Transcript Metabolic 2ndary Conditions Washington State Newborn Screening

Newborn Screening in
Washington
Cristine M Trahms, MS, RD, FADA
Center on Human Development and
Disability
Division of Genetics and Development
Department of Pediatrics
Objectives
• Discuss the Newborn Screening
Program
– Rationale
– Plans
• Discuss nutrition intervention in
disorders identified by newborn
screening
– Treatment paradigm
– Medical nutrition therapy
What is newborn screening?
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A system that includes
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Universal screening of all infants
Follow up to assure appropriate
clinical response
Diagnosis of affected infants
Appropriate treatment and clinical
care
Evaluation of system effectiveness
Criteria to Screen for a
Disease
• Symptoms usually
absent in newborns
• Disease results in
developmental
impairment, serious
illness, or death
• Sensitive, specific
laboratory tests
available on a mass
population basis
• Disease occurs
frequently enough to
warrant screening
• Successful
treatment
procedures
available
• Benefits of
screening justify the
cost
NBS at the national level
The Advisory Committee on Heritable Disorders
and Genetic Diseases in Newborns and Children
(ACHDGDNC)
shall advise and guide the Secretary of HHS
regarding the most appropriate application of
universal newborn screening tests, technologies,
policies, guidelines and programs for effectively
reducing morbidity and mortality in newborns and
children having or at risk for heritable disorders.
The Scoring System
Core
Conditions
Core
Conditions:
Metabolic
2ndary
Conditions
Washington State
Newborn Screening
WA State system
Informed
Consent
Supporting understanding for
families
How is screening done?
Newborn Screening in
Washington
• Newborns currently
screened in Washington– phenylketonuria
(1963)
– congenital
hypothyroidism (1977)
– congenital adrenal
hyperplasia (1984)
– hemoglobinopathies
(1991)
– galactosemia
– medium-chain acylCoA dehydrogenase
deficiency (MCAD)
– biotinidase deficiency
– maple syrup urine
disease (MSUD)
– homocystinuria
– early hearing loss
By The Numbers
Each year the Newborn Screening
Program…
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Screens76,000 infants
Receives 150,000 specimens
Performs 1.5 million screening tests
Follows up 3,000 abnormal findings
Saves 80-100 babies from lifelong
disability or death
What’s on the Horizon?
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Cystic fibrosis?
Organic acid disorders?
Other amino acid disorders?
Other fatty acid oxidation disorders?
Resources
• Washington State Office of Newborn
Screening
– http://www.doh.wa.gov/EHSPHL/PHL/
Newborn/default.htm
• National Newborn Screening and
Genetics Resource Center
– http://genes-r-us.uthscsa.edu/
• Genetics Home Reference
– http://www.ghr.nlm.nih.gov/
Phenylketonuria
Newborn Screening
Guidelines
• Phenylalanine (serum)
– Normal: <180 mmol/L
– Borderline: 189-239 mmol/L
– Presumptive positive: >240 mmol/L
Phenylketonuria:
Establish Diagnosis
• The enzymatic
defect
– Phenylalanine
hydroxylase
– Dihydropteridine
reductase
– Biopterin
synthetase
Phenylketonuria:
Establish Diagnosis
• Presumptive positive Newborn
Screening results
– >3 mg/dl >24 hours of age
• Differential diagnosis
–  serum phenylalanine level, normal
tyrosine level
– R/O DHPR and Biopterin defects
Monitoring Adequacy of
Treatment
• Measure plasma amino acids
– maintain in treatment range
• Monitor nutrient intake
– restrict phenylalanine, supplement tyrosine,
adequate protein, energy, nutrients to support
growth and ensure good health
• Monitor growth increments
– typical growth expected
• Monitor cognitive development
– typical achievement expected
Outcome Expectations
• With Newborn Screening and blood
phenylalanine levels consistently in the
treatment range
– Normal IQ and physical growth are
expected
• With delayed diagnosis or consistently
elevated blood levels
– IQ is diminished and physical growth is
compromised
Galactosemia
Newborn Screening
Guidelines
• Fluorometric assay of GALT activity
(units/gHb)
• Normal: >3.0 units/gHb
• Borderline: 2.1-3.0 units/gHb
• Presumptive positive: <2.0 units/gHb
• Elevated galactose-1phosphate levels:
– Poor suck
– Failure to thrive
– Jaundice
– Vomiting
– Diarrhea
• If untreated then,
– E. coli sepsis
– Shock, Death
• If neonatal survival but
untreated:
– Cataracts
– Mental retardation
– Cerebellar tract
signs
Galactosemia
Galactosemia
• Washington State NBS
– Semi-quantitative assay of GALT
