Galactosemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactosemia is a genetic metabolic disorder which affects an individual’s ability to properly metabolize galactose. In individuals with galactosemia, the enzymes needed for further metabolism of galactose are dysfunctional or entirely absent, leading to toxic levels of galactose and phosphorylated intermediates to build up in the blood, resulting inliver and kidney failure, cataract, and brain damage.

The first case of galactosemia was reported in 1908. The disease was fully described in 1935 by Mason and Turner followed by elucidation of the gene in 1956. Since then, screening tests for galactosemia have been widely used.

Galactosemia consists of four types of disorders resulting from abnormal activity of the enzymes involved in galactose metabolism. Type I/ Classical is the most serious form of the disease.

Galactose is an important metabolite of the human body both for neonatal and adult health, playing a vital role in systemic and cognitive development .Abnormalities in any of the enzymes involved in any of the steps of the Leloir pathway can give rise to the pathological condition called galactosemia.

Galactosemia is an autosomal recessive disorder which is caused by dysfunction of the enzymes involved in the Leloir pathway of galactose metabolism.

Galactosemia closely resembles other metabolic disorders which form important differential diagnoses in clinical practice.

Galactosemia is quite widespread among different countries of the world with significant demographic differences with race and ethnicity. In spite of that, typical symptoms and clinical signs are manifested in most of the patients.

Galactosemia satisfies the criteria for newborn screening successfully. Since most babies are born apparently healthy, there is a considerable window for prompt detection of the disease and appropriate intervention.

The major risk factor for galactosemia is the presence of the defective gene(s).

Galactosemia is an inherited metabolic disorder with a variable natural history. It can lead to severe systemic complications if neglected. The prognosis depends on various factors.

Galactosemia is primarily seen in the neonatal period with a wide range of symptoms.

Galactosemia gives rise to varied signs on clinical examination.

Galactosemia can be confirmed by a panel of laboratory investigations which provide both direct and indirect evidence of the disease by detecting abnormalities in blood, urine and/or other body tissues.

There are no significant electrocardiographic findings in galactosemia.

Chest Xray is normal in galactosemia.

CT Scan of the brain is useful in galactosemia.

MRI findings of galactosemic patients indicate abnormal myelination secondary to the inability to produce sufficient and/or normal galactocerebroside due to defective enzyme activity.

Echocardiography is not useful in the diagnosis of galactosemia. On the other hand, ultrasonography provides useful information.

Additional imaging with diffusion weighted MRI and radionuclides also aid in the diagnosis of galactosemia.

In addition to the commonly performed laboratory tests, histopathology and genetics also aid in confirmation of galactosemia.

Medical therapy is of limited importance in galactosemia.

Surgicaltreatment is rarely indicated for management of galactosemia.

Preventive strategies of galactosemia are primarily aimed at early detection through screening and prompt intervention.

Secondary prevention of galactosemia consists of newborn screening and dietary modifications.

The cost-effectiveness of the therapy of galactosemia has primarily been studied with respect to the screening program for the disease and the benefits reaped from it.

A number of therapeutic modalities are currently being explored.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

The first case of galactosemia was reported in 1908. The disease was fully described in 1935 by Mason and Turner followed by elucidation of the gene in 1956. Since then, screening tests for galactosemia have been widely used.

• Galactosemia was first discovered by Von Ruess in 1908 on a breast- fed infant with failure to thrive, hepatosplenomegaly and galactosuria (increased galactose excretion in urine). The galactosuria stopped after elimination of dietary milk products but the infant ultimately succumbed to death. Autopsy showed liver cirrhosis, but the confirmation of the cause was not possible. It has been generally accepted that this was the first report of galactosemia.
• The first detailed report was given by Friedrich Goppert in 1917. ^[1]

• The disease was first recognized in detail in 1935 by Mason and Turner. ^[2]
• The defective gene (GALT) was found in 1988 after identification of the gene in 1956. ^[3]
• In 1963, it was first detected in a newborn using a screening method developed by Guthrie and Paigen. This was the second disorder detected by this method.^[1]
• Increased newborn screening is a significant development for the galactosemic community.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dayana Davidis, M.D. [2]

Galactosemia consists of four types of disorders resulting from abnormal activity of the enzymes involved in galactose metabolism. Type I/ Classical is the most serious form of the disease.

Galactosemia refers to a group of autosomal recessive disorders of galactose metabolism. They are classified into the following types based on the enzymatic activity ^[1]

• Defects in both copies of the gene that codes for the enzyme galactose-1-phosphate uridyl transferase or GALT.^[2].
• Most common and severe form.
  • Duarte galactosemia
    • Variant of classic galactosemia.
    • Galactose metabolised to some extent as GALT not completely absent
    • Less severe symptoms than other forms

• Defect in both copies of the gene that codes for the enzyme galactokinase or GALK.^[3]
• Less common and harmful than classic galactosemia.
• Does not generally lead to hepatomegaly or brain damage.

