Duarte galactosemia

Last updated
Duarte galactosemia
Other namesDuarte variant galactosemia, DG, or Biochemical variant galactosemia)
Leloir pathway cropped.jpg
Leloir metabolic pathway: Galactose-1Puridylyltransferase (GALT, red font) is the middle enzyme in the Leloir pathway of galactose metabolism.

Duarte galactosemia is an inherited condition associated with diminished ability to metabolize galactose due to a partial deficiency of the enzyme galactose-1-phosphate uridylyltransferase. [1] DG differs from classic galactosemia in that patients with Duarte galactosemia have partial GALT deficiency whereas patients with classic galactosemia have complete, or almost complete, GALT deficiency. [2] Duarte galactosemia (DG) is much more common than classic galactosemia, and is estimated to affect close to one in 4,000 infants born in the United States. Historically, most healthcare professionals have considered DG to be clinically mild [1] based on pilot studies and anecdotal experience, and in 2019 a large study confirmed that children with DG are not at increased risk for developmental problems relative to children who do not have DG. [3] Due to regional variations in newborn screening (NBS) protocols, some infants with DG are identified by NBS but others are not. [4]

Contents

Symptoms and signs

Infants with DG often show biochemical differences from infants who do not have DG, especially if exposed to milk, but may not show any acute or developmental symptoms. Specifically, when exposed to high levels of dietary galactose, a sugar abundant in breast milk, milk formula, and most dairy products, [5] infants with DG may show elevated levels of galactose and galactose metabolites such as galactose-1-phosphate (Gal-1P) and galactitol in blood and urine, respectively. Like many infants who do not have DG, some infants with DG may also show acute symptoms of milk sensitivity, such as Jaundice or vomiting, after exposure to milk but these symptoms may reflect sensitivity of the child to components of milk other than galactose, and typically resolve quickly when the baby is switched to a non-dairy diet, such as soy formula. [1] A large study of developmental outcomes in 6- to 12-year-old children with Duarte galactosemia published in 2019 [3] demonstrated that children with DG do not show increased prevalence of developmental problems relative to children who do not have DG. This suggests that if a child with DG does show developmental problems, other possible causes should be explored. [1]

Cause

Duarte Galactosemia Inheritance: The above figure demonstrates the autosomal recessive mode of DG inheritance. DG autosomal recessive cropped.jpeg
Duarte Galactosemia Inheritance: The above figure demonstrates the autosomal recessive mode of DG inheritance.

Duarte galactosemia is inherited as a Mendelian autosomal recessive trait. A child with DG carries two different types of GALT alleles, one inherited from each parent. One of these GALT alleles, the G allele, carries a mutation that severely inhibits the function of the encoded GALT enzyme. The other GALT allele, called the D or D2 allele, carries mutations that partially compromise the expression and change some biochemical properties of the encoded GALT enzyme. Together, the G and D alleles only produce about 25% of the normal level of GALT enzyme activity found in a person with two normal (N) GALT alleles. [1] Both parents of a child with DG are considered carriers for GALT variant alleles. One parent carries the G allele and the other carries the D allele. The genotypes of these parents would be written GN and DN, respectively. Without follow-up testing of the parents, it is not possible to know which parent contributed which GALT allele to a child with DG. Like other autosomal recessive conditions, the recurrence risk for DG is 1 in 4, meaning that for each successive child born to parents who already have a child with DG there is a 1 in 4 chance the new baby will also have DG (Figure 2). In rare cases, one parent may actually have DG, while the other parent is a carrier for a G allele (GN). For these couples, there is a 1 in 4 recurrence risk for DG and also a 1 in 4 risk with each pregnancy that the new baby will have classic galactosemia (GG). In extremely rare cases a GALT gene mutation may arise de novo, so that only one parent is a carrier; however, only one case of this has been reported in the literature for galactosemia. [6]