– 2 screens below cutoff (2.5) referred
for diagnostic confirmation (if 0.9-1.0
referred after 1st screen)
– Quantitative measurement of GALT
requires venous blood draw, not blood
spot
Galactosemia
• 1/30 000 - 1/50 000 classic galactosemia
• Galactose-1-phosphate uridyltransferase
deficiency
• Also called GALT deficiency
• Catalyzes the production of glucose-1phosphate & UDP-galactose from galactose1-phosphate and UDP-glucose
• Determine genotype
• Monitor galactose-1-phosphate levels
Galactosemia
• Types of Galactosemia
– Classic galactosemia (denoted G/G)
• Two severe mutations
• GALT activity 0 or 1 (~0%)
– Usually symptomatic at the time NBS results
received
– Duarte/Classic compound heterozygote (denoted
D/G)
• One classic allele with Duarte allele (N314D)
• ~25% enzyme activity, rarely symptomatic
– Duarte homozygote (denoted D/D)
• 50% enzyme activity, not symptomatic
Galactosemia - Treatment
G/G Galactosemia
• Lactose/galactose restriction
– Lactose = galactose + glucose
– Use soy-based infant formula (Isomil, Prosobee)
– All dairy products, tomatoes, legumes, some other
vegetables
– Supplemental calcium
• Even well treated can have some issues:
– ~80% of girls have ovarian failure (more likely if Q188R +/+)
– Growth delay
– Some learning disabilities (delayed vocab and articulation)
Galactosemia - Treatment
D/G Galactosemia
• Controversy among BGC centers
• Treat for 6 months, treat for 1 year, don’t treat
at all……
• Recent outcome studies suggest no difference
• WA: if feeding difficulties (vomiting, diarrhea),
switch to soy, otherwise, no need to treat
D/D Galactosemia
• No treatment necessary (unlikely to see these)
Biotinidase Deficiency
Newborn Screening
Guidelines
• Biotinidase enzyme (% activity)
– Normal: >30%
– Borderline: 10-30%
– Presumptive positive: <10%
Biotinidase Deficiency
• Washington State NBS
– Fluorescence assay (qualitative)
– Two positive screens referred for follow-up
• Diagnostic confirmation done at CHRMC on
new sample, measures biotinidase enzyme
directly
• <10% activity = profound deficiency
• 10-30% activity = partial deficiency
Biotinidase Deficiency
• Inability to recycle
biotin
• Symptoms- skin
rash, alopecia,
lactic acidosis,
seizures, can lead
to acute metabolic
acidosis, death
• Also ataxia,
hypotonia,
developmental
delay, hearing loss
Biotinidase Deficiency
• 1/40 000 - 1/60 000
• Disorder of biotin recycling
• Cannot recycle endogenous biotin and
cannot release dietary protein-bound
biotin
• Free biotin (not protein bound)
necessary co-factor for many enzyme
reactions
Biotinidase Deficiency
• Profound - untreated
– May have: seizures, hypotonia, rash, alopecia,
ataxia, developmental delay, hearing loss, recurrent
infections
– Variable expression and symptoms generally
develop between 1 week and 10 years, mean age
3.5 years
• Partial - untreated
– May have: hypotonia, rash, hair loss
– Particularly in times of stress
– Some are only symptomatic during times of stress
Biotinidase Deficiency
Treatment guidelines (UW BGC)
Profound deficiency = 10mg free biotin daily
Partial deficiency = 5-10 mg free biotin daily for 6
months, then discontinue. If symptomatic
during times of stress can add biotin back
All symptomatic children improve after biotin
treatment (seizures, hair loss, rash). Hearing
and vision loss may be resistant to therapy.
• Food sources of biotin:
– Eggs, cauliflower, peanuts, almonds, tomato,
carrots, fresh cheese (cottage, ricotta, fresh
mozzarella)
Medium Chain Acyl-CoA Dehydrogenase
Deficiency
(MCAD)
Medium-chain acyl-CoA
dehydrogenase deficiency
• Disorder of ßoxidation of
fatty acids with
fasting
• Vomiting,
hypotonia,
coma c fasting
• Elevated
C6-C12
dicarboxylic
acids in urine
Newborn Screening
Guidelines
• Measure octanoyl carnitine: C8
• Measure acyl carnitine: C2
Normal: C8 = <0.5
Borderline: C8= 0.5-0.79
Presumptive positive MCAD: C8= >0.8;
C8 to C2 ratio = >0.02
MCAD
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1/15 000
Disorder of medium chain fatty acid breakdown
C6-C10 considered medium chain fats
Fats are major source of energy once hepatic
glycogen stores (source of glucose) are
depleted
• Fats are converted to ketones can be used for
energy
• Acylcarnitines are used to transport fats
into the mitochondria
MCAD
• Washington State measuring C8
• Elevated C8 not specific for MCAD, but MCAD is
most common
• Elevations of C6, C8 and C10 acylcarnitines,
with C8 elevations predominant is indicative
of MCAD
• Diagnostic confirmation done with quantitative
acylcarnitine profile.
