Galactosemia

Overview

Galactosemia is an inherited metabolic disorder that can lead to life-threatening complications unless a lactose-restricted diet is immediately provided after birth. During normal digestion, the enzyme lactase breaks lactose (primarily found in dairy products, including baby formula) into galactose and glucose. Individuals with galactosemia lack, or are missing, specific enzymes needed for further breakdown of galactose into uridine diphosphate (UDP)-glucose and, ultimately, carbon dioxide.
As shown in the table below, 3 types of galactosemia can occur.


Enzyme Deficiency	Differentiating Characteristics
Galactose-1-phosphate uridyl-transferase (GALT)	Results in classic galactosemia, in which homozygotes have absent or barely detectable enzyme activity. If untreated, severe feeding difficulties, failure to thrive, and liver failure can occur within the first few days of life and lead to death if not managed appropriately. Children with Duarte variant galactosemia generally have a residual 25% GALT enzyme activity of approximately 25%. It occurs when a child inherits a classic galactosemia mutation from one parent and the Duarte variant from the other. Once previously thought to cause a milder type of classic galactosemia, it has since been shown to have no measurable clinical impact when left untreated.
Galactokinase 1 (GALK1)	Results in early cataract development that is reversible if treated appropriately. Occasionally may also cause increased cranial pressure, but individuals are otherwise asymptomatic.
UDP-galactose-4-epimerase (GALE)	Can be subtyped as a generalized deficiency in which all tissues are affected and can result in similar signs/symptoms of classic galactosemia. Alternatively, those with peripheral or intermediate GALE deficiency are generally asymptomatic and do not require therapy.

GALT deficiency causes the most common and severe form of galactosemia and will be the focus of the following discussion.

Other Names & Coding

Classic galactosemia (GALT deficiency, galactose-1-phosphate uridyltransferase deficiency, galactosemia type I) Duarte galactosemia Galactokinase deficiency (GALK deficiency, galactosemia type II) UDP-galactose-4-epimerase deficiency (GALE deficiency, epimerase deficiency galactosemia, galactosemia type III)

ICD-10 coding

E74.21, Galactosemia

Further coding details can be found at ICD-10 for Galactosemia (icd10data.com).

Prevalence

GALT deficiency occurs approximately in 1:48,000 individuals. [Therrell: 2015] The Duarte variant occurs in about 1:16,000.
GALK deficiency seems to be rare; although there have been no large population studies, the estimated prevalence is less than 1:100,000. [Berry: 2021]
GALE deficiency in its generalized symptomatic form is exceedingly rare, with only a few reported patients ever identified in the United States. The asymptomatic peripheral and intermediate forms are much more common with estimates of 1:6,700 newborn African Americans and 1:70,000 newborn Caucasian Americans. [Alano: 1997] [Fridovich-Keil: 2008]

Genetics

All types of galactosemia are inherited in an autosomal recessive manner, though involving different genes. More than 200 known genetic mutations cause classic galactosemia or variants, such as the Duarte variant. [McCorvie: 2011]

Prognosis

Regarding classic galactosemia, most clinical complications can be prevented and a normal life expectancy achieved if treatment is initiated early in life; however, developmental delays, speech problems, reduced coordination, and primary amenorrhea or premature menopause can still occur despite adherence to galactose-restricted diets. [Hoffmann: 2012] [Bosch: 2009]

Practice Guidelines

Specific guidelines for the diagnosis, treatment, and follow-up have been established by an international consortium of specialists and the Galactosemia Network as follows:

Welling L, Bernstein LE, Berry GT, Burlina AB, Eyskens F, Gautschi M, Grünewald S, Gubbels CS, Knerr I, Labrune P, van der Lee JH, MacDonald A, Murphy E, Portnoi PA, Õunap K, Potter NL, Rubio-Gozalbo ME, Spencer JB, Timmers I, Treacy EP, Van Calcar SC, Waisbren SE, Bosch AM.
International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up.
J Inherit Metab Dis. 2017;40(2):171-176. PubMed abstract / Full Text

Roles of the Medical Home

In addition to providing primary care, the medical home works collaboratively with families to reinforce successful dietary strategies at home and in the classroom. Families often need substantial support in understanding and implementing the dietary restrictions, which work best when the entire family participates, and managing the unavoidable effects of the condition. Parents likely will benefit from accessing family-supported and community-based organizations.

