Provider’s Next Steps after an

Abnormal Newborn Screen

James B. Gibson, MD, Ph.D.Clinical Biochemical Geneticist

Dell Children’s Medical Group, Ascension Texas

Clinical Assistant Professor, Dell School of Medicine, UT Austin

Conflict Disclosure Statement

– Site PI for a phase II/III trial, in Niemann-Pick type C1 disease, sponsored by Mallinckrodt Pharmaceuticals

– Advisory Board /Data Reviewer phase II/II trial, N-PC1 sponsored by Mallinckrodt Pharmaceuticals

– Offer intrathecal cyclodextrin under expanded access/ Phase III for Niemann-Pick C1 patients, sponsored by Mallinckrodt Pharmaceuticals

– Site PI for a urea cycle disease registry sponsored by Horizon Pharma

• While these corporations manufacture or market products for treatment of metabolic diseases, none of the content of this CME activity refers to or involves any product of any of these corporations or is biased by those relationships.

• Volunteer metabolic disease consultant to the Texas DSHS Newborn Screening Program

Objectives

• Know what the provider responses should be for abnormal dried blood spot screening results

• Appreciate the difference between abnormal screening results and a confirmed diagnosis

• Understand the initial management of a patient with a presumed/confirmed diagnosis of a screened disorder

• Recognize the limitations of newborn screens

Screening

• A smaller population of individuals, who are at higher risk, are selected from a larger population with a low average risk

– rapidly separate those who probably have the condition from those who probably do not have the condition

– from the smaller population, a definitive diagnosis can be made, in order that a disorder can be predicted and/or prevented

Categories of Testing that are

Considered Screening

1. Selective screening of an infant , child or

adult, based on clinical suspicion

2. Screening of populations at risk from

environmental or medical hazards

3. Detection of asymptomatic heterozygotes

4. Screening of the pregnant woman for

diseases affecting the fetus

5. Non-selective screening of newborns

Principles for Population Screening

• Disorders– Inheritance and ‘Natural’ history must be known

– High but preventable burden to the affected person

– Benefit/cost ratio greater than 1.0

• Test– A method for screening which is acceptable to the

screened population

– Easy to perform with validity

• Process– The infrastructure is available

– Testing is available to the whole population

– Screened individual’s rights are protected

Wilson J, Jungner G. 1968 The principles and practice of screening for disease. WHO

Why Screen Newborns for

Genetic Disorders?

• Conditions are important public health issues– ‘Reasonable’ prevalence

– Cost to society if not screened or treated• Monetary or Resources

• Prevention of irreversible manifestations – Mental retardation, disability or death– A latent or early symptomatic phase exists

– The natural history of the condition is known

• Prompt and early therapy improves outcome

– Effective treatment exists

– Treatment is less expensive than the care of the untreated individual

Newborn Screening for

Genetic Diseases in the US

• Over 4 million infants are screened

each year

– Texas screens over 390,000 infants/yr

– Texas has the largest NBS lab in the world

• 790,000+ screens per year

• The most commonly performed testing

for genetic diseases in the United

States – by far

8

• Critical Congenital Heart Disease

• Hearing loss

• Congenital adrenal hyperplasia• Congenital hypothyroidism

• Sickle cell anemia • Hb S/Beta-thalassemia • Hb S/C disease

• Severe Combined Immunodeficiencies

• Cystic Fibrosis

• Propionic acidemia• Methylmalonic acidemia (mutase) • Methylmalonic acidemia (Cbl A,B) • Isovaleric acidemia • 3-Methylcrotonyl-CoA carboxylase

deficiency • 3-hydroxy-3-methylglutaric aciduria• Holocarboxylase Synthase

deficiency• Beta-ketothiolase deficiency• Glutaric acidemia type I

Recommended Uniform Screening Panel

• Carnitine uptake defect

• Long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency

• Medium chain acyl-CoA dehydrogenase deficiency

• Trifunctional protein deficiency

• Very long-chain acyl-CoA dehydrogenase deficiency

• Argininosuccinic acidemia

• Citrullinemia

• Homocystinuria

• Maple syrup urine disease

• Phenylketonuria

• Tyrosinemia type I

• Biotinidase deficiency

• Classic Galactosemia

• X-linked Adrenoleukodystrophy

• Glycogen storage disease II (Pompe)

