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Pediatric Genetics and
Genomics
January 28, 2020
Newborn Screening part III
1 Genetics | 1/28/20
Leah Burke, MD
University of Vermont
Mark Korson, MD
VMP Genetics, LLC
Get the Most Out of Your Experience
 Use the Q&A Button to submit questions
during today’s session
 Recording and slides will be sent by email
 For further information, contact
WeitzmanLearning@chc1.com
Genetics | 1/28/202
3
The Weitzman Instituteworks to improve primary care and its delivery to medically
underserved and special populationsthrough research, innovation, and the education and
training of health professionals.
3Genetics | 1/28/203
 Founding year: 1972
 Hubs/Locations: 15/210
 Patients per year: 100,000
The Weitzman Institute is a program of
Genetics | 1/28/204
New England Regional Genetics
Network
The NERGN project is supported by the Health Resources and
Services Administration (HRSA) of the U.S. Department of Health
and Human Services (HHS) under grant number UH7MC30778;
New England Regional Genetics Network; total award amount:
1.5 million; 100% from governmental sources. This information
or content and conclusions are those of the author and should
not be construed as the official position or policy of, nor should
any endorsements be inferred by HRSA, HHS or the U.S.
Government.
Genetics | 1/28/205
CME Credits Available
 CME credits available to live webinar
participants only
 A brief survey will be sent after this session to
those who registered and attended this webinar
 CME certificate will be sent to participants who
complete the survey
American Academy
Family Physicians
(AAFP)
Genetics | 1/28/206
Disclosures
No Disclosures
Genetics | 1/28/207
Today’s Presenters
Dr. Leah W. Burke, MD
Dr. Mark Korson, MD
Genetics | 1/28/208
LEARNING OBJECTIVES
1. Review the important aspects about newborn screening
discussed in Part I and II (2019)
2. Discuss key clinical aspects of the latest diseases added to the
newborn screen
3. Clarify the roles of primary care providers and specialists in the
newborn screening process associated with these disorders
4. Identify what diseases on the screen require urgent
referrals and why
5. Determine the role of the PCP in supporting families whose
children are identified through newborn screening
ESSENTIAL POINTS FROM
NEWBORN SCREENING PARTS I & II
• NB screening is a screen, not a diagnostic test.
• Remember:
• The (ACMG) ACT sheets and algorithms
• Other educational resources
• Concerns? Questions?  call a geneticist!
REMEMBER!
• Discuss the screening results and potential clinical
implications.
• Assess the need for a repeat specimen.
• Discern disease from diet impact from artifact.
• Figure out if and how management should change.
HOW A GENETICIST CAN HELP YOU…
https://www.acmg.net
RESOURCES FOR INFORMATION: NEWBORN SCREENING
https://www.babysfirsttest.org/
Genereviews.org
https://newenglandconsortium.org/
INFORMATION ABOUT MEDICAL CONDITIONS
THE LATEST ADDITIONS TO THE NEWBORN SCREEN
• Severe Combined ImmunoDeficiency (SCID)
• MucoPolySaccharidosis (MPS) type I
• Pompe disease
• X-linked AdrenoLeukoDystrophy (X-ALD)
• Spinal Muscular Atrophy (SMA)
SEVERE COMBINED
IMMUNODEFICIENCY (SCID)
David Phillip Vetter (September 21, 1971 – February 22, 1984)
“THE BOY IN A BUBBLE”
• Frequency - ? 1:50,000 - 1:100,000.
• A set of disorders that results in a failure to form T cells.
• Infants have problems with both T cells and B cells  onset of
severe infections in the first few months of life.
• The newborn screen detects other conditions that have low
numbers of T cells.
SEVERE COMBINED IMMUNODEFICIENCY
• A screen for numbers of ‘T cell Receptor Excision
Circles’ (‘TREC’).
• TRECs small circles of DNA created in T-cells during their passage
through the thymus as they rearrange their TCR genes.
• Presence indicates maturation of T cells.
• Found in every healthy newborn’s blood.
• SCID babies have few/no T cells, so have few/no TRECs
in their blood.
NEWBORN SCREEN FOR SCID
David A. Randolph et al. Neoreviews 2013;14:e448-e455
©2013 by American Academy of Pediatrics
MOLECULAR BASIS FOR SCID SCREENING
• Low blood TREC levels can also be caused by prematurity, other
less severe immune disorders, or other syndromes.
• A baby can have a positive screening result but have a normal
immune system, so…
• If the screen is positive  further testing must be done to
confirm or rule out SCID.
• If parent(s) is/are are known carriers of SCID, diagnostic
testing and newborn screen should be done.
THE SCID NEWBORN SCREEN – TAKE NOTE!
THE SCID NBS REPORTING ALGORITHM
Newborn Screening
Specimen
TREC  252
TREC  252
normal
TREC  252
TREC undetectable
Repeat
test
TREC  252
Repeat
test
positive
• Flow cytometry:
–Numbers of CD4 + CD8 T cells, CD56 NK cells, & C19 B cells.
–CD45RA + CD45RO analysis to determine the numbers of
naïve T cells.
EVALUATION OF A POSITIVE SCID SCREEN
• Most common form of inheritance in SCID is X-linked:
– IL2RG gene mutations  X-linked SCID.
– IL2RG encodes for a protein critical for normal immune function.
• Also autosomal recessive form:
– ADA gene mutations  adenosine deaminase deficiency.
– ADA encodes for the enzyme adenosine deaminase.
– Found throughout the body, most active in lymphocytes.
• Multiple other rare forms.
THE GENETICS OF SCIDS
• Bone Marrow (BMT) / Hematopoietic Stem Cell Transplantation (HSCT):
– If BMT <3.5 months old - 95% chance of long-term survival & healthy life.
– If BMT > 3.5 months old - 60-70% chance of long-term survival.
• Enzyme Replacement Therapy (ERT):
– For ADA deficiency - pegademase bovine (PEG-ADA) allows lymphocytes to
recover.
– Long-term treatment for some children but not a cure; BMT may still be
needed.
• Gene therapy:
– Clinical trials - positive outcomes for children.
– More evidence for ADA deficiency type.
– Still investigational.
SCID TREATMENT
• Newborn screening showed <200 TRECs.
• Subsequent flow cytometry showed the following:
Test Result Flag reference range
Absolute CD3
% CD3
1218 cells/cmm
48%
2500 – 5500 cells/cmm
53-84%
Absolute CD4
% CD4
812 cells/cmm
32%
1600-4000 cells/cmm
35-64%
Absolute CD8
% CD8
381 cells/cmm
15%
560-1700 cells/cmm
12-28%
Absolute CD19
% CD19
1041 cells/cmm
41%
300-2000 cells/cmm
6-32%
% CD45 100% 99-100%
CD4 CD8 Ratio 2.13
CASE
• Seen in Genetics Clinic.
• Examination – hypotonia.
• Testing - positive for 22q deletion.
