Med Gen Block C

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purpose of NBS

identify pre-symptomatic children with treatable disorders and begin treatment as early as possible

Who developed the Newborn Screen?

Robert Guthrie

What are essential considerations for adding a condition to NBS?

• accepted treatment available

• facilities present for diagnosis and treatment

• has a recognizable latent or early symptomatic stage

• test is acceptable to the population (heel stick acceptable, spinal tap not)

• cost of finding the case early is cheaper than finding it later

• the screen keeps developing

Which condition on the NBS is the ideal condition for NBS?

MCADD, because it has a high mortality if unscreened, has a latent phase where babies seem healthy, has a inexpensive and effective treatment, and is very easy to validate on tandem mass spec.

Recommended Uniform Screening Panel (RUSP)

scored conditions that could be tested on NBS out of 2100 using 19 criteria, in 2006 it was initially approved for 29 core disorders and 25 secondary disorders and through 2025 more conditions were evaluated through committee review

When was the RUSP approved by the U.S. Department of Health and Human Services (HHS)?

2006

When did Texas begin screening for PKU?

1965

U.T. Southwestern/Children’s Health handle how many NBS cases in Texas?

45%

What percent of babies undergoing the Texas two-screen NBS have abnormal screens?

1%

What percent of cases from NBS actually are diagnosed with diseases on NBS?

0.03%

Steps that occur when a NBS comes back abnormal

1. State lab contacts the pediatrician and newborn screen referral center

2. Pediatrician is sent disease-specific information (lab result, ACT sheet, FACT sheet, list of metabolic referral centers) and advised about confirmatory testing

3. Newborn screen referral team fields questions about potential diagnosis and treatment

4. Definitive labs are sent by the pediatrician and reviewed by the newborn screen referral center

5. For selected disorders, the patients are evaluated in the newborn screening clinic

6. If diagnosis is established, patient is then referred to genetics and metabolism clinic

Critical Conditions on Screen

conditions where the patient gets sick very quickly after birth, often presenting with lethargy, irritability, and poor feeding

ex: Maple Syrup Urine Disease, Methylmalonic Acidemia and Propionic Acidemia, Isovaleric Acidemia, Citrullinemia and Argininosuccinic aciduria, Galactosemia

Phenylketonuria (PKU)

PAH (AR), deficiency of phenylalanine hydroxylase resulting in elevated blood phenylalanine (over 360 umol/L)

without treatment, patients have severe ID, seziures, and behavior problems

treatment consists of a phenylalanine-restricted diet with supplementation of tyrosine

NBS for PKU

tests phenylalanine level but can also look at Phe/Tyr ratio as this is specific early on whereas just phenylalanine may not be

follow up is through testing quantitative amino acids and then molecular testing to confirm PAH variants

Medium Chain Acyl CoA Dehydrogenase Deficiency (MCADD)

ACADM (AR), patient often has elevated C8 (can also have elevated C10 and C6) because they cannot break down and oxidize fatty acids if they are medium length

symptoms are hypoglycemia, lethargy, coma, seizures, and death (with pre-NBS ¼ of patients passing or becoming permanently disabled)

treatments are avoiding fasting especially while ill and monitoring carnitine levels

NBS for MCADD

tests C8 levels and it is very easy to tell if they are elevated (especially on first screen), after which urine is often tested for hexanoyl and suberylglyceride

then can go into diagnostic testing, a four variant panel accounts for 85% of patients

Galactosemia

GALT (AR), deficiency of galactose-1-phosphate uridyltransferase that converts galactose to glucose

symptoms are edema, not eating, vomiting, jaundice, sepsis, kidney problems, and liver failure, as well as DD, apraxia, and female infertility if untreated

treatment consists of a switch away from lactose-based milks to soy formulas

NBS for Galactosemia

assesses GALT enzyme and looks if it is active, exposure to heat can lead to false positive results due to enzyme denaturation

if around 50% it is possible infant is a carrier, if at 25% activity it is likely they have Duarte variant (N314D), and if 0% they have two non-working copies