• Mucopolysaccharidosis Type 1

• Spinal Muscular Atrophy (exon 7 SMN1 deletion)

RUSP Secondary Target

Disorders• Amino Acid Disorders

– Arginase deficiency

– (Hyperphenylalaninemia)

– (Biopterin biosynthesis defects)

– (Biopterin regeneration defects)

– (Tyrosinemia, type 2)

– (Tyrosinemia, type 3)

– (Citrullinemia, type 2) Citrin defect

– (Hypermethioninemia)

• Organic Acid Disorders

– (Cobalamin C, D)

– Malonic acidemia

– Isobutyryl-CoA dehydrogenase

deficiency (isobutyrylglycinuria)

– 2-methyl-3-hydroxybutyric acidemia

– 2-methylbutyryl-CoA dehydrogenase

deficiency

– (3-Methylglutaconic acidemia)

• Fatty acid Disorders

– Short chain acyl-CoA dehydrogenase

deficiency

– Glutaric Aciduria, type 2

– Medium/short chain 3-hydroxyacyl-coA

dehydrogenase deficiency

– Medium chain 3-ketoacyl-CoA thiolase

– (Carnitine palmitoyl transferase 1A

deficiency)

– Carnitine palmitoyl transferase 2

deficiency

– Carnitine-acylcarnitine translocase

deficiency

– 2,4 dienoyl-CoA reductase deficiency

• Other– Other hemoglobinopathies

– T-cell related lymphocyte deficiencies

– Galactoepimerase deficiency

– Galactokinase deficiency

Reorder

NBS

Result Received

In range

(Normal)

Do definitive

testing

+/- Repeat NBS

Reassure

family &

Document

results

Yes

Identify as

CSHCN Initiate chronic

management

Provide

Parental

Education

Disorder

Identified?

No

Yes

Discuss false

positive, reassure

family & document

No

Yes

2 to 4 week Visit

Call for

NBS

results

Both NBS

results

available?

Re-contact

Consultant

Consult ACT

Sheets & DSHS

Contact Consultant

No

The Screen is Abnormal)

• What is the abnormality?

– Endocrine: Refer appropriately• Some are emergencies – evaluate patient now

– Hematologic: Refer appropriately

– SCID: Refer appropriately

– Metabolic: Evaluate the patient now

• Evaluate, confirm diagnosis and treat patient based on a presumption of disease

• What about multiple abnormalities on a single screen?

What to do

• Algorithmic approach

• Even a short delay may harm an infant

• Follow the ACT sheet and algorithm

– Find the patient

– Evaluate the patient

– Obtain recommended labs

– Speak with a metabolic geneticist

DSHS

ACT Sheets

What Analyte

PCP’s Actions

Diagnostic

Evaluations

Clinical

Snapshot

More

Information

Now What?

• Infant looks well– Information to parents

– Confirmatory lab studies

• Infant is unwell– History of poor feeding or constipation

– Emesis

– Any seizure-like activity

– Lethargy or not awakening to eat

– Worsening jaundice

Admission or Confirmatory Testing

• Some NBS values will be very high– Metabolic Emergencies requiring immediate

admission• Intravenous fluids

• May require specialized medications

• Many values will require repeat screening, or– Acylcarnitine profile

– Urine organic acids

– Plasma amino acids

– Ammonia

– Urine Orotic acid

– Carnitine profile

• What if the infant is already admitted?– Change of therapies

But the 2nd MS/MS Screen

was NormalK• Term infant

• MS/MS abnormal for C14:1(tetradecenoyl-carnitine)

– Possible VLCAD

• Get plasma acylcarnitine profile

– Plasma carnitine profile

– Urine organic acids – no longer recommended

• NOT CLEARED if a subsequent NBS is normal or if

labs are normal

• Need functional testing or DNA

– State doing reflexive ACADVL sequencing ( 7/2017)

• Confer with consultant

Schymik I, Liebig M, Mueller M, et al. 2006. Pitfalls of neonatal screening for very-long-chain

acyl-CoA dehydrogenase deficiency using tandem mass spectrometry. J Pediatr 149:128-30

The Pre-Diagnosis Patient

• What was abnormal on the NBS?

