NBME - 6/12 - Disorders of AA and Nucleotide Metabolism Flashcards
What is PKU? What chromosome mutation is involved with it?
Phenylketonuria is an AR disorder involving severe decrease in phenylalanine hydroxylase, leading to a buildup of phenylalanine.
The gene is located on Chromosome 12
PKU progression in children clinically
These kids are hyperactive, have purposeless movements, rhythmic rocking and athetosis.
We smell a musty odor secondary to phenylacetic acid, and these guys can develop seizures
Infants of mothers who have too much Phenylalanine during pregnancy
They are mentally retarded and may have microcephaly and/or congenital heart defects
How does PKU present initially?
Normal infant at first, but mental retardation begins with an estimated loss of 50 IQ points in the first 12 months. If left untreated, it increases in severity.
Other early symptoms include vomiting, which can be misdiagnosed as pyloric stenosis
What is tyrosinemia?
This is an error of metabolism due to lack of fumarylacetoacetate hydrolase (FAH).
This is the most frequent autosomal recessive enzyme issue.
The body cannot break down tyrosine, leading to liver and kidney issues as well as mental retardation
Tyrosinemia in infants
Begins as failure to thrive and hepatomegaly, progressing to liver and kidney dysfunction
What liver manifestations of Tyrosinemia do we see?
Causes cirrhosis, conjugated hyperbilirubin, increased AFP, coagulation abnormalities and decreased blood sugar.
This leads to jaundice, ascites, hemorrhage, and puts you at an increased risk for hepatocellular carcinoma (50% of the these children by age 2)
Kidney manifestations of Tyrosinemia
Fanconi Syndrome - Renal Tubular Acidosis, hypophosphatemia, aminoaciduria
Besides the liver and kidney, Tyrosinemia can creep up in other locations. What are they?
- Cardio
- Neuro
- Derm
How do we treat tyrosinemia?
First line therapy is just a low protein diet, but eventually, transplant of the liver is needed.
What is A1AT deficiency?
Autosomal recessive disorder marked by abnormally low or no serum A1AT in the blood. It is the most common cause of liver disease in kids and emphysema in adults.
What does A1AT normally do?
This is a protease inhibitor made by the liver that inhibits neutrophil elastase released by WBCs
A1AT deficiency presents how?
Leads to fatigue and SOB due to the lung damage, as well as jaundice that can lead to hepatitis and cirrhosis if it affects the liver.
How does A1AT damage the liver?
In response to tissue injury or inflammation, A1AT in this disease still responds, it just can’t get out of the ER, polymerizing with it. Accumulation damages the hepatocytes.
How can we see A1AT deficiency in the lab?
Immunostaining and EM for the neonatal and light microscopy after 3 months
What is albinism?
Congenital disorder characterized by complete or partial absence of pigment secondary to absence or defect in tyrosinase, a copper enzyme involved with melanin production from Tyrosine.
It affects about 1:16,000 in U.S.
Hallmark of albinism besides the skin
Eye changes. All of them can be seen (Nystagmus, strabismus, astigmatism, photophobia, foveal hypoplasia, optic nerve hypoplasia, abnormal decussation of optic nerves at the optic chiasm, ambylopia, really anything you can think of)
What causes Gaucher Disease?
This is an autosomal recessive disorder caused by deficiency of glucocerebrosidase, the lysosomal enzyme that degrades sphingolipids with terminal residues in a B linkage
Who gets Gaucher Disease and what chromosome do we associate with it?
Ashkenazi Jews
Chromosome 1 (1q21-q31)
Discuss the three types of Gaucher Disease
1 - Young adults, mild to severe effects with no CNS involvement and some glucocerebrosidase activity
2 - Infants. Die in infancy and it affects the CNS. Very little glucocerebrosidase activity
- Children and young adults - Late onset CNS that becomes very severe with little glucocerebrosidase activity.
Clinical presentation of Gaucher disease
Splenomegaly is usually the first sign. Storage of glucocerebroside in the spleen and bone marrow leads to Anemia, Leukopenia, and Thrombocytopenia
Most common way to diagnose Gaucher
Bone marrow biopsy
How do we treat Gaucher?
Enzyme replacement therapy with macrophage-targeted glucocerebrosidase
Signs of Acute hepatitis in Wilsons (remember, that Copper one that gets in your eye)
Ballooning degeneration, acidophilic bodies, cholestasis, lots of lymphocytes
Late you will see your mallory bodies like with alcoholism
In Cystic Fibrosis, the problem is with CFTR. What does this do?
It regulates transport of electrolytes across epithelial cell membranes
Most common manifestations of CF:
Pulmonary
Recurrent Pneumonias, particularly involving Psuedomonas aeruginosa.
“____ in a neonate is CF until proven otherwise”
Meconium Ileus
How do we diagnose CF?
Abnormal sweat chloride plus characteristic clinical findings of GI or pulmonary disease
Persistently elevated
concentrations of electrolytes in
the sweat (e.g., sweat chloride >60 mmol per liter; normal usually
Genetic testing for CFTR issues?
Failure to find two abnormal genes does not rule out CF