• Urine for organic acids requested and blood
sample for mutation analysis
– Organic acids show excess medium chain
dicarboxylic acids (C6>C8>C10), absence of
ketones
MCAD genotypes
• Homozygous:
– 985A>G/985A>G = 70% of patients
– 985A>G/985A>G = increased C8/C10
ratios
• Heterozygous:
– 985A>G/ +/- 985A>G = includes 90% of
patients
MCAD
• Symptoms all related to hypoglycemia
– Lethargy, Pallor, Sweating
– Decreased consciousness, Coma,
– Death
• Treatment- general
– Avoidance of fasting
– +/- L-carnitine
– +/- cornstarch
– +/- low fat diet (<30% calories from fat)
Maple Syrup Urine Disease
(MSUD)
Newborn Screening
Guidelines
• Leucine (serum)
– Normal: <300 mmol/L
– Borderline: 300-349 mmol/L
– Presumptive positive: >350 mmol/L
Maple syrup urine disease
(Branched-chain ketoaciduria)
• Deficiency of
enzyme that
control pathway of
metabolism or
leucine,
isoleucine, valine
• Death from
profound
ketoacidosis
Maple Syrup Urine Disease
(MSUD)
• 1/200 000 (higher in Mennonite,
Hutterite pop’ns)
• Disorder of branched chain amino acid
breakdown
• Leucine, isoleucine, valine
• deficiency branched-chain alpha-ketoacid dehydrogenase (BCKDH)
Maple Syrup Urine Disease
(MSUD)
• If unrecognized, elevation of leucine leads to
encephalopathy:
– Lethargy
– Vomiting
– Ataxia
– Hallucinations
– Coma and death.
– When symptomatic, urine, skin and hair take
on a characteristic sweet smell reminiscent
of maple syrup.
Maple Syrup Urine Disease
(MSUD)
Washington State NBS
• Measures leucine and isoleucine (single peak)
• Diagnostic testing:
– Full quantitative amino acid profile:
• Marked elevations of leucine, isoleucine,
valine and presence of alloisoleucine
• Mild or moderate elevations without
alloisoleucine can indicate non-specific
liver disease, hyperalimentation or other
organic acidemias
MSUD
Treatment
• Precisely measured low protein diet
– Medical food (low in branched chain amino
acids)
Supplemental valine and isoleucine for some
• chronically elevated leucine can lead to
deficiency of val and ile
– Aggressive management of routine illness
– Risk of decompensation always exists
– Hemodialysis sometimes necessary to rapidly
lower blood leucine
Homocystinuria
1/200 000 - 1/335 000
Disorder of homocysteine breakdown
Newborn Screening
Guidelines
• Methionine (serum)
– Normal: <80 mmol/L
– Borderline: 80-89 mmol/L
– Presumptive positive >90 mmol/L
Homocystinuria
Washington State NBS
• Measure methionine concentration
• Two positive screens referred for follow-up
• Diagnostic confirmation:
– Quantitative plasma amino acids
– Total homocysteine
• Elevated methionine can also indicate nonspecific liver disease, excess protein intake,
benign hypermethioninemia
• Other causes of homocystinuria– Cobalamin disorders
– MTHFR deficiency
Homocystinuria
• Deficiency in metabolism
of homocystinecystathionine βsynthetase
• Homocystine and
methionine accumulate
• Slow development of
symptoms
• downward dislocation of
lenses
• thinning and lengthening
of long bones
• seizures
• vascular thrombosis
• mental illness
Homocystinuria
(Cystathionine Beta Synthase Deficiency)
• Elevations of hcys leads to:
– developmental delay
– ectopia lentis and/or severe
myopia
– skeletal abnormalities (tall
stature and very long limbs,
scoliosis, kyphosis)
– increased risk of blood clots
– Psychiatric and (some
Treatment
• Low methionine
diet
• Betaine
• Folate
• B12
• Some are B6
responsive
Summary
• Newborn Screening is a critical part of
identification of fragile infants
• Immediate diagnosis and treatment of
inborn errors saves lives
• Treatment modalities have become
more effective over time
• Outlook (and outcomes) are brighter for
many infants and children
Eventual Goal