Biotinidase Deficiency

BTD (AR), dysfunction of the enzyme that allows the body to use and recycle biotin. can look at enzyme activity for diagnosis with 0-10% activity being profound deficiency and 11-30% being partial deficiency. over 30% does not require treatment

symptoms are seizures, muscle weakness, ataxia, eczema, DD, vision loss, hearing loss, and hair loss

treatment is 5 (if partial) -10 (if profound) mg of biotin a day

•First screen positive dol 6

•Phe 270umol/L (RR <225)

•Phe/Tyr 7.65 (RR <2.55)

•Follow up amino acids collected

•Phe 910umol/L (RR: 26-91)

•Plan for molecular confirmation

•Diet therapy initiated dol 10

PKU

•First screen positive on dol 5

•Phe 427umol/L (RR <225)

•Phe/Tyr 6.885 (RR <2.55)

•Follow-up amino acids collected

•Phe 800.8 (RR 26-91)

•Plan for molecular confirmation

•Diet Therapy Initiated dol 6

•Two pathogenic variants in PTPS

biopterin deficiency

•First screen positive on dol 8

•Phe 243x (RR <225)

•Phe/Tyr 4.08 (RR <2.55) elevated

•Follow-up amino acids collected

•Phe 150umol/L (RR 26-91) 

•Plan for molecular confirmation

•No therapy needed at this time 

benign hyperphenylalaninemia

•First screen positive dol 5

•C8 17x elevated

•TDSH four variant panel results on dol 10 with homozygous K304E variant

•Acylcarnitine profile results on dol 18

•C8 10x elevated

•C6 7x elevated

•C10 & C10:1 normal

•Urine organic acids result on dol 18

•Elevations of suberylglycine and hexanoylglycine

MCADD

•First screen positive dol 8

•C8 2x elevated

•TDSH four variant panel results on dol 15 with a heterozygous K304E variant

•Acylcarnitine profile results on dol 18

•C8 2x elevated

•C6 3x elevated

•C10 2x elevated

•C10:1 normal

•Urine  organic acids result on dol 20

•Normal

MCADD carrier

•First screen normal

•Second screen positive dol 22

•C8 borderline elevation

•TDSH four variant panel results on dol 23 with one R123K variant

•Acylcarnitine profile results on dol 29

•C8 3.5x elevated

•C6 1.5x elevated

•C10 1.8x elevated

•C10:1 1.5x elevated

•Urine  organic acids result on dol 28

•A tiny amount of hexanoylglycine is present, suberylglycine at upper limit of normal 

MCADD with VUS

•First screen positive dol 4

•Possible galactosemia flag

•Second screen positive dol 19

•Possible galactosemia flag

•TDSH four variant panel (dol 7): Homozygous Q188R variant

•GALT assay: 0 nmol/h/mg Hb (RR >=24.5 nmol/h/mg Hb)

Classical Galactosemia

•First screen positive (dol 15)

•Possible galactosemia flag

•Second screen normal

•TDSH four variant panel: Inconclusive (no variants identified)

•GALT assay: 25 nmol/h/mg Hb (RR >=24.5 nmol/h/mg Hb)

Cleared

•First screen normal

•Second screen positive dol 17

•Possible galactosemia flag

•TDSH four variant panel (dol 21)

•heterozygous Q188R and heterozygous N314D

•GALT assay: 5.4 nmol/h/mg HB (RR >= 24.5 nmol/h/mg Hb)

Duarte Variant Galactosemia

•First screen possible biotinidase deficiency (dol 7)

•Second Screen possible biotinidase deficiency (dol 19)

•Biotinidase assay (dol 17): 0.0nmol/min/mL (RR: 4.8-12.0)

Profound Biotinidase Deficiency

•First screen normal

•Second screen possible biotinidase deficiency (dol 21)

•Biotinidase assay (dol 32): 2.3nmol/min/mL (RR: 4.8-12.0)

Cleared

•First screen normal

•Second Screen possible biotinidase deficiency (dol 20)

•Biotinidase assay (dol 30): 1.9nmol/min/mL (RR: 4.8-12.0)

Partial Biotinidase Deficiency

Lysosome

the cell’s garbage disposal system that contains many different enzymes which break down macromolecules into smaller components that can be recycled

Danon Disease

LAMP2 (XL), encodes a lysosome-associated membrane protein

affects cardiac muscle, skeletal muscle, and the brain (producing neurological symptoms), some also have retinal disease. treatment is mainly focused on heart symptoms, like heart transplant, defibrillators, cardiac ablation therapy

Pompe Disease

GAA (AR), encodes an enzyme that breaks down glycogen in the lysosome

two types: infantile onset (before age 1) and late onset (after age 1). symptoms are hypotonia, respiratory insufficiency, and cardiomegaly. found on NBS, treated often with ERT

Which set of lysosomal storage diseases have pseudodeficiency alleles?

