adenosine Deaminase Deficiency
What enzyme is deficient in Lesch Nyhan?
HGPRT (hypoxanthine guanine phosphoribosyltransferase)
- involved in salvage pathway of purine
What product builds up due to inability to salvage purines?
hypoxanthine
guanine
PRPP
**also causes a feed forward reaction to de novo synthesis
Increased levels of PRPP causes activation of what pathway?
de novo synthesis of purines
-levels can be 200x higher
Breakdown of excess purines will result in accumulation of ?
uric acid
What results from too much uric acid?
crystals form»>gout
“sand in diaper”
What are the symptoms of Lesch Nyhan?
uncontrolled movements
spasticity
mental retardation
compulsive self-mutilation
What is the treatment for Lesch Nyhan?
Allopurinol, but does NOT seem to treat the neurological symptoms
What enzyme is responsible for 15% of all cases of SCID (Severe combined immunodeficiency syndrome)?
adenosine deaminase
How does adenosine deaminase deficiency present?
in infancy with recurrent bacterial and viral infections
**if untreated can lead to death
What is adenosine deaminase responsible for converting?
AMP to IMP in the purine salvage pathway
What immune deficiencies are seen in patients with adenosine deaminase deficiency?
deficient in T and B cells leaving them without a functional immune system
What is the treatment for adenosine deaminase deficiency?
no current treatment
clinical trials under way using gene therapy to treat SCID
What is a porphyrin?
ringed structures that can chelate metal
List two Porphyrin Metabolism Disorders?
Acute Intermittent Porphyria
Congenital Erythropoietic Porphyria
What enzyme is deficient in Acute Intermittent Prophyria?
uroporphyrinogen I synthase
- used in bone marrow heme synthesis
- leads to increased excretion of the precursors porphobilinogen and delta-aminolevulinc acid in urine
What are the symptoms of Acute Intermittent Prophyria?
abdominal pain weakness vomiting mental and emotional disturbances anemia some: hallucinations coma
What can precipitate Acute Intermittent Prophyria?
use of certain drugs
steroids
anticonvulsants
barbituates
What enzyme is deficient in Congenital Erythropoietic Porphyria?
uroporphyrinogen III synthase
- in bone marrow heme synthesis
What are the symptoms of Congenital Erythropoietic Porphyria?
- extreme photosensitivity
- hemolytic anemia - require blood transfusions and splenectomy
- red/brown discoloration of teeth, fluoresce red under UV light
6 month old is brought in for recurrent respiratory infection. The child seems to be moving backwards developmentally and has a history of seizures. Testing reveals a deficiency in _______ , leading to a diagnosis of _____.
glucosylceramide b-glucodidase
Gaucher