– Get the information from DSHS if possible

– Some offices still call it a PKU screen

• Determine if the disorder has a long

pre-symptomatic period

• Evaluate, confirm diagnosis and treat

patient based on a presumption of

disease

AW

• FT infant to 17 yo G1 with good PNC

• Home at 48h

– Passed NB hearing screen

– Breast and Bottle feeding

• Ill on DOL #4 (evening) with poor feeding, no fever, less wet diapers

• At presentation thought to be septic with glucose 27

– CSF normal

– UA ‘normal’

AW has K.

• DSHS notifies Birth Hospital of

abnormal NBS on AM of DOL #5

• NBS #1

– C8 acylcarnitine very elevated

– C8/C2 ratio elevated

Flow Diagram

format

Algorithms

Actionsin shaded boxes

Results in Unshaded box

Plasma AC (C8) – high

Urine OA – Normal/high dicarboxylic acids

Urine AG – high hexanoylglycine

MCAD Deficiency

http://www.acmg.net/resources/policies/ACT/condition-analyte-links.htm

Fatty Acid Oxidation Defect

• Eating, lethargy, pain or abnormal urine?

• Labs

– Glucose, LFTs, CK, pancreatic function

– NH3, CBC and ? Carnitine

• Cardiac status?

• Treatment: Carbohydrates first

– Generally carnitine supplementation

– Prevent rhabdomyolysis / complications

Glucose in IEMs

• MINIMUM

– D10 at maintenance (40 cal/kg/day)

• Better

– D12.5 at 1.25 x maintenance (60 cal/kg/d)

– Use insulin as needed

• Better yet (other than FAOD)

– D12.5 TPN (0.5 g AAs) w/ Lipids (80+ cal/kg)

• Best: >120 Kcal/kg/day ‘sick day’ recipe

Medications

• L-Carnitine

– 100 mg/kg/day – or more

– IV more effective as < 1/3 of enteral dose

is absorbed

• Alkali

– Bicarbonate

• Get serum HCO3 to ≥20 mEq/L

• Ongoing acid production requires ongoing

alkali

Common Concerns

• When does diet need to be changed?

• Heterozygotes do not have any of the

metabolic diseases

• Do the patient need to be referred to

Genetics?

• Getting DNA testing done

• Testing older siblings

• Anticipating next sibling

Diet Therapy in IEMs

• Important part of the management

toolkit

• Goals of more normal growth and

development

• Life-long therapy

– unless alternative correction of the

phenotype or genotype occurs

• Medical risks if not done properly

Amino acid restriction

• Classic examples

– Branch chain amino acid catabolic disorders

• Maple Syrup (Urine) Disease• Branch chain ketoacid (BCKA) dehydrogenase

deficiency

• 50% of the BCKA are derived from leucine and the rest from isoleucine and valine

• Diet restricted in protein leads to malnutrition

• Use of medical food product to promote anabolism– Supply all the other essential amino acids and enough energy

• Paradoxical need to balance isoleucine and valine– May actually need supplementation

• Methylmalonic acidemia

Premature Infant with K

• 36 week infant with very abnormal first

screen for C3 acylcarnitine

• DSHS locates infant being admitted to a

PICU for lethargy, poor feeding and

‘funny breathing’

– Labs: pH 7.11

• Ketones (+++)

• NH3 653

• Transaminases < 2 x UL reference range

hypoglycemia metabolic acidosis

hyperammonemiano abnormality

Critically ill infant: coma, intractable seizures,

respiratory distress, cardiovascular collapse, etc.

