Mark ở vũ trụ khác · Another Universe Genes and Rare Diseases #4 · Genetics · Newborn screening

A drop of blood from the heel

Følling 1934 · Bickel 1953 · Guthrie and Susi, Pediatrics 1963 · newborn screening

DiseasePhenylketonuria (PKU): the body cannot process phenylalanine from protein
GenePAH on chromosome 12, recessive inheritance
StoryA mother in Norway, a diet in England, a filter paper in the USA
LabelSolid: find it early and harm can be prevented

Source: Følling (1934), Hoppe-Seyler's Zeitschrift für physiologische Chemie 227: 169–176; Bickel, Gerrard, Hickmans (1953), Lancet 265: 812–813; Guthrie and Susi (1963), Pediatrics 32: 338–343; GeneReviews "Phenylalanine Hydroxylase Deficiency" (Regier, Greene, revised 2017).

For reading and understanding, not a substitute for medical advice.

Recap in 1 minute

Essence

1934: urine changes colourA mother in Norway brought her two children's urine to Dr Følling. A drop of ferric chloride turned it green.
One missing enzymeThe PAH enzyme converts phenylalanine (found in protein). Without it, phenylalanine builds up and harms the growing brain.
The right diet, normal growthIn 1953 a low-phenylalanine diet helped a little girl in England for the first time. It is still the basis of treatment.
A drop from the heelRobert Guthrie created a test from blood dried on paper (1963). Since then, a whole generation has been checked right after birth.
Vietnam, 2026From 1 July 2026, PKU is on the Ministry of Health's list of 33 conditions recommended for newborn screening.

Source: Følling (1934) and Science History Institute, "On the scent: the discovery of PKU" (secondary, on the mother); GeneReviews; Bickel et al. (1953), Lancet; Guthrie and Susi (1963), Pediatrics; Vietnam Circular 12/2026/TT-BYT (15 May 2026), Appendix II.

Part 1

The question

Some genetic diseases cannot be cured but their harm can be prevented, if found in the first few days of life. So when your child is born, do you know what they are tested for?

The question is Mark's, based on GeneReviews (untreated PKU causes irreversible brain damage) and Vietnam's newborn screening regulations.

1934Finding the diseaseA mother who would not give up, a doctor willing to add one more drop of reagent.
→
1951–1953Finding a treatmentLess phenylalanine in the diet, no more harm to the brain.
→
1963 to nowFinding it before harmA drop of blood from the heel, right after birth.
Part 2

The story

Who, where, when: three countries, three decades, one disease.

1934 · Norway: a mother who would not give upBorgny had two children with developmental delays and noticed a strange smell in their urine. After many doctors had no answer, she went to Asbjørn Følling, a physician and chemist. He added ferric chloride to the urine: it should have turned purple, but it turned green.
1934 · A substance no one had seen in the bodyFølling isolated phenylpyruvic acid, tested other people with developmental delays, and published in 1934. The disease later became known as phenylketonuria, PKU.
1951–1953 · England: a little girl and a dietSheila Jones, aged 2, in Birmingham, was diagnosed with PKU. Her mother pressed the doctors for help. Horst Bickel, with John Gerrard and Evelyn Hickmans, made a protein formula with most phenylalanine removed, following an idea from Louis Woolf. She improved clearly. The paper appeared in the Lancet on 17 October 1953.
The remaining problemThe diet helps most only if started very early, before the brain is harmed. But at birth, a baby with PKU looks completely normal.
1963 · USA: a filter paperRobert Guthrie, a microbiologist in Buffalo, had a niece with PKU. He devised a cheap test: blot a drop of heel blood on paper and place it on a plate of bacteria; the more phenylalanine, the wider the bacteria grow. His paper with Ada Susi tested 682 infants.
Early 1960s · From the lab to the nationA trial across 29 US states with about 400,000 newborns, then states began screening every baby. The heel-prick blood spot became routine in many countries.