Diagnosis

Infants with DG are generally diagnosed in follow-up to a positive newborn screening (NBS) result for galactosemia. Specifically, dried blood spots collected for NBS from infants with DG may show low (but generally non-zero) GALT enzyme activity, elevated galactose metabolite levels, or both. DG can also be identified by genetic testing. [1]

Of note, not all NBS tests for galactosemia are designed to detect DG so infants with DG born in one jurisdiction may be detected while those born in another may not. [4] For example, all states in the US screen for classic galactosemia in their NBS panel, but some states have lower GALT enzyme activity cut-off levels than others. NBS in states with a low GALT cut off level still detect classic galactosemia, but are likely to miss many infants with DG. In those states, a normal NBS result for galactosemia may not be informative about an infant's DG status.[ citation needed ]

Most infants with DG who are flagged by a positive NBS result for galactosemia have their diagnosis confirmed in a follow-up evaluation. The differential diagnosis for a positive newborn screening result for galactosemia, especially if based on galactose metabolite levels, includes: classic galactosemia, clinical variant galactosemia, DG, GALE (epimerase) deficiency, GALK (galactokinase) deficiency, or a false positive result. [1] There are also other rare conditions, such as portosystemic venous shunting and hepatic arteriovenous malformations, or Fanconi-Bickel Syndrome (GSDXI) that can lead to elevated blood galactose or urinary galactitol, potentially triggering an initial suspicion of galactosemia. [1] [7] If the NBS result is based only on GALT activity and not on metabolite levels then the differential diagnosis would include classic galactosemia, clinical variant galactosemia, DG, and false positive.[ citation needed ]

Management

Historically, there has been no broadly accepted standard of care for infants with DG. [8] At present, some healthcare providers recommend partial to complete restriction of milk and other high galactose foods for infants with DG; others do not. Because children with DG develop increased tolerance for dietary galactose as they grow, few healthcare providers recommend dietary restriction of galactose beyond early childhood. A revised perspective on clinical care for infants with Duarte galactosemia was published in 2019. [9]

The rationale for NOT restricting milk exposure of infants with DG: Healthcare providers who do not recommend dietary restriction of milk for infants with DG generally consider DG to be of no clinical significance—meaning most infants and children with DG seem to be doing clinically well. A large study reported in 2019 [3] supported this conclusion. Further, these providers may be opposed to interrupting or reducing breastfeeding when there is no clear evidence it is contraindicated. These providers may argue that the recognized health benefits of breastfeeding outweigh the potential risks of as yet unknown negative effects of continued milk exposure for these infants. [8] For infants with DG who continue to drink milk, some doctors recommend that blood galactose-1-phosphate (Gal-1P) or urinary galactitol be rechecked by age 12 months to ensure that these metabolite levels are normalizing. [1]

The rationale FOR restricting milk exposure of infants with DG: Healthcare providers who recommend partial or complete dietary restriction of milk for infants with DG generally cite concern about the unknown long-term consequences of abnormally elevated galactose metabolites in a young child's blood and tissues. Infants with DG who continue to drink milk accumulate the same set of abnormal galactose metabolites seen in babies with classic galactosemia – e.g. galactose, Gal-1P, galactonate, and galactitol [10] – but to a lesser extent. While it remains unclear whether any of these metabolites contribute to the long-term developmental complications experienced by so many older children with classic galactosemia, the theoretical possibility that they might cause problems in children with DG serves to motivate some healthcare providers to recommend dietary galactose restriction for infants with DG. Switching an infant with DG from milk or milk formula (high galactose) to a low-galactose formula rapidly normalizes their galactose metabolites. This approach is considered potentially preventative rather than responsive to symptoms. [8] Of course, if a baby with DG, like any other baby, shows acute signs of milk sensitivity then switching the baby to a non-dairy formula would be responsive to those acute symptoms.[ citation needed ]

