Database: OMIM
Entry: 230400
LinkDB: 230400
MIM Entry: 230400
  A number sign (#) is used with this entry because classic galactosemia
  is caused by mutation in the galactose-1-phosphate uridylyltransferase
  gene (GALT; 606999).
  The cardinal features of classic galactosemia are hepatomegaly,
  cataracts, and mental retardation.
  The first detailed description of galactosemia was given by Goppert
  (1917). The proband (A.G.) presented with large liver, icterus, failure
  to thrive, and urinary excretion of albumen and sugar. After exclusion
  of galactose from the diet, these signs and symptoms normalized. He was
  mentally retarded (developmental quotient of 14 months at 36 months of
  age). He tolerated sucrose, maltose, glucose, and fructose at doses of 2
  g/kg, but after lactose or galactose there was dose-dependent
  galactosuria. His oldest brother had suffered from icterus and liver
  enlargement a few days after birth and had had a life-threatening bleed
  after ritual circumcision. He died after 6 weeks. At autopsy, a huge
  liver tumor was present (attributed to syphilis, although subsequent
  Wassermann reactions were negative), and the cause of his death was
  attributed to nephritis. His third sib, born somewhat prematurely,
  became icteric, and died after 4 weeks. Goppert (1917) concluded that
  the patient was suffering from a familial liver disorder and that in
  such cases lactose must be replaced by another sugar, e.g., sucrose or
  maltose. Another early detailed description of galactosemia was given by
  Mason and Turner (1935). Segal (1989) presented a picture of a
  30-year-old man diagnosed in infancy by Mason and Turner (1935).
  Failure to thrive is the most common initial clinical symptom of
  galactosemia. Vomiting or diarrhea usually begins within a few days of
  milk ingestion. Jaundice of intrinsic liver disease may be accentuated
  by the severe hemolysis occurring in some patients. Cataracts have been
  observed within a few days of birth. These may be found only on
  slit-lamp examination and missed with an ophthalmoscope, since they
  consist of punctate lesions in the fetal lens nucleus (Holton et al.,
  2001). There appears to be a high frequency of neonatal death due to E.
  coli sepsis, with a fulminant course (Levy et al., 1977). Litchfield and
  Wells (1978) suggested that this proneness to sepsis is due to
  inhibition of leukocyte bactericidal activity.
  Ruiz et al. (1999) concluded that coagulopathy may be present in
  galactosemia with little evidence of liver disease (Levy et al., 1996).
  They suggested, furthermore, that the association of jaundice and
  hemorrhagic diathesis in the first 2 weeks of life is a clinical
  presentation in which galactosemia must be considered.
  - Pregnancy
  Ovarian failure in many affected girls (Kaufman et al., 1979) may
  indicate in utero damage from galactosemia. Pregnancy is rare in women
  with galactosemia because of the high frequency of hypergonadotropic
  hypogonadism with ovarian atrophy.
  Harley et al. (1974) found low levels (presumably indicative of the
  heterozygous state) of galactose-1-phosphate uridylyltransferase and
  galactokinase in mothers of children with otherwise unexplained
  infantile cataract. They suggested that a lactose load in combination
  with the low enzyme level leads to cataract.
  Brivet et al. (1989) described a 24-year-old woman homozygous for GALT
  deficiency who, despite strict galactose-free diet, suffered
  self-intoxication probably due to lactose biosynthesis while
  breastfeeding her baby. Lactosuria is a common finding in pregnant women
  because of lactose biosynthesis by the mammary glands beginning in the
  second trimester. Brivet et al. (1989) described the development of
  cataracts in a healthy lactating 28-year-old woman heterozygous for GALT
  deficiency. Avisar et al. (1982) had likewise observed rapidly
  progressing cataract in a lactating heterozygote.