Source: Følling (1934), Hoppe-Seyler's Z Physiol Chem 227: 169–176; Science History Institute, Distillations (the mother, ferric chloride test; secondary); Bickel, Gerrard, Hickmans (1953), Lancet 265: 812–813; "The First Treatment for PKU: The Pioneers, Birmingham 1951", International Journal of Neonatal Screening (2021) (Sheila Jones, Louis Woolf); Guthrie and Susi (1963), Pediatrics 32: 338–343 (682 infants); "Robert Guthrie and the Trials and Tribulations of Newborn Screening", International Journal of Neonatal Screening (2021) (niece); Wadsworth Center, New York State Department of Health (29 states, 400,000 infants; secondary).

How the Guthrie test works, illustrated: a blood-soaked paper disc placed on a bacteria plate. Normal blood: bacteria grow in a small ring. High-phenylalanine blood: bacteria grow in a large ring. Guthrie test: more phenylalanine, wider ring of bacteria (illustration) normal bloodhigh-phenylalanine blood why cheap and fast? • only a few drops of blood on paper • dried paper can be posted • one plate reads many samples • today replaced by mass spectrometry, one drop checks many diseases at once
The best idea was the filter paper. Dried blood on paper is easy to collect, post and store, so millions of babies could be screened.Source: Guthrie and Susi (1963), Pediatrics 32: 338–343 (bacterial inhibition method); reviews of tandem mass spectrometry newborn screening (secondary). The figure is an illustration, not a photo of a real test.
Part 3

How the gene works, in 3 sentences

1. The PAH gene (chromosome 12) is the recipe for the liver enzyme phenylalanine hydroxylase, which turns phenylalanine, found in all protein, into tyrosine.

2. When both copies of PAH are faulty, the enzyme barely works, phenylalanine piles up in the blood and harms the developing brain.

3. It is recessive: parents are usually healthy, each carrying one faulty copy; with each pregnancy, the child has a 25% chance of the disease.

How PKU works. Normally: phenylalanine from food is turned into tyrosine by the PAH enzyme. In PKU: PAH is broken, this route is blocked, phenylalanine builds up in the blood, some becomes phenylpyruvic acid in urine, and it harms the developing brain. normally phenylalanine (protein) PAH enzyme tyrosine in PKU phenylalanine builds up PAH broken phenylpyruvic acid in urine harms the developing brain
The substance Følling saw in 1934 is the "detour" of piled-up phenylalanine. So less phenylalanine in the diet means less harm.Source: GeneReviews "Phenylalanine Hydroxylase Deficiency"; Følling (1934). Simplified illustrative diagram.
Recessive inheritance. Father and mother each carry one faulty copy and one normal copy, and are healthy. Four possibilities for a child: one has two faulty copies (affected, 25%), two carry one faulty copy (healthy, 50%), one carries none (25%). healthy parents, both carriers: at each birth father (healthy) mother (healthy) affected carrier carrier not a carrier 1 in 4 = 25% affected, at each birth
Why do recessive diseases seem to "come out of nowhere"? Carriers of one faulty copy are completely healthy and usually do not know it. Only when two carriers have a child does the disease show.Source: GeneReviews "Phenylalanine Hydroxylase Deficiency" (autosomal recessive); MedlinePlus Genetics "Phenylketonuria". The figure is an illustrative diagram.
More: why take blood after 24 hours, not right at birth?

In the womb, the placenta helps clear phenylalanine, so at birth a baby with PKU does not yet have high levels. Only after feeding (milk contains protein) for a while does phenylalanine rise enough to measure. Vietnam's Ministry of Health guidance: take the screening sample between 24 and 72 hours of age, ideally around 48 hours; if the baby leaves the facility before 24 hours, take it before discharge.

Source: Decision 1807/QĐ-BYT (21 April 2020), technical guidance on prenatal and newborn screening (sampling time, from the summary on hoatieu.vn; this decision was replaced by new guidance in 2026); explanation about the placenta after GeneReviews.

