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Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

MedGen UID:
82777
Concept ID:
C0268151
Disease or Syndrome
Synonyms: Galactose-1-phosphate uridyltransferase deficiency; GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; Galactosemia, classic; GALT deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
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)
 
Gene (location): GALT (9p13.3)
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. 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 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 (NBS) 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 GTR]

Additional descriptions

From GeneReviews
The term galactosemia refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia. 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 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 (NBS) 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.  https://www.ncbi.nlm.nih.gov/books/NBK1518
From OMIM
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).  http://www.omim.org/entry/230400
From GHR
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.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.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.  https://ghr.nlm.nih.gov/condition/galactosemia

Clinical features

Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.(NICHD)
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Premature ovarian failure
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Cessation of menstruation before the age of 40. Symptoms include hot flashes, night sweats, mood swings, and decreased sex drive.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.(NICHD)
Abnormal urinary amino-acid findings
MedGen UID:
892939
Concept ID:
C4020843
Finding
An increased concentration of an amino acid in the urine.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
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 of loose or watery bowel movements.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Liver Cirrhosis
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:
39248
Concept ID:
C0086565
Pathologic Function
A finding that indicates abnormal liver function.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Hemolytic anemia
MedGen UID:
1916
Concept ID:
C0002878
Disease or Syndrome
A condition of inadequate circulating red blood cells (ANEMIA) or insufficient HEMOGLOBIN due to premature destruction of red blood cells (ERYTHROCYTES).
Premature ovarian failure
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Cessation of menstruation before the age of 40. Symptoms include hot flashes, night sweats, mood swings, and decreased sex drive.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.(NICHD)
Abnormal urinary amino-acid findings
MedGen UID:
892939
Concept ID:
C4020843
Finding
An increased concentration of an amino acid in the urine.
Galactosemia
MedGen UID:
8943
Concept ID:
C0016952
Disease or Syndrome
The term galactosemia refers to disorders of galactose metabolism that include classic galactosemia, clinical variant galactosemia, and biochemical variant galactosemia. 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 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 (NBS) 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.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Acid accumulation or depletion of base in the body due to buildup of metabolic acids.
Galactosuria
MedGen UID:
120615
Concept ID:
C0268157
Disease or Syndrome
Elevated concentration of galactose in the urine.
Hyperchloremic metabolic acidosis
MedGen UID:
369924
Concept ID:
C1969073
Finding
Abnormal urinary amino-acid findings
MedGen UID:
892939
Concept ID:
C4020843
Finding
An increased concentration of an amino acid in the urine.
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Ovarian or testicular dysfunction associated with high levels of gonadotropins.(NICHD)

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.

Recent clinical studies

Etiology

Welling L, Boelen A, Derks TG, Schielen PC, de Vries M, Williams M, Wijburg FA, Bosch AM
Mol Genet Metab 2017 Mar;120(3):223-228. Epub 2016 Dec 29 doi: 10.1016/j.ymgme.2016.12.012. PMID: 28065439
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
Timmers I, Zhang H, Bastiani M, Jansma BM, Roebroeck A, Rubio-Gozalbo ME
J Inherit Metab Dis 2015 Mar;38(2):295-304. Epub 2014 Oct 25 doi: 10.1007/s10545-014-9780-x. PMID: 25344151Free PMC Article
Spencer JB, Badik JR, Ryan EL, Gleason TJ, Broadaway KA, Epstein MP, Fridovich-Keil JL
J Clin Endocrinol Metab 2013 Jul;98(7):E1257-65. Epub 2013 May 20 doi: 10.1210/jc.2013-1374. PMID: 23690308Free PMC Article
Ryan EL, Lynch ME, Taddeo E, Gleason TJ, Epstein MP, Fridovich-Keil JL
J Inherit Metab Dis 2013 Nov;36(6):1049-61. Epub 2013 Jan 15 doi: 10.1007/s10545-012-9575-x. PMID: 23319291Free PMC Article

Diagnosis

Welling L, Boelen A, Derks TG, Schielen PC, de Vries M, Williams M, Wijburg FA, Bosch AM
Mol Genet Metab 2017 Mar;120(3):223-228. Epub 2016 Dec 29 doi: 10.1016/j.ymgme.2016.12.012. PMID: 28065439
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
Narravula A, Garber KB, Askree SH, Hegde M, Hall PL
Genet Med 2017 Jan;19(1):77-82. Epub 2016 Jun 16 doi: 10.1038/gim.2016.67. PMID: 27308838
Timmers I, Zhang H, Bastiani M, Jansma BM, Roebroeck A, Rubio-Gozalbo ME
J Inherit Metab Dis 2015 Mar;38(2):295-304. Epub 2014 Oct 25 doi: 10.1007/s10545-014-9780-x. PMID: 25344151Free PMC Article
Ryan EL, Lynch ME, Taddeo E, Gleason TJ, Epstein MP, Fridovich-Keil JL
J Inherit Metab Dis 2013 Nov;36(6):1049-61. Epub 2013 Jan 15 doi: 10.1007/s10545-012-9575-x. PMID: 23319291Free PMC Article

