Galactosemia
Overview
Galactose Degradation PathwayThree 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.
Other Names & Coding
Duarte galactosemia (mild galactosemia)
Galactokinase deficiency disease (GALK deficiency, galactosemia type II)
UDP-galactose-4-epimerase deficiency disease (GALE deficiency, galactosemia III)
E74.21, galactosemia
Further coding details can be found at ICD-10 for Galactosemia (ICD10Data.com).
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]Practice Guidelines
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 galactosemiaEscherichia 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 galactosemiaCalcium 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 resultsMost 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.
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)
- 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:- Fructose 1-phosphate aldolase deficiency (fructose intolerance) [Gerard: 2014]
- Hemochromatosis, neonatal [Gerard: 2014]
- Portosystemic vascular shunts [Ono: 1998]
- Biliary atresia [Müller: 1997]
- Fanconi-Bickel syndrome [Sakura: 2000]
History & Examination
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
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
Pediatric Metabolics (see MT providers [1])
Provides diagnostic confirmation, management of dietary treatment, and monitoring for complications.
Nutrition, Metabolic (see MT providers [17])
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 for Treatment & Management
Complications despite dietary restrictionDespite 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 foodsLactose 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 medicationCertain 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 controversyFree 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. [Gropper: 2000] [Segal: 1998] [Zlatunich: 2005]
Systems
Genetics
Specialty Collaborations & Other Services
Pediatric Metabolics (see MT providers [1])
Co-management should be established with metabolic genetics.
Nutrition, Metabolic (see MT providers [17])
Initiates and adjusts a lactose-free diet.
Genetic Testing and Counseling (see MT providers [8])
Helps families understand the inheritance pattern and risks for subsequent children.
Development (general)
Specialty Collaborations & Other Services
Early Intervention for Children with Disabilities/Delays (see MT providers [28])
All children who test positive for classic galactosemia should be referred for early intervention evaluation and, if indicated, treatment.
Developmental - Behavioral Pediatrics (see MT providers [8])
An evaluation by developmental pediatrics may be helpful for children who are behind developmentally or who have attention or learning problems.
Physical Therapy (see MT providers [44])
May be helpful for patients with gross motor developmental delays and/or coordination problems/ataxia.
Occupational Therapy (see MT providers [39])
May be helpful for patients with fine motor delays or problems with activities of daily living.
Speech - Language Pathologists (see MT providers [52])
May be helpful for patients with language delay or articulation problems.
Pediatric Physical Medicine & Rehabilitation (see MT providers [5])
Depending on local expertise and availability, may help with physical evaluation and management plan.
Eyes/Vision
Specialty Collaborations & Other Services
Pediatric Ophthalmology (see MT providers [14])
Periodic visits with pediatric ophthalmology are necessary to monitor for cataracts and treat as needed.
Endocrine/Metabolism
Specialty Collaborations & Other Services
Pediatric Endocrinology (see MT providers [15])
Assists in evaluation and management of girls with ovarian insufficiency.
Issues Related to Galactosemia
No Related Issues were found for this diagnosis.Ask the Specialist
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.
Resources for Clinicians
On the Web
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.
ACT Sheet for Classic Galactosemia (ACMG) ( 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) ( 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.
Resources for Patients & Families
Information on the Web
Galactosemia (MedlinePlus)
Excellent, detailed review of condition for patients and families; National Library of Medicine and National Institutes of
Health.
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.
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.
National & Local Support
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 in Montana (MT)
Service Categories | # of providers* in: | MT | NW | Other states (5) (show) | | ID | NM | NV | RI | UT |
---|---|---|---|---|---|---|---|---|---|---|
Developmental - Behavioral Pediatrics | 8 | 1 | 2 | 2 | 3 | 11 | 8 | |||
Early Intervention for Children with Disabilities/Delays | 28 | 2 | 148 | 156 | 30 | 14 | 55 | |||
Genetic Testing and Counseling | 8 | 2 | 6 | 59 | 20 | 4 | 12 | |||
Nutrition, Metabolic | 17 | 16 | 16 | 16 | 17 | 18 | 17 | |||
Occupational Therapy | 39 | 27 | 298 | 21 | 11 | 41 | ||||
Pediatric Endocrinology | 15 | 1 | 2 | 29 | 6 | 14 | 5 | |||
Pediatric Metabolics | 1 | 1 | 1 | 2 | 2 | |||||
Pediatric Ophthalmology | 14 | 1 | 9 | 9 | 6 | 8 | 6 | |||
Pediatric Physical Medicine & Rehabilitation | 5 | 1 | 1 | 4 | 1 | 3 | 13 | |||
Physical Therapy | 44 | 34 | 321 | 22 | 3 | 49 | ||||
Speech - Language Pathologists | 52 | 3 | 67 | 377 | 22 | 24 | 74 |
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.
Bibliography
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.
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.
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.
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PubMed abstract
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Waggoner DD, Buist NR, Donnell GN.
Long-term prognosis in galactosaemia: results of a survey of 350 cases.
J Inherit Metab Dis.
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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.
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Galactosaemia: early treatment with an elemental formula.
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