Galactosemia

A number sign (#) is used with this entry because classic galactosemia is caused by homozygous or compound heterozygous mutation in the galactose-1-phosphate uridylyltransferase gene (GALT; 606999) on chromosome 9p13.

Description

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).

Clinical Features

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.

Heterogeneity

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 reported.

Using G for the allele causing classic galactosemia and D for the Duarte allele (N314D; 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; 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).

Diagnosis

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 E. 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 clinician.

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.

Clinical Management

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.

Mapping

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.

Pathogenesis

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.

Feillet et al. (2008) reported a 7-week-old girl with liver failure, ascites, and generalized edema. Laboratory studies showed increased citrulline and increased levels of other amino acids, suggesting the diagnosis of citrin deficiency (605814). There were low levels of urinary citric acid cycle intermediates, and administration of citrate resulted in improvement in liver function. Introduction of oral galactose resulted in vomiting, galactose aversion, and hepatic dysfunction, consistent with classic galactosemia, and the diagnosis was confirmed by molecular analysis. Feillet et al. (2008) noted the unusual metabolic pattern in this patient and suggested that depletion of citric acid intermediates and resultant energy deprivation could play a role in the pathophysiology of liver disease seen in classic galactosemia.

Molecular Genetics

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 outcomes.

Genotype/Phenotype Correlations

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.

Population Genetics

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., 1995).

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.

Carney et al. (2009) noted that Duarte galactosemia has an incidence as high as 1 in 4,000 live births.