• Alterations in the gene coding for epimerase enzyme.^[4] This is the mildest type.

• This type has only been discovered recently.
• Abnormal changes in the galactose mutatrose enzyme, encoded by the GALM gene, have been proven to cause the disorder. ^[5]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactose is an important metabolite of the human body both for neonatal and adult health, playing a vital role in systemic and cognitive development .Abnormalities in any of the enzymes involved in each of the steps of the Leloir pathway can give rise to the pathological condition called galactosemia.

• Galactose is an important metabolite of the human body both for neonatal and adult health, playing a vital role in systemic and cognitive development. ^[1]

Galactose is metabolised in the body through the Leloir pathway. ^[2]

• It begins with conversion of B-D-galactose] to A-D-galactose catalysed by the enzyme galactose mutarotase
• A-D-galactose is then converted to galactose-1-phosphate by the enzyme galactokinase with utilisation of 1 molecule of ATP
• Galactose-1-phosphate combines with UDP-glucose to form UDP-galactose and the metabolically more useful glucose-1-phosphate with the help of the enzyme galactose-1-phosphate uridyl transferase.
• UDP-Galactose can undergo isomerisation in a reversible manner into UDP-glucose by the enzyme epimerase.

Abnormalities in any of the enzymes involved in each of the steps of the Leloir pathway can give rise to the pathological condition called galactosemia.

• Deficiency or reduced activity of galactose-1-phosphate uridyl transferase enzyme leads to accumulation of galactose-1-phosphate ^[3] which:
  • Sequesters phosphate essential for energy production in the human body ^[4]
  • Inhibits enzymes involved in glucose metabolism, such as pyrophosphorylase ^[5]
  • Inhibits galactosyl trasnferase thereby leading to defects in glycosylation ^[6]
• Galactokinase deficiency results in accumulation of galactose which gets converted to galactitol by a minor pathway.^[7] This molecule predisposes to cataract by causing:
  • Swelling of the lens
  • Denaturation of the proteins
  • Rupture of cell membranes ^[8]
• Epimerase deficiency results in increased UDP-galactose and suppressed UDP-glucose with the ratio changing with the galactose concentration. This can have affects on the glycoprotein and glycolipid synthesis. ^[9]
• Galactose mutarotase enzyme deficiency results in galactose not being able to enter the Leloir pathway due to specificity of the enzymes for the B-isomer. This can have serious clinical consequences.^[10]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactosemia is an autosomal recessive disorder which is caused by dysfunction of the enzymes] involved in the Leloir pathway of galactose metabolism.

Galactosemia is inherited in an autosomal recessive manner when one faulty gene is acquired from each of the carrier parents. The mutations responsible are as follows ^[1]:

Impaired functioning of the GALT gene, leading to absence of the galactose-1-phosphate uridyl transferase enzyme ^[2].

GALT gene dysfunction causes reduction of enzyme activity to 50 % ^[2]

Abnormality in the GALK1 gene ^[3]

Variation in the activity of the GALE gene ^[4]

Biallelic mutations in the GALM gene ^[5]

Template:Metabolic pathology

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactosemia closely resembles other metabolic disorders which form important differential diagnoses in clinical practice.

Galactosemia needs to differentiated from other diseases like:

• Biliary atresia ^[1]
• Fanconi-Bickel syndrome ^[2]
• Glucose-6-phosphate dehydrogenase deficiency ^[3]

Template:WH Template:WS

Differential diagnosis of galactosemia

Diseases	Clinical manifestations	Para-clinical findings	Gold standard	Additional findings
Galactosemia	Hepatomegaly, jaundice, vomiting, cataract, sepsis, psychomotor retardation [4]	Direct and indirect hyperbilirubinemia [4]	Measurement of GALT/GALK/Epimerase activity in erthrocytes [5]	Hemophagocytosis, purpura fulminans [4]
Biliary atresia	Persistent jaundice, dark urine, clay-colored stools, hepatomegaly [6]	Elevated total and direct bilirubin, ALT, AST, GGT [7]	Atretic biliary tree on liver biopsy [6]	Ascites, splenomegaly [7]
Fanconi Bickel syndrome	Hepatomegaly, glucose and galactose intolerance, severe growth retardation [8]	Hyperlipidemia, tubular nephropathy [9]	Mutation analysis of SLC2A2 gene encoding GLUT2 transporter [10]	Genu varum, hypophosphatemic rickets, Fanconi syndrome [11]
Glucose-6-phosphate dehydrogenase deficiency	Severe neonatal jaundice [12]	Acute hemolytic anemia after certain infections