  Reports of 14 pregnancies in patients with galactosemia were noted by
  Waggoner et al. (1990). De Jongh et al. (1999) reported a galactosemic
  woman who had an uncomplicated full-term pregnancy and produced a
  clinically normal infant. The diagnosis in the mother had been made when
  she was 2 weeks old, and she had been maintained on a lactose- and
  galactose-free diet. The pregnancy occurred at the age of 30 years. She
  had slight mental retardation (IQ, 85). She remained on a lactose- and
  galactose-free diet throughout her pregnancy. This patient was
  Caucasian; all but one of the previously reported patients were black
  and may not have had classic galactosemia. The mother in this case was
  found to be heterozygous for the common Q188R mutation (606999.0006).
  Since no GALT activity was detected in erythrocytes, a mutation in the
  other allele was suspected but not found. The obligate heterozygous
  offspring of this woman had no apparent adverse effects of the maternal
  galactosemic state.
  - Clinical Heterogeneity
  With the several mutations that have been identified at the GALT locus,
  the tendency for clinical complications to develop varies from apparent
  clinical normality in the relatively common Duarte type to perhaps mild
  symptoms in the S135L variant and to the severe galactosemia syndrome in
  the 'classic,' Indiana, and Rennes variants (Hammersen et al., 1975).
  Beutler et al. (1965) suggested that some persons with intermediate
  levels of the enzyme are not heterozygotes for the usual galactosemia
  but rather are homozygotes for what they termed the 'Duarte' variant.
  Heterozygotes for this variant have about 75% normal activity. This new
  form was discovered in the course of a screening program. Patients with
  the Duarte variant of galactosemia are usually healthy, despite
  functional and structural abnormality in their galactose-1-phosphate
  uridylyltransferase. An 8-month-old boy who had jaundice and liver
  enlargement during the first 2 months was reported by Kelly et al.
  (1972). He was homozygous for the Duarte variant. Both parents and 2
  sisters were carriers. Surgical biopsy of the liver showed marked fatty
  infiltration, periportal fibrosis, and cirrhosis. His subsequent
  development was normal. Improvement, the authors suggested, may have
  been due to maturation of the enzyme. Two similar cases had been
  Using G for the allele causing classic galactosemia and D for the Duarte
  allele (N314D; dbSNP rs2070074; 606999.0005), Elsas et al. (1994)
  proposed that the D/N, D/D, and D/G genotypes show approximately 75%,
  50%, and 25% of normal GALT activity, respectively. The Duarte allele is
  associated with an isoform of the enzyme that has more acidic pI than
  normal. This variant, with decreased activity of GALT, is known as D2
  (Holton et al., 2001). Langley et al. (1997) noted that the homozygous
  Duarte phenotype is usually associated with approximately 50% of normal
  GALT enzyme activity, but sometimes the Duarte biochemical phenotype, as
  defined by a shift in its isozyme-banding pattern toward the anode on
  isoelectric focusing, is associated with increased GALT enzyme activity;
  this biochemical variant has been called the 'Los Angeles (LA) variant',
  or 'D1' by Ng et al. (1973) and others. The LA variant occurs when the
  N314D allele is in cis with L218L (652C-T; dbSNP rs2070075;
  606999.0012). Subsequently, Kozak et al. (1999) showed that a 4-bp
  deletion (-119delGTCA; 606999.0017) in the 5-prime region of the GALT
  gene was linked with the Duarte allele and conferred reduced enzymatic
  activity. Carney et al. (2009) showed that the 5-prime 4-bp deletion is
  the causal mutation in Duarte galactosemia and suggested that direct
  tests for this deletion could enhance or supplant current tests.
  Another type of galactosemia is associated with the S135L mutation
  (606999.0010), previously called the 'Negro' variant. The difference in
  behavior of the metabolism of galactose in these patients may be due to
  the development of an alternative pathway (Cuatrecasas and Segal, 1966).
  Other relevant observations on the S135L variant were reported by Baker
  et al. (1966), Mellman et al. (1965), and Hsia (1967). Mellman et al.
  (1965) showed that heterozygous parents with the S135L variant show
  nearly normal enzyme levels in white cells whereas classically
  galactosemic heterozygotes have about 50% activity in both red cells and
  white cells. Heterogeneity was demonstrated by the studies of Segal and
  Cuatrecasas (1968). Patients with the S135L mutation have a less severe
  phenotype (De Jongh et al., 1999).
