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Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase(GALAC1)

MedGen UID:
82777
Concept ID:
C0268151
Disease or Syndrome
Synonyms: Galactose-1-phosphate uridyltransferase deficiency; GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; GALACTOSEMIA I; Galactosemia, classic; GALT deficiency; Transferase Deficiency Galactosemia
SNOMED CT: Deficiency of UTP-hexose-1-phosphate uridylyltransferase (398664009); UTP-hexose-1-phosphate uridyltransferase deficiency (398664009); Deficiency of uridyl transferase (124354006); Deficiency of hexose-1-phosphate uridylyltransferase (124354006); Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (124354006); GALT deficiency (124354006); Classical galactosemia (124354006); Deficiency of galactose-1-phosphate uridyl transferase (124354006); Transferase deficiency galactosemia (124354006); Deficiency of uridine triphosphate-hexose-1-phosphate uridylyltransferase (398664009); Deficiency of uridine diphosphate-glucose-hexose-1-phosphate uridylyltransferase (124354006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GALT (9p13.3)
 
Monarch Initiative: MONDO:0009258
OMIM®: 230400
Orphanet: ORPHA79239

Definition

The term "galactosemia" refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia (not covered in this chapter). This GeneReview focuses on: Classic galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage, bleeding, and E coli sepsis in untreated infants. If a lactose-restricted diet is provided during the first ten days of life, the neonatal signs usually quickly resolve and the complications of liver failure, sepsis, and neonatal death are prevented; however, despite adequate treatment from an early age, children with classic galactosemia remain at increased risk for developmental delays, speech problems (termed childhood apraxia of speech and dysarthria), and abnormalities of motor function. Almost all females with classic galactosemia manifest hypergonadatropic hypogonadism or premature ovarian insufficiency (POI). Clinical variant galactosemia, which can result in life-threatening complications including feeding problems, failure to thrive, hepatocellular damage including cirrhosis, and bleeding in untreated infants. This is exemplified by the disease that occurs in African Americans and native Africans in South Africa. Persons with clinical variant galactosemia may be missed with newborn screening as the hypergalactosemia is not as marked as in classic galactosemia and breath testing is normal. If a lactose-restricted diet is provided during the first ten days of life, the severe acute neonatal complications are usually prevented. African Americans with clinical variant galactosemia and adequate early treatment do not appear to be at risk for long-term complications, including POI. [from GeneReviews]

Additional descriptions

From OMIM
Galactosemia I (GALAC1), or classic galactosemia, is an autosomal recessive disorder of galactose metabolism. Most patients present in the neonatal period, after ingestion of galactose, with jaundice, hepatosplenomegaly, hepatocellular insufficiency, food intolerance, hypoglycemia, renal tubular dysfunction, muscle hypotonia, sepsis, and cataract. Long-term complications include mental retardation, verbal dyspraxia, motor abnormalities, and hypergonadotropic hypogonadism (summary by Bosch, 2006). Genetic Heterogeneity of Galactosemia Also see galactosemia II (GALAC2; 230200), caused by mutation in the GALK1 gene (604313), which encodes the first enzyme in the Leloir pathway, and galactosemia III (GALAC3; 230350), caused by mutation in the GALE gene (606953), which encodes the third enzyme in the Leloir pathway.  http://www.omim.org/entry/230400
From MedlinePlus Genetics
Classic galactosemia, also known as type I, is the most common and most severe form of the condition. If infants with classic galactosemia are not treated promptly with a low-galactose diet, life-threatening complications appear within a few days after birth. Affected infants typically develop feeding difficulties, a lack of energy (lethargy), a failure to gain weight and grow as expected (failure to thrive), yellowing of the skin and whites of the eyes (jaundice), liver damage, and abnormal bleeding. Other serious complications of this condition can include overwhelming bacterial infections (sepsis) and shock. Affected children are also at increased risk of delayed development, clouding of the lens of the eye (cataract), speech difficulties, and intellectual disability. Females with classic galactosemia may develop reproductive problems caused by an early loss of function of the ovaries (premature ovarian insufficiency).

