INborn errors of metabolism - Weisfield/Adams Flashcards
What sequelae might be seen in the child of a mother with improperly managed PKU?
Microcephaly
Cardiac defects
Mental retardation
Describe the normal history of PKU.
Normal pregnancy and delivery, no consanguinity
“Normal” development for 6-9 months, fed well
9-12 months: signs of slowing in developmental progress, head growth slows
About 1 year: clearly developmentally delayed, light hair, eczema, unfamiliar odor, seizures
Urine ferric chloride spot test done, diagnosis of PKU made
Severe intellectual disability; eventual institutionalization
What residual level of phe in the blood defines “severe classical PKU?”
To what level should be the degree of treatment?
Greater than 1200 µM
Less than 300-400 µM
Must treat for life, particularly during pregnancy.
Newborn term breast-fed female Poor feeding, progressive lethargy Coma and seizures at 6 days age Mild hypoglycemia Mild metabolic acidosis Ketonuria
Defect in what enzyme?
MSUD.
Branched chain ketoacid dehydrogenase (BCKD) deficiency
[Leucine is very neurotoxic. 4 different genes can cause mutations. There are 4 monomers in the enzymatic complex. Any 1 of the 4 can have a mutation that causes upstream of these upstream of these branched chain amino acids.]
Pennsylvania amish and menonnite populations have much higher rates of this disease.
What is the acute Tx of MSUD?
Eliminate dietary protein intake
Supplement valine and isoleucine
Provide adequate non-protein energy source and amino acids that are not BCAA
1-month-old breast-fed female Direct hyperbilirubinemia Prolonged PTT, elevated transaminases Hepatomegaly Edema (low albumin) No hypoglycemia; no acidosis
Give a broad ddx, including things other than inborn errors of metabolism.
Infectious hepatitis – viral/bacterial
Biliary atresia
Pancreatic cyst or malformation
Cystic fibrosis
Inborn error of metabolism?
fructosemia, galactosemia, α1-antitrypsin deficiency, tyrosinemia type 1, hemochromatosis
Diagnosis: Tyrosinemia type I
(fumarylacetoacetate hydrolase deficiency)
Diagnosis: Tyrosinemia type I
(fumarylacetoacetate hydrolase deficiency)
Is common in which populations (founder populations).
Quebecois, Finland
14-day-old healthy male infant
Breast-fed
Newborn screen reveals elevated methionine
Methionine = 210 µM (cutoff = 100 µM)
Urine Homoystine = 2mmol/mg creatinine (should be undetectable).
What is the natural history?
CBS - Cystathionine b-synthase deficiency
Can look a lot like Marfan syndrome (both have connective tissue problems) Osteoporosis Scoliosis High risk of recurrent thromboembolism Ectopia lentis Myopia
**Cases often missed on newborn screens obtained during the first week of life. Poor feeding can decrease Met levels leading to false negative screens.
50% of cases are B6 responsive.
4-day old male
Presented with lethargy, poor feeding, emesis
Now with altered mental status, minimally responsive
Hypertonic, hyperreflexic, possible seizures
Venous blood gas: pH 7.55, pCO2 24
Plasma ammonia 470 umol/L (normal
OTC (Orthinine Transcarbamylase) Deficiency: the most common urea cycle disorder
Will see:
Low citrulline
Elevated glutamine (>1200 uM)
Respiratory alkalosis with no apparent pulmonary disease?
Think of urea cycle disorders and hyperammonemia. Particularly if they have mental status changes.
What are the ammonia scavenging agents that smell really bad?
Sodium phenylacetate
Sodium benzoate
What is the dangerous aspect of the natural history of OTC deficiency?
Hyperammonemia can cause permanent sequelae (unlike an episode of DKA, for instance). So it is important to manage the protein intake tightly to prevent these episodes happening even 1x.
[20-30g of natural protein/day is the upper limit for adults with these disorders, which is very restrictive.]
What is the inheritance of OTC deficiency?
X-linked. Male hemizygotes with no enzyme activity may not survive the newborn period
15% of female heterozygotes will have clinical symptoms ranging from mild to severe (dependent on pattern of X-inactivation)
What is the presentation of classical homocystinuria?
What is the missing enzyme?
What is the inheritance pattern?
What is the treatment?
Cystathionine β-synthase deficiency
Autosomal recessive inheritance
Incidence = 1/200,000 to 1/400,000 births
Incomplete ascertainment
Cases often missed on newborn screens obtained during the first week of life
50% of CBS mutations are pyridoxine (vitamin B6) responsive
Restrict dietary protein