Basic Lab tests: glucose, electrolytes

arterial blood gas, ammonia, urinalysis

Major Abnormality

ketosis

Encephalopathy, Acidosis & Ketosis– Increased anion gap

– NH3 may be moderately to greatly increased

– Lactate normal to increased

– Glucose may be normal to increased

– Calcium is normal to decreased

– Leukopenia or thrombocytopenia

• Organic acidemias or Ketolytic defects– Some with odors

• Isovaleric acidemia

• 3-methylcrotonyl carboxylase

• Urine: Organic Acids, (Acyclglycines)

• Blood: Acylcarnitine & Carnitine Profiles

• Treatment: STOP PROTEIN – and give calories, carnitine

Methylmalonic Acidemia• Methylmalonyl coenzyme A mutase

• Accumulation of propionate– From valine, isoleucine, methionine, threonine

• or propiogenic bowel flora

• side chain of cholesterol

− β-oxidation of odd-numbered fatty acids

• Usual long term treatment plan– Cobalamin

– Protein limitation

– Hydration for good urinary excretion

– Carnitine

– Monitoring and anticipation

NBS # 1 Abnormal

• Term infant

• Abnormal first screen for galactosemia

• Stop lactose/galactose intake– Stop breastfeeding pending lab results

– Change to soy (or elemental) formula

• Evaluate for signs of galactose intoxication

• Parental education

• GALT assay

• (State does a limited DNA panel)

• Refer to geneticist-metabolic specialist

Kand if it is the 2nd screen?

• Probably not going to be classic galactosemia

• Pause lactose/galactose-containing feeds

• Still need to do GALT enzyme assay

• May wish to evaluate galactose metabolites

– Urinary galactitol

– RBC galactose-1-phosphate

• Discuss with consultant

Don’t Panic

• 724 gram 26 week premature female

• First screen normal for MS/MS

• Second screen abnormal for low carnitine (C0) and elevated tyrosine with normal succinylacetone

• The low carnitine may be due to prematurity and no supplementation

• The elevated tyrosine maybe hepatic immaturity or a TPN effect

Carnitine Accumulation• Low carnitine

– Majority of a term infant’s carnitine is

obtained transplacentally in the third

trimester

• Can give very low values in premature infant

• Pattern often is of slow increase

– Respond to relatively low dose carnitine

supplementation

• Maintain their blood carnitine levels after

supplementation is stopped

Chace DH et al 2003. Neonatal Blood Carnitine Concentrations: Normative data by

electrospray tandem mass spectrometry. Pediatr Res 53:823-829

Is it a disease?

• 37 week 2.9 kg male infant ‘JH’

• NBS #1 abnormal for C5-OH on MS/MS

• 7 disease possibilities (3MCC, BKT, 2M3HBD, HMG-CoAL, 3MGA, MCD, BIOT)

– And the infant might just be ‘tattling’ on mom

• Looks well in resident’s clinic on DOL #7; BF only

• Get recommended labs– Plasma acylcarnitine profile

– Urine organic acids

• Results– C5OH elevated on acylcarnitine profile

– Urine OAs → 3-methylcrotonylglycine in excess

• Urine acylglycine profile – some reference labs

• Maternal labs: UOA, pACP, UAG

JH has K.

• No Disease

• His carboxylases are normal

• His C5OH acylcarnitine disappears by 6

months

– Mom changed to bottle feeding

• Mother might have mild 3MCC

– No insurance to pay for testing

Ex-28 Week Infant Going Home

• Are there still NBS issues?

– Elevated tyrosine concentrations• Hepatic immaturity even without significant

transaminasemia

• Resolving TPN cholestasis

– What to do with medications• Continuation of supplemental carnitine

– Confirmatory labs are not back• Can the PCP get to those results?

• Does the PCP know to look for those results?