Clinical Assessment

Pearls & Alerts for Assessment

Sepsis in newborns may signal galactosemia

Escherichia coli is the most common bacteria causing sepsis in infants with galactosemia, but Klebsiella, Enterobacter, Staphylococcus, group-B strep, and Streptococcus faecalis also have been observed.

Osteoporosis common in children with galactosemia

Evaluation of calcium intake while avoiding galactose rich foods is necessary to optimize bone health. Regular assessments of vitamin D levels and supplementation, if necessary, are recommended as well. Surveillance with DEXA scanning is recommended at six years of age, during puberty, through adolescence, and every 5 years as an adult. [Berry: 2021]

High false positive newborn screen results

Most children who have a positive newborn screening test will ultimately be found to carriers of classic galactosemia or Duarte galactosemia. Nonetheless, a newborn with questionable screening results should be treated with soy-based formula pending definitive results from further tests.

Screening

For the Condition

Virtually 100% of affected infants can be detected in state newborn screening programs that test for galactosemia by measuring GALT activity. [Berry: 2021] Most centers also measure galactose levels that become elevated in GALK and GALE deficient galactosemia. Enzyme isoelectric focusing can be helpful in cases of intermediate enzyme activity levels, where ranges for Duarte galactosemia and other carrier states may overlap. Prenatal diagnosis is possible for pregnancies at 25% risk for classic galactosemia using molecular genetic testing if the disease-causing GALT mutations in the family are known. [Berry: 2021] The Medical Home Portal's Newborn Disorder page on Galactosemia contains more detailed information. The Medical Home Portal's Newborn Disorder page on Galactosemia contains more detailed information.

Of Family Members

Couples who have had 1 affected child have a 25% chance of having an affected child in each subsequent pregnancy. Subsequent siblings of children with galactosemia should be screened either prenatally or at birth (GALT enzyme activity and genetic testing). Lactose containing substances, including breast milk, should not be given until results are available.

For Complications

Because of their relative frequency in individuals with classic galactosemia, screening for the following are indicated:

Delays in speech and language development
Delays in cognitive or learning development
Cataracts (though they may have little impact on vision) [Widger: 2010]
Sudden increases in toxic analytes – RBC gal-1-P and urinary galactitol, generally monitored through periodic visits with metabolic genetics
Plasma 17-beta-estradiol and FSH in girls suspected to have primary ovarian insufficiency/failure [Welling: 2017]

Presentations

Newborns with classic galactosemia are usually symptom-free for the first couple days until ingestion of breast milk or lactose-containing formula results in:

Jaundice
Vomiting
Hepatomegaly
Failure to thrive
Poor feeding
Lethargy and Irritability
Diarrhea
Sepsis (usually Escherichia coli sepsis)

Long-term complications, even when treatment is initiated early with good compliance, may include: [Michael: 2014]

Poor growth
Learning disabilities
Speech apraxia
Unsteady gait
Developmental delays
Cataracts (reversible with dietary treatment)
Decreased bone mineral density
Premature ovarian insufficiency
Ataxia and tremor

The Q188R and K285N variants common in European populations are generally associated with more severe disease and risk for complication. [Berry: 2021]

Clinical Classification

In classic (G/G) galactosemia, GALT enzyme activity is absent or barely detectable compared to control samples, and erythrocyte Gal-1-P is higher than 10 mg/dL. In Duarte variant (D/G) galactosemia, GALT enzyme activity is usually higher than 5% and often approximates 25% of control values.

Differential Diagnosis

Any condition that causes liver damage in neonates may be confused with galactosemia, including:

Biliary atresia [Müller: 1997]
Fanconi-Bickel syndrome [Sakura: 2000]
Gestational alloimmune liver disease
Portosystemic vascular shunts

Also, false positives on newborn screening have been reported in newborns eventually found to have glucose-6-phosphate dehydrogenase deficiency. [Stuhrman: 2017]

History & Examination

Current & Past Medical History

Symptoms typically present soon after exposure to lactose containing nutrition (breastmilk and most baby formulas) with jaundice, vomiting, and liver disease that may progress to failure to thrive, lethargy, sepsis, and liver failure if timely treatment not initiated.

Family History

Because this is an autosomal recessive condition, there is often no family history.

Developmental & Educational Progress

Delays in development, if any, are not usually very severe unless there is brain damage from the initial event. Ongoing surveillance of development and periodic assessment of school performance may help identify delays/problems early. The impact of specific interventions is not known.