Part 4

Fact check: what is true and what is myth

14 things often said about PKU and newborn screening, checked against the original sources. Tap a row to see why.

How many births per case of PKU: Italy about 1 in 4,500; world average about 1 in 23,930; Japan about 1 in 125,000. Converted per 100,000 births: about 22, 4 and 0.8. babies with PKU per 100,000 births (converted) Italy (1/4,500)≈ 22 world (1/23,930)≈ 4 Japan (1/125,000)≈ 0.8
Same disease, about 28 times apart between two countries. Mark found no reliable figures for PKU frequency in Vietnam.Source: Hillert et al. (2020), American Journal of Human Genetics 107(2): 234–250 (16,092 patients in 51 countries). Conversion per 100,000 is Mark's.
SOLIDPKU is caused by a lack of the PAH enzyme; phenylalanine builds up and harms the brain

GeneReviews "Phenylalanine Hydroxylase Deficiency".

SOLIDHealthy parents who both carry one faulty copy have a 25% chance with each birth

Autosomal recessive (GeneReviews; MedlinePlus Genetics).

SOLIDPKU was found because urine turned green with ferric chloride

Følling (1934); Science History Institute (secondary).

SOLIDA low-phenylalanine diet was the first treatment

Started in December 1951 with Sheila Jones, published in the Lancet in 1953 (Bickel, Gerrard, Hickmans).

SOLIDThe Guthrie test uses a drop of blood dried on paper and works for large numbers of babies

Guthrie and Susi (1963), Pediatrics 32: 338–343; tested on 682 infants, most aged 4 days.

SOLIDUntreated severe PKU causes profound, irreversible intellectual disability

GeneReviews. A 2018 review found 59 rare cases without severe effects despite late treatment; they are exceptions (Orphanet Journal of Rare Diseases 2018).

SOLIDWomen with PKU need to control phenylalanine before pregnancy

High maternal phenylalanine harms the fetus even if the child does not have PKU: with classic maternal PKU and Phe of 1,200 µmol/L or more, 75–90% of children have microcephaly and developmental delay (Levy and Ghavami 1996). European guidelines: keep 120–360 µmol/L (van Wegberg et al. 2017).

SOLIDFrom 1 July 2026, PKU is on Vietnam's newborn screening list

Circular 12/2026/TT-BYT, Appendix II, codes E70.0 (classical phenylketonuria) and E70.1 (other hyperphenylalaninaemia), among 33 conditions recommended for newborn screening.

CAUTION"PKU is equally rare everywhere"

From about 1 in 4,500 in Italy to 1 in 125,000 in Japan (Hillert et al. 2020).

CAUTION"Every baby in Vietnam is already screened for PKU"

The basic package since 2021 covers 5 conditions and not PKU (Decision 3845/QĐ-BYT). The 2026 Circular adds PKU to a "recommended" list; ask the hospital whether your baby's package includes PKU.

FALSE"A positive screen means the baby definitely has the disease"

Screening only flags babies who need more testing. As early as 1963, Guthrie and Susi recommended a second blood sample to confirm.

FALSE"You can stop the diet when you grow up"

For severe PKU (untreated phenylalanine above 600 µmol/L), European guidelines recommend lifelong treatment. Milder forms may only need treatment until age 12 (van Wegberg et al. 2017).

FALSE"The phenylalanine warning on diet sweets is for everyone"

In the USA, foods with aspartame must state "Phenylketonurics: contains phenylalanine", a reminder for people with PKU (21 CFR 172.804; HHS).

FALSE"There is a drug that cures PKU"

FDA-approved drugs (sapropterin, pegvaliase in 2018, sepiapterin in 2025) lower phenylalanine in some people, alongside diet or close monitoring. Gene editing is only at the stage of starting trials (2026).

Source: as given in each row; full list in Part 9.