CASE
Non-SCID Reasons for a Positive Screen
When TRECs are >0 and < 252
• Prematurity
• 22q deletion syndrome
• Down syndrome
• Other milder forms of immunodeficiency
• Transient immunodeficiency
• Normal
** VERY IMPORTANT TO KNOW THIS WHEN
CALLING THE FAMILY WITH A POSITIVE RESULT !!
• Any patient that identifies positive for SCID in the newborn
screen needs medical attention.
• However, this is a disease that requires urgent referral given
the time-sensitive nature of making a diagnosis and starting
therapy.
True or False
QUESTION
• Acute concerns:
• Parental counseling.
• Infectious risk.
• Better outcome with earlier intervention.
• Action items:
• Support the Newborn Screening process.
• Facilitate an urgent referral for assessment and
treatment.
ATTENTION PRIMARY PEDIATRICIANS!
• Acute concerns:
• Parental counseling.
• Infectious risk.
• Better outcome with earlier intervention.
• Action items:
• Support the Newborn Screening process.
• Facilitate an urgent referral for assessment and
treatment.
ATTENTION PRIMARY PEDIATRICIANS!
MUCOPOLYSACCHARIDOSIS (MPS)
TYPE I
MUCOPOLYSACCHARIDOSIS (MPS) TYPE I
• A classic type of lysosomal storage disease.
• Frequency:
• LSDs ~1:25,000.
• Severe MPS I ~1:100,000.
• Autosomal recessive mode of inheritance.
Courtesy of
SIMD-NAMA
Severe Attenuated
Hurler
MPS I H
Hurler-Scheie
MPS I HS
Scheie
MPS I S
57% 24% 10%
Severe Attenuated
Under 1 year:
• Respiratory:
• Ear infections  hearing loss
• Loud breathing
• Snoring
• Hernias – inguinal, umbilical
• Coarse facies – after 1 year
Severe Attenuated
• Severe cognitive impairment
• Hepatosplenomegaly
• Obstructive airway disease
• Valvular heart disease
• Corneal clouding
• Joint stiffness/contractures
• Hearing loss
• Death <10 years of age
Adapted from SIMD-NAMA
Severe Attenuated
• Mild/no cognitive impairment
• +/- Hepatomegaly
• Obstructive airway disease
• Valvular heart disease
• Corneal clouding
• Joint stiffness/contractures
• Hearing loss
• Death – 2nd/3rd decade or later
Adapted from SIMD-NAMA
MUCOPOLYSACCHARIDOSIS (MPS) TYPE I
• Accumulation of glycosaminoglycans
(GAGs) (heparan sulfate & dermatan
sulfate), detected in urine.
• ⍺-L-iduronidase (IDUA) deficiency.
Courtesy of
SIMD-NAMA
MPS TYPE I SCREEN: LOW/ABSENT ⍺-L-iduronidase (IDUA)
IDUA Activity
 7% of Median
7-15% of Median
Moderate
probability MPS1
> 15% of Median
Low
probability MPS1
No further work-up
Molecular analysis
MPS TYPE I SCREEN: LOW/ABSENT IDUA  DNA TESTING
One Pathogenic/
VUS Variant
No pathogenic/
VUS variants
Urine GAGs
Plasma IDUA
Genetic counseling
Molecular analysis
Urine GAGs
Plasma IDUA
Genetic counseling
Two Pathogenic/
VUS Variants
Urine GAGs
Plasma IDUA
Variant phasing
Genetic counseling
• Hematopoietic Stem Cell Transplantation (HSCT):
– Good standard for severe MPS I only.
– Outcome depends on severity of disease at the time of HSCT.
– Recommendation for transplant <2 - 2.5 years of age.
• Enzyme Replacement Therapy (ERT) (laronidase):
– For attenuated MPS I.
– Cannot cross the blood-brain barrier.
MPS I TREATMENT
• Any patient that identifies positive for MPS I in the newborn
screen needs medical attention.
• However, this is a disease that requires urgent referral given
the time-sensitive nature of making a diagnosis and starting
therapy.
True or False
QUESTION
• Acute concerns:
• Parental counseling.
• Action items:
• Support the Newborn Screening process.
• Facilitate a non-urgent referral for assessment and
development of a treatment plan.
ATTENTION PRIMARY PEDIATRICIANS!
POMPE DISEASE
POMPE DISEASE
• Glycogen storage disease type II.
• Due to a defect in acid ⍺-glucosidase caused
by mutations in the GAA gene).
• Autosomal recessive mode of inheritance.
• Frequency varies with the ethnic group:
• European descent – 1:100,000
• African-Americans – 1:14,000
Courtesy of
SIMD-NAMA
Infantile-onset Late-onset
• Onset before 12 months of age
• Cardiomyopathy is present
• Onset before 12 months of
age without cardiomyopathy
• Any affected individual with
onset after 12 months
Infantile-onset
IOPD
Late-onset
LOPD
• Feeding difficulties, failure to thrive
• Muscle weakness  motor delays
• Respiratory weakness  infection
• Cardiac disease:
• Shortened PR interval with a broad,
wide QRS complex
• Cardiomegaly
• Left ventricular outflow obstruction
• Cardiomyopathy Courtesy of SIMD-NAMA
Vermont Department of Health
POMPE DISEASE:
DIAGNOSTIC
ALGORITHM
• Start with acid
⍺-glucosidase
POMPE DISEASE:
DIAGNOSTIC
ALGORITHM
• When DNA
testing is
included in the
NBS lab
protocol
• Enzyme Replacement Therapy (ERT) (alglucosidase alfa)
• Determine CRIM (Cross-Reacting Immunologic Material) status
TREATMENT FOR INFANTILE-ONSET POMPE DISEASE
TREATMENT: IOPD
(INFANTILE-ONSET)
David F. Kronn et al. Pediatrics 2017;140:S24-S45
• <6 months (before ventilator dependence)
• Improved survival
• Improved chance of ventilator-independence
• Improved motor development
• <2 weeks
• Improved motor development first 2 years
OUTCOME OF THERAPY FOR IOPD
TREATMENT: LOPD
(LATE-ONSET)
• Based on the presence or
absence of symptoms
David F. Kronn et al. Pediatrics 2017;140:S24-S45
• Improved motor strength
• Improved respiratory function
OUTCOME OF THERAPY FOR LOPD
• Any patient that identifies positive for Pompe in the newborn
screen needs medical attention.
• However, this is a disease that requires urgent referral given
the time-sensitive nature of making a diagnosis and starting
therapy.
True or False
QUESTION
• Acute concerns:
• Parental counseling.
• Heart failure.
• Better outcome with earlier intervention.
• Action items:
• Support the Newborn Screening process.
• Facilitate an urgent referral for assessment and
treatment.
ATTENTION PRIMARY PEDIATRICIANS!
X-LINKED
ADRENOLEUKODYSTROPHY
X-LINKED ADRENOLEUKODYSTROPHY
• A defect in the transport of very long chain fats into the
peroxisome where they are broken down (ALDP protein).
• ABCD1 is the gene that encodes for the ALDP protein.
• Inheritance – x-linked.