If a baby with DG is switched to a low-galactose diet due to concern about elevated galactose metabolites, the healthcare provider may recommend a galactose challenge to re-evaluate galactose tolerance before the restrictive diet is discontinued. Most infants or young children with DG who are followed by a metabolic specialist are discharged from follow up after a successful galactose challenge.[ citation needed ]

The goal of a galactose challenge is to learn whether a child is able to metabolize dietary galactose sufficiently to prevent the abnormal accumulation of galactose metabolites, generally measured as Gal-1P in the blood or galactitol in the urine. [1] For infants with DG who showed elevated galactose metabolites at diagnosis, this test can be used to see if the child's ability to process galactose has improved.[ citation needed ]

For example, to test galactose metabolism, a baseline Gal-1P level is measured while the child is on a galactose-restricted diet. If the level is within the normal range (e.g. <1.0 mg/dL), the parent/guardian is advised to challenge their child with dietary galactose—meaning feed the child a diet that includes normal levels of milk and dairy for 2–4 weeks. Immediately after that time, another blood sample is collected and analyzed for Gal-1P level. If this second result is still in the normal range, the child is said to have passed their galactose challenge, and dietary galactose restrictions are typically relaxed or discontinued. If the second test shows elevated Gal-1P levels, the parent/guardian may be advised to resume galactose restriction for the child, and the challenge may be repeated after a few months. [1]

Prognosis

Until recently, very little was known about outcomes in DG after early childhood. This was because many infants with DG were born in states where they were not diagnosed by NBS, and of those who were diagnosed, most were discharged from metabolic follow-up as toddlers. It was therefore unclear whether older children with DG were at increased risk for long-term developmental problems, and also unclear whether long-term developmental outcomes in DG might be modified by exposure to milk in the first year of life. [1] Of note, premature ovarian insufficiency, a common outcome among girls and women with classic galactosemia, was checked by hormone studies of girls with DG and demonstrated not to be a problem. [11]

Prior Research Concerning Developmental Outcomes of Children with DG: Four studies of developmental outcomes of children with DG have been published.

Epidemiology

The prevalence of DG in the United States (US) can only be estimated because there is no true population surveillance for this condition. Differences in NBS methods result in very different detection rates in different states. For example, in some US states, DG is detected by NBS in up to 1 in 3500 infants screened, while in other states it is essentially not detected. [4] DG prevalence in the US population is estimated to be approximately 1 in 4,000, [12] which is more than 10 times the prevalence of classic galactosemia. [1] [2] Of note, because of different allele frequencies for the G and D2 GALT alleles in different human populations, [15] DG is found predominantly among infants of European ancestry and only very rarely among infants of African or Asian ancestry.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Galactose</span> Monosaccharide sugar

Galactose, sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molecule linked with a glucose molecule forms a lactose molecule.

<span class="mw-page-title-main">Lactose intolerance</span> Inability to digest lactose

Lactose intolerance is caused by a lessened ability or a complete inability to digest lactose, a sugar found in dairy products. Humans vary in the amount of lactose they can tolerate before symptoms develop. Symptoms may include abdominal pain, bloating, diarrhea, flatulence, and nausea. These symptoms typically start thirty minutes to two hours after eating or drinking something containing lactose, with the severity typically depending on the amount consumed. Lactose intolerance does not cause damage to the gastrointestinal tract.

<span class="mw-page-title-main">Galactosemia</span> Medical condition

Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.

<span class="mw-page-title-main">Newborn screening</span> Practice of testing infants for diseases

Newborn screening (NBS) is a public health program of screening in infants shortly after birth for conditions that are treatable, but not clinically evident in the newborn period. The goal is to identify infants at risk for these conditions early enough to confirm the diagnosis and provide intervention that will alter the clinical course of the disease and prevent or ameliorate the clinical manifestations. NBS started with the discovery that the amino acid disorder phenylketonuria (PKU) could be treated by dietary adjustment, and that early intervention was required for the best outcome. Infants with PKU appear normal at birth, but are unable to metabolize the essential amino acid phenylalanine, resulting in irreversible intellectual disability. In the 1960s, Robert Guthrie developed a simple method using a bacterial inhibition assay that could detect high levels of phenylalanine in blood shortly after a baby was born. Guthrie also pioneered the collection of blood on filter paper which could be easily transported, recognizing the need for a simple system if the screening was going to be done on a large scale. Newborn screening around the world is still done using similar filter paper. NBS was first introduced as a public health program in the United States in the early 1960s, and has expanded to countries around the world.

