MIM Entry: 230400
;;GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY;;
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.
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
- 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
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
- 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.
Andersen et al. (1983); Andersen et al. (1984); Benson et al. (1979);
Bruns et al. (1978); Dawson et al. (1960); Elsevier and Fridovich-Keil
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et al. (1982); Gitzelmann et al. (1967); Haschemian and Menne (1972);
Hill and Puck (1973); Houghton and Levy (1975); Hsia (1969); Ibarra
et al. (1979); Lang et al. (1980); Robinson et al. (1984); Sparkes
et al. (1968); Sparkes et al. (1980); Sun et al. (1974); Tedesco and
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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Failure to thrive
HEAD AND NECK:
Decreased liver function, progressive;
Cirrhosis if untreated;
[External genitalia, female];
Ovarian failure due to hypergonadotropic hypogonadism
Mental retardation if untreated;
Speech abnormality if untreated
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
Michael J. Wright - revised: 6/22/1999
Ada Hamosh - revised: 6/22/1999
John F. Jackson: 6/15/1995
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
Victor A. McKusick: 6/3/1986