Guthrie test

Embryology - 1 Dec 2023        Expand to Translate
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Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.

ICD-11
5C50.0 Phenylketonuria | 8B61 Spinal muscular atrophy

Introduction

Guthrie card

The Guthrie test (Newborn Blood Spot Screening, "Heel Prick" test, dried blood spots, dried-blood spots, DBS) is a neonatal blood screening test originally developed by Dr Robert Guthrie (1916-95) at the University of Buffalo. By 1963 the test had become a routine neonatal test for phenylketonuria.

The "Heel Prick" test.

The Guthrie test or "Heel Prick" test is routinely carried out on neonatal (newborn 48-72 hours of age) blood for a variety of known genetic disorders. The clinical term "phlebotomy" describes the act of drawing or removing blood from the circulatory system through an incision or puncture to obtain a sample for analysis and diagnosis. In Australia screening currently includes 25 rare conditions.

Note that different countries have different policies on:

1. disorders included in the test
2. archiving of this material
3. deidentified availability for genetic research purposes.

An ultrasound study has identified the shortest depth of perichondrium was in the centre of the heel and ranged from 3 to 8 mm. In 78 of the 80 infants in the study (GA24 to 42 weeks), the distance was 4 mm or more. Showing that the standard automated lancets for preterm use (puncture to a depth of 2.4 mm) may be safely used anywhere over the plantar surface of the heel avoiding the posterior aspect of the heel. A more recent study identified the whole heel plantar surface is safe for obtaining blood in term and preterm infants of more than GA 33 weeks. A small amount of sucrose (0.012–0.12 g) can be given as an analgesic for newborns undergoing venepuncture or capillary heel-pricks.

Blood is collected using a heelprick and spotted onto a test sheet to dry for later testing. Different countries and medical services have different policies on not only what will be tested for but also how long the test card will be kept following analysis. Check your local service for specific information.

Historic Embryology

Dr Robert Guthrie (1916-1995) was an American microbiologist at University of Buffalo who developed the collection of whole blood on filter paper "Guthrie cards" for transportation, storage, and testing for metabolic and genetic disorders of the newborn. The test today also has a number of names: "heel prick", "neonatal blood" test, and dried-blood spots. Guthrie is best known for developing the diagnostic test for phenylketonuria.

Some Recent Findings

UK Neonatal blood spot test (August 2013)

Dried blood spot versus venous blood sampling for phenylalanine and tyrosine "Overall agreement between plasma and DBS is good. However, bias is specimen - (LH vs EDTA), and possibly concentration - (low phenylalanine) dependent. Because of the overall good agreement, we recommend the use of a DBS-plasma correction factor for DBS measurement. Each laboratory should determine their own factor dependent on filter card type, extraction and calibration protocols taking the LH plasma values as gold standard." Diagnosing congenital Cytomegalovirus infection: don't get rid of dried blood spots "Congenital cytomegalovirus (cCMV) is a serious global public health issue that can cause irreversible fetal and neonatal congenital defects in symptomatic or asymptomatic newborns at birth. In absence of universal cCMV screening, the retrospective diagnosis of cCMV infection in children is only possible by examining Dried Blood Spot (DBS) samples routinely collected at birth and stored for different time spans depending on the newborn screening regulations in force in different countries. In this article, we summarize the arguments in favor of long-term DBS sample storage for detecting cCMV infection. Conclusion: DBS sampling is a reliable and inexpensive method for long-term bio-banking, which enables to diagnose known infectious diseases - including cCMV - as well as diseases not jet recognized, therefore their storage sites and long-term storage conditions and durations should be the subject of political decision-making." UK - Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme "A decision tree model was built to estimate the economic impact of introducing screening for X-linked adrenoleukodystrophy (X-ALD) into an existing tandem mass spectrometry based newborn screening programme. The model was based upon the UK National Health Service (NHS) Newborn Blood Spot Screening Programme and a public service perspective was used with a lifetime horizon. The model structure and parameterisation were based upon literature reviews and expert clinical judgment. Outcomes included health, social care and education costs and quality adjusted life years (QALYs). The model assessed screening of boys only and evaluated the impact of improved outcomes from hematopoietic stem cell transplantation in patients with cerebral childhood X-ALD (CCALD). Threshold analyses were used to examine the potential impact of utility decrements for non-CCALD patients identified by screening. ...Including screening of boys for X-ALD into an existing tandem mass spectrometry based newborn screening programme is projected to reduce lifetime costs and improve outcomes for those with CCALD. The potential disbenefit to those identified with non-CCALD conditions would need to be substantial in order to outweigh the benefit to those with CCALD. Further evidence is required on the potential QALY impact of early diagnosis both for non-CCALD X-ALD and other peroxisomal disorders. The favourable economic results are driven by estimated reductions in the social care and education costs.