  On the basis of a screening of newborns in Massachusetts, Shih et al.
  (1971) found only 2 cases of galactosemia among 374,341 births. Both
  infants died with Escherichia coli sepsis in the neonatal period. Since
  E. coli sepsis can be a presenting manifestation of galactosemia,
  results of the neonatal screening must be reported promptly to the
  - Differential Diagnosis
  Gitzelmann et al. (1992) demonstrated that hypergalactosemia in the
  newborn with positive routine metabolic screening tests but with no
  evidence of enzyme deficiency and persistence of hypergalactosemia can
  be due to open ductus venosus Arantii, resulting in portacaval shunt.
  They concluded that color Doppler sonography is the method of choice for
  the diagnosis of an open duct; pulsed wave Doppler sonography was
  recommended for pathophysiologic characterization of splanchnic venous
  return. At age 3.5 years, their patient developed symptoms of
  portosystemic encephalopathy which progressed and was treated by protein
  restriction, oral lactulose and flumazenil, with some success.
  Long-term results of treatment have been disappointing; IQ is low in
  many despite early and seemingly adequate therapy. See, for example, the
  retrospective study by Schweitzer et al. (1993) of 134 galactosemic
  patients born between 1955 and 1989 in the Federal Republic of Germany.
  The cause of the unsatisfactory outcome of seemingly good control of
  galactose intake and the disturbances in long-term development despite
  treatment are unclear. Possibilities include chronic intoxication by
  galactose metabolites or deficiency of galactose-containing
  glycoproteins and/or glycolipids as a result of an overrestrictive
  galactose-free diet.
  An international survey of the long-term results of treating
  galactosemia in 350 cases yielded overall unsatisfactory results which
  could not be related to variables such as delayed diagnosis or poor
  dietary compliance (Waggoner et al., 1990).
  Webb et al. (2003) noted that verbal dyspraxia (chaotic speech) is found
  in many children with classic galactosemia. They reported that a
  simplified breath test evaluating total body galactose oxidation is a
  sensitive predictor of verbal dyspraxia in patients with galactosemia.
  Of 24 patients who underwent a formal speech evaluation, 15 had verbal
  dyspraxia. Cumulative percentage dose (CUMPCD) values of 13CO(2) in
  breath less than 5% and mean erythrocyte galactose-1-phosphate values
  greater than 2.7 mg/dL were associated with dyspraxic outcome with odds
  ratios of 21 (95% CI, 1.68-265) and 13 (95% CI, 1.81-139), respectively.
  By gene dosage studies, Aitken and Ferguson-Smith (1979) assigned the
  structural gene for GALT to the short arm of chromosome 9. Studying a
  family in which both the Los Angeles variant of GALT and a 9qh
  heterochromatin variant were segregating, Sparkes et al. (1979)
  concluded that the 2 are close together (maximal lod score 3.67 at theta
  of 0.0). Since GALT had previously been assigned to 9p, this finding
  suggested that GALT is near the centromere. Using different chromosomal
  aberrations involving 9p and dosage effects, Sparkes et al. (1979)
  assigned GALT to p11-p22. Mulcahy and Wilson (1980) concluded that the
  GALT locus is probably in the segment 9p22-p13. Dagna Bricarelli et al.
  (1981) studied quantitative expression of GALT and galactose utilization
  in 2 patients with 9p deletion. A patient with deletion of 9pter-p22 had
  normal values; a patient with deletion of 9p23-p133 had decrease in both
  values. The authors interpreted the findings as indicating location of
  the GALT locus in the 9p21 band. Shih et al. (1982, 1984) assigned the
  GALT locus to 9p13 by gene dosage. By deletion mapping, Kondo and
  Nakamura (1984) corroborated the 9p13 localization.
  Nadler et al. (1970) found restoration of enzyme activity when cells
  from 2 patients with galactosemia were hybridized. They interpreted this
  as evidence of interallelic complementation. Tedesco and Mellman (1971)
  demonstrated that in galactosemia gal-1-P uridylyltransferase is
  immunologically intact although enzymatically defective; thus, a
  structural gene mutation is involved.
