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Abnormality of structure, function or metabolism
birth defect
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Inborn Erros of Metabolism
- ~1 in 500 newborns (not rare)
- Many present at neonatal interval
- Signs and symptoms are nonspecific
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Normal parents, one affected offsprin, typcially one affected generation. (Parental recurrence risk is 1 in 4 in each subsequent pregnancy)
Autosomal Recessive
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Consanguinity and incest issues found in what type of inheritance?
AR
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Affected males in multiple generations are maternally related by unaffected carrier females.
X-linked inheritance patterns
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Recurrence risk for X-linked inheritance.
1/4
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Half the sons of a carrier mother will be affected and half of her daughters are carriers.
Lyonization issues
X-linked inheritance pattern
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Proband-based testing: Diagnostic, confirmatory test... it has
High specificity
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Population screening: Complex health initiatives, newborn screening...it has
High sensitivity
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Ecogenetic Concerns:
Includes locus and allelic heterogeneity. Genotype classification is needed.
Genetic Heterogeneity
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Ecogenetic Concerns: Metabolic tolerance will change with physiologic maturation and the catabolic stress of fasting.
Clinical heterogeneity
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Goal in multidisciplinary management issues:
- Ecogenetic control
- Overall goal: support the family
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Urine Odor:
Musty or mousy
Phenylketonuria
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Urine Odor:
Maple Syrup
Maple Syrup Urine Disease
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Urine Odor:
Sweaty feet
- Isovaleric acidemia
- Glutaric Aciduria II
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Urine Odor:
Rotting fish
Trimethylaminuria
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Urine Odor:
Tomcat urine
3-methylcrotonylglycinuria
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Urine Odor:
Rancid or "fishy"
Tyrosinemia
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Urine Odor:
Cabbage
Methionine malabsorption
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PKU is negative for low glucose, metabolic acidosis, ketosis, and elevated ammonia
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Elevated galactose, galactose-1 phosphate and galactitol.
Urine reducing substances (galactose).
GALT Deficiency
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Name 2 things found in GALT deficiency.
- Hemolytic anemia
- Unconjugated hyperbilirubinemia
- Hepatomegaly (liver failure)
- Cataracts
- Cerebral edema
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Which disease has static encephalopathy (not reversed by galactose restriction)
GALT Deficiency
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What is the rate of female infertility in hypergonadotropic hypogonadism (GALT Deficiency)?
- >75% female infertility
- Elevated LH and FSH
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In Galactosemia managment you use formulas derived from
soybeans (or hydrolysates)
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What things can give you false-negative test for GALT.
- Blood transfusion
- Before they start breast-feeding
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What can give you false-positive test rate for GALT Deficiency?
Improper processing of newborn screening cards and mailing them during hot, humid summer months.
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What 3 things do the MS Newborn Screen identigy?
GALT, GALE, GALK deficiency
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GALK
Galactokinase Deficiency
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UDP Galactose-4-epimerase deficiency
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Galactose-1-phosphate uridyltransferase deficiency
Classic galactosemia
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Two different recessive alleles that work at the same gene.
Compound heterozygote
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Blood Levels of Phenylalanine
Hyperphenylalaninemia:
Atypical PKU:
PAH:
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Phenylalanine Neurotoxicity: Acute or Chronic?
Irreversible CNS damage in infancy and childhood
Acute phenylalanine neurotoxicity
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Phenylalanine Neurotoxicity: Acute or Chronic?
Functional impairment and progressive neuropsychiatric abnormalities later in life.
Chronic Phenylalanine Neurotoxicity
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Incidence of Tetrahydrobiopterin deficiency is about __% that of hyperphenylalaninemia due to ____ mutations.
1%, PAH
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Major symptom of PKU
Profound mental retardation (IQ <35) in about 50%
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Phenylketonuria: Folling's Ferric Chloride "Diaper" Test for?
Urinary Phenylpyruvate
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Inhibition of bacterial growth by B-2-thienylalanine is overcome by phenylalanine that diffuses out of the blood spot.
Guthrie Screening Test (PKU)
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Confirmation of PKU Diagnostic Testing in Newborns shows _____ levels of plasma phenylalanine and _____ levels of tyrosine.
Increase phenylalanine, normal tyrosine
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Phenylalanine is an ______
essential amino acid
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Restriction of dietary phenylalanine is recommended for all infants with plasma levels greater than?
6 mg/dL
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How many people with PKU have not been identified?
1/70
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BMI=
(Weight in Kg)(Stature in meters)2
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Children with optimally managed PKU appear normal but may have significant problems.
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Phenylketonuria therapy: Tetrahydrobiopteran (BH4) cofactor therapy
Kuvan
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Pregnancy in a woman with hyperphenylalaninemia is a high-risk event. The highest fetal risk is in women with intrapartum plasma phenylalanin levels greater than
18 mg/dL
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Poor maternal compliance in PKU leads to children with
Microcephaly
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Clinical features include:
Eye: Ectopia, lentis, myopia
Skeleton: Osteoporosis, biconcave vertebrae
CNS: Mental retardation
Homocystinuria
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What is a critical factor in the health of individuals with IEM?
Protein catabolism
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MCADD (Medium Chain Acyl CoA Dehydrogenase Deficiency)
- AR
- Sudden onset, very rapid progression
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1st event: ALTE, SIDS
MCADD
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Hypoketotic hypoglycemia (Low-moderate urinary ketones, Hypoglycemia)
Hypoketotic Hypoglycemia
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How do you manage MCADD?
- Avoid prolonged fasting (including Night feedings)
- IV glucose and early hospitalization are necesary if there is emesis or if adequate oral intake to maintain normal glucose levels are needed.
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Rate of MCAD Deficieny in US.
Carrier Frequency?
- 1/16,000
- Carrier Frequency = 1/60
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Propionic or Methylmalonic Acidemia normal metabolism is dependent on ?
Biotin & B12
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