Maturationalprogress

Premature ovarian insufficiency is present in a majority of girls with galactosemia and may present as primary or secondary amenorrhea. [Elsas: 2010]

Physical Exam

Growth Parameters

Growth may be delayed during childhood.

Skin

Girls with abnormal estrogen levels due to premature ovarian insufficiency may present with cutaneous rashes.

HEENT/Oral

Although rarely needing treatment, cataracts may be visible.

Neurologic Exam

Delayed acquisition of motor skills, poor coordination, and ataxia may be noted.

Testing

Genetic Testing

Enzyme assay in red blood cells and gene testing in consultation with metabolic genetics is necessary to distinguish among galactosemia types. [Berry: 2012]

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see OH providers [0])

Provides diagnostic confirmation, management of dietary treatment, and monitoring for complications

Nutrition, Metabolic (see OH providers [1])

Provides expertise in initiating and managing dietary restrictions and works with the family to address dietary challenges

Treatment & Management

Overview

Children with classic galactosemia are treated with a life-long lactose-restricted diet. Despite therapy, affected individuals can have life-long problems. These problems are thought to be due to endogenous production of galactose and the accumulation of galactose-1-phosphate. Patients with Duarte variant galactosemia usually do not need lactose restriction and are not at risk for the associated complications seen in classic galactosemia.

Pearls & Alerts for Treatment & Management

Complications despite dietary restriction

Despite even rigorous galactose avoidance, individuals may still have symptoms including developmental delays, mild to moderate intellectual disability, growth problems, speech and language problems, ataxia, and tremors. Additionally, many women will develop premature ovarian insufficiency.

Hidden lactose in foods

Lactose may be found in whey, milk solids, and dry milk powder, as well as in some non-milk products like fermented soy, legumes, tomato sauces, and organ meats.

Hidden lactose in medication

Certain medications have galactose or lactose fillers. These are not required to be listed in supplements. Avoid casein hydrolysates (Alimentum®, Nutramigen®, Pregestimil®) and medications with lactulose. [Berry: 2021]

Fruit and vegetable galactose controversy

Free galactose is present in some fruits and vegetables, such as tomatoes, Brussels sprouts, bananas, and apples. There is no consensus about whether these should be eliminated from the diet because endogenous synthesis of galactose also occurs. Some have suggested that an elemental formula (galactose-free) may be preferable to soy formula in the treatment of galactosemia. [Gropper: 2000] [Segal: 1998] [Zlatunich: 2005]

Systems

Genetics

Upon presentation, refer infants to metabolic genetics. The child will need frequent follow-up during the first couple of years. Adherence to the diet should be life-long but can be relaxed a little after puberty. Genetic counseling will usually be provided to discuss risk recurrence and support decision-making regarding future children.

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see OH providers [0])

Co-management should be established with metabolic genetics.

Nutrition, Metabolic (see OH providers [1])

Initiates and monitors a lactose-free diet

Genetic Testing and Counseling (see OH providers [1])

Helps families understand the inheritance pattern and risks for subsequent children

Development (general)

Despite optimal adherence to a lactose-free diet, measurable levels of galactose will persist, most likely due to endogenous galactose production. Currently, there is no way to prevent this, although studies are in progress. The primary care clinician should monitor children for developmental delays/intellectual disability, order appropriate therapies when needed, and evaluate periodically for coordination problems or problems with balance.

Specialty Collaborations & Other Services

Early Intervention for Children with Disabilities/Delays (see OH providers [0])

All children who test positive for classic galactosemia should be referred to an early intervention program for evaluation and, if indicated, treatment.

Developmental - Behavioral Pediatrics (see OH providers [1])

An evaluation by developmental pediatrics may be helpful for children who are behind developmentally or who have attention or learning problems.

Physical Therapy (see OH providers [1])

May be helpful for patients with gross motor developmental delays and/or coordination problems/ataxia

Occupational Therapy (see OH providers [1])

May be helpful for patients with fine motor delays or problems with activities of daily living

Speech - Language Pathologists (see OH providers [0])

May be helpful for patients with language delay or articulation problems.

Eyes/Vision

Cataracts are seen in approximately 30% of children with galactosemia. [Berry: 2021] Although they may not cause serious visual problems, children should be monitored yearly.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see OH providers [0])

Periodic visits with pediatric ophthalmology are necessary to monitor for cataracts and treat as needed.