• Are additional lab studies needed in 1-4 weeks?

Illness after Confirmed

Diagnosis

• The disorder determines the work-up

– Biotinidase should not present with any

acute symptoms

– PKU has no acute symptoms altering

management

• Acute management is to prevent

disease-specific decompensation and

organ damage

Emergency Protocol?

• If available, gives guidance for

treatment

– Written by treating metabolic physician

– Generic on-line resource

• Disease and age specific

• Covers the majority of situations

• Requires clinical judgment

• If no protocol availableK.

Primary Evaluation Labs

• Organic Acidemias– Ketones, glucose, CMP, (ABG), NH3, CBC

• Fatty Acid Oxidation Defects– Glucose, NH3, CMP, ketones, carnitine, CK

• Urea cycle defects– NH3, CMP, CBC

• MSUD– Ketones, CMP, ABG, CBC

• Tyrosinemia– LFTs, PT/PTT, NH3, glucose, bilirubin

• Galactosemia*– Glucose, CMP, PT/PTT, CBC, bilirubin

Organic acidemia

• Eating or not?

– Emesis, lethargy, seizures, abnormal VS?

• Why sick? Decompensation risk?

• Labs:

– Ketones and Acid-Base status

– Glucose, pancreatic function, CBC, lactate

• Treat with non-protein calories

• Carnitine and Alkali

Some Core Screened IEM May

Have Long Latency Periods*

• Biotinidase deficiency • Glucose-6-phosphate dehydrogenase

deficiency (G6PD) (depends on mutation)

• Glutaric acidemia type I• Homocystinuria• Methylmalonic acidemia in Cbl A, B

– Not Methylmalonic acidemia (mutase deficiency) (MUT)

• Phenylketonuria• Tyrosinemia type I• Medium chain acyl-CoA dehydrogenase (MCAD) deficiency

• X-linked Adrenoleukodystrophy

* More than 4 weeks after birth to symptoms

JC

• Term infant to 18 year old

• Abnormal screen for C5DC (glutaryl

carnitine)

• Diagnosis confirmed

– Acylcarnitine profile and urine organic

acids

• Presents with winter URI at 9 months

– Emergency protocol letter shown in ED

JC is at risk of?

• Irreversible CNS damage

– Especially under 5 years of age

• Establish access and give IV carnitine

• Calories without lysine

– Sick day formula if tolerated

– IV glucose and lipids since special formula

not available in house

• Home when?

Glutaric Aciduria

• Any illness is a risk

– No prior CNS decompensation

• Labs: generally normal

• Treat with non-protein calories

• IV carnitine

• Serial Neurologic Exams

• 90% effective treatment plan

Newborn Screening is not...

• Enough for a diagnosis

– False positives will occur

• Abnormal analyte but no disease

• Fail-safe

– False negatives will occur

• No abnormality for a screened disorder

• As complex to interpret as you thought

Won’t Newborn Screening

Solve Sick Neonates?

• NBS may not give an answer until after the infant is ill– Critical window of time

– Turn-around is not fast enough

• NBS will detect– most of the severe or moderate cases of screened

disorders

• NBS will not detect– non-screened disorders

– all mild cases of a disorder (later presentations)

What Newborn Screening

Does Not Detect in 2019• All acute hyperammonemia disorders

– Proximal urea cycle defects

• Lactic acidemias– May pick up other metabolites

• Respiratory chain (Mitochondrial) Disease

• Many Cholestasis / Jaundice disorders

• Most Storage diseases: lysosomal or glycogen

• Congenital Disorders of Glycosylation

• Many transporter defects

• Peroxisomal diseases – yet (X-ALD)

Summary

• Newborn screening has come a long way in just over 50 years– It remains a major public health effort

• What is screened, and how it is done, has changed in the last 12 years– Continual evolution

• Requires careful evaluation before and after diagnosis

• Core management principles include prevent of catabolism and obtaining the diagnostic labs

• The consultants are available 24/7 to help.