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: neonatal blood test | Guthrie test | heel prick test | congenital metaboloc disorder | phenylketonuria | hypothyroidism | cystic fibrosis | homocystinuria | | maple syrup urine disease | glutaric aciduria type 1 | spinal muscular atrophy

Older papers

These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table. See also the Discussion Page for other references listed by year and References on this current page. Screening for spinal muscular atrophy SMA added to newborn heel prick (Guthrie test) in 'profound' change in medical screening "In an Australian first, newborn babies are now being routinely screened for the genetic condition SMA, or spinal muscular atrophy". SMA leads to a loss of motor neurons and progressive muscle wasting and has several different forms: Type 1, Type 2, and Type 3a SMA. ABC News Review - Aminoacidopathies - Prevalence, Etiology, Screening, and Treatment Options Inborn Errors of Metabolism That Cause Sudden Infant Death: A Systematic Review with Implications for Population Neonatal Screening Programmes "Many inborn errors of metabolism (IEMs) may present as sudden infant death (SID). Nowadays, increasing numbers of patients with IEMs are identified pre-symptomatically by population neonatal bloodspot screening (NBS) programmes. However, some patients escape early detection because their symptoms and signs start before NBS test results become available, they even die even before the sample for NBS has been drawn or because there are IEMs which are not included in the NBS programmes. This was a comprehensive systematic literature review to identify all IEMs associated with SID, including their treatability and detectability by NBS technologies. Reye syndrome (RS) was included in the search strategy because this condition can be considered a possible pre-stage of SID in a continuum of aggravating symptoms. RESULTS: 43 IEMs were identified that were associated with SID and/or RS. Of these, (1) 26 can already present during the neonatal period, (2) treatment is available for at least 32, and (3) 26 can currently be identified by the analysis of acylcarnitines and amino acids in dried bloodspots (DBS). We advocate an extensive analysis of amino acids and acylcarnitines in blood/plasma/DBS and urine for all children who died suddenly and/or unexpectedly, including neonates in whom blood had not yet been drawn for the routine NBS test. The application of combined metabolite screening and DNA-sequencing techniques would facilitate fast identification and maximal diagnostic yield." UK National Screening Committee - Newborn babies will be tested for four more disorders "The test is already used to screen for phenylketonuria, hypothyroidism, sickle cell disease, cystic fibrosis, and medium chain acyl-CoA dehydrogenase deficiency. To these five conditions four more will now be added: homocystinuria, maple syrup urine disease, glutaric aciduria type 1, and isovaleric acidaemia." The stability of markers in dried-blood spots for recommended newborn screening disorders in the United States "We aimed to measure separately the contributions of heat and humidity to changes in levels of 34 markers of inborn disorders in dried-blood-spot (DBS) samples. We stored paired sets of DBSs at 37°C for predetermined intervals in low-humidity and high-humidity environments. Marker levels of all samples in each complete sample set were measured in a single analytic run. During the 30 ± 5 day studies, galactose-1-phosphate uridyltransferase and biotinidase lost almost 65% of initial activities in low-humidity storage; most of the degradation in 27 other markers was attributable to adverse effects of high-humidity storage; seven markers in DBSs stored at high humidity lost more than 90% of initial levels by the end of the study and 4 of the 7 lost more than 50% of initial levels within the first week of storage." Newborn hearing screening and genetic testing in 8974 Brazilian neonates. "We have found 17 individuals who failed in transient otoacoustic emissions (TOAE). Among them, we detected 4 homozygous newborns for 35delG mutation and 3 individuals with A827G mutation in the MTRNR1 mitochondrial gene." Whole genome microarray analysis, from neonatal blood cards. "Neonatal blood, obtained from a heel stick and stored dry on paper cards, has been the standard for birth defects screening for 50 years. Such dried blood samples are used, primarily, for analysis of small-molecule analytes. More recently, the DNA complement of such dried blood cards has been used for targeted genetic testing, such as for single nucleotide polymorphism in cystic fibrosis. Expansion of such testing to include polygenic traits, and perhaps whole genome scanning, has been discussed as a formal possibility. However, until now the amount of DNA that might be obtained from such dried blood cards has been limiting, due to inefficient DNA recovery technology. ...Together, these data suggest that DNA obtained from less than 10% of a standard neonatal blood specimen, stored dry for several years on a Guthrie card, can support a program of genome-wide neonatal genetic testing."