Therapy

Timson DJ
Gene 2016 Sep 10;589(2):133-41. Epub 2015 Jul 2 doi: 10.1016/j.gene.2015.06.077. PMID: 26143117
Davies P, Connor E, MacKenzie J, Jamieson MA
J Pediatr Adolesc Gynecol 2015 Aug;28(4):e101-3. Epub 2014 Sep 16 doi: 10.1016/j.jpag.2014.09.003. PMID: 26024933
Batey LA, Welt CK, Rohr F, Wessel A, Anastasoaie V, Feldman HA, Guo CY, Rubio-Gozalbo E, Berry G, Gordon CM
Osteoporos Int 2013 Feb;24(2):501-9. Epub 2012 Apr 19 doi: 10.1007/s00198-012-1983-0. PMID: 22525982
Jumbo-Lucioni PP, Garber K, Kiel J, Baric I, Berry GT, Bosch A, Burlina A, Chiesa A, Pico ML, Estrada SC, Henderson H, Leslie N, Longo N, Morris AA, Ramirez-Farias C, Schweitzer-Krantz S, Silao CL, Vela-Amieva M, Waisbren S, Fridovich-Keil JL
J Inherit Metab Dis 2012 Nov;35(6):1037-49. Epub 2012 Mar 27 doi: 10.1007/s10545-012-9477-y. PMID: 22450714Free PMC Article
Verma S, Bharti B, Inusha P
Indian J Pediatr 2010 Jun;77(6):695-6. Epub 2010 Jun 8 doi: 10.1007/s12098-010-0082-5. PMID: 20532692

Prognosis

Welling L, Boelen A, Derks TG, Schielen PC, de Vries M, Williams M, Wijburg FA, Bosch AM
Mol Genet Metab 2017 Mar;120(3):223-228. Epub 2016 Dec 29 doi: 10.1016/j.ymgme.2016.12.012. PMID: 28065439
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
Maratha A, Stockmann H, Coss KP, Estela Rubio-Gozalbo M, Knerr I, Fitzgibbon M, McVeigh TP, Foley P, Moss C, Colhoun HO, van Erven B, Stephens K, Doran P, Rudd P, Treacy E
Eur J Hum Genet 2016 Jul;24(7):976-84. Epub 2016 Jan 6 doi: 10.1038/ejhg.2015.254. PMID: 26733289Free PMC Article
Timmers I, Zhang H, Bastiani M, Jansma BM, Roebroeck A, Rubio-Gozalbo ME
J Inherit Metab Dis 2015 Mar;38(2):295-304. Epub 2014 Oct 25 doi: 10.1007/s10545-014-9780-x. PMID: 25344151Free PMC Article
Ryan EL, Lynch ME, Taddeo E, Gleason TJ, Epstein MP, Fridovich-Keil JL
J Inherit Metab Dis 2013 Nov;36(6):1049-61. Epub 2013 Jan 15 doi: 10.1007/s10545-012-9575-x. PMID: 23319291Free PMC Article

Clinical prediction guides

Staubach S, Müller S, Pekmez M, Hanisch FG
J Proteome Res 2017 Feb 3;16(2):516-527. Epub 2017 Jan 24 doi: 10.1021/acs.jproteome.6b00658. PMID: 28075131
Welling L, Boelen A, Derks TG, Schielen PC, de Vries M, Williams M, Wijburg FA, Bosch AM
Mol Genet Metab 2017 Mar;120(3):223-228. Epub 2016 Dec 29 doi: 10.1016/j.ymgme.2016.12.012. PMID: 28065439
Narravula A, Garber KB, Askree SH, Hegde M, Hall PL
Genet Med 2017 Jan;19(1):77-82. Epub 2016 Jun 16 doi: 10.1038/gim.2016.67. PMID: 27308838
Timmers I, Zhang H, Bastiani M, Jansma BM, Roebroeck A, Rubio-Gozalbo ME
J Inherit Metab Dis 2015 Mar;38(2):295-304. Epub 2014 Oct 25 doi: 10.1007/s10545-014-9780-x. PMID: 25344151Free PMC Article
Ryan EL, Lynch ME, Taddeo E, Gleason TJ, Epstein MP, Fridovich-Keil JL
J Inherit Metab Dis 2013 Nov;36(6):1049-61. Epub 2013 Jan 15 doi: 10.1007/s10545-012-9575-x. PMID: 23319291Free PMC Article

Recent systematic reviews

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):633-49. Epub 2016 Apr 26 doi: 10.1007/s10545-016-9936-y. PMID: 27116003
Van Calcar SC, Bernstein LE, Rohr FJ, Scaman CH, Yannicelli S, Berry GT
Mol Genet Metab 2014 Jul;112(3):191-7. Epub 2014 May 2 doi: 10.1016/j.ymgme.2014.04.004. PMID: 24857409
Walter JH, Collins JE, Leonard JV
Arch Dis Child 1999 Jan;80(1):93-6. PMID: 10325771Free PMC Article

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