Galactosemia

Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice. Serious neurologic complications such as speech and motor deficits (e.g., ataxia) may occur. Diagnosis is made through blood testing, which detects an absence or low level of the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes necessary to process galactose. Treatment is avoidance of lactose and galactose in the diet.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Galactosemia is an autosomal recessive, inborn error of carbohydrate metabolism resulting in the inability of the body to metabolize galactose into glucose.

Classification

  • Type I (classic):
    • Most common and severe form
    • Deficiency of galactose-1-phosphate uridyltransferase
    • Presents days after birth with lethargy, failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive (FTT), jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, and other features of liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver injury
  • Type II:
    • Deficiency of galactose kinase
    • Mild variety (limited or no symptoms)
  • Type III:
    • Deficiency in galactose-6-phosphate epimerase
    • Presentation varies from mild to severe disease; may include cataracts, delayed development, and kidney disease

Etiology

Galactosemia is an inherited disorder caused by a genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, which leads to enzyme deficiency.

  • Type I: GALT gene (chromosome 9p13) encodes for galactose-1-phosphate uridylyltransferase, converting galactose-1-phosphate to UDP-galactose
  • Type II: GALK1 gene (chromosome 17q24) encodes for galactokinase, converting galactose to galactose-1-phosphate
  • Type III: GALE gene (chromosome 1p36–p35) encodes for UDP-galactose-4-epimerase, converting UDP-galactose to UDP-glucose

The condition is autosomal recessive: Each child has a 25% chance of inheriting the disease if both parents are affected.

Epidemiology

  • Type I galactosemia prevalence: 1 per 30,000–60,000 live births
  • Type II and type III galactosemia prevalence: fewer than 1 per 100,000 live births
  • Prevalence varies: 
    • Geographically:
      • 1 per 30,000 in Europe
      • 1 per 1,000,000 in Japan
    • By ethnicity:
      • Most prevalent in the Irish Traveller population (prevalence: 1 per 480)
Galactose (haworth projection)

A structure of the monosaccharide galactose (Haworth projection):
Patients with galactosemia are unable to degrade galactose. Glucose and galactose have the same chemical formula but differ in the location of the 1 hydroxyl group.

Image: “Beta-D-Galactopyranose” by NEUROtiker. License: Public Domain

Clinical Presentation

Symptoms may appear days to weeks after birth.

  • Constitutional:
    • Declining weight or failure to gain weight
    • FTT
    • Lethargy
  • GI:
    • Anorexia
    • Nausea and vomiting
    • Diarrhea
    • Hepatomegaly and splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly
    • Ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Renal: kidney failure
  • Neurologic:
    • Convulsions
    • Irritability
    • Developmental delay
    • Hypotonia
    • Sensorineural hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
  • Ocular: cataracts
Baby with galactosemia

A baby with galactosemia:
As noted in the image, galactosemia has numerous clinical signs and symptoms. Neurologic, renal, hepatic, and ocular side effects may occur. The symptoms appear early and are often apparent within the 1st month of life.

Image by Lecturio.

Diagnosis

Screening

  • The newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening test is common in many regions.
  • Amniocentesis or chorionic villus sampling is advised for families with a history of galactosemia.

Galactosemia test

The test should be performed on all infants who exhibit symptoms.

  • Blood or urine test: checks for the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes necessary to process galactose
  • Galactose-1-phosphate elevated in RBCs
  • Low GALT enzyme activity = positive test

Management and Complications

Management

  • Lifelong avoidance of lactose and galactose:
    • Soy formula
    • Lactose-free formula
    • Avoid milk products
  • Calcium supplements
  • Speech therapy for patients with language deficits
  • Hormonal therapy for patients with delayed puberty Delayed Puberty Delayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay. Delayed Puberty
  • Consider genetic counseling

Complications

  • Premature ovarian failure
  • Permanent neurologic deficits (e.g., speech deficits)
  • Decreased bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones density with increased risk of fracture Fracture A fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma. Overview of Bone Fractures

Differential Diagnosis

  • Lactose intolerance Lactose intolerance Lactose intolerance (LI) describes a constellation of symptoms due to lactase deficiency (LD), the enzyme located in the brush border of the absorptive cells in the small intestine. Lactose is the disaccharide present in milk and requires hydrolysis by lactase to break it down into its 2 absorbable constituents, glucose and galactose. Lactose intolerance typically presents with bloating, abdominal cramping, diarrhea, and flatulence. Lactose Intolerance: a condition caused by an inability to process lactose. Symptoms occur after lactose ingestion. Patients present with GI complaints such as abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, flatus, and nausea. Diagnosis is based upon clinical history. Treatment involves removing lactose from the diet. Lactase supplementation can be offered to patients who continue to consume lactose products. Unlike lactose intolerance, no supplement is available for patients with galactosemia. Galactosemia may result in severe neurologic and renal impairment, however, the clinical presentation is milder in lactose intolerance.
  • Biliary atresia: a condition caused by fibrosis and obliteration of the bile ducts. Biliary atresia is a rare condition and slightly more common in women. Within the 1st 2 months of life, children present with progressive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, white stools, cola-colored urine, and hepatosplenomegaly. Liver biopsy is required for definitive diagnosis and the definitive treatment modality is surgery. Unlike galactosemia, presentation with neurologic deficits is uncommon in children. 
  • Hemochromatosis: an autosomal-recessive disorder causing severe iron overload. The condition is caused by gene mutations, which lead to low production of hepcidin and resultant increased iron absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption. The classic triad of symptoms includes cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, diabetes, and increased skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin pigmentation. Patients are diagnosed through a combination of iron studies, genetic testing (showing known genetic mutations), and biopsy (when the initial approach is nondiagnostic). Patients require phlebotomy, iron chelation, and dietary restriction for management. Unlike galactosemia, hemochromatosis usually presents later in life (5th or 6th decade). Juvenile hemochromatosis is uncommon but can present in the 2nd decade of life.

References

  1. Sutton, V.R. (2021). Galactosemia: Clinical features and diagnosis. UpToDate. Retrieved April 15, 2021, from https://www.uptodate.com/contents/galactosemia-clinical-features-and-diagnosis
  2. Powell, K.K., et al. (2009). Long-term speech and language developmental issues among children with Duarte Galactosemia. Genetics in Medicine. 11(12), 874–9. https://pubmed.ncbi.nlm.nih.gov/19904210
  3. Coelho, A.I., Rubio-Gozalbo, M.E., Vicente, J.B., Rivera, I. (2017). Sweet and sour: an update on classic galactosemia. Journal of Inherited Metabolic Disease. 40(3), 325–42. https://pubmed.ncbi.nlm.nih.gov/28281081/

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