Galactosemia

Description

Other Names

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

Diagnosis Coding

ICD-10

E74.21, galactosemia

Further coding details can be found at ICD-10 for Galactosemia.

Description

Galactose Degradation Pathway
Galactose Pathway



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.

Permission to use image granted from
The Medical Biochemistry Page.

Three types of galactosemia can occur:
Enzyme Deficiency Differentiating Characteristics
Galactose-1-phosphate
uridyl-transferase (GALT)
Results in classic galactosemia, in which homozygotes have less than 5% enzyme activity. If untreated, severe damage of body systems can occur; if undetected, death.

Children with Duarte variant galactosemia generally have a residual 10-25% GALT enzyme activity. It occurs when a child inherits a classic mutation from one parent and the Duarte variant from the other. It is similar to Classic galactosemia, but less severe. Depending on severity, no treatment may be needed.
Galactokinase 1 (GALK1) Results in relatively mild symptoms, although may cause cataracts. Individuals still have normal GALT enzyme activity.
UDP-galactose-4-epimerase (GALE) Either results in deficiency that is found only in red blood cells and no symptoms occur, or a deficiency that affects most tissues and results in symptoms similar to those found in classic galactosemia.

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

Prevalence

GALT deficiency occurs approximately 1 in 30,000 individuals. [Bosch: 2005] The Duarte variant occurs in about 1 in 16,000.

GALK deficiency seems to be rare; although there have been no large population studies, the estimated prevalence is less than 1 in 100,000. [Elsas: 2010]

GALE deficiency occurs in two forms. One form is confined to red blood cells and has no symptoms and the second form, which is exceedingly rare, involves most body systems; only a few patients have been reported nationally. [Holton: 2001] [Openo: 2006]

Genetics

Galactosemia is inherited in an autosomal recessive manner. More than 200 known genetic mutations cause classic galactosemia or variants, such as the Duarte variant. [McCorvie: 2011]

Prognosis

With treatment, most clinical complications can be prevented and a normal life expectancy achieved; however, intellectual disability, speech problems, reduced coordination, and primary amenorrhea or premature menopause can occur despite adherence to galactose-restricted diets. [Hoffmann: 2012] [Bosch: 2009]

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.

Practice Guidelines

There are no published guidelines for the diagnosis or management of children with galactosemia.

Helpful Articles

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

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

Bosch AM.
Classical galactosaemia revisited.
J Inherit Metab Dis. 2006;29(4):516-25. PubMed abstract / Full Text
Review of classic galactosemia from the University Hospital of Amsterdam.

Walter, JH, Collins, JE, Leonard, JV.
Recommendations for the management of galactosemia.
Arch Dis Child. 1999;80:93-96. PubMed abstract / Full Text
Recommendations for the evaluation and management of galactosemia. Despite being written in 1999, still contains pertinent information; from the UK Galactosemia Screening Group.

Clinical Assessment

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. [Elsas: 2010] Some 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. [Elsas: 2010] The Medical Home Portal's Newborn Disorder page on Galactosemia contains more detailed information.

Of Family Members

Couples who have had one affected child have a 25% chance of having an affected child in each subsequent pregnancy. [Elsas: 2010] 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. [Elsas: 2010]

For Complications

Because of their relative frequency in individuals with 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
  • Primary ovarian insufficiency/failure in girls

Presentations

Newborns with classic galactosemia are usually symptom-free for the first few days or week of life, until ingestion of breast milk or lactose-containing formula results in: [Waggoner: 1990]
  • Jaundice
  • Vomiting
  • Hepatomegaly
  • Failure to thrive
  • Poor feeding
  • Lethargy and Irritability
  • Diarrhea
  • Sepsis (usually Escherichia coli sepsis)
Presentations of long-term problems, even when treatment is initiated before the acute event, may include: [Michael: 2014]
  • Poor growth
  • Learning disabilities
  • Speech apraxia
  • Unsteady gait
  • Fine and gross motor skill delays
  • Cataracts, which usually regress with dietary treatment and leave no remaining visual impairment
  • Decreased bone mineral density
  • Ataxia and tremor

Ataxia and tremor may become evident with time in some patients. Some mutations, such as Q188R or K285N, are more likely to be associated with severe outcome. Mild GALT may show similar, but less severe, symptoms than classic galactosemia.

Children deficient in GALK may have increased blood galactose and cataracts but no other problems.

GALE deficiency may present with liver disease and a high galactose-1-phosphate level, but normal GALT activity. There are two variants of this condition: one restricted to the red cells that is usually benign, and one where the liver is affected, causing the same symptoms of classic galactosemia.

Clinical Classification

In classic (G/G) galactosemia, GALT enzyme activity is less than 5% of control values 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:

Pearls & Alerts

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

Calcium supplementation at 750 mg/day in neonates and >1200 mg/day in children, along with vitamin D3 (cholecalciferol) at 1000 IU/day, may prevent decreased bone mineralization. It is not clear how to prevent chronic secondary effects such as hypergonadotropic hypogonadism in females, ataxia, and growth delays. [Elsas: 2010]

High false positive newborn screen results

Most children who have a positive screening test will have neither classic galactosemia nor Duarte variant. The newborn with questionable screening results should be treated with soy-based formula pending definitive results from further tests.