• Resources available on line and in print

Resources for the Provider

• DSHS website– www.dshs.state.tx.us/newborn/default.shtm

– ACT and FACT sheets

– CME for an education module: http://txhealthsteps.com/

– NBS Brochures for office use

• AAP– www.medicalhomeinfo.org/screening/newborn.html

– Multiple links to genetic resources

• New England Consortium Emergency Protocols– www.metabolicprotocols.org

March of Dimes Resources

• A Parents Guide to Newborn Screening

– 5 minutes long DVD (English and Spanish)

– Also as streaming video from the

Pregnancy/Newborn section

– www.marchofdimes.com

– www.nacersano.org

• Or from DSHS http://www.dshs.state.tx.us/newborn/expandparent.shtm

Questions?

Selected References• ACMG ACT sheets and confirmatory algorithms:

https://www.ncbi.nlm.nih.gov/books/NBK55827/

• Basic information for families and physicians: STAR-G

http://www.newbornscreening.info/index.html

• American College of Medical Genetics Newborn Screening Expert Group. 2006. Newborn

Screening: Toward a Uniform Screening Panel and System: Executive Summary and Main

Report. Genet Med 9 (5):1S-252S.

• Arnold GA et al. 2009 A Delphi clinical practice protocol for the management of very long

chain acyl-CoA dehydrogenase deficiency. Mol Gen Metab 96:85-90

• Miller MJ et al 2015. Recurrent ACADVL molecular findings in individuals with a positive

newborn screen for very long chain acyl-coA dehydrogenase (VLCAD) deficiency in the

United States Mol Gen Metab 116:139-145

• https://www.dshs.state.tx.us/newborn/expandprofessional.shtm

• Lindner M et al. 2011. Efficacy and outcome of expanded newborn screening for metabolic

diseases - Report of 10 years from South-West Germany Orphanet Journal of Rare

Diseases, 6:44-53

• Longo N, et al. 2006 Disorders of Carnitine transport and the Carnitine cycle Am J Med

Genet Pt C 142C:77-85

• Wilson JMG, Junger G. 1968 Principles and practice of screening for disease, WHO

Geneva

• Textbook: Inherited Metabolic Diseases 2nd Ed. Hoffmann GF, Zschocke J, Nyhan WL, ed.

2017 Springer Verlag GmbH Berlin ISBN 978-3-66-49408-0

Appendix for

Provider’s Next Steps after an

Abnormal Newborn Screen

• Disease Burden

• Outcomes: NBS vs Clinical Detection

• Resources for Provider and Family

• Clinical Memory Aids

• Supplementary materials

Screening is a Preventative

Public Health Measure

• Newborn screening was the first

accepted entry of genetics into public

health

• First disorder: Phenylketonuria (PKU)

– 1962; 32 states, 400,000 infants; 39 cases

– first population-based screening for a

genetic disorder

• And nowK..

True Positives Requiring Intervention

2014-2016*

• MS/MS

– 128 Fatty acid oxidation

• 73 MCAD

– 79 Amino acid disorders

• 43 phenylalanine-related

• 12 urea cycle defects

• 24 other

– 40 Organic acidemias

• 25 C3 related

• 10 Glutaric Aciduria type 1

• 247 cases

• Enzyme assay

– 17 profound

Biotinidase

Defects

• 74 partial

Biotinidase Defects

– 16 classic

Galactosemia

• 33 cases• Minimal numbers as, under some conditions, some other screen (+) infants may

have symptoms over their lifetime

• DSHS Metabolic Consultants Meeting 10 Feb 2017

Minimal estimates based on

2007 data• 220 / 404,510 = A detectable inborn error in

1/1850 births (significant in 1/3580)

– ~1/15000 have CAH, ~1/3000 CH

– ~1/2500 have a hemoglobinopathy

• Thus ~ 1/ 750 infants have one of these

(DBS) screened disorders

– Hearing loss is found in 1/400 infants

• 1/260 Texas infants have a screened disorder

• (1/760 infants die from a recognized birth defect)