• Frequency (males)
• 1/21,000 (NY)
• 1/3,900 MN)
X-LINKED ADRENOLEUKODYSTROPHY
• Classic childhood cerebral form of X-ALD:
• Male presents with behavioral/learning
problems (ADD?) in early school years.
• Loss of cognitive skills.
• GM and FM impairment.
• Hearing loss.
• ADRENOCORTICAL DYSFUNCTION (90%).
• Rapid decline.
X-LINKED ADRENOLEUKODYSTROPHY
Childhood
cerebral ALD
Onset – 4-8 years (peak 7 years)
Adreno-
myeloneuropathy
(AMN)
Onset – 3rd-6th decades
Addison disease Onset – Age 2 years to adulthood
(commonly around 7-8 years)
X-LINKED ADRENOLEUKODYSTROPHY
Childhood
cerebral ALD
Adreno-
myeloneuropathy
(AMN)
Addison disease
35% of cases
40-45% of cases
10% of cases
X-LINKED ADRENOMYELONEUROPATHY
• Problems with walking due to weakness, stiffness
• Incontinence
• +/- severe cognitive/behavioral issues (10-20%)
• +/- dysfunctional adrenal cortex (70%)
X-LINKED ADDISON DISEASE
• Vomiting, weakness, stupor, coma
• +/- hyperpigmentation
• Presentation in childhood:
• No neurologic signs at onset
• Neurologic disease over decades (like AMN)
X-LINKED ALD SCREEN: C26:0-LPC (LYSOPHOSPHATIDYLCHOLINE)
C26:0 LPC
Molecular analysis of
ABCD1 gene
Pathogenic
variant found
No pathogenic
variant or VUS
Initial Screen
X-LINKED ALD SCREEN: C26:0-LPC (LYSOPHOSPHATIDYLCHOLINE)
DNA Screen Pathogenic variant found in ABCD1
Genetic Male Genetic Female
Plasma VLCFA
Repeat NBS
VLCFA
X-linked ALD
Normal VLCFA
Asymptomatic
X-linked ALD
Carrier
Clinical Symptoms
Possible Peroxisomal
Disorder
Plasma VLCFA
Repeat NBS
• Genotype does NOT predict the phenotype or prognosis.
• A positive family history does NOT predict the phenotype.
• The degree of VLCFA elevation does NOT predict the phenotype.
NO PHENOTYPE PREDICTABILITY IN X-ALD
• Hematopoietic Stem Cell Transplantation (HSCT):
– Indicated for Childhood Cerebral form of xALD only.
– But cannot predict when a screen-positive male will develop
clinical symptoms (in childhood or middle age?).
– Treatment recommended at this juncture:
• MRI findings of brain involvement
• Minimal neuropsychological findings
• Normal clinical neurological exam
TREATMENT FOR X-LINKED ADRENOLEUKODYSTROPHY
• Corticosteroid replacement is lifesaving when adrenal
dysfunction is present.
X-ALD TREATMENT
• Any patient that identifies positive for X-ALD in the newborn
screen needs medical attention.
• However, this is a disease that requires urgent referral given
the time-sensitive nature of making a diagnosis and starting
therapy.
True or False
QUESTION
• Acute concerns:
• Parental counseling.
• Action items:
• Support the Newborn Screening process.
• Facilitate a non-urgent referral for assessment and
development of a treatment plan.
ATTENTION PRIMARY PEDIATRICIANS!
SPINAL MUSCULAR ATROPHY (SMA)
SPINAL MUSCULAR ATROPHY
• Onset range - before birth to adolescence or young adulthood.
SPINAL MUSCULAR ATROPHY - MYOPATHY
• Muscle weakness and atrophy:
• Due to progressive degeneration and loss of the anterior
horn cells in the spinal cord (i.e., lower motor neurons) and
the brain stem nuclei.
• Symmetric, proximal > distal, and progressive.
SPINAL MUSCULAR ATROPHY - COMPLICATIONS
• Poor weight gain with growth failure
• Restrictive lung disease
• Scoliosis
• Joint contractures
• Sleep difficulties
SMA – CLINICAL PHENOTYPES
Phenotype Age of Onset Life Span
Motor
Milestones
Other Findings
SMA 0 Prenatal <6 months None achieved
•Severe neonatal hypotonia
•Severe weakness
•Early respiratory failure
•Facial diplegia
SMA I <6 months
Most ≤2
years, but
may live
longer
Sit w/support
only
•Mild joint contractures
•Normal or minimal
facial weakness
•Variable suck &
swallow difficulties
SMA II 6-18 months
70% alive at age
25 years
Independent sitting
when placed
Postural tremor
of fingers
SMA III >18 months Normal
Independent
ambulation
SMA IV Adulthood Normal Normal
SMN2 SMN1
GENETICS OF SMA: SURVIVAL MOTOR NEURON GENES
• SMN1 produces a full-length survival motor neuron protein
necessary for lower motor neuron function
• SMN2 predominantly produces a survival motor neuron
protein that is lacking in exon 7, a less stable protein
GENETICS OF SMA
• SMA is caused by loss of SMN1 because SMN2 cannot fully
compensate for loss of SMN1-produced protein
• When SMN2 (dosage) copy number is increased, the small
amount of full-length transcript generated by SMN2 can
produce a milder type II or type III phenotype
– An affected child with 4 copies is at an 88% risk of
having type III SMA
GENETICS OF SMA
• Real time PCR Real-time PCR (RT-PCR) detection of SMN1
exon7. Carriers are NOT identified.
• 95% of SMA cases show absence of exon 7.
• Positive newborn screen is when there is no detectable
functional SMN1 gene.
• There is no genotype/phenotype correlation based on just
SMN1  a positive screening result cannot predict severity.
• 2nd tier testing identifies the number of copies of
SMN2
NEWBORN SCREENING FOR SMA
SMA TREATMENT ALGORITHM
No functional copies
of SMN1 detected
• Spinraza (nusinerisen)
– Increases the production of full-length SMN protein by increasing the
proportion of SMN2 mRNA transcripts that include exon 7.
– Binds to a specific sequence in the intron downstream of exon 7.
– Requires intrathecal injection
– Does not reverse disease
• Zolgensma (onasemnogene abeparvovec)
– Gene therapy (one-time adeno-associated virus vector-based)
– Inserts and functional copy of SMN1 gene into motor neurons
• Supportive care
TREATMENT FOR SPINAL MUSCULAR ATROPHY
• Any patient that identifies positive for SMA in the newborn
screen needs medical attention.
• However, this is a disease that requires urgent referral given
the time-sensitive nature of making a diagnosis and starting
therapy.
True or False
QUESTION
• Acute concerns:
• Parental counseling.
• Better outcome with earlier intervention.
• Action items:
• Support the Newborn Screening process.
• Facilitate an urgent referral for assessment and
treatment.
ATTENTION PRIMARY PEDIATRICIANS!
WHAT IS THE ROLE OF
THE PRIMARY CARE PROVIDER?
• Newborn screening is beneficial to patients and families.
• Lots of work to do !!
