Genetics: Newborn Screening

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Diseases suitable for newborn screening

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Relatively high incidence w/ effective treatment, inexpensive test w/ high sensitivity and specificity, natural hx of disease is understood

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screening issues

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determined state-by-state; false pos/neg more common before 24 hours old; positive tests need confirmation

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PKU

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decreased activity of the liver enzyme phenylalanine hydroxylase causes high serum phenylalanine.
*small percentage of cases are due to deficiency of BH4 cofactor instead

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untreated PKU

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progressive dev delay, ID, hyperactivity, eczema and seizures, musty odor. Behavioral/learning issues in later life, even with good tx.

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PKU inheritance

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AR; 1:20K; 500+ mutations and most patients are compound heterozygotes.

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PKU screening

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tandem mass spec for serum phenylalanine

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PKU tx

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Substrate Reduction: Dietary restriction of phenylalanine for life can allow normal growth/dev. Successful tx begins prior to 3 wks of age. Compliance can be a problem for teens.

BH4 deficiency is managed with biopterin replacement therapy, no low Phe diet needed.

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Maternal PKU

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offspring have higher incidence of birth defects, miscarriage; best outcomes occur when blood Phe levels are 120-360 throughout pregnancy
**maternal blood levels are >600 micromoles/L during pregnancy, there is a very high risk for intrauterine growth retardation (IUGR), microcephaly and intellectual disability and a moderate risk for specific dysmorphic features (hypertelorism, epicanthal folds, upturned nose, long philtrum, high arched palate) and congenital heart defects.

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Congenital Hypothyroidism

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due to inadequate TH production; usually sporadic

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screening hypothyroidism

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FIA for T4 and TSH; confirm w/ serum T4 and TSH

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Sickle Cell dz

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due to abnormal synthesis of hemoglobin beta chains

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incidence and inheritance

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AR inheritance; 1:375 A-A

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screening for Sickle Cell

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isoelectric focusing

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Galactosemia

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due to deficiency of galactose-1-phosphate uridyltransferase (GALT) enzyme

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Galactosemia presentation

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presents in first 2 weeks of life w/ jaundice (conjugated hyperbilirubinemia), lethargy, cataracs, hepatomegaly, can proceed to death rapidly

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Galactosemia inheritance

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AR

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screening for galactosemia

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Fluorometric assay for total galactose (normal <10); confirm w/ quantitative RBC GALT activity and galactose-1-phosphate testing

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Galactosemia tx

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Substrate reduction: Any infant suspected of galactosemia should be put on galactose-free diet of soy formula. Lifelong restriction of galactose/lactose is essential.

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Galactosemia complications

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short stature, ovarian failure, learning disabiliities in pts treated from birth, despite dietary compliance

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CAH

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family of disorders due to defect in corticosteroid synthesis

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21-OH deficiency

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Most common CAH; ambiguous genitalia in girls, salt-wasting dz

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CAH inheritance

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AR

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screening for CAH

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FIA for 17-hydroxyprogesterone and confirm w/ serum 17-hydroxyprogesterone

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MS/MS

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tandem mass spec; quick, small sample size, able to detect multiple things w/ high sensitivity and spec.

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disorders detected by MS/MS

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amino acidopathies (where AA build up)
organic acidemias (problem breaking AA down)
fatty acid oxidation disorders (trouble w/ fasting)

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acyl carnitine

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used as a marker for organic acidemias

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CF testing paradigm

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Screen for IRT immunoreactive trypsinogen >> If abnormal, follow-up DNA testing >> If mutation found, do sweat testing

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Borderline result of newborn screen

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repeat specimen is requested

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Diagnostic result

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metabolic specialist will follow up, contact PCP

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screening for critical congenital heart defect

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Use pulse oximetry to test oxygen saturation and pulse rate

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Newborn hearing screening

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Automated auditory brainstem response AABR; otoacustic emission OAE

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SCID screening

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Absence of humoral/cellular immunity; screen w/ PCR for T-cell receptor excision circles (TREC). Early stem cell transplant prior to onset of infections offers best outcome. Can prolong life but not cure

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Urea Cycle Disorders

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involve specific enzymes involved in ammonia detoxification; wide range of clinical severity

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Sx of urea cycle disorders

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abnormal brain function, cerebral edema, mental status changes, vomiting, unstable gait, LOC

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substrate reduction for Urea cycle disorders

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Limit dietary protein, give lots of calories to prevent endogenous protein breakdown, hemodialysis

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Pharmacologic diversion for urea cycle disorders

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Increase nitrogen excretion by giving arginine, citrulline, Sodium benzoate that combine w/ glutamine/glycine to form water-sol compounds that can be excreted in urine.

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Gaucher Disease

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lysosomal storage disorder due to defic of glucocerebrosidase, causing glycolipids to build up in macrophages and CNS

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Gaucher sx

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progressive enlargement of spleen and liver, anemia, thrombocytopenia, neurologic dz

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treating gaucher dz

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recombinant glucocerebrosidase enzyme improves Hgb, platelet, liver/spleen size

Pharmacologic diversion: Give N-butyldeoxynojirimycin to inhibit formation of glucosphingolipids

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GSD Type 1

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G6P defic; hypoglycemia 2-3 hours after meal due to inability to release free glucose from the liver.

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G6P defic sx

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hepatomegaly, poor growth, lactic acidosis, hyperlipidemia, easy bruising, hypoglycemic seizures

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treating G6P defic

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frequent feedings with glucose; raw cornstarch can be used as a time-release source of glucose that can maintain glucose levels for 4-6hrs

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Biotinidase

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cleaves biotin from proteins so it can be reused in body

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Biotinidase deficiency

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seizures, ataxia, hypotonia, dev delay, rash, alopecia

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treating Biotinidase deficiency

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5-20mg oral biotin

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ubiquitin-proteosome pathway

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eliminates misfolded or unstable proteins

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chaperones

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aid in normal folding of proteins

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activation/chaperone therapy

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enhancement of dysfunctional enzyme can be possible w/ vitamin cofactor or chaperone; can improve or normalize metabolic activity.
**may only benefit patients with a missense mutation

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treating homocystinuria

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large doses of pyridoxine can lower plasma homocystine in pts w/ beta synthase defic.

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stop codon read-through therapy

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chemical compounds can allow ribosome to bypass premature stop codon in mRNA to make functional protein

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mucopolysaccharidoses

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lysosomal storage disorder due to deficiency of enzymes that break down GAGs

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enzyme replacement for MPS

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reduces liver/spleen size, improves PFT, energy, joint range

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liver transplant

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treatment for hepatic enzyme deficiency

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BMT for LSD

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improves somatic, not skeletal symptoms. Due to normal macrophages that circulate through body and remove harmful compounds; may take a year for neural effects to be seen

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MCAD

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deficiency of enzyme involved in FA oxidation leads to buildup to medium-chain FA, which are further metabolized or esterified w/ carnitine.

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MCAD presentation

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metabolic decompensation before the age of 5 is typical; hypoglycemia, vomiting and lethargy triggered by prolonged fasting or illness.

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MCAD inheritance

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AR, variable age of onset

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MCAD screening

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Tandem MS for acycarnitine

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Management of MCAD

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avoid hypoglycemic state, carry emergency letter

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Direct in vivo gene transfer

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Direct (in vivo) - Vector is directly injected into the bloodstream.

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Direct in situ gene transfer

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Direct (in situ) - Vector is placed directly on or into the affected tissue. Examples are the placement of a vector into the trachea of a patient with CF or injection of a tumor with a vector containing a cytotoxic gene.