Galactosemia type II (also called galactokinase deficiency) and type III (also called galactose epimerase deficiency) cause different patterns of signs and symptoms. Galactosemia type II causes fewer medical problems than the classic type. Affected infants develop cataracts but otherwise experience few long-term complications. The signs and symptoms of galactosemia type III vary from mild to severe and can include cataracts, delayed growth and development, intellectual disability, liver disease, and kidney problems.

Researchers have identified several types of galactosemia. These conditions are each caused by mutations in a particular gene and affect different enzymes involved in breaking down galactose.

Galactosemia is a disorder that affects how the body processes a simple sugar called galactose. A small amount of galactose is present in many foods. It is primarily part of a larger sugar called lactose, which is found in all dairy products and many baby formulas. The signs and symptoms of galactosemia result from an inability to use galactose to produce energy.  https://medlineplus.gov/genetics/condition/galactosemia

Clinical features

From HPO
Albuminuria
MedGen UID:
1394
Concept ID:
C0001925
Finding
Increased concentration of albumin in the urine.
Premature ovarian insufficiency
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Amenorrhea due to loss of ovarian function before the age of 40. Primary ovarian inssuficiency (POI) is a state of female hypergonadotropic hypogonadism. It can manifest as primary amenorrhea with onset before menarche or secondary amenorrhea.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Disease or Syndrome
An increased concentration of an amino acid in the urine.
Galactosuria
MedGen UID:
120615
Concept ID:
C0268157
Disease or Syndrome
Elevated concentration of galactose in the urine.
Increased level of galactitol in urine
MedGen UID:
1639504
Concept ID:
C4703628
Finding
An increase in the level of galactitol in the urine.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Decreased liver function
MedGen UID:
65430
Concept ID:
C0232744
Finding
Reduced ability of the liver to perform its functions.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A type of anemia caused by premature destruction of red blood cells (hemolysis).
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hyperchloremic metabolic acidosis
MedGen UID:
369924
Concept ID:
C1969073
Disease or Syndrome
A form of metabolic acidosis with increased serum chloride levels.
Hypergalactosemia
MedGen UID:
892325
Concept ID:
C4023071
Finding
Elevated concentration of galactose in the blood.
Increased level of galactitol in plasma
MedGen UID:
1647478
Concept ID:
C4703627
Finding
An increase in the level of galactitol in the plasma.
Increased level of galactonate in red blood cells
MedGen UID:
1639833
Concept ID:
C4703629
Finding
An increase in the level of galactonate in the red blood cells.
Increased level of galactitol in red blood cells
MedGen UID:
1643634
Concept ID:
C4703630
Finding
An increase in the level of galactitol in the red blood cells.
Reduced erythrocyte galactose-1-phosphate uridylyltransferase activity
MedGen UID:
1051799
Concept ID:
CN375679
Finding
Activity or concentration of in the level of galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12) in erythrocytes below the lower limit of normal.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase in Orphanet.

Professional guidelines

PubMed

Badiu Tișa I, Achim AC, Cozma-Petruț A
Nutrients 2022 Dec 20;15(1) doi: 10.3390/nu15010010. PMID: 36615667Free PMC Article
Succoio M, Sacchettini R, Rossi A, Parenti G, Ruoppolo M
Biomolecules 2022 Jul 11;12(7) doi: 10.3390/biom12070968. PMID: 35883524Free PMC Article
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; Galactosemia Network (GalNet)
J Inherit Metab Dis 2017 Mar;40(2):171-176. Epub 2016 Nov 17 doi: 10.1007/s10545-016-9990-5. PMID: 27858262Free PMC Article

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated total galactose with normal GALT enzyme activity, Primary or Secondary Hypergalactosemia, 2022

American College of Medical Genetics Algorithm, Primary or Secondary Hypergalactosemia (Galactose Elevated)

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Absent/Reduced Galactose-1-Phosphate Uridyltransferase (GALT), Classic Galactosemia, 2021

American College of Medical Genetics and Genomics, Algorithm, Galactosemia (GALT Deficiency), 2021