• Identifying new, treatable diseases at birth generates a lot of
work for all involved.
• These patients would demand attention anyway.
• Identifying them shifts priorities, sometimes urgently.
NEWBORN SCREENING – BENEFICIAL + INTENSIVE!
ACUTE RESPONSIBILITIES FOR THE PCP
• Support the Newborn Screening process.
• Facilitate a referral for assessment and treatment.
• In certain situations, direct contact and advocacy may be
required to ensure an urgent referral:
• SCID
• Pompe disease
• SMA
RESPONSIBILITIES FOR PATIENTS WITH CHRONIC DISEASE
• The issues at hand:
• Parents/families are faced quickly with severe, progressive,
potentially lethal disease.
• The diseases are complex, often multi-systemic.
• The diagnostic testing is complex and hard to understand.
• The treatment is invasive and intensive, and relatively new.
• Treatment protocols are demanding and inflexible.
RESPONSIBILITIES FOR PATIENTS WITH CHRONIC DISEASE
• Care in tertiary centers is usually required:
• Multiple doctors and services are often involved.
• Care coordination is often lacking or inadequate.
• Advocacy is needed and patients will do better when
parents can learn to advocate early.
QUESTIONS
• The following are personal professional questions for PCPs
around issues that become relevant when a patient is
identified with a complex genetic disease through newborn
screening.
• Answer honestly about your capability now, based on how
busy your clinical practice is.
QUESTIONS
• If needed, is your practice able to assist in helping to
coordinate care for a patient at the tertiary medical center?
A. Yes
B. No
C. Partly
QUESTIONS
• As the patient’s medical home, can you/your staff (along with
the patient/family) learn about the disease and its medical
implications (assuming informative educational materials are
provided)?
A. Yes
B. No
C. Maybe
QUESTIONS
• Lots of clinical information will come in about the patient. Can
you/your staff be a resource for the parents in deciphering this
information and help them to understand it in order to make
informed decisions?
A. Yes
B. No
C. Maybe
QUESTIONS
• Would you be willing to talk to us so we can support you in
your care of these patients and families?
A. Yes
B. No
THANK YOU!
• We as geneticists know that training about genetic and
metabolic conditions is often inadequate in medical school and
post-graduate training.
• We appreciate your efforts in helping us help your patients!

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Newborn Screening: Part III

  • 1. Pediatric Genetics and Genomics January 28, 2020 Newborn Screening part III 1 Genetics | 1/28/20 Leah Burke, MD University of Vermont Mark Korson, MD VMP Genetics, LLC
  • 2. Get the Most Out of Your Experience  Use the Q&A Button to submit questions during today’s session  Recording and slides will be sent by email  For further information, contact WeitzmanLearning@chc1.com Genetics | 1/28/202
  • 3. 3 The Weitzman Instituteworks to improve primary care and its delivery to medically underserved and special populationsthrough research, innovation, and the education and training of health professionals. 3Genetics | 1/28/203
  • 4.  Founding year: 1972  Hubs/Locations: 15/210  Patients per year: 100,000 The Weitzman Institute is a program of Genetics | 1/28/204
  • 5. New England Regional Genetics Network The NERGN project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number UH7MC30778; New England Regional Genetics Network; total award amount: 1.5 million; 100% from governmental sources. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government. Genetics | 1/28/205
  • 6. CME Credits Available  CME credits available to live webinar participants only  A brief survey will be sent after this session to those who registered and attended this webinar  CME certificate will be sent to participants who complete the survey American Academy Family Physicians (AAFP) Genetics | 1/28/206
  • 8. Today’s Presenters Dr. Leah W. Burke, MD Dr. Mark Korson, MD Genetics | 1/28/208
  • 9. LEARNING OBJECTIVES 1. Review the important aspects about newborn screening discussed in Part I and II (2019) 2. Discuss key clinical aspects of the latest diseases added to the newborn screen 3. Clarify the roles of primary care providers and specialists in the newborn screening process associated with these disorders 4. Identify what diseases on the screen require urgent referrals and why 5. Determine the role of the PCP in supporting families whose children are identified through newborn screening
  • 10. ESSENTIAL POINTS FROM NEWBORN SCREENING PARTS I & II
  • 11. • NB screening is a screen, not a diagnostic test. • Remember: • The (ACMG) ACT sheets and algorithms • Other educational resources • Concerns? Questions?  call a geneticist! REMEMBER!
  • 12. • Discuss the screening results and potential clinical implications. • Assess the need for a repeat specimen. • Discern disease from diet impact from artifact. • Figure out if and how management should change. HOW A GENETICIST CAN HELP YOU…
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  • 25. RESOURCES FOR INFORMATION: NEWBORN SCREENING https://www.babysfirsttest.org/
  • 27. THE LATEST ADDITIONS TO THE NEWBORN SCREEN • Severe Combined ImmunoDeficiency (SCID) • MucoPolySaccharidosis (MPS) type I • Pompe disease • X-linked AdrenoLeukoDystrophy (X-ALD) • Spinal Muscular Atrophy (SMA)
  • 29. David Phillip Vetter (September 21, 1971 – February 22, 1984) “THE BOY IN A BUBBLE”
  • 30. • Frequency - ? 1:50,000 - 1:100,000. • A set of disorders that results in a failure to form T cells. • Infants have problems with both T cells and B cells  onset of severe infections in the first few months of life. • The newborn screen detects other conditions that have low numbers of T cells. SEVERE COMBINED IMMUNODEFICIENCY
  • 31. • A screen for numbers of ‘T cell Receptor Excision Circles’ (‘TREC’). • TRECs small circles of DNA created in T-cells during their passage through the thymus as they rearrange their TCR genes. • Presence indicates maturation of T cells. • Found in every healthy newborn’s blood. • SCID babies have few/no T cells, so have few/no TRECs in their blood. NEWBORN SCREEN FOR SCID
  • 32. David A. Randolph et al. Neoreviews 2013;14:e448-e455 ©2013 by American Academy of Pediatrics MOLECULAR BASIS FOR SCID SCREENING
  • 33. • Low blood TREC levels can also be caused by prematurity, other less severe immune disorders, or other syndromes. • A baby can have a positive screening result but have a normal immune system, so… • If the screen is positive  further testing must be done to confirm or rule out SCID. • If parent(s) is/are are known carriers of SCID, diagnostic testing and newborn screen should be done. THE SCID NEWBORN SCREEN – TAKE NOTE!