<span class="mw-page-title-main">Galactose-1-phosphate uridylyltransferase</span> Mammalian protein found in Homo sapiens

Galactose-1-phosphate uridyltransferase is an enzyme responsible for converting ingested galactose to glucose.

A delayed milestone, which is also known as a developmental delay, refers to a situation where a child does not reach a particular developmental milestone at the expected age. Developmental milestones refer to a collection of indicators that a child is anticipated to reach as they grow older.

<span class="mw-page-title-main">Medical genetics</span> Medicine focused on hereditary disorders

Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders. Medical genetics differs from human genetics in that human genetics is a field of scientific research that may or may not apply to medicine, while medical genetics refers to the application of genetics to medical care. For example, research on the causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counselling people with genetic disorders would be considered part of medical genetics.

<span class="mw-page-title-main">Child development</span> Stages in the development of children

Child development involves the biological, psychological and emotional changes that occur in human beings between birth and the conclusion of adolescence. It is—particularly from birth to five years— a foundation for a prosperous and sustainable society.

<span class="mw-page-title-main">Galactokinase deficiency</span> Medical condition

Galactokinase deficiency is an autosomal recessive metabolic disorder marked by an accumulation of galactose and galactitol secondary to the decreased conversion of galactose to galactose-1-phosphate by galactokinase. The disorder is caused by mutations in the GALK1 gene, located on chromosome 17q24. Galactokinase catalyzes the first step of galactose phosphorylation in the Leloir pathway of intermediate metabolism. Galactokinase deficiency is one of the three inborn errors of metabolism that lead to hypergalactosemia. The disorder is inherited as an autosomal recessive trait. Unlike classic galactosemia, which is caused by a deficiency of galactose-1-phosphate uridyltransferase, galactokinase deficiency does not present with severe manifestations in early infancy. Its major clinical symptom is the development of cataracts during the first weeks or months of life, as a result of the accumulation, in the lens, of galactitol, a product of an alternative route of galactose utilization. The development of early cataracts in homozygous affected infants is fully preventable through early diagnosis and treatment with a galactose-restricted diet. Some studies have suggested that, depending on milk consumption later in life, heterozygous carriers of galactokinase deficiency may be prone to presenile cataracts at 20–50 years of age.

<span class="mw-page-title-main">Galactose epimerase deficiency</span> Medical condition

Galactose epimerase deficiency, also known as GALE deficiency, Galactosemia III and UDP-galactose-4-epimerase deficiency, is a rare, autosomal recessive form of galactosemia associated with a deficiency of the enzyme galactose epimerase.

<span class="mw-page-title-main">Galactose 1-phosphate</span> Chemical compound

D-Galactose-1-phosphate is an intermediate in the intraconversion of glucose and uridine diphosphate galactose. It is formed from galactose by galactokinase.The improper metabolism of galactose-1-phosphate is a characteristic of galactosemia. The Leloir pathway is responsible for such metabolism of galactose and its intermediate, galactose-1-phosphate. Deficiency of enzymes found in this pathway can result in galactosemia; therefore, diagnosis of this genetic disorder occasionally involves measuring the concentration of these enzymes. One of such enzymes is galactose-1-phosphate uridylyltransferase (GALT). The enzyme catalyzes the transfer of a UDP-activator group from UDP-glucose to galactose-1-phosphate. Although the cause of enzyme deficiency in the Leloir pathway is still disputed amongst researchers, some studies suggest that protein misfolding of GALT, which may lead to an unfavorable conformational change that impacts its thermal stability and substrate-binding affinity, may play a role in the deficiency of GALT in Type 1 galactosemia. Increase in galactitol concentration can be seen in patients with galactosemia; putting patients at higher risk for presenile cataract.