Pompe, Tay-Sachs, Krabbe

What is one of the variants known to be associated with LOPD?

c.-32-13T>G

MPS I (Hurler/Hurler-Scheie/Scheie Syndrome)

IDUA (AR), encodes enzyme involved in breaking down large sugar molecules (glycosaminoglycans) in the lysosome

first symptoms are skeletal anomalies, corneal clouding, respiratory problems, developmental delay, umbilical hernias. symptoms are progressive. found on NBS, treatment is ERT or stem cell transplants (latter if patient is more severely affected)

MPS II (Hunter Syndrome)

IDS (XL), encodes enzyme involved in breaking down large sugar molecules (glycosaminoglycans) in the lysosome

symptoms are short stature, ID, coarse face, hepatosplenomegaly, joint contractures, respiratory problems. found on NBS, treatment is ERT (two types, one does not treat CNS symptoms, one does)

MPS III (Sanfilippo Syndrome)

4 genes (AR): SGSH (A), NAGLU (B), HGSNAT (C), GNS (D), all encode enzymes involved in breaking down large sugar molecules (glycosaminoglycans) in the lysosome

less somatic involvement than other MPS, mainly CNS/neurocognitive decline symptoms and sleep disturbances. no treatments for B-D so focus there is on supportive care, but A has a gene therapy released in Sep 2026

MPS IV (Morquio Syndrome)

2 genes (AR): GALNS (95%) and GLB1 (5%), which encode enzymes that break down glycosaminoglycan keratan sulfate

less CNS involvement than other MPS, mainly skeletal differences, more subtle facial features, and patients have typical intellect. has an ERT for treatment

Which MPS does not have corneal clouding?

Hunter Syndrome

Which MPS does not have intellectual disability?

MPS IV

Which mucopolysaccharidoses have less hepatosplenomegaly?

MPS III and MPS IV

Batten Disease

CLN1, CLN2, CLN3 genes (AR), enzyme cannot break down ceroid lipoduscin, which is a lipid waste in neurons. there are 14 total progressive disorders

CLN1: classic infantile onset - symptoms before 3 years old

CLN2: classic late infantile onset - symptoms between 4-5 years old

CLN3: classic juvenile onset - symptoms at 5.5-8.5 years old

symptoms are progressive and are vision loss, muscle weakness, seizures, loss of coordination, and cognitive impairment. CLN2 can be treated with ERT

Fabry Disease

GLA (XL), encodes enzyme involved in breaking down sphingolipids, classic form is men with less than 1% enzyme activity (but now is being broadened to include women)

classic form has onset in childhood or adolescence (but only 20-25% of patients with this form). symptoms are severe pain crises in hands and feet, angiokeratomas, sweating abnormalities, corneal and lenticular opacities, and kidney problems (often end-stage kidney disease), and cardiac disease. treated with ERT or chaperone therapy

chaperone therapy

a therapy that works for patients with misfolded proteins that cause disease, introduces small molecules that stabilize the misfolded proteins in the body so that they can function right

enzyme replacement therapy (ERT)

a therapy that works for patients with missing or deficient enzymes that cause disease, introduces a functional, lab-made version of the missing enzyme to clear out toxic build-ups or aid in body function

Gaucher Disease

GBAI (AR), encodes glucocerebrosidase enzyme involved in breaking down glucosylceramide in the lysosome

can be adult onset (type 1), infantile onset (type 2), childhood onset (type 3), perinatal lethal, or cardiac form (late child to early adolescence). symptoms are hepatosplenomegaly, anemia, and CNS issues. treated with ERT, substrate reduction therapy, or stem cell transplant

substrate reduction therapy

a therapy where a patient takes an oral drug and it results in the enzyme that is responsible for building the molecules that normally build up being inhibited (slows down rate of production) so that molecules do not accumulate