  • 34. THE SCID NBS REPORTING ALGORITHM Newborn Screening Specimen TREC  252 TREC  252 normal TREC  252 TREC undetectable Repeat test TREC  252 Repeat test positive
  • 35. • Flow cytometry: –Numbers of CD4 + CD8 T cells, CD56 NK cells, & C19 B cells. –CD45RA + CD45RO analysis to determine the numbers of naïve T cells. EVALUATION OF A POSITIVE SCID SCREEN
  • 36. • Most common form of inheritance in SCID is X-linked: – IL2RG gene mutations  X-linked SCID. – IL2RG encodes for a protein critical for normal immune function. • Also autosomal recessive form: – ADA gene mutations  adenosine deaminase deficiency. – ADA encodes for the enzyme adenosine deaminase. – Found throughout the body, most active in lymphocytes. • Multiple other rare forms. THE GENETICS OF SCIDS
  • 37. • Bone Marrow (BMT) / Hematopoietic Stem Cell Transplantation (HSCT): – If BMT <3.5 months old - 95% chance of long-term survival & healthy life. – If BMT > 3.5 months old - 60-70% chance of long-term survival. • Enzyme Replacement Therapy (ERT): – For ADA deficiency - pegademase bovine (PEG-ADA) allows lymphocytes to recover. – Long-term treatment for some children but not a cure; BMT may still be needed. • Gene therapy: – Clinical trials - positive outcomes for children. – More evidence for ADA deficiency type. – Still investigational. SCID TREATMENT
  • 38. • Newborn screening showed <200 TRECs. • Subsequent flow cytometry showed the following: Test Result Flag reference range Absolute CD3 % CD3 1218 cells/cmm 48% 2500 – 5500 cells/cmm 53-84% Absolute CD4 % CD4 812 cells/cmm 32% 1600-4000 cells/cmm 35-64% Absolute CD8 % CD8 381 cells/cmm 15% 560-1700 cells/cmm 12-28% Absolute CD19 % CD19 1041 cells/cmm 41% 300-2000 cells/cmm 6-32% % CD45 100% 99-100% CD4 CD8 Ratio 2.13 CASE
  • 39. • Seen in Genetics Clinic. • Examination – hypotonia. • Testing - positive for 22q deletion. CASE
  • 40. Non-SCID Reasons for a Positive Screen When TRECs are >0 and < 252 • Prematurity • 22q deletion syndrome • Down syndrome • Other milder forms of immunodeficiency • Transient immunodeficiency • Normal ** VERY IMPORTANT TO KNOW THIS WHEN CALLING THE FAMILY WITH A POSITIVE RESULT !!
  • 41. • Any patient that identifies positive for SCID in the newborn screen needs medical attention. • However, this is a disease that requires urgent referral given the time-sensitive nature of making a diagnosis and starting therapy. True or False QUESTION
  • 42. • Acute concerns: • Parental counseling. • Infectious risk. • Better outcome with earlier intervention. • Action items: • Support the Newborn Screening process. • Facilitate an urgent referral for assessment and treatment. ATTENTION PRIMARY PEDIATRICIANS!
  • 43. • Acute concerns: • Parental counseling. • Infectious risk. • Better outcome with earlier intervention. • Action items: • Support the Newborn Screening process. • Facilitate an urgent referral for assessment and treatment. ATTENTION PRIMARY PEDIATRICIANS!
  • 45. MUCOPOLYSACCHARIDOSIS (MPS) TYPE I • A classic type of lysosomal storage disease. • Frequency: • LSDs ~1:25,000. • Severe MPS I ~1:100,000. • Autosomal recessive mode of inheritance. Courtesy of SIMD-NAMA
  • 46. Severe Attenuated Hurler MPS I H Hurler-Scheie MPS I HS Scheie MPS I S 57% 24% 10%
  • 47. Severe Attenuated Under 1 year: • Respiratory: • Ear infections  hearing loss • Loud breathing • Snoring • Hernias – inguinal, umbilical • Coarse facies – after 1 year
  • 48. Severe Attenuated • Severe cognitive impairment • Hepatosplenomegaly • Obstructive airway disease • Valvular heart disease • Corneal clouding • Joint stiffness/contractures • Hearing loss • Death <10 years of age Adapted from SIMD-NAMA
  • 49. Severe Attenuated • Mild/no cognitive impairment • +/- Hepatomegaly • Obstructive airway disease • Valvular heart disease • Corneal clouding • Joint stiffness/contractures • Hearing loss • Death – 2nd/3rd decade or later Adapted from SIMD-NAMA
  • 50. MUCOPOLYSACCHARIDOSIS (MPS) TYPE I • Accumulation of glycosaminoglycans (GAGs) (heparan sulfate & dermatan sulfate), detected in urine. • ⍺-L-iduronidase (IDUA) deficiency. Courtesy of SIMD-NAMA
  • 51. MPS TYPE I SCREEN: LOW/ABSENT ⍺-L-iduronidase (IDUA) IDUA Activity  7% of Median 7-15% of Median Moderate probability MPS1 > 15% of Median Low probability MPS1 No further work-up Molecular analysis
  • 52. MPS TYPE I SCREEN: LOW/ABSENT IDUA  DNA TESTING One Pathogenic/ VUS Variant No pathogenic/ VUS variants Urine GAGs Plasma IDUA Genetic counseling Molecular analysis Urine GAGs Plasma IDUA Genetic counseling Two Pathogenic/ VUS Variants Urine GAGs Plasma IDUA Variant phasing Genetic counseling
  • 53. • Hematopoietic Stem Cell Transplantation (HSCT): – Good standard for severe MPS I only. – Outcome depends on severity of disease at the time of HSCT. – Recommendation for transplant <2 - 2.5 years of age. • Enzyme Replacement Therapy (ERT) (laronidase): – For attenuated MPS I. – Cannot cross the blood-brain barrier. MPS I TREATMENT
  • 54. • Any patient that identifies positive for MPS I in the newborn screen needs medical attention. • However, this is a disease that requires urgent referral given the time-sensitive nature of making a diagnosis and starting therapy. True or False QUESTION
  • 55. • Acute concerns: • Parental counseling. • Action items: • Support the Newborn Screening process. • Facilitate a non-urgent referral for assessment and development of a treatment plan. ATTENTION PRIMARY PEDIATRICIANS!
  • 57. POMPE DISEASE • Glycogen storage disease type II. • Due to a defect in acid ⍺-glucosidase caused by mutations in the GAA gene). • Autosomal recessive mode of inheritance. • Frequency varies with the ethnic group: • European descent – 1:100,000 • African-Americans – 1:14,000 Courtesy of SIMD-NAMA
  • 58. Infantile-onset Late-onset • Onset before 12 months of age • Cardiomyopathy is present • Onset before 12 months of age without cardiomyopathy • Any affected individual with onset after 12 months
  • 59. Infantile-onset IOPD Late-onset LOPD • Feeding difficulties, failure to thrive • Muscle weakness  motor delays • Respiratory weakness  infection • Cardiac disease: • Shortened PR interval with a broad, wide QRS complex • Cardiomegaly • Left ventricular outflow obstruction • Cardiomyopathy Courtesy of SIMD-NAMA
  • 60. Vermont Department of Health POMPE DISEASE: DIAGNOSTIC ALGORITHM • Start with acid ⍺-glucosidase
  • 61. POMPE DISEASE: DIAGNOSTIC ALGORITHM • When DNA testing is included in the NBS lab protocol
  • 62. • Enzyme Replacement Therapy (ERT) (alglucosidase alfa) • Determine CRIM (Cross-Reacting Immunologic Material) status TREATMENT FOR INFANTILE-ONSET POMPE DISEASE
  • 63. TREATMENT: IOPD (INFANTILE-ONSET) David F. Kronn et al. Pediatrics 2017;140:S24-S45
  • 64. • <6 months (before ventilator dependence) • Improved survival • Improved chance of ventilator-independence • Improved motor development • <2 weeks • Improved motor development first 2 years OUTCOME OF THERAPY FOR IOPD
  • 65. TREATMENT: LOPD (LATE-ONSET) • Based on the presence or absence of symptoms David F. Kronn et al. Pediatrics 2017;140:S24-S45
  • 66. • Improved motor strength • Improved respiratory function OUTCOME OF THERAPY FOR LOPD
  • 67. • Any patient that identifies positive for Pompe in the newborn screen needs medical attention. • However, this is a disease that requires urgent referral given the time-sensitive nature of making a diagnosis and starting therapy. True or False QUESTION
  • 68. • Acute concerns: • Parental counseling. • Heart failure. • Better outcome with earlier intervention. • Action items: • Support the Newborn Screening process. • Facilitate an urgent referral for assessment and treatment. ATTENTION PRIMARY PEDIATRICIANS!