Endocrine/Metabolism

Premature ovarian insufficiency/failure is common in girls with galactosemia. This can lead to failure to develop secondary sexual characters, infertility, and early menopause (in some cases by age 20). Anti-mullerian hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol should be measured in pre-teen girls; referral to an endocrinologist should be offered when hormone treatment is indicated.

Specialty Collaborations & Other Services

Pediatric Endocrinology (see OH providers [0])

Assists in evaluation and management of girls with ovarian insufficiency

No Related Issues were found for this diagnosis.

Ask the Specialist

An older sibling had a false positive NBS for galactosemia, so do I still need to put the baby on soy formula?

Yes, all newborns with an abnormal NBS, regardless of symptoms or family history, should be placed on soy formula until confirmatory testing has resolved whether the newborn is actually affected.

Should siblings of an affect child be tested for galactosemia?

For classic galactosemia, if the siblings were born in the USA, they would have been screened for the condition already by the state Newborn Screen and if normal, are not at risk. However, they may be carriers for the condition, which would be important to know when they are old enough to have children. Genetic testing for carrier status is not recommended for children until they are adults and can make their own reproductive decisions.

How does galactosemia differ from lactose intolerance?

Persons with galactosemia are unable to produce the GALT enzyme, and therefore are unable to fully metabolize galactose and lactose. This causes a toxic build-up of other metabolites that cause significant liver dysfunction and damage. Alternatively, lactose intolerance is a deficiency of the enzyme lactase produced by the intestinal tract, which results in intestinal gas, bloating, and diarrhea when exposed to lactose. Though there are similarities in the restricted foods, persons with lactose intolerance may be able to tolerate small amounts of lactose safely and are not generally at risk for serious health consequences if exposed. Additionally, persons with lactose intolerance may take lactase medications orally to help digest the lactose, which does not resolve the defect in galactosemia patients.

Resources for Clinicians

On the Web

Galactosemia
The Medical Home Portal's newborn disorders page for galactosemia provides information about the newborn screening process, follow-up on positive screening results, and steps to be taken after diagnosis confirmation.

Galactosemia (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Classic Galactosemia (Orphanet)
Overview of galactosemia and links to more information, services, and other resources; from Orphanet, a French-coordinated consortium involving over 40 countries to provide a portal for information about rare diseases and orphan drugs.

Helpful Articles

PubMed search for galactosemia and neonatal screening, last 5 years.

Welling L, Meester-Delver A, Derks TG, Janssen MCH, Hollak CEM, de Vries M, Bosch AM.
The need for additional care in patients with classical galactosaemia.
Disabil Rehabil. 2019;41(22):2663-2668. PubMed abstract

Rubio-Gozalbo ME, Haskovic M, Bosch AM, Burnyte B, Coelho AI, Cassiman D, Couce ML, Dawson C, Demirbas D, Derks T, Eyskens F, Forga MT, Grunewald S, Häberle J, Hochuli M, Hubert A, Huidekoper HH, Janeiro P, Kotzka J, Knerr I, Labrune P, Landau YE, Langendonk JG, Möslinger D, Müller-Wieland D, Murphy E, Õunap K, Ramadza D, Rivera IA, Scholl-Buergi S, Stepien KM, Thijs A, Tran C, Vara R, Visser G, Vos R, de Vries M, Waisbren SE, Welsink-Karssies MM, Wortmann SB, Gautschi M, Treacy EP, Berry GT.
The natural history of classic galactosemia: lessons from the GalNet registry.
Orphanet J Rare Dis. 2019;14(1):86. PubMed abstract / Full Text

Clinical Tools

Care Processes & Protocols

ACT Sheet for Classical Galactosemia (ACMG)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

ACT Sheet for Primary or Secondary Hypergalactosemia (ACMG)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Resources for Patients & Families

Galactosemia (FAQ)

Information on the Web

Galactosemia (MedlinePlus)
Information for families includes a description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Galactosemia (GARD)
Includes information about symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations; Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.

Resources for Galactosemia (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.

National & Local Support

Galactosemia Foundation
Provides information about galactosemia and facilitates networking among families, clinicians, and researchers.