Routine Screened Disorders

This list may differ between countries.

• phenylketonuria (PKU) (OMIM)
• Biotinidase Deficiency (OMIM)
• Congenital Adrenal Hyperplasia (CAH) (OMIM)
• Congenital Hypothyroidism (CH)
• Congenital Toxoplasmosis
• Cystic Fibrosis (CF) (OMIM)
• Galactosemia (GAL) (OMIM)
• Homocystinuria (OMIM)
• Maple Syrup Urine Disease (MSUD) (OMIM)
• Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD) (OMIM)
• Toxoplasma gondii IgM antibodies

Phenylketonuria

ICD-11

5C50.0 Phenylketonuria Phenylketonuria is a hereditary metabolic disease, characterized by deficiency of phenylalanine hydroxylase, an enzyme necessary for the transformation of phenylalanine into tyrosine. Untreated, phenylketonuria leads to mental retardation, sometimes profound, as well as hypopigmentation. Dietary phenylalanine restriction allows patients to lead almost normal lives. 5C50.00 Classical phenylketonuria | 5C50.01 Nonclassical phenylketonuria | 5C50.02 Embryofetopathy due to maternal phenylketonuria

Incidence is about 1 in 10,000 live births (about 10 babies per year). PKU causes high blood levels of phenylalanine and severe intellectual disability. A diet low in phenylalanine, started in the first two to three weeks results in normal development.

5C50.00 Classical phenylketonuria - Classical phenylketonuria is a severe form of phenylketonuria (PKU, ) an inborn error of amino acid metabolism characterized in untreated patients by severe intellectual deficit and neuropsychiatric complications.

5C50.01 Nonclassical phenylketonuria - Mild phenylketonuria is a rare form of phenylketouria (PKU, ), an inborn error of amino acid metabolism, characterized by symptoms of PKU of mild to moderate severity.

5C50.02 Embryofetopathy due to maternal phenylketonuria - Maternal phenylalaninemia refers to developmental anomalies that may occur in offspring of women affected by phenylketonuria (PKU), and include fetal development disorders, including microcephaly, intrauterine growth retardation, and subsequent intellectual deficit, and embryo development disorders such as heart defects (usually conotruncal), corpus callosus agenesis, neuronal migration disorders, facial dysmorphism and more rarely cleft palate, tracheo-esophageal abnormalities.

PubMed Search - Phenylketonuria

Galactosaemia

ICD-11
5C51.4 Disorders of galactose metabolism Classic galactosemia is a life-threatening metabolic disease with onset in the neonatal period. Infants usually develop feeding difficulties, lethargy, and severe liver disease. 5C51.40 Galactose-1-phosphate uridyltransferase deficiency | 5C51.41 Galactokinase deficiency | 5C51.42 Glucose or galactose intolerance of newborn

Galactosaemia incidence is about 1 in 40,000 births, about 1-3 cases per year. See a recent disease review and a Cochrane Database review. Babies cannot process galactose, a component of lactose. Life-threatening liver failure and infections can occur. A galactose-free diet instituted in the first week can be life saving.

5C51.41 Galactokinase deficiency - is a rare mild form of galactosemia characterized by early onset of cataract and an absence of the usual signs of classic galactosemia, i.e. feeding difficulties, poor weight gain and growth, lethargy, and jaundice.

Links: milk | OMIM)

PubMed Search - Galactosaemia

Krabbe Disease

ICD-11 8A44.4 Krabbe disease Krabbe disease, also called globoid cell leukodystrophy, is a sphingolipidosis resulting from galactosylceramidase (or galactocerebrosidase) deficiency, a lysosomal enzyme that catabolizes a major lipid component of myelin. The disease leads to demyelination of the central and peripheral nervous system which is rapidly progressive from the first year of life, but juvenile, adolescent or adult onset forms have also been reported, with a more variable rate of progression.