  • 70. X-LINKED ADRENOLEUKODYSTROPHY • A defect in the transport of very long chain fats into the peroxisome where they are broken down (ALDP protein). • ABCD1 is the gene that encodes for the ALDP protein. • Inheritance – x-linked. • Frequency (males) • 1/21,000 (NY) • 1/3,900 MN)
  • 71. X-LINKED ADRENOLEUKODYSTROPHY • Classic childhood cerebral form of X-ALD: • Male presents with behavioral/learning problems (ADD?) in early school years. • Loss of cognitive skills. • GM and FM impairment. • Hearing loss. • ADRENOCORTICAL DYSFUNCTION (90%). • Rapid decline.
  • 72. X-LINKED ADRENOLEUKODYSTROPHY Childhood cerebral ALD Onset – 4-8 years (peak 7 years) Adreno- myeloneuropathy (AMN) Onset – 3rd-6th decades Addison disease Onset – Age 2 years to adulthood (commonly around 7-8 years)
  • 74. X-LINKED ADRENOMYELONEUROPATHY • Problems with walking due to weakness, stiffness • Incontinence • +/- severe cognitive/behavioral issues (10-20%) • +/- dysfunctional adrenal cortex (70%)
  • 75. X-LINKED ADDISON DISEASE • Vomiting, weakness, stupor, coma • +/- hyperpigmentation • Presentation in childhood: • No neurologic signs at onset • Neurologic disease over decades (like AMN)
  • 76. X-LINKED ALD SCREEN: C26:0-LPC (LYSOPHOSPHATIDYLCHOLINE) C26:0 LPC Molecular analysis of ABCD1 gene Pathogenic variant found No pathogenic variant or VUS Initial Screen
  • 77. X-LINKED ALD SCREEN: C26:0-LPC (LYSOPHOSPHATIDYLCHOLINE) DNA Screen Pathogenic variant found in ABCD1 Genetic Male Genetic Female Plasma VLCFA Repeat NBS VLCFA X-linked ALD Normal VLCFA Asymptomatic X-linked ALD Carrier Clinical Symptoms Possible Peroxisomal Disorder Plasma VLCFA Repeat NBS
  • 78. • Genotype does NOT predict the phenotype or prognosis. • A positive family history does NOT predict the phenotype. • The degree of VLCFA elevation does NOT predict the phenotype. NO PHENOTYPE PREDICTABILITY IN X-ALD
  • 79. • Hematopoietic Stem Cell Transplantation (HSCT): – Indicated for Childhood Cerebral form of xALD only. – But cannot predict when a screen-positive male will develop clinical symptoms (in childhood or middle age?). – Treatment recommended at this juncture: • MRI findings of brain involvement • Minimal neuropsychological findings • Normal clinical neurological exam TREATMENT FOR X-LINKED ADRENOLEUKODYSTROPHY
  • 80. • Corticosteroid replacement is lifesaving when adrenal dysfunction is present. X-ALD TREATMENT
  • 81. • Any patient that identifies positive for X-ALD in the newborn screen needs medical attention. • However, this is a disease that requires urgent referral given the time-sensitive nature of making a diagnosis and starting therapy. True or False QUESTION
  • 82. • Acute concerns: • Parental counseling. • Action items: • Support the Newborn Screening process. • Facilitate a non-urgent referral for assessment and development of a treatment plan. ATTENTION PRIMARY PEDIATRICIANS!
  • 84. SPINAL MUSCULAR ATROPHY • Onset range - before birth to adolescence or young adulthood.
  • 85. SPINAL MUSCULAR ATROPHY - MYOPATHY • Muscle weakness and atrophy: • Due to progressive degeneration and loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. • Symmetric, proximal > distal, and progressive.
  • 86. SPINAL MUSCULAR ATROPHY - COMPLICATIONS • Poor weight gain with growth failure • Restrictive lung disease • Scoliosis • Joint contractures • Sleep difficulties
  • 87. SMA – CLINICAL PHENOTYPES Phenotype Age of Onset Life Span Motor Milestones Other Findings SMA 0 Prenatal <6 months None achieved •Severe neonatal hypotonia •Severe weakness •Early respiratory failure •Facial diplegia SMA I <6 months Most ≤2 years, but may live longer Sit w/support only •Mild joint contractures •Normal or minimal facial weakness •Variable suck & swallow difficulties SMA II 6-18 months 70% alive at age 25 years Independent sitting when placed Postural tremor of fingers SMA III >18 months Normal Independent ambulation SMA IV Adulthood Normal Normal
  • 88. SMN2 SMN1 GENETICS OF SMA: SURVIVAL MOTOR NEURON GENES
  • 89. • SMN1 produces a full-length survival motor neuron protein necessary for lower motor neuron function • SMN2 predominantly produces a survival motor neuron protein that is lacking in exon 7, a less stable protein GENETICS OF SMA
  • 90. • SMA is caused by loss of SMN1 because SMN2 cannot fully compensate for loss of SMN1-produced protein • When SMN2 (dosage) copy number is increased, the small amount of full-length transcript generated by SMN2 can produce a milder type II or type III phenotype – An affected child with 4 copies is at an 88% risk of having type III SMA GENETICS OF SMA
  • 91. • Real time PCR Real-time PCR (RT-PCR) detection of SMN1 exon7. Carriers are NOT identified. • 95% of SMA cases show absence of exon 7. • Positive newborn screen is when there is no detectable functional SMN1 gene. • There is no genotype/phenotype correlation based on just SMN1  a positive screening result cannot predict severity. • 2nd tier testing identifies the number of copies of SMN2 NEWBORN SCREENING FOR SMA
  • 92. SMA TREATMENT ALGORITHM No functional copies of SMN1 detected
  • 93. • Spinraza (nusinerisen) – Increases the production of full-length SMN protein by increasing the proportion of SMN2 mRNA transcripts that include exon 7. – Binds to a specific sequence in the intron downstream of exon 7. – Requires intrathecal injection – Does not reverse disease • Zolgensma (onasemnogene abeparvovec) – Gene therapy (one-time adeno-associated virus vector-based) – Inserts and functional copy of SMN1 gene into motor neurons • Supportive care TREATMENT FOR SPINAL MUSCULAR ATROPHY
  • 94. • Any patient that identifies positive for SMA in the newborn screen needs medical attention. • However, this is a disease that requires urgent referral given the time-sensitive nature of making a diagnosis and starting therapy. True or False QUESTION
  • 95. • Acute concerns: • Parental counseling. • Better outcome with earlier intervention. • Action items: • Support the Newborn Screening process. • Facilitate an urgent referral for assessment and treatment. ATTENTION PRIMARY PEDIATRICIANS!