  Segal et al. (2006) performed a metabolic analysis of radiolabeled
  galactose administered to 3 galactosemic patients and 2 controls. The
  galactosemic patients formed labeled UDPglucose, implying that the
  classic galactosemic possesses residual GALT activity or some other
  pathway for forming UDPglucose from galactose.
  Elsas and Lai (1998) stated that more than 130 mutations in the GALT
  gene (606999) had been associated with GALT deficiency. Two common
  mutations, Q188R (606999.0006) and K285N (606999.0013), accounted for
  more than 70% of galactosemia-producing alleles in the white population
  and were associated with classic galactosemia and impaired GALT
  function. In the black population, S135L (606999.0010) accounted for 62%
  of the alleles causing galactosemia and was associated with good
  Elsas et al. (1995) described a strategy for identifying new mutations
  in the GALT gene. A total of 12 new and 21 previously reported rare
  mutations were found. Among the novel group of 12 new mutations, an
  unusual biochemical phenotype was found in a family in which the newborn
  proband had classic galactosemia. From the father, he had inherited 2
  mutations in cis: asn314 to asp (N314D; 606999.0005) and glu203 to lys
  (E203K; 606999.0014). From the mother, he had inherited a mutation in
  the splice acceptor site of intron C of the GALT gene. The GALT activity
  in erythrocytes of the father, who was heterozygous for the double
  mutation, was near normal. An asymptomatic sister showed compound
  heterozygosity for 3 mutations: E203K-N314D/N314D. Surprisingly, her
  erythrocytes had normal GALT activity. Elsas et al. (1995) speculated
  that E203K and N314D codon changes produce intraallelic complementation
  when in cis. The E203K mutation was located in codon 7 and was the
  result of a GAG-to-AAG transition; the N314D mutation was in exon 10 and
  resulted from an AAC-to-GAC transition. The latter mutation is a
  frequent basis of the Duarte variant; the former was a new mutation
  found in this study. The chromosome with only one mutation, N314D, came
  from the proband's mother.
  One of the fundamental questions concerning expression and function of
  dimeric enzymes involves impact of naturally occurring mutations on
  subunit assembly and heterodimer activity. The question is of particular
  interest for GALT, the enzyme deficient in galactosemia, because most
  patients are compound heterozygotes rather than true molecular
  homozygotes. Furthermore, the broad range of phenotypic severity
  observed in these patients raises the possibility that allelic
  combination, not just allelic constitution, may play some role in
  determining outcome. Elsevier et al. (1996) studied the Q188R
  (606999.0006) and R333W mutations to determine the impact of them on
  subunit assembly and the activity of heterodimers if formed. In a yeast
  system, they found that both homodimers and heterodimers formed
  involving each of the mutant subunits tested, and that both heterodimer
  pools retained substantial enzymatic activity. The yeast system they
  described was promoted as a model for similar studies of other complexes
  composed of multiple subunits. The experiments of Elsevier et al. (1996)
  addressed at the molecular level the issue of functional interaction of
  subunits studied by Nadler et al. (1970) when they demonstrated
  interallelic complementation of naturally occurring mutant GALT enzymes
  in hybrid cells derived by pairwise fusion of skin fibroblasts from 7
  galactosemic patients.