American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Galactosemia (GALT Deficiency, Classical Galactosemia), 2012

Recent clinical studies

Etiology

Banford S, Timson DJ
Biochimie 2021 Apr;183:13-17. Epub 2020 Nov 9 doi: 10.1016/j.biochi.2020.11.001. PMID: 33181226
Anderson S
MCN Am J Matern Child Nurs 2018 Jan/Feb;43(1):44-51. doi: 10.1097/NMC.0000000000000388. PMID: 29215423
Lak R, Yazdizadeh B, Davari M, Nouhi M, Kelishadi R
Cochrane Database Syst Rev 2017 Dec 23;12(12):CD012272. doi: 10.1002/14651858.CD012272.pub2. PMID: 29274129Free PMC Article
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; Galactosemia Network (GalNet)
J Inherit Metab Dis 2017 Mar;40(2):171-176. Epub 2016 Nov 17 doi: 10.1007/s10545-016-9990-5. PMID: 27858262Free PMC Article
Sardharwalla IB, Wraith JE
Nutr Health 1987;5(3-4):175-88. doi: 10.1177/026010608700500408. PMID: 3328119

Diagnosis

Badiu Tișa I, Achim AC, Cozma-Petruț A
Nutrients 2022 Dec 20;15(1) doi: 10.3390/nu15010010. PMID: 36615667Free PMC Article
Succoio M, Sacchettini R, Rossi A, Parenti G, Ruoppolo M
Biomolecules 2022 Jul 11;12(7) doi: 10.3390/biom12070968. PMID: 35883524Free PMC Article
Demirbas D, Coelho AI, Rubio-Gozalbo ME, Berry GT
Metabolism 2018 Jun;83:188-196. Epub 2018 Jan 31 doi: 10.1016/j.metabol.2018.01.025. PMID: 29409891
Anderson S
MCN Am J Matern Child Nurs 2018 Jan/Feb;43(1):44-51. doi: 10.1097/NMC.0000000000000388. PMID: 29215423
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; Galactosemia Network (GalNet)
J Inherit Metab Dis 2017 Mar;40(2):171-176. Epub 2016 Nov 17 doi: 10.1007/s10545-016-9990-5. PMID: 27858262Free PMC Article

Therapy

Lak R, Yazdizadeh B, Davari M, Nouhi M, Kelishadi R
Cochrane Database Syst Rev 2020 Jun 22;6(6):CD012272. doi: 10.1002/14651858.CD012272.pub3. PMID: 32567677Free PMC Article
Lak R, Yazdizadeh B, Davari M, Nouhi M, Kelishadi R
Cochrane Database Syst Rev 2017 Dec 23;12(12):CD012272. doi: 10.1002/14651858.CD012272.pub2. PMID: 29274129Free PMC Article
Coelho AI, Berry GT, Rubio-Gozalbo ME
Curr Opin Clin Nutr Metab Care 2015 Jul;18(4):422-7. doi: 10.1097/MCO.0000000000000189. PMID: 26001656
Lawrence RM
Pediatr Clin North Am 2013 Feb;60(1):295-318. Epub 2012 Oct 30 doi: 10.1016/j.pcl.2012.09.012. PMID: 23178071
Friedmann T, Roblin R
Science 1972 Mar 3;175(4025):949-55. doi: 10.1126/science.175.4025.949. PMID: 5061866

Prognosis

Badiu Tișa I, Achim AC, Cozma-Petruț A
Nutrients 2022 Dec 20;15(1) doi: 10.3390/nu15010010. PMID: 36615667Free PMC Article
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; Galactosemia Network (GalNet)
J Inherit Metab Dis 2017 Mar;40(2):171-176. Epub 2016 Nov 17 doi: 10.1007/s10545-016-9990-5. PMID: 27858262Free PMC Article
McCorvie TJ, Gleason TJ, Fridovich-Keil JL, Timson DJ
Biochim Biophys Acta 2013 Aug;1832(8):1279-93. Epub 2013 Apr 11 doi: 10.1016/j.bbadis.2013.04.004. PMID: 23583749Free PMC Article
Sardharwalla IB, Wraith JE
Nutr Health 1987;5(3-4):175-88. doi: 10.1177/026010608700500408. PMID: 3328119
Kliegman RM, Sparks JW
J Pediatr 1985 Dec;107(6):831-41. doi: 10.1016/s0022-3476(85)80173-6. PMID: 3906069