  • 96. WHAT IS THE ROLE OF THE PRIMARY CARE PROVIDER?
  • 97. • Newborn screening is beneficial to patients and families. • Lots of work to do !! • Identifying new, treatable diseases at birth generates a lot of work for all involved. • These patients would demand attention anyway. • Identifying them shifts priorities, sometimes urgently. NEWBORN SCREENING – BENEFICIAL + INTENSIVE!
  • 98. ACUTE RESPONSIBILITIES FOR THE PCP • Support the Newborn Screening process. • Facilitate a referral for assessment and treatment. • In certain situations, direct contact and advocacy may be required to ensure an urgent referral: • SCID • Pompe disease • SMA
  • 99. RESPONSIBILITIES FOR PATIENTS WITH CHRONIC DISEASE • The issues at hand: • Parents/families are faced quickly with severe, progressive, potentially lethal disease. • The diseases are complex, often multi-systemic. • The diagnostic testing is complex and hard to understand. • The treatment is invasive and intensive, and relatively new. • Treatment protocols are demanding and inflexible.
  • 100. RESPONSIBILITIES FOR PATIENTS WITH CHRONIC DISEASE • Care in tertiary centers is usually required: • Multiple doctors and services are often involved. • Care coordination is often lacking or inadequate. • Advocacy is needed and patients will do better when parents can learn to advocate early.
  • 101. QUESTIONS • The following are personal professional questions for PCPs around issues that become relevant when a patient is identified with a complex genetic disease through newborn screening. • Answer honestly about your capability now, based on how busy your clinical practice is.
  • 102. QUESTIONS • If needed, is your practice able to assist in helping to coordinate care for a patient at the tertiary medical center? A. Yes B. No C. Partly
  • 103. QUESTIONS • As the patient’s medical home, can you/your staff (along with the patient/family) learn about the disease and its medical implications (assuming informative educational materials are provided)? A. Yes B. No C. Maybe
  • 104. QUESTIONS • Lots of clinical information will come in about the patient. Can you/your staff be a resource for the parents in deciphering this information and help them to understand it in order to make informed decisions? A. Yes B. No C. Maybe
  • 105. QUESTIONS • Would you be willing to talk to us so we can support you in your care of these patients and families? A. Yes B. No
  • 106. THANK YOU! • We as geneticists know that training about genetic and metabolic conditions is often inadequate in medical school and post-graduate training. • We appreciate your efforts in helping us help your patients!

Editor's Notes

  1. Hand over to Mark after this slide
  2. So in summary, when faced with an abnormal NB screen  remember that there is help. In addition to your state-provided NB screening follow-up center(s), you can also help yourself with ACMG’s ACT sheets and algorithms
  3. Before you change a diet or treatment or withhold a repeat screen, talk to your genetics or metabolic referral center. We can nearly always work with it without putting the infant at additional risk or depriving them of essential nutrients unnecessarily.
  4. This is the website – acmg.net
  5. Under that tab, one can find the ACT Sheets and Algorithms
  6. There are ACT sheets for more that just the conditions screened at birth. There is information for a range of genetic diseases, about genetic testing and test results, in order to help with clinical decision-making. Take a look sometime.
  7. We are focusing now on Newborn Screening though.
  8. All the diseases – whether metabolic in origin or not – are listed here…
  9. Let’s consider one group of disorders as an example - the fatty acid oxidation defects.
  10. Here is a standard form that included the name of the disorder and the differential diagnosis, and emergency instructions – what to worry about, what to do and whom to call?
  11. And an algorithm with the testing to do to evaluate an abnormal screen. But of course, your metabolic consultant will join you in the task of evaluating each case. Use us as a resource!
  12. To find more information on your particular state’s newborn screening practices as well as patient appropriate information visit Baby’s First Test. Baby's First Test houses the nation's newborn screening clearinghouse. Provides current educational and family support and services information, materials, and resources about newborn screening at the local, state, and national levels Supported and funded as a result of the Newborn Screening Saves Lives Act passed in 2008 and the Newborn Screening Saves Lives Reauthorization Act passed in 2014
  13. For more practitioner-oriented information there are two sites that can be helpful. The New England Metabolic Consortium has information on many of the metabolic conditions on the newborn screening panel Information includes acute illness protocols as well as information on transition planning and patient brochures GeneReviews provides condition specific information on many genetic conditions, including those on the newborn screening panel. You search for a particular condition.
  14. There are some of you in the audience who are old enough to remember the story of David Vetter who was the original boy in a bubble and lived more than 12 years. NASA developed a suit for him so he could be more mobile. This is the type of condition for which the newborn screening was designed.
  15. Severe Combined Immunodeficiency or SCID As in most screened conditions, the screening picks up other related conditions.
  16. Molecular basis for severe combined immunodeficiency screening. In the germline state, the T-cell receptor (TCR) locus contains numerous V, D, and J gene segments shown schematically as red, blue, and green blocks. The recombinase-activating genes RAG1 and RAG2 act in concert with DNA repair enzymes to rearrange the TCR locus. Distal gene segments are brought together to create the rearranged TCR locus while the intervening DNA is looped out as T-cell receptor excision circles (TRECs). One particular TREC, the δRec-ψJα TREC, is found in the majority of newly minted αβT-cells and can be detected by PCR at high levels in the peripheral blood of normal infants but not in infants who have severe combined immunodeficiency.