<span class="mw-page-title-main">Galactose-1-phosphate uridylyltransferase deficiency</span> Medical condition

Galactose-1-phosphate uridylyltransferase deficiency(classic galactosemia) is the most common type of galactosemia, an inborn error of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridylyltransferase. It is an autosomal recessive metabolic disorder that can cause liver disease and death if untreated. Treatment of galactosemia is most successful if initiated early and includes dietary restriction of lactose intake. Because early intervention is key, galactosemia is included in newborn screening programs in many areas. On initial screening, which often involves measuring the concentration of galactose in blood, classic galactosemia may be indistinguishable from other inborn errors of galactose metabolism, including galactokinase deficiency and galactose epimerase deficiency. Further analysis of metabolites and enzyme activities are needed to identify the specific metabolic error.

<span class="mw-page-title-main">Guanidinoacetate methyltransferase deficiency</span> Medical condition

Guanidinoacetate methyltransferase deficiency is an autosomal recessive cerebral creatine deficiency that primarily affects the nervous system and muscles. It is the first described disorder of creatine metabolism, and results from deficient activity of guanidinoacetate methyltransferase, an enzyme involved in the synthesis of creatine. Clinically, affected individuals often present with hypotonia, seizures and developmental delay. Diagnosis can be suspected on clinical findings, and confirmed by specific biochemical tests, brain magnetic resonance spectroscopy, or genetic testing. Biallelic pathogenic variants in GAMT are the underlying cause of the disorder. After GAMT deficiency is diagnosed, it can be treated by dietary adjustments, including supplementation with creatine. Treatment is highly effective if started early in life. If treatment is started late, it cannot reverse brain damage which has already taken place.

A galactosemic cataract is cataract which is associated with the consequences of galactosemia.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

<span class="mw-page-title-main">Congenital cytomegalovirus infection</span> Medical condition

Congenital cytomegalovirus (cCMV) is cytomegalovirus (CMV) infection in a newborn baby. Most have no symptoms. Some affected babies are small. Other signs and symptoms include a rash, jaundice, hepatomegaly, retinitis, and seizures. It may lead to loss of hearing or vision, developmental disability, or a small head.

Child neglect, often overlooked, is the most common form of child maltreatment. Most perpetrators of child abuse and neglect are the parents themselves. A total of 79.4% of the perpetrators of abused and neglected children are the parents of the victims, and of those 79.4% parents, 61% exclusively neglect their children. The physical, emotional, and cognitive developmental impacts from early childhood neglect can be detrimental, as the effects from the neglect can carry on into adulthood.

<span class="mw-page-title-main">Milk fat globule membrane</span>

Milk fat globule membrane (MFGM) is a complex and unique structure composed primarily of lipids and proteins that surrounds milk fat globule secreted from the milk producing cells of humans and other mammals. It is a source of multiple bioactive compounds, including phospholipids, glycolipids, glycoproteins, and carbohydrates that have important functional roles within the brain and gut.

The first 1,000 days describes the period from conception to 24 months of age in child development. This is considered a "critical period" in which sufficient nutrition and environmental factors have life-long effects on a child's overall health. While adequate nutrition can be exceptionally beneficial during this critical period, inadequate nutrition may also be detrimental to the child. This is because children establish many of their lifetime epigenetic characteristics in their first 1,000 days. Medical and public health interventions early on in child development during the first 1,000 days may have higher rates of success compared to those achieved outside of this period.