Krabbe Disease (globoid cell leukodystrophy, galactosylcerebrosidase deficiency, galactosylceramidase deficiency) Rare abnormality lysosomal disorderdue to mutation in the GALC gene producing less galactosylceramidase, an enzyme required for glial cells to make myelin that insulates nerve cells. This is also classified as a lysosomal disorder. There is a neonatal test for the disease that has an autosomal recessive inheritance

1. Early-onset form - appears first months of life, lethal before age 2). See this recent review.
2. Late-onset form - appears in late childhood or early adolescence). pattern.

Links: autosomal recessive inheritance | Neural Exam Movies | Inheritance Genetics

Maple Syrup Urine Disease

ICD-11 5C50.D0 Maple-syrup-urine disease Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acids metabolism. Four forms are described. The early onset classic form manifests after birth by lethargy, poor feeding and neurological signs of intoxication. Clinical course without treatment is characterized by deepening coma with maple syrup odor of urine. Subacute MSUD manifests later with encephalopathy, mental disability, major hypotonia, opisthotonus and cerebral atrophy with severe outcome. The intermittent form of MSUD may manifest at any age and presents with repeated ketoacidotic coma. Thiamine-responsive MSUD is a very rare form characterized by improvement of the biochemical profile with thiamine therapy.

Links: OMIM | Search PubMed

Biotinidase Deficiency

ICD-11 5C50.E Organic aciduria - 5C50.E0 Classical organic aciduria This a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder characterized primarily by cutaneous and neurologic abnormalities. Symptoms result from the patient's inability to reutilize biotin, a necessary nutrient. (text from OMIM)

Links: OMIM

Spinal Muscular Atrophy

ICD-11 8B61 Spinal muscular atrophy Spinal muscular atrophy (SMA) is a progressive disorder with loss of anterior horn cells leading to muscle weakness and wasting. The weakness is typically symmetrical. Typically, upper motor neuron signs are absent and there is no sensory deficit. Feeding and swallowing can be affected, and involvement of respiratory muscles may occur. SMA is an autosomal recessive disorder linked to chromosome 5q13 and the disorder is caused by deletion or mutation of SMN 1 (spinal motor neuron 1) gene. The four types of SMA I, II, III and IV are categorised based on the age of onset of the disease and the ability to achieve motor milestones. 8B61.0 Infantile spinal muscular atrophy, Type I | 8B61.1 Late infantile spinal muscular atrophy, Type II

There are various forms of spinal muscular atrophy designated by the time of onset:

• Infantile - SMA type 1, onset of weakness may be prenatal (decreased fetal movements toward the end of pregnancy) or within the first six months of life.
• Late infantile - SMA type 2, muscle weakness is seen between the ages of 6 to 18 months.
• Juvenile - SMA type 3, weakness of muscles is seen after 18 months of age. The child is able to sit and stand independently.
• Adult - SMA type 4 weakness, most commonly develops after 35 years of age (less commonly between 18 to 35 years old).

Australia now (2018) includes heel prick screening for spinal muscular atrophy (More? see ABC News)

Links: PubMed - spinal muscular atrophy

Australia

<html5media width="600" height="400">https://www.youtube.com/embed/KVmLpVcnI1w</html5media>

NSW Newborn Screening Programme

NSW Newborn Screening Programme

Each year test more than 90,000 babies and detects about 90 who need urgent assessment and treatment. In NSW and Victoria, the bloodspot cards are currently stored indefinitely.

• Phenylketonuria (PKU) - 1 in 10,000 live births (about 10 babies per year). PKU causes high blood levels of phenylalanine and severe intellectual disability. A diet low in phenylalanine, started in the first two to three weeks results in normal development.

• Primary congenital hypothyroidism - 1 in 3,500 live births (about 26 babies per year). It is caused by the absence or abnormal formation or function of the thyroid gland. This causes growth and intellectual disability if not treated. Medication with thyroid hormone started early, results in normal growth and development.

