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UDPglucose-4-epimerase deficiency(GALE)

MedGen UID:
199598
Concept ID:
C0751161
Disease or Syndrome
Synonyms: Epimerase Deficiency Galactosemia; Galactose epimerase deficiency; Galactosemia 3; GALACTOSEMIA III; GALE; UDP-Galactose-4-epimerase deficiency; UDPglucose 4-Epimerase Deficiency Disease
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: Galactosemia - epimerase deficiency (8849004); Epimerase deficiency (8849004); Uridine diphosphate galactose-4-epimerase deficiency (8849004); UDPglucose-4-epimerase deficiency (8849004); Galactose epimerase deficiency (8849004); UDPgalactose-4-epimerase deficiency (8849004); Uridine diphosphate galactose-4 epimerase deficiency (8849004); GALE (8849004); Galactosemia III (8849004); Uridine diphosphate (UDP) glucose-4-epimerase deficiency (8849004); Uridine diphosphate glucose-4-epimerase deficiency (8849004)
 
Gene (location): GALE (1p36.11)
OMIM®: 230350
Orphanet: ORPHA79238

Disease characteristics

Excerpted from the GeneReview: Epimerase Deficiency Galactosemia
Epimerase deficiency galactosemia (GALE deficiency galactosemia) is a continuum comprising three forms: Generalized. Enzyme activity is profoundly decreased in all tissues tested. Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues. Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested. Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs. [from GeneReviews]
Authors:
Judith Fridovich-Keil  |  Lora Bean  |  Miao He, et. al.   view full author information

Additional descriptions

From OMIM
Epimerase-deficiency galactosemia was originally described as a benign condition in which GALE impairment is restricted to circulating red and white blood cells (Gitzelmann, 1972). Fibroblasts, liver, phytohemagglutinin-stimulated leukocyes, and Epstein Barr virus-transformed lymphoblasts from these patients all demonstrated normal or near-normal levels of GALE, leading to the designation 'peripheral' (or 'isolated') epimerase deficiency. A second form of epimerase deficiency became apparent in which a patient, despite normal GALT activity, presented with symptoms reminiscent of classic galactosemia and demonstrated severely impaired GALE activity in both red blood cells and fibroblasts (Holton et al., 1981). This form was designated 'generalized' epimerase deficiency. Openo et al. (2006) demonstrated that epimerase deficiency is in fact not a binary condition but is, rather, a continuum disorder. GALE encodes the third enzyme in the Leloir pathway of galactose metabolism. Galactosemia I is classic galactosemia (230400), caused by deficiency of the second enzyme in the Leloir pathway, galactose-1-phosphate uridylyl-transferase (GALT; 606999). Galactosemia II (230200) is caused by deficiency of the first enzyme in the Leloir pathway, galactokinase (GALK; 604313).  http://www.omim.org/entry/230350
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

Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Jaundice causes your skin and the whites of your eyes to turn yellow. Too much bilirubin causes jaundice. Bilirubin is a yellow chemical in hemoglobin, the substance that carries oxygen in your red blood cells. As red blood cells break down, your body builds new cells to replace them. The old ones are processed by the liver. If the liver cannot handle the blood cells as they break down, bilirubin builds up in the body and your skin may look yellow. . Many healthy babies have some jaundice during the first week of life. It usually goes away. However, jaundice can happen at any age and may be a sign of a problem. Jaundice can happen for many reasons, such as. - Blood diseases. - Genetic syndromes. - Liver diseases, such as hepatitis or cirrhosis. - Blockage of bile ducts . - Infections . - Medicines .
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
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.
Sensorineural hearing loss
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
Hearing loss resulting from damage to the COCHLEA and the sensorineural elements which lie internally beyond the oval and round windows. These elements include the AUDITORY NERVE and its connections in the BRAINSTEM.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.
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.
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.

Recent clinical studies

Etiology

Sarma MS, Srivastava A, Yachha SK, Poddar U, Mathias A
Indian Pediatr 2016 Jan;53(1):27-31. PMID: 26840667
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
Coss KP, Doran PP, Owoeye C, Codd MB, Hamid N, Mayne PD, Crushell E, Knerr I, Monavari AA, Treacy EP
J Inherit Metab Dis 2013 Jan;36(1):21-7. Epub 2012 Jul 3 doi: 10.1007/s10545-012-9507-9. PMID: 22870861

Diagnosis

Sarma MS, Srivastava A, Yachha SK, Poddar U, Mathias A
Indian Pediatr 2016 Jan;53(1):27-31. PMID: 26840667
Martinelli D, Bernardi B, Napolitano A, Colafati GS, Dionisi-Vici C
Neurology 2016 Jan 19;86(3):e32-3. doi: 10.1212/WNL.0000000000002284. PMID: 26783274
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

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
Ryan EL, DuBoff B, Feany MB, Fridovich-Keil JL
Dis Model Mech 2012 Nov;5(6):796-803. Epub 2012 Jun 26 doi: 10.1242/dmm.009050. PMID: 22736462Free 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

Sarma MS, Srivastava A, Yachha SK, Poddar U, Mathias A
Indian Pediatr 2016 Jan;53(1):27-31. PMID: 26840667
Martinelli D, Bernardi B, Napolitano A, Colafati GS, Dionisi-Vici C
Neurology 2016 Jan 19;86(3):e32-3. doi: 10.1212/WNL.0000000000002284. PMID: 26783274
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

Clinical prediction guides

Sarma MS, Srivastava A, Yachha SK, Poddar U, Mathias A
Indian Pediatr 2016 Jan;53(1):27-31. PMID: 26840667
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
Jumbo-Lucioni PP, Hopson ML, Hang D, Liang Y, Jones DP, Fridovich-Keil JL
Dis Model Mech 2013 Jan;6(1):84-94. Epub 2012 Jul 5 doi: 10.1242/dmm.010207. PMID: 22773758Free PMC Article

Recent systematic reviews

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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