Outcomes

• New England/Pennsylvania

– Prospective inception cohort

– Combined state and private programs

– Comparison groups

• Identified by expanded screening, n = 50

• Identified clinically, n = 33

• ‘False positive’ initial screens, n = 94

• Unaffected, n = 81

Waisbren et al. Nov 19, 2003 JAMA 290:2564-2572

Outcomes: Medical Status 2

NB Screened Clinical DX P value

Symptoms at Dx 22% 88% <0.001

Medical

complications

22% 64% <.001

Neurologic

Complications

14% 58% <.001

Special Services 20% 73% <.001

Gastrostomy

tube

4% 24% .01

Waisbren et al. Nov 19, 2003 JAMA 290:2564-2572

Developmental Outcomes

NB Screened

N = 50

Clinical Dx

N = 33

Bayley

Motor 101 (70-123) 72 (49-108)

Score <71 4% 42%

Mental 106 (66-145) 92 (49-114)

Score <71 2% 42%

Vineland Composite 107 (71-153)

[0% <71]

85 (48-114)

[36% < 71]

Waisbren et al. Nov 19, 2003 JAMA 290:2564-2572

Resources for Providers and

Parents

• Screening Technology and Research in Genetics: STAR-G

– HRSA funded multi-state consortium with consumer input

• http://www.newbornscreening.info/index.html

• Description of newborn screening process

• ‘Parent fact’ sheets for each disorder

• Overview of Genetics/Genes/Inheritance

• Glossary of screening terms, amino acid, etc.

10-11 pages

Covers the same points

for each disorder

Printable form

Written for parents

Cause

Problems

Treatment

Inheritance

Testing

More Information

NBS BrochuresTexas DSHS

Texas Department of State Health Services

Newborn Screening Program

MC 1918

P.O. Box 149347

Austin, Texas 78714-9347

1-800-252-8023 ext. 3957www.dshs.state.tx.us/newborn

State Materials

in SpanishFact Sheets and NBS Brochures

Starting a discussion with parents:

Help for Brief Discussions:

1. Screening is required

2. Infant is generally healthy at

birth

3. Serious consequences

4. Tested at 1-2 and 7-14 D

5. Blood sample from the heel

6. Results go to MD and birth

hospital

7. Retesting may be needed

8. Storage of cards for 2 years

9. Voluntary longer storage

10. For more information: call your

PCP or Department of State

Health Services

Newborn Screening Directory1-800-252-8023

• Case Management Extensions• General Information 3957• Ombudsman 3386• Hearing 7726• Congenital Adrenal Hyperplasia 2819 / 3237• Congenital Hypothyroidism 3898 / 3237• Biotinidase Deficiency 6311 / 3237• Cystic Fibrosis 6382 / 3666• Hemoglobinopathies 6832 / 3666• MS/MS, GALT and SCID

– Includes all Fatty Acid Disorders, Organic AcidDisorders, Amino Acid Disorders, (X-ALD)

• 7724, 3874, 3871, 2853, 3734, 2133– Assigned by case not disorder– Most SCID 2133

• Team Lead Ginger Scott, RN 6827

Updated 07/20/2019

Sx

Lo

w p

H

Ke

tos

is

La

cta

te

NH

3

Glu

co

se

Po

ss

ible

DX

Neuro 0 ++ 0 0 N MSUD

Neuro + ++ 0 + N Organic acidemia

Neuro ++ + ++ 0 N,D Lactic acidemia

Neuro 0 0 0 ++ N Urea Cycle Disorder

Neuro 0 0 0 0 N Non-Ketotic Hyperglycinemia, Respiratory. Chain Dx, Peroxisomal Dx, Sulfite Oxidase, etc

Liver + + + 0 D Glycogen Storage Dx +

Liver Heart

+ 0 0 0 D Fatty Acid Oxidation Defect

Modified from J-M Saudubray, MMBID 2001

Add the clinical features to the labs)