• Cystic Fibrosis (CF) - 1 in 2,500 live births (about 34 babies per year). Without treatment babies develop chest infections and often have very serious failure to thrive. Early institution of treatment greatly improves the health of babies with CF. Newborn bloodspot screening detects about 95% of babies with CF but also detects a few babies who may only be healthy carriers. For these babies a sweat test at about six weeks of age determines whether the baby has CF or is a healthy carrier.

• Galactosaemia - 1 in 40,000 births (about 1-3 cases per year). Babies cannot process galactose, a component of lactose. Life-threatening liver failure and infections can occur. A galactose-free diet instituted in the first week is life saving.

• Rarer metabolic disorders - Some fatty acid, organic acid and other amino acid defects can now be detected using Tandem Mass Spectrometry. These much rarer metabolic disorders affect about 15 – 18 babies per year. Early detection is important as diet and medications can treat most of these disorders. Without appropriate management they can cause severe disability or death.

Potential uses and access of stored bloodspots

• Identified cards may be used for family benefit or research and only with separate consent obtained before testing.
• Non-identifiable cards (identifiers permanently removed) may be used for research approved by a Health Research Ethics Committee – consent is not required.
• Parents have a right to access their child’s information. Other access requires parental consent except where there is a court order, to date this has not occurred.

Genetics services in NSW - coordinated by the NSW Genetics Service Advisory Committee, which is supported by the Statewide Services Development Branch of the Strategic Development Division, NSW Department of Health. (Information from NSW Health - Newborn Bloodspot Screening Policy 13-Nov-2006)

Links: NSW Genetics Health

New Zealand

<html5media width="600" height="400">https://www.youtube.com/embed/xRbu8gV-JvI</html5media>

Links: NZ newborn screening

USA

State laws mandate that blood be drawn from all newborn infants to screen for health-threatening conditions.

References

Reviews

van der Spek J, Groenwold RH, van der Burg M & van Montfrans JM. (2015). TREC Based Newborn Screening for Severe Combined Immunodeficiency Disease: A Systematic Review. J. Clin. Immunol. , 35, 416-30. PMID: 25893636 DOI.

Articles

Abdelhakim M, McMurray E, Syed AR, Kafkas S, Kamau AA, Schofield PN & Hoehndorf R. (2020). DDIEM: drug database for inborn errors of metabolism. Orphanet J Rare Dis , 15, 146. PMID: 32527280 DOI.

Adam BW, Hall EM, Sternberg M, Lim TH, Flores SR, O'Brien S, Simms D, Li LX, De Jesus VR & Hannon WH. (2011). The stability of markers in dried-blood spots for recommended newborn screening disorders in the United States. Clin. Biochem. , 44, 1445-50. PMID: 21963384 DOI.

Streetly A, Latinovic R, Hall K & Henthorn J. (2009). Implementation of universal newborn bloodspot screening for sickle cell disease and other clinically significant haemoglobinopathies in England: screening results for 2005-7. J. Clin. Pathol. , 62, 26-30. PMID: 19103854 DOI.

Whiteman PD, Clayton BE, Ersser RS, Lilly P & Seakins JW. (1979). Changing incidence of neonatal hypermethioninaemia: implications for the detection of homocystinuria. Arch. Dis. Child. , 54, 593-8. PMID: 507913

Search PubMed

Search Pubmed: Guthrie test | neonatal blood spot test

External Links

External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.

• Geneva: World Health Organization; 2010. WHO Guidelines on Drawing Blood: Best Practices in Phlebotomy.

• Drug Database for inborn errors of metabolism DDIEM a manually curated, ontologically formalized knowledgebase of drugs, therapeutic procedures, and mitigated phenotypes.

Australia

• PDF Screening Guidelines (2015)
• PDF Newborn Bloodspot Screening - NSW Health (2016)
• Australian Institute of Health and Welfare (AIHW)
• NSW Genetics Health

New Zealand

• NZ newborn screening
• Information Video

United Kingdom

• Screening Programmes
• UK National Screening Committee
• UK National Screening Committee - Meetings
• newborn blood spot
• newborn blood spot

USA

• Medline Plus - Newborn screening tests

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Cite this page: Hill, M.A. (2023, December 1) Embryology Guthrie test. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Guthrie_test

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© Dr Mark Hill 2023, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G