  - Classic Galactosemia
  Data on gene frequencies of allelic variants were tabulated by
  Roychoudhury and Nei (1988). Tyfield et al. (1999) stated that by the
  end of 1998 more than 150 different base changes in the GALT gene were
  recorded in 24 different populations and ethnic groups of 15 countries
  worldwide. Suzuki et al. (2001) estimated that the birth incidence of
  classic galactosemia is 1 per 47,000 in the white population. In Japan,
  classic galactosemia is thought to be only one-twentieth as frequent as
  it is in Caucasian populations of the United States (Ashino et al.,
  Murphy et al. (1999) estimated the incidence of classic
  transferase-deficient galactosemia in Ireland and determined the
  underlying GALT mutation spectrum in the Irish population and in the
  Traveller group (an endogamous group of commercial/industrial nomads
  within the Irish population). Based on a survey of newborn screening
  records, the incidence of classic transferase-deficient galactosemia was
  estimated to be 1 in 480 and 1 in 30,000 among Traveller and
  non-Traveller communities, respectively. Fifty-six classic galactosemic
  patients were screened for mutations in the GALT gene. Q188R was the
  sole mutant allele among the Travellers, as well as being the most
  frequent mutant allele among the non-Travellers (89.1%). Of the 5
  non-Q188R mutant alleles in the non-Traveller group, one was R333G
  (606999.0015) and one was F194L (606999.0016), with 3 remaining
  uncharacterized. Anonymous population screening had shown the Q188R
  carrier frequency to be 0.092 or 1 in 11 among the Travellers, as
  compared with 0.009 or 1 in 107 among the non-Travellers. The Q188R
  mutation was shown to be in linkage disequilibrium with a SacI RFLP
  flanking exon 6 of the GALT gene. Lin and Reichardt (1995) demonstrated
  that the Q188R mutation is in linkage disequilibrium with the SacI RFLP
  in African American, Asian, Caucasian, and Latino galactosemic patients.
  This was interpreted to indicate that the Q188R mutation arose once in
  the history of the modern human population and was spread worldwide by
  demic diffusion. The same disequilibrium in the Irish population
  suggested that the Q188R mutation was present in the indigenous
  population before the Travellers separated and was carried into the
  Traveller population by its founders. The findings suggested,
  furthermore, that the modern Traveller subpopulation in Ireland had an
  endogenous origin. The high frequency of the Q188R allele appears to be
  due to founder effect coupled with rapid expansion of this population.
  - Duarte-1 and Duarte-2 Alleles 
  Vaccaro et al. (1984) studied the frequency of the Duarte (D2) and Los
  Angeles (D1) variants of red cell gal-1-P uridylyltransferase in Italy;
  the 2 have similar electrophoretic patterns but the enzyme activity in
  heterozygotes is about half normal in the former and about 1.5 times
  normal in the latter. No apparent clinical abnormality accompanies
  either. The allele frequencies were: N = 0.9192; G (for galactosemia) =
  0.0036; D (for Duarte) = 0.0372 and LA (for Los Angeles) = 0.0400.
  Carney et al. (2009) reported that the frequency of the D314 allele
  (606999.0005) in the CEPH HapMap sample is 11.3%, which is unusually
  high compared with Yoruba, Chinese, and Japanese populations, which each
  exhibit frequencies of D314 well under 3%. The frequency of the TTA(Leu)
  codon (606999.0012) accounted for 4.5% of alleles in the CEPH sample,
  whereas the frequency is even rarer in non-European populations, with an
  observed frequency of about 1% in the Chinese sample and a complete
  absence in the Yoruba and Japanese samples.
See Also:
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  Miller (1979); Tedesco et al. (1975); Urbanowski et al. (1982); Walker
  et al. (1962); Wharton et al. (1978); Xu and Ng (1983)
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  36. Ibarra, B.; Vaca, G.; Sanchez-Corona, J.; Hernandez, A.; Ramirez,
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  37. Kaufman, F.; Kogut, M. D.; Donnell, G. N.; Koch, R.; Goehelsmann,
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  Note: Originally Volume II.