Clinical prediction guides

Forte G, Buonadonna AL, Pantaleo A, Fasano C, Capodiferro D, Grossi V, Sanese P, Cariola F, De Marco K, Lepore Signorile M, Manghisi A, Guglielmi AF, Simonetti S, Laforgia N, Disciglio V, Simone C
Int J Mol Sci 2023 Dec 12;24(24) doi: 10.3390/ijms242417388. PMID: 38139222Free PMC Article
Stettner NM, Cutler DJ, Fridovich-Keil JL
Mol Genet Metab 2023 Apr;138(4):107542. Epub 2023 Feb 21 doi: 10.1016/j.ymgme.2023.107542. PMID: 36848716Free PMC Article
Yuzyuk T, Balakrishnan B, Schwarz EL, De Biase I, Hobert J, Longo N, Mao R, Lai K, Pasquali M
Mol Genet Metab 2018 Nov;125(3):258-265. Epub 2018 Aug 23 doi: 10.1016/j.ymgme.2018.08.012. PMID: 30172461
McCorvie TJ, Gleason TJ, Fridovich-Keil JL, Timson DJ
Biochim Biophys Acta 2013 Aug;1832(8):1279-93. Epub 2013 Apr 11 doi: 10.1016/j.bbadis.2013.04.004. PMID: 23583749Free PMC Article
Sardharwalla IB, Wraith JE
Nutr Health 1987;5(3-4):175-88. doi: 10.1177/026010608700500408. PMID: 3328119

Recent systematic reviews

Lak R, Yazdizadeh B, Davari M, Nouhi M, Kelishadi R
Cochrane Database Syst Rev 2020 Jun 22;6(6):CD012272. doi: 10.1002/14651858.CD012272.pub3. PMID: 32567677Free PMC Article
Haskovic M, Coelho AI, Bierau J, Vanoevelen JM, Steinbusch LKM, Zimmermann LJI, Villamor-Martinez E, Berry GT, Rubio-Gozalbo ME
J Inherit Metab Dis 2020 May;43(3):392-408. Epub 2020 Jan 14 doi: 10.1002/jimd.12202. PMID: 31808946Free PMC Article
Lak R, Yazdizadeh B, Davari M, Nouhi M, Kelishadi R
Cochrane Database Syst Rev 2017 Dec 23;12(12):CD012272. doi: 10.1002/14651858.CD012272.pub2. PMID: 29274129Free PMC Article
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; Galactosemia Network (GalNet)
J Inherit Metab Dis 2017 Mar;40(2):171-176. Epub 2016 Nov 17 doi: 10.1007/s10545-016-9990-5. PMID: 27858262Free PMC Article
Varela-Lema L, Paz-Valinas L, Atienza-Merino G, Zubizarreta-Alberdi R, Villares RV, López-García M
J Inherit Metab Dis 2016 Sep;39(5):633-649. Epub 2016 Apr 26 doi: 10.1007/s10545-016-9936-y. PMID: 27116003

Supplemental Content

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    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated total galactose with normal GALT enzyme activity, Primary or Secondary Hypergalactosemia, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics Algorithm, Primary or Secondary Hypergalactosemia (Galactose Elevated)
    • ACMG ACT, 2021
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Absent/Reduced Galactose-1-Phosphate Uridyltransferase (GALT), Classic Galactosemia, 2021
    • ACMG Algorithm, 2021
      American College of Medical Genetics and Genomics, Algorithm, Galactosemia (GALT Deficiency), 2021
    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics, Transition to Adult Health Care ACT Sheet, Galactosemia (GALT Deficiency, Classical Galactosemia), 2012

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