Part 5

Where things stand today

The diet is still the foundation. New drugs let some people eat more freely. Screening keeps expanding, including in Vietnam.

2007 · The first oral drug that helps some peopleSapropterin (a form of the BH4 cofactor) was approved by the FDA for patients with some remaining PAH activity.
24 May 2018 · An enzyme substitute for adultsPegvaliase (injection) was approved by the FDA for adults with phenylalanine above 600 µmol/L despite treatment. It carries a warning for severe allergic reactions.
28 July 2025 · A new oral drugSepiapterin was approved by the FDA for responsive patients from 1 month of age, used with diet. In the trial, phenylalanine fell by 64.2% on average compared with placebo.
1 July 2026 · Vietnam expands its listCircular 12/2026/TT-BYT takes effect: 70 conditions recommended for prenatal screening and 33 for newborn screening, PKU among them.
June 2026 · Gene editing heads for human trialsA therapy that edits one letter of the PAH gene in the liver was cleared by the FDA to begin trials (secondary source). No human results yet.

Source: PKU patient association page (sapropterin 2007, secondary); ESPKU 28 May 2018 and thepharmaletter (pegvaliase); company release filed with the SEC 28 July 2025, Drugs.com (sepiapterin, 64.2%); Circular 12/2026/TT-BYT (via luatvietnam.vn, thuvienphapluat.vn); sentisense, June 2026, and the company's FASEB 2026 poster (gene editing; secondary). Checked 16 October 2026.

Part 6

Rating

Scores are Mark's rating based on the sources in Part 9, not data from a study.

How solid the science is
5/5
Impact on preventive health
5/5
Treatment so far
3/5
Lessons for readers
5/5
What worked
  • Turned a severely disabling disease into one people can live with
  • Opened the whole field of newborn screening from one drop of blood
  • Began with the persistence of two mothers
What is still hard
  • A lifelong diet is very hard to keep, especially for teens and adults
  • New drugs suit only some people, and are expensive
  • Not every baby is screened for PKU

One drop of blood, at the right time, changes a whole life: the most successful "know early" story in genetics.

More: why is PKU the "model disease" for screening?

In 1968, Wilson and Jungner wrote 10 principles for WHO to decide whether a disease should be screened for: it must be important, have a detectable early stage, a suitable test, an effective treatment if found early... PKU fits almost all of them, which made it the textbook example.

Source for "More": Wilson and Jungner (1968), Principles and practice of screening for disease, WHO Public Health Papers 34. The other lines are Mark's commentary based on Parts 2 to 5.

Part 7

Lessons: ask about the drop of blood from the heel

For reading and understanding, not a substitute for medical advice. These are questions worth asking, not treatment advice.

Four questions about newborn screening: has the baby had the heel prick, and at what age in hours; which diseases does the package include, is PKU one; when will results come and who calls if abnormal; if the result says "retest needed", what to do next. 1 · sample taken?at how many hoursideally around 48 hours 2 · which diseases?is PKU includedbasic or extended package 3 · when are results?who calls if abnormalleave the right phone number 4 · "retest needed"?not a diagnosis yetget the confirmatory test now With PKU, time is brain: a few days earlier makes a difference.
Each question rests on something sourced in this piece. Sampling time from Ministry of Health guidance; disease lists from Decision 3845/QĐ-BYT and Circular 12/2026; "a positive screen needs a second sample" from Guthrie and Susi (1963).Source: as above. The four questions are Mark's suggestions.
Ask before the birthAt a late antenatal visit, ask the hospital: which diseases does newborn screening here cover, is PKU included, is there a fee?
Watch the timingIf you go home early, ask whether the sample has been taken. Too early may mean a repeat.
Read "suspected" correctly"High risk, retest needed" is an invitation to a confirmatory test right away, not a verdict.
Read labels for their reason"Contains phenylalanine" on diet sweets is a reminder for people with PKU, not a sign the product is toxic for everyone.
Self-check: your baby's screening slip in 5 minutes

1. Find the slip or record of your baby's heel prick (or your own, if your parents kept it).

2. Write down: date and time of birth, date and time of the sample. How many hours apart?

3. Which diseases does the slip list? Is "phenylketonuria" or "PKU" there?

4. Does the result say "normal", "low risk" or "retest needed"?

5. If anything is unclear, write the question down for the next doctor's visit.

The self-check is Mark's suggestion, not a protocol from a study or the Ministry of Health.