The effects of early-life exposures to anesthesia on the brain in humans are controversial. Evidence from nonhuman primate research suggests significant developmental neurotoxicity and long-term social impairment, with a dose–response relationship where repeated exposures cause a more severe impact than single ones. Research in humans has not found conclusive clinical evidence of cognitive impairment; however, systematic reviews imply the possibility of greater behavioural impairments in children exposed to anesthesia before the age of three than control subjects.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 Fridovich-Keil, J., et al., Duarte Variant Galactosemia, in GeneReviews, R. Pagon, et al., Editors. 2014, University of Washington, Seattle. Review. PMID   25473725
  2. 1 2 Berry, G., Classic Galactosemia and Clinical Variant Galactosemia, in GeneReviews, R. Pagon, et al., Editors. 2014, University of Washington, Seattle. Review.
  3. 1 2 3 4 Carlock, G., Fischer, S. T., Lynch, M. E., Potter, N. L., Coles, C. D., Epstein, M. P., ... & Wilson, E., Developmental outcomes in Duarte galactosemia. 2018 Pediatrics, doi: 10.1542/peds.2018-2516. PMID   30593450
  4. 1 2 3 Pyhtila, B.M., et al., Newborn screening for galactosemia in the United States: looking back, looking around, and looking ahead. JIMD Rep, 2015. 15: p. 79-93. Review. PMID   24718839
  5. ↑ Van Calcar SC, Bernstein LE, Rohr FJ, Scaman CH, Yannicelli S, Berry GT. A re-evaluation of life-long severe galactose restriction for the nutrition management of classic galactosemia. Mol Genet Metab. 2014 Jul;112(3):191-7. doi: 10.1016/j.ymgme.2014.04.004. Epub 2014 May 2. Review. PMID   24857409
  6. ↑ Tran, T.T., et al., A De Novo Variant in Galactose-1-P Uridylyltransferase (GALT) Leading to Classic Galactosemia. JIMD Rep, 2015. 19: p. 1-6
  7. ↑ 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. Differential diagnosis of neonatal mild hypergalactosaemia detected by mass screening: clinical significance of portal vein imaging. J Inherit Metab Dis. 2004;27(1):11-8. PMID   14970742
  8. 1 2 3 Fernhoff, P.M., Duarte galactosemia: how sweet is it? Clin Chem, 2010. 56(7): p. 1045-6.
  9. ↑ McCandless, S. E., 2019. Answering a Question Older Than Most Pediatricians: What to Do About Duarte Variant Galactosemia. Pediatrics, 143(1). doi: 10.1542/peds.2018-3292 PMID   30593448
  10. 1 2 Ficicioglu, C., et al., Monitoring of biochemical status in children with Duarte galactosemia: utility of galactose, galactitol, galactonate, and galactose 1-phosphate. Clin Chem, 2010. 56(7): p. 1177-82. PMID   20489133
  11. ↑ Badik, J.R., et al., Ovarian function in Duarte galactosemia. Fertil Steril, 2011. 96(2): p. 469-473 e1. PMID   21719007
  12. 1 2 Ficicioglu, C., et al., Duarte (DG) galactosemia: a pilot study of biochemical and neurodevelopmental assessment in children detected by newborn screening. Mol Genet Metab, 2008. 95(4): p. 206-12.
  13. ↑ Powell KK, Van Naarden Braun K, Singh RH, Shapira SK, Olney RS, Yeargin-Allsopp M. Long-term speech and language developmental issues among children with Duarte galactosemia. Genet Med. 2009 Dec;11(12):874-9. doi: 10.1097/GIM.0b013e3181c0c38d. PMID   19904210
  14. ↑ Lynch ME, Potter NL, Coles CD, Fridovich-Keil JL. Developmental Outcomes of School-Age Children with Duarte Galactosemia: A Pilot Study. JIMD Rep. 2015;19:75-84. doi: 10.1007/8904_2014_370. Epub 2015 Feb 15. PMID   25681083
  15. ↑ Carney et al. Origins, distribution and expression of the Duarte-2 (D2) allele of galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2009 May 1;18(9):1624-32. doi: 10.1093/hmg/ddp080. Epub 2009 Feb 18.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.