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UDPglucose-4-epimerase deficiency(GALAC3)

MedGen UID:
199598
Concept ID:
C0751161
Disease or Syndrome
Synonyms: Epimerase Deficiency Galactosemia; Galactose epimerase deficiency; Galactosemia 3; GALACTOSEMIA III; UDP-Galactose-4-epimerase deficiency; UDPglucose 4-Epimerase Deficiency Disease
SNOMED CT: Galactosemia - epimerase deficiency (8849004); Epimerase deficiency (8849004); Uridine diphosphate galactose-4-epimerase deficiency (8849004); Galactose epimerase deficiency (8849004); Uridine diphosphate galactose-4 epimerase deficiency (8849004); Galactosemia III (8849004); Uridine diphosphate glucose-4-epimerase deficiency (8849004); GALE (UDP-galactose-4-epimerase) deficiency (8849004); UDP (uridine diphosphate) galactose-4-epimerase deficiency (8849004); UDP (uridine diphosphate) glucose-4-epimerase deficiency (8849004)
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): GALE (1p36.11)
 
Monarch Initiative: MONDO:0009257
OMIM®: 230350
Orphanet: ORPHA79238

Disease characteristics

Excerpted from the GeneReview: Epimerase Deficiency Galactosemia
Epimerase deficiency galactosemia (GALE deficiency galactosemia) is generally considered a continuum comprising several 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. Longer-term features that may be seen in those with generalized epimerase deficiency include short stature, developmental delay, sensorineural hearing loss, and skeletal anomalies. 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
Galactosemia III (GALAC3), or 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 leukocytes, 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. For a discussion of genetic heterogeneity of galactosemia, see GALAC1 (230400).  http://www.omim.org/entry/230350
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).

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 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.

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
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.
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.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
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 disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Delayed gross motor development
MedGen UID:
332508
Concept ID:
C1837658
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
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.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Decreased beta-galactosidase activity
MedGen UID:
383939
Concept ID:
C1856559
Finding
Abnormally decreased rate of beta-galactosidase activity. Beta-galactosidase activity can be measured in leukocyte, fibroblast, or plasma.
Hypergalactosemia
MedGen UID:
892325
Concept ID:
C4023071
Finding
Elevated concentration of galactose in the blood.

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 Algorithm, Primary or Secondary Hypergalactosemia (Galactose Elevated)

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 ACT Sheet, Newborn Screening ACT Sheet Primary or Secondary Hypergalactosemia

American College of Medical Genetics ACT SHEETs, Primary or Secondary Hypergalactosemia, 2010

American College of Medical Genetics Algorithm, Primary or Secondary Hypergalactosemia, 2009

Recent clinical studies

Etiology

Markovitz R, Owen N, Satter LF, Kirk S, Mahoney DH, Bertuch AA, Scaglia F
Am J Med Genet A 2021 Oct;185(10):3118-3121. Epub 2021 Jun 22 doi: 10.1002/ajmg.a.62384. PMID: 34159722
Bowling FG, Brown AR
J Inherit Metab Dis 1986;9(1):99-104. doi: 10.1007/BF01813911. PMID: 3014213
Kliegman RM, Sparks JW
J Pediatr 1985 Dec;107(6):831-41. doi: 10.1016/s0022-3476(85)80173-6. PMID: 3906069
Gitzelmann R, Steinmann B, Mitchell B, Haigis E
Helv Paediatr Acta 1977 Apr;31(6):441-52. PMID: 404274

Diagnosis

Markovitz R, Owen N, Satter LF, Kirk S, Mahoney DH, Bertuch AA, Scaglia F
Am J Med Genet A 2021 Oct;185(10):3118-3121. Epub 2021 Jun 22 doi: 10.1002/ajmg.a.62384. PMID: 34159722
Tong F, Yang R, Hong F, Qian G, Jiang P, Gao R
J Pediatr Endocrinol Metab 2016 Mar;29(3):379-83. doi: 10.1515/jpem-2014-0462. PMID: 26565537
Daenzer JM, Sanders RD, Hang D, Fridovich-Keil JL
PLoS Genet 2012;8(5):e1002721. Epub 2012 May 24 doi: 10.1371/journal.pgen.1002721. PMID: 22654673Free PMC Article
Sarkar M, Bose SS, Mondal G, Chatterjee S
Indian J Pediatr 2010 Aug;77(8):909-10. Epub 2010 Aug 20 doi: 10.1007/s12098-010-0135-9. PMID: 20725869
Cuthbert C, Klapper H, Elsas L
Curr Protoc Hum Genet 2008 Jan;Chapter 17:Unit 17.5. doi: 10.1002/0471142905.hg1705s56. PMID: 18428423

Therapy

Nishimura Y, Tajima G, Dwi Bahagia A, Sakamoto A, Ono H, Sakura N, Naito K, Hamakawa M, Yoshii C, Kubota M, Kobayashi K, Saheki T
J Inherit Metab Dis 2004;27(1):11-8. doi: 10.1023/B:BOLI.0000016621.29854.d6. PMID: 14970742
McCutchan JA, Wolf JL, Ziegler EJ, Braude AI
Schweiz Med Wochenschr Suppl 1983;14:40-5. PMID: 6361990
Glauser MP
Schweiz Med Wochenschr Suppl 1983;14:35-9. PMID: 6361989

Prognosis

Tong F, Yang R, Hong F, Qian G, Jiang P, Gao R
J Pediatr Endocrinol Metab 2016 Mar;29(3):379-83. doi: 10.1515/jpem-2014-0462. PMID: 26565537
Walter JH, Roberts RE, Besley GT, Wraith JE, Cleary MA, Holton JB, MacFaul R
Arch Dis Child 1999 Apr;80(4):374-6. doi: 10.1136/adc.80.4.374. PMID: 10086948Free PMC Article
Daude N, Gallaher TK, Zeschnigk M, Starzinski-Powitz A, Petry KG, Haworth IS, Reichardt JK
Biochem Mol Med 1995 Oct;56(1):1-7. doi: 10.1006/bmme.1995.1048. PMID: 8593531
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

Daude N, Gallaher TK, Zeschnigk M, Starzinski-Powitz A, Petry KG, Haworth IS, Reichardt JK
Biochem Mol Med 1995 Oct;56(1):1-7. doi: 10.1006/bmme.1995.1048. PMID: 8593531
Henderson MJ, Holton JB, MacFaul R
J Inherit Metab Dis 1983;6(1):17-20. doi: 10.1007/BF02391187. PMID: 6408303

Supplemental Content

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    Clinical resources

    Practice guidelines

    • PubMed
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      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG Algorithm, 2022
      American College of Medical Genetics Algorithm, Primary or Secondary Hypergalactosemia (Galactose Elevated)
    • 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 ACT, 2022
      American College of Medical Genetics ACT Sheet, Newborn Screening ACT Sheet Primary or Secondary Hypergalactosemia
    • ACMG ACT Sheet, 2010
      American College of Medical Genetics ACT SHEETs, Primary or Secondary Hypergalactosemia, 2010
    • ACMG Algorithm, 2009
      American College of Medical Genetics Algorithm, Primary or Secondary Hypergalactosemia, 2009

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