Odors As Clues for Metabolic Disorders

ODOR COMPOUND DISORDER

Maple syrup

Sweet

Isoleucine metabolites:

keto-and hydroxy-acids

Maple Syrup Urine

Disease

Musty Phenylacetic acid Phenylketonuria (PKU)

Sweaty feet

Cheesy

Isovaleric acid Isovaleric Acidemia

Glutaric Aciduria, type II

Cabbage a-ketomethylbutyrate Tyrosinemia, type I

Hypermethionemia

Tomcat’s Urine Methylcrotonyl acid Methylcrotonic acidemia

Multiple Carboxylase

Deficiency

Fishy Trimethylamine

Carnitine

Dimethylglycine

Trimethylaminuria

Dimethylglycinuria

Oasthouse a-Hydroxybutyric acid Methionine

malabsorption

Flag

charts of

unscreened

patients

Order

NBS

Provide

Parental

Education

Obtain

Written

Waiver

Parents

Decline

NBS?

No

Yes

Await

Results

No Yes

Concern:

NBS not

conducted

3 to 5 day old

Visit

Parents

Decline

NBS?

No

Yes

Order

NBS

In range

(Normal)

Reorder

NBS

Result Received

Do definitive

testing

+/- Repeat NBS

Reassure

family &

Document

results

Yes

Identify as

CSHCN Initiate chronic

management

Provide

Parental

Education

Disorder

Identified?

No

Yes

Discuss false

positive, reassure

family & document

No

Yes

2 to 4 week Visit

Call for

NBS

results

Both NBS

results

available?

Re-contact

Consultant

Consult ACT

Sheets & DSHS

Contact Consultant

No

Screening or Diagnostic Test

• Could argue that CF testing with a DNA

panel is a diagnostic rather than

screening algorithm

• Whole exome sequencing

– Issues of variants of unclear significance

– Targeted next-gen sequencing panels

• Whole genome sequencing

– Epigenetic screening?

Challenges of the Premature

• Transfusions

– RBCs interfere with GALT assay

• False negative

• Enzyme is intracellular

– Biotin is a serum enzyme so less

interference

– WBCs - (currently) Theoretical risk when

lysosomal enzymes are assayed

Prevention- worth 0.454 Kg of ‘cure’

• 33 week ‘feeder/grower’ twins in the NICU

• Both have abnormal MS/MS for elevated citrulline

• Prematurity limits therapeutic options– Decompensation could occur in the first week of life

– Cannot dialyze to treat any hyperammonemia (due to weight)

• Get the labs and get infants where care can be optimized if needed– Immediate NH3 measurement

– LFTs

– Plasma amino acids

– Urine orotic acid

• Urgent telephone consultation• Outcome

– Tolerated > 2g/kg/day total amino acids

– Ammonia scavenger agents used

Diet Therapy in IEMs

• An accepted part of the management toolkit

• Intended to supply product of a blocked reaction or to help bypass the consequences of loss of an irreversible enzymatic reaction– Enhance anabolism

– Depress catabolism

– Correct imbalance in metabolic relationship

– Depress absorption of nutrients that are toxic when ingested in excess

– Provide alternative metabolic pathway to decrease toxic precursors in blocked metabolic cycle

• Goals of more normal growth and development

• Life-long therapy – unless alternative correction of the phenotype or genotype

occurs

• Medical risks if not done properly

Populations needing TPN

• Increased challenges if an IEM is

identified

• Specialized TPN requires custom

synthesis

– Several day lag to get this

– Current US supplier not actively doing this

– Costly

– Not great shelf-life

MCAD Signs and Symptoms

Iafolla et al., J Pediatr 124:409-415, 1994

Data is from clinically identified cases. Has not applied to cases once identified by NBS

Symptom/Sign Percent affected

Lethargy 84

Emesis 66

Encephalopathy 49

Respiratory arrest 48

Hepatomegaly 44

Seizures 43

Apnea 37

Cardiac arrest 36

Sudden Death 18