  17. This repeat specimen that you see here is a common step. Sometimes the protocol is to repeat the specimen while you are gather
  18. Old names – Hurler for the severe type, Scheie for the mild type, and Hurler-Scheie for the intermediate type No good biochemical markers that distinguish the three types and the symptoms overlap, so reclassified into “severe” vs “attenuated” phenotypes Relative frequency, taken from an MPS registry (2011, n=891) About 9% were indeterminate re: type
  19. Severe intellectual disability, delay apparent by 18 months – plateaus for year  decline Large liver and spleen (but without dysfunction) Obstructive airway disease – snoring, sleep apnea Valvular heart disease – mitral > aortic valve thickening  regurgitation. Later cardiomyopathy, arrhythmia Corneal clouding, can be severe and impair vision. Also glaucoma and retinal deterioration. Joint stiffness and contractures are progressive in nature – “dysostosis multiplex” and gibbus deformity, usually within the first year (6-14months). Complications may include spinal nerve entrapment, acute spinal injury, and atlanto-occipital instability. Claw-hand deformity Linear growth slows by 3 years Hearing loss is common Death is usually from cardio-respiratory failure
  20. Normal development at age 24 months with moderate somatic involvement  attenuated Onset usually between 3 and 10 years In the attenuated forms, there can be no neurocognitive involvement but some show a learning disability No correlation between somatic disease and cognitive involvement Variable growth delays Variable liver enlargement Valvular heart disease by 11 years (88%) Corneal clouding in 82%, onset by ~8 years Milder forms of the bony dysplasia impacting the joints and if more serious, can cause joint contractures (85%). Disease focus in the vertebrae and femora  scoliosis and kyphosis, bone pain Moderate-severe hearing loss Death may occur in 20s or 30s, but life span can be normal though with significant morbidity
  21. Accumulation of GAGs in lysosomes.
  22. HSCT recommended only for MPS I severe type given the morbidity and mortality risks associated with the treatment. Slowing of cognitive delays only possible if HSCT occurs early, before 2 years of age (before 12-18 months is optimal). Once significant delays are established, not reversible. Note: neither HSCT and ERT are not very effective in treating the Joint/bone disease and the corneal clouding.
  23. Diagnostic algorithm for Pompe disease with DNA sequencing as part of the NBS laboratory protocol. Modified from the New York Mid-Atlantic Consortium for Genetic and Newborn Screening Services (NYMAC) Pompe Disease NBS Symposium 2013. a Obtain as a baseline for monitoring response to treatment; can also be postponed until a definitive diagnosis is obtained. b The diagnosis of LOPD based on enzymatic and molecular analyses remains a clinical challenge, because these patients by definition will be normal at the time of diagnosis. Patients will need to be followed closely for the development of clinical signs and symptoms; however, currently, we do not know if all patients with enzymatic and molecular variants suggesting LOPD will actually go on to develop disease. Patients with low GAA activity and molecular variants in trans previously identified in patients with LOPD will be at very high risk of developing LOPD, although patients with low GAA activity and molecular variants not previously identified have less certain clinical outcomes. There are also patients with low GAA activity above the range seen in previous LOPD patients with VUS (not a pseudodeficiency allele) who will need to be followed for possible LOPD. In situations where greater ambiguity exists, analysis in another tissue, as noted, may help to more clearly delineate the patients’ disease status. c Includes VUS with borderline low GAA activity.
  24. Diagnostic algorithm for Pompe disease with DNA sequencing as part of the NBS laboratory protocol. Modified from the New York Mid-Atlantic Consortium for Genetic and Newborn Screening Services (NYMAC) Pompe Disease NBS Symposium 2013. a Obtain as a baseline for monitoring response to treatment; can also be postponed until a definitive diagnosis is obtained. b The diagnosis of LOPD based on enzymatic and molecular analyses remains a clinical challenge, because these patients by definition will be normal at the time of diagnosis. Patients will need to be followed closely for the development of clinical signs and symptoms; however, currently, we do not know if all patients with enzymatic and molecular variants suggesting LOPD will actually go on to develop disease. Patients with low GAA activity and molecular variants in trans previously identified in patients with LOPD will be at very high risk of developing LOPD, although patients with low GAA activity and molecular variants not previously identified have less certain clinical outcomes. There are also patients with low GAA activity above the range seen in previous LOPD patients with VUS (not a pseudodeficiency allele) who will need to be followed for possible LOPD. In situations where greater ambiguity exists, analysis in another tissue, as noted, may help to more clearly delineate the patients’ disease status. c Includes VUS with borderline low GAA activity.
  25. Recommended treatment algorithm for patients with classic IOPD in year 1. Two ways to determine the CRIM status of an individual with Pompe disease are: Acid alpha-glucosidase protein quantitation performed by an antibody-based method in cultured fibroblasts; Molecular genetic testing to determine if the pathogenic variants result in total absence of enzyme activity (i.e., are CRIM-negative) Immunomodulation therapy – should be started early in CRIM NEG states CRIM status evaluation use to require a skin biopsy for fibroblast culture, but now can usually be inferred from the molecular genetics
  26. Recommended treatment algorithm for patients with classic IOPD in year 1. a See “The Importance of CRIM Status in ERT.” b See prescribing information for alglucosidase alfa.1,2
  27. Recommended follow-up and treatment algorithm for patients with LOPD based on the presence or absence of symptoms. PFT, pulmonary function test. a See Table 5. b See Table 4. c If no concerns emerge and the patient remains clinically stable during the first 12 months, then evaluations can be spaced out accordingly, but are not to exceed 12-month intervals. If the results of evaluations raise questions or concerns, then closer follow-up will be needed. Parents of patients are asked to return if they have any concerns or questions of their own. d Based on decisions made after discussions between clinicians and individual patients and/or families.
  28. However, 20% of females are symptomatic carriers.
  29. The movie “Lorenzo’s Oil” portrayed the true personal journey of Lorenzo Odone and his parents as they encountered x-linked ALD. Remarkably, the parents did the research and identified the benefit of providing certain dietary fats (in a combination named “Lorenzo’s Oil”) which could successfully reduce the accumulation of very long chain fatty acids. Unfortunately, it did not prove to be a successful therapy in the majority of cases; it remains an investigational drug. However, their efforts paved the way for parents and disease foundations to recognize their roles as assertive advocates in moving forward the science of rare disease.
  30. Now that the most common form of the disease is the later-onset adrenomyeloneuropathy Problems with walking due to weakness, stiffness Incontinence +/- severe cognitive/behavioral issues (10-20%) +/- dysfunctional adrenal cortex (70%) Females present in a similar neurologic way but have no adrenal dysfunction
  31. C26:0 confirmed by MS/MS method. Remeasured again by MS/LC/MS. Then molecular testing.
  32. Note that some patients with who have elevated VLCFAs but are NOT found to have a genetic alteration in ABCD1 may have elevated levels because of some other peroxisomal disorder like Zellweger disease which has many biochemical disturbances including elevated VLCFAs, so this screen may pick up those disorders as well.
  33. Brain MRIs are done yearly prior to age 3 years, then every 6 months until age 12 years, then yearly to monitor.
  34. Caused by alteration in SMN1 gene, which is necessary for the Survival of Motor Neurons 95% of SMA cases show absence of exon 7. Screening seeks to identify infants with absent SMN1. Carriers are NOT identified. Without functional SMN1, motor neurons degenerate and progressive neuromuscular disease. A “rescue” or paralog gene, SMN2, has low function and may modify disease progression if multi-copy
  35. Repeat newborn screen and SMN2 testing is sent out
  36. MPS type I requires urgent counseling but treatment within days/weeks is not as imperative. Same with x-ALD. Aside from Addison disease (which does not occur in infants), the natural history needs to be followed with serial MRI scans and neurologic examinations.
  37. This is not a judgment. The point here is to generate thinking based on our experience seeing these patients and families in a clinic setting.