  38. Kelly, S.; Desjardins, L.; Khera, S. A.: A Duarte variant with
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  39. Kondo, I.; Nakamura, N.: Regional mapping of GALT in the short
  arm of chromosome 9. (Abstract) Cytogenet. Cell Genet. 37: 514,
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  of the GALT gene in Duarte (D2) alleles. J. Med. Genet. 36: 576-578,
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  50. Murphy, M.; McHugh, B.; Tighe, O.; Mayne, P.; O'Neill, C.; Naughten,
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Clinical Synopsis:
     Autosomal recessive
     Failure to thrive
     Decreased liver function, progressive;
     Cirrhosis if untreated;
     [External genitalia, female];
     Ovarian failure due to hypergonadotropic hypogonadism
     Mental retardation if untreated;
     Speech abnormality if untreated
     Hemolytic anemia
     Galactose-1-phosphate uridyltransferase deficiency;
     In untreated patients - elevated blood galactose urine reducing substances
     (galactosuria), hyperchloremic metabolic acidosis, aminoaciduria,
     elevated liver enzymes, albuminuria
     High incidence of E. coli sepsis in untreated neonates
     Caused by mutations in galactose-1-phosphate uridyltransferase gene
     (GALT, 230400.0001)
  Michael J. Wright  - revised: 6/22/1999
  Ada Hamosh - revised: 6/22/1999
Creation Date: 
  John F. Jackson: 6/15/1995
Edit Dates: 
  ckniffin: 10/03/2005
  joanna: 5/7/2002
  joanna: 5/6/2002
  joanna: 2/19/2002
  root: 6/24/1999
  kayiaros: 6/22/1999
  George E. Tiller - updated: 06/04/2010
  Marla J. F. O'Neill - updated: 2/16/2010
  Natalie E. Krasikov - updated: 12/16/2003
  Cassandra L. Kniffin - reorganized: 6/7/2002
  Victor A. McKusick - updated: 10/9/2001
  Victor A. McKusick - updated: 9/5/2001
  Ada Hamosh - updated: 9/25/2000
  Victor A. McKusick - updated: 12/21/1999
  Victor A. McKusick - updated: 10/6/1999
  Victor A. McKusick - updated: 9/8/1999
  Victor A. McKusick - updated: 7/6/1999
  Victor A. McKusick - updated: 5/14/1999
  Victor A. McKusick - edited: 1/29/1998
  Victor A. McKusick - updated: 9/19/1997
  Victor A. McKusick - updated: 4/1/1997
  Victor A. McKusick - updated: 2/17/1997
  Victor A. McKusick - updated: 2/6/1997
  Orest Hurko - updated: 5/14/1996
Creation Date: 
  Victor A. McKusick: 6/3/1986
Edit Dates: 
  wwang: 06/04/2010
  wwang: 2/16/2010
  terry: 2/27/2009
  joanna: 2/2/2009
  terry: 11/15/2006
  terry: 5/17/2005
  carol: 12/16/2003
  ckniffin: 6/10/2002
  carol: 6/7/2002
  ckniffin: 6/7/2002
  ckniffin: 6/5/2002
  terry: 3/8/2002
  carol: 11/14/2001
  mcapotos: 10/24/2001
  terry: 10/9/2001
  terry: 9/5/2001
  alopez: 3/12/2001
  terry: 10/6/2000
  alopez: 10/3/2000
  terry: 9/25/2000
  carol: 1/3/2000
  mcapotos: 1/3/2000
  terry: 12/21/1999
  alopez: 11/22/1999
  carol: 10/6/1999
  carol: 10/4/1999
  carol: 9/22/1999
  jlewis: 9/16/1999
  terry: 9/8/1999
  carol: 8/3/1999
  carol: 7/19/1999
  terry: 7/6/1999
  terry: 6/11/1999
  mgross: 6/1/1999
  carol: 6/1/1999
  mgross: 5/26/1999
  terry: 5/14/1999
  dkim: 9/11/1998
  dkim: 7/24/1998
  mark: 1/29/1998
  mark: 9/23/1997
  terry: 9/19/1997
  alopez: 6/23/1997
  jenny: 4/1/1997
  terry: 3/21/1997
  mark: 2/17/1997
  terry: 2/10/1997
  terry: 2/6/1997
  terry: 2/5/1997
  terry: 11/12/1996
  terry: 11/1/1996
  terry: 5/17/1996
  terry: 5/14/1996
  terry: 3/26/1996
  mark: 3/21/1996
  terry: 3/8/1996
  terry: 8/3/1995
  mark: 3/29/1995
  davew: 8/19/1994
  jason: 6/15/1994
  warfield: 3/30/1994
  carol: 2/24/1994
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