History & Examination

Family History

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

Current & Past Medical History

Children usually present at 5-14 days of age. Many have history of hyperbilirubinemia.

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.

Maturational Progress

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

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]

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

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

Nutrition, Metabolic (see Services below for relevant providers)

Provides expertise in initiation and management of dietary restrictions and will work with the family to address dietary challenges.

Treatment & Management

Overview

Children with classic galactosemia are treated with a 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 sepsis.

Pearls & Alerts

Complications despite dietary restriction

Despite even rigorous galactose avoidance, individuals may still have symptoms, including mild to moderate intellectual disability, growth problems, speech and language problems, and ataxia.

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. [Elsas: 2010]

Fruit and vegetable galactose controversy

Free galactose is present in some fruits and vegetables, such as tomatoes, brussel 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. [Sareen: 2000] [Segal: 1998] [Zlatunich: 2005]

Systems

Genetics

Upon presentation, infants will be referred to metabolic genetics. The child will need frequent follow-up in 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 support decision-making regarding future children.

Subspecialist Collaborations & Other Resources

Pediatric Metabolic Genetics (see Services below for relevant providers)

Co-management should be established with metabolic genetics.

Nutrition, Metabolic (see Services below for relevant providers)

Initiates and adjusts a lactose-free diet.

Pediatric Genetic Counseling (see Services below for relevant providers)

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.

Subspecialist Collaborations & Other Resources

Early Intervention Programs (see Services below for relevant providers)

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

Developmental Pediatrics (see Services below for relevant providers)

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

Physical Therapy (see Services below for relevant providers)

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

Occupational Therapy, Pediatric (see Services below for relevant providers)

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

Speech/Language Therapy (see Services below for relevant providers)

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

Pediatric Physical Medicine & Rehab (see Services below for relevant providers)

Depending on local expertise and availability, may help with physical evaluation and management plan.

Eyes/Vision

Cataracts are seen in approximately 30% of children with galactosemia. [Elsas: 2010] Although they may not cause serious visual problems, children should be monitored yearly.

Subspecialist Collaborations & Other Resources

Pediatric Ophthalmology (see Services below for relevant providers)

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

Endocrine/Metabolism

Primary 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.

Subspecialist Collaborations & Other Resources

Pediatric Endocrinology (see Services below for relevant providers)

Assists in evaluation and management of girls with ovarian insufficiency.

Frequently Asked Questions

My daughter was diagnosed with galactosemia when she was 2 days old, since then we have always avoided galactose. Despite this, she struggles in school and with her speech. Why is she not doing better?

Individuals with galactosemia are often developmentally delayed, even when families have strictly adhered to a galactose free diet. Some children may receive galactose in foods that are not expected to contain galactose, or their bodies produce galactose as part of their normal metabolism. Either situation may contribute to higher than normal galactose levels and subsequent problems. The Lactose-Free Diet Guidelines (Sutter Health) may be helpful for answering questions about food inclusions.

Issues Related to Galactosemia

Resources

Information for Clinicians

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)
Excellent review by Louis Elsas, MD including clinical description, differential, management, genetic counseling, molecular genetics, and a bibliography; sponsored by the National Institutes of Health.

Galactosemia (GARD)
Overview and links to more information and resources; Genetic and Rare Diseases Information Center, Office of Rare Diseases Research, National Center for Advancing Translational Sciences.

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.

Galactosemia Information (UDOH)
Detailed newsletter and family education pages; Utah Newborn Screening Program, Utah Department of Health.

ACT Sheet for Classic Galactosemia (ACMG) (PDF Document 348 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

ACT Sheet for Primary or Secondary Hypergalactosemia (ACMG) (PDF Document 345 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Helpful Articles

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

Bosch AM.
Classical galactosaemia revisited.
J Inherit Metab Dis. 2006;29(4):516-25. PubMed abstract / Full Text
Review of classic galactosemia from the University Hospital of Amsterdam.

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

Walter, JH, Collins, JE, Leonard, JV.
Recommendations for the management of galactosemia.
Arch Dis Child. 1999;80:93-96. PubMed abstract / Full Text
Recommendations for the evaluation and management of galactosemia. Despite being written in 1999, still contains pertinent information; from the UK Galactosemia Screening Group.

Information & Support for Families

Family Diagnosis Page

Information on the Web

Galactosemia (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

What is Galactosemia? (GSLC)
An overview of the genetics of galactosemia; Genetic Science Learning Center at the University of Utah.

Galactosemia Tutorial for Parents (English and Spanish)
Tutorials on congenital conditions; Patient Education Institute, Iowa Department of Health's Center for Congenital and Inherited Disorders.

Galactosemia Information (UDOH)
Detailed newsletter and family education pages; Utah Newborn Screening Program, Utah Department of Health.