Part 8

Further reading

Science History Institute, "On the scent: the discovery of PKU"The story of the mother and Dr Følling, told in detail.
GeneReviews, "Phenylalanine Hydroxylase Deficiency"The full medical review.
MSD Manual, "Phenylketonuria (PKU)"A medical reference, also available in Vietnamese.
Genes and Rare Diseases #03: Huntington's and the villages by the lakeAnother genetic disease, where knowing early does not yet prevent it: a story about the right to know. Read
Genes and Rare Diseases #05: ThalassemiaA recessive disease fairly common in Vietnam, and premarital testing.
Part 9

Sources

The main sources are original papers, Vietnam's Ministry of Health documents, FDA decisions and medical databases. The working environment blocks NCBI, legal-document portals and the Ministry of Health site, so figures were checked against excerpts in search results, without opening the full text. Secondary sources are marked. Checked 16 October 2026.

  1. Følling A (1934), "Über Ausscheidung von Phenylbrenztraubensäure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillität", Hoppe-Seyler's Zeitschrift für physiologische Chemie 227: 169–176.
  2. Bickel H, Gerrard J, Hickmans EM (1953), "Influence of phenylalanine intake on phenylketonuria", Lancet 265(6790): 812–813. James Lind Library
  3. Guthrie R, Susi A (1963), "A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants", Pediatrics 32(3): 338–343.
  4. Woo SLC et al. (1983), "Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria", Nature 306: 151–155; Lidsky AS et al., "The PKU locus in man is on chromosome 12", American Journal of Human Genetics.
  5. Regier DS, Greene CL, "Phenylalanine Hydroxylase Deficiency", GeneReviews (2000, revised 2017). NCBI Bookshelf
  6. van Wegberg AMJ et al. (2017), "The complete European guidelines on phenylketonuria: diagnosis and treatment", Orphanet Journal of Rare Diseases 12: 162. PubMed
  7. Hillert A et al. (2020), "The genetic landscape and epidemiology of phenylketonuria", American Journal of Human Genetics 107(2): 234–250.
  8. Levy HL, Ghavami M (1996), "Maternal phenylketonuria: a metabolic teratogen", Teratology (PubMed 8761885); Koch R et al. (2000), Maternal PKU Collaborative Study.
  9. Wilson JMG, Jungner G (1968), Principles and practice of screening for disease, WHO Public Health Papers 34.
  10. Vietnam Ministry of Health and Government: Decision 1999/QĐ-TTg (7 December 2020); Decision 3845/QĐ-BYT (11 August 2021); Decision 1807/QĐ-BYT (21 April 2020); Circular 12/2026/TT-BYT (15 May 2026, in force 1 July 2026). luatvietnam.vn
  11. FDA: 21 CFR 172.804 (aspartame label) eCFR; approvals of pegvaliase (24 May 2018) and sepiapterin (28 July 2025).
  12. Historical reviews: "The First Treatment for PKU: The Pioneers, Birmingham 1951" (PMC8006244) and "Robert Guthrie and the Trials and Tribulations of Newborn Screening" (PMC7838808), International Journal of Neonatal Screening (2021).
  13. Secondary sources: Science History Institute, Distillations (the mother, ferric chloride test); Wadsworth Center, New York State Department of Health (29-state trial, 400,000 infants); hoatieu.vn (summary of Decision 1807); ESPKU, thepharmaletter, Drugs.com, epocrates (drugs); sentisense, June 2026 (gene editing).