Studies/Registries

Studies of Galactosemia (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Ohio (OH)

Service Categories	NW		NM	NV	RI
Biochemical Genetics (Metabolics)	1	1	2	3	2
Developmental - Behavioral Pediatrics	1	2	3	12	9
Early Intervention for Children with Disabilities/Delays	3	34	30	13	51
Genetic Testing and Counseling	6	6	12	8	11
Nutrition, Metabolic	11	11	13	13	11
Occupational Therapy	1	17	22	21	37
Pediatric Endocrinology	1	4	6	12	7
Pediatric Ophthalmology	1	6	6	8	4
Physical Therapy		12	9	6	40
Speech - Language Pathologists	4	23	11	33	65

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: April 2014; last update/revision: April 2021

Current Authors and Reviewers:

Author:

Brian J. Shayota, MD, MPH

Authoring history

2014: first version: Nicola Longo, MD, Ph.D.^A

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

Bibliography

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UDP-galactose-4-epimerase deficiency among African-Americans: evidence for multiple alleles.
J Invest Med. 1997;45:191A.

Berry GT.
Classic Galactosemia and Clinical Variant Galactosemia.
GeneReviews. 2021. PubMed abstract / Full Text

Berry GT.
Galactosemia: when is it a newborn screening emergency?.
Mol Genet Metab. 2012;106(1):7-11. PubMed abstract
An excellent review regarding response to, and family counseling for, children who have a positive newborn screening result for galactosemia.

Bosch AM, Maurice-Stam H, Wijburg FA, Grootenhuis MA.
Remarkable differences: the course of life of young adults with galactosaemia and PKU.
J Inherit Metab Dis. 2009;32(6):706-12. PubMed abstract
Investigates the course of life and the social demographical outcomes in young adults with galactosaemia and compares them with the general population and with PKU patients.

Elsas LJ.
Galactosemia.
GeneReview. 2010. PubMed abstract / Full Text
Includes disease characteristics and genetic, diagnosis, and management information.

Fridovich-Keil JL, Walter JH.
Galactosemia. In: Valle D, Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 72.
McGraw-Hill; 2008.

Gropper S.
Free Galactose Content of Fresh Fruits and Strained Fruit and Vegetable Baby Foods: More Foods to Consider for the Galactose-restricted Diet.
Journal of the American Dietetic Association. 2000;100(5). PubMed abstract
Examines free galactose content of foods and discusses restriction issues.

Hoffmann B, Dragano N, Schweitzer-Krantz S.
Living situation, occupation and health-related quality of life in adult patients with classic galactosemia.
J Inherit Metab Dis. 2012. PubMed abstract
Evaluates psychosocial, educational, and occupational outcome as well as health-related quality of life in adult German patients with galactosemia. Compares information with data from patients with phenylketonuria as well as the general German population.

McCorvie TJ, Timson DJ.
Structural and molecular biology of type I galactosemia: disease-associated mutations.
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Michael Woods.
Galactosemia.
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Müller D, Santer R, Krawinkel M, Christiansen B, Schaub J.
Fanconi-Bickel syndrome presenting in neonatal screening for galactosaemia.
J Inherit Metab Dis. 1997;20(4):607-8. PubMed abstract

Sakura N, Mizoguchi N, Ono H, Yamaoka H, Hamakawa M.
Congenital biliary atresia detected as a result of galactosemia screening by the Beutler method.
Clin Chim Acta. 2000;298(1-2):175-9. PubMed abstract

Segal S. .
Galactosaemia today: the enigma and the challenge - Komrower Lecture.
J Inherit Metab Dis.. 1998; (21):455-471. Netherlands.: SSIEM and Klower Academic Publishers; http://link.springer.com/article/10.1023%2FA%3A1005402618384#page-1
Presents the challenges of managing galactosemia.

Stuhrman G, Perez Juanazo SJ, Crivelly K, Smith J, Andersson H, Morava E.
False-Positive Newborn Screen Using the Beutler Spot Assay for Galactosemia in Glucose-6-Phosphate Dehydrogenase Deficiency.
JIMD Rep. 2017;36:1-5. PubMed abstract / Full Text

Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, Adams J.
Current status of newborn screening worldwide: 2015.
Semin Perinatol. 2015 Apr;39(3):171-187.; (2015) https://pubmed.ncbi.nlm.nih.gov/25979780/. Accessed on 6/28/2021.

Widger J, O'Toole J, Geoghegan O, O'Keefe M, Manning R.
Diet and visually significant cataracts in galactosaemia: is regular follow up necessary?.
J Inherit Metab Dis. 2010;33(2):129-32. PubMed abstract

Zlatunich CO, Packman S.
Galactosaemia: early treatment with an elemental formula.
J Inherit Metab Dis. 2005;28(2):163-8. PubMed abstract