Galactosemia Parent Info Sheet (Nebraska Newborn Screening Program) (PDF Document 28 KB)
Single-page information sheet for parents whose child has a positive screening test; Nebraska Dept. of Health and Human Services.

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

Lactose-Free Diet Guidelines (Sutter Health)
A comprehensive guide to dietary restrictions needed to avoid lactose.

Support National & Local

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

Studies/Registries

Studies of Galactosemia (clinicaltrials.gov)
Current listings of registered studies of galactosemia; sponsored by the National Institutes of Health.

Services for Patients & Families

Developmental Pediatrics

See all Developmental Pediatrics services providers (5) in our database.

Early Intervention Programs

See all Early Intervention Programs services providers (52) in our database.

Nutrition, Metabolic

We currently have no Nutrition, Metabolic service providers listed; search our Services database for related services.

Occupational Therapy, Pediatric

See all Occupational Therapy, Pediatric services providers (42) in our database.

Pediatric Endocrinology

See all Pediatric Endocrinology services providers (2) in our database.

Pediatric Genetic Counseling

See all Pediatric Genetic Counseling services providers (5) in our database.

Pediatric Metabolic Genetics

See all Pediatric Metabolic Genetics services providers (2) in our database.

Pediatric Ophthalmology

See all Pediatric Ophthalmology services providers (8) in our database.

Pediatric Physical Medicine & Rehab

See all Pediatric Physical Medicine & Rehab services providers (8) in our database.

Physical Therapy

See all Physical Therapy services providers (62) in our database.

Speech/Language Therapy

See all Speech/Language Therapy services providers (80) in our database.

For other services related to this condition, browse our Services categories or search our database.

Authors

Author: Nicola Longo, MD, PhD - 4/2014
Content Last Updated: 4/2014

Bibliography

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

Bosch AM.
Classical galactosaemia revisited.
J Inherit Metab Dis. 2006;29(4):516-25. PubMed abstract / Full Text
Review of classic galactosemia from the University Hospital of Amsterdam.

Bosch AM, Ijlst L, Oostheim W, Mulders J, Bakker HD, Wijburg FA, Wanders RJ, Waterham HR.
Identification of novel mutations in classical galactosemia.
Hum Mutat. 2005;25(5):502. PubMed abstract / Full Text
Report of the mutational spectrum of classical galactosemia in a cohort of 123 Dutch patients, all with biochemically proven classical 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.

Gerard T Berry, MD; Chief Editor: Bruce Buehler, MD.
Galactose-1-phosphate uridyltransferase deficiency (galactosemia) differential diagnoses.
Medscape; (2014) http://emedicine.medscape.com/article/944069-differential. Accessed on 2/17/2014.
Diagnosis and treatment information for galactosemia.

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.

Holton JB, Walter JH, Tyfield LA. .
The Metabolic and Molecular Bases of Inherited Disease.
8th ed. ed. New York, NY: McGraw-Hill; 2001. 0079130356
Holton JB, Walter JH, Tyfield LA. Galactosemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001: 1553–1588

McCorvie TJ, Timson DJ.
Structural and molecular biology of type I galactosemia: disease-associated mutations.
IUBMB Life. 2011;63(11):949-54. PubMed abstract

Michael Woods.
Galactosemia.
EBSCO Publishing; (2014) http://westsideprimarycare.com/your-health/?/2010815185/Galactosemia. Westside Regional Medical Center website. Accessed on 3/17/2014.

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

Ono H, Mawatari H, Mizoguchi N, Eguchi T, Sakura N.
Clinical features and outcome of eight infants with intrahepatic porto-venous shunts detected in neonatal screening for galactosaemia.
Acta Paediatr. 1998;87(6):631-4. PubMed abstract

Openo KK, Schulz JM, Vargas CA, et al.
Epimerase-deficiency galactosemia is not a binary condition.
American Journal of Human Genetics. 2006:89–102. / Full Text
Openo KK, Schulz JM, Vargas CA, et al. Epimerase-deficiency galactosemia is not a binary condition. Am J Hum Genet. 2006; 78: 89–102[CrossRef][ISI][Medline]

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

Sareen Stepnick Gropper, PhD, RD, S. Jean Olds Weese, PhD, RD, Patricia A. West, Kenneth C. Gross, PhD.
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). / Full Text
Examines free galactose content of foods and discusses restriction issues.

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.

Waggoner DD, Buist NR, Donnell GN.
Long-term prognosis in galactosaemia: results of a survey of 350 cases.
J Inherit Metab Dis. 1990;13(6):802-18. PubMed abstract
An international survey of the long-term results of galactosemia treatment and results.

Walter, JH, Collins, JE, Leonard, JV.
Recommendations for the management of galactosemia.
Arch Dis Child. 1999;80:93-96. PubMed abstract / Full Text
Recommendations for the evaluation and management of galactosemia. Despite being written in 1999, still contains pertinent information; from the UK Galactosemia Screening Group.

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 / Full Text
Discussion about an infant whose erythrocyte galactose 1-phosphate (gal-1-P) levels remained well above the treatment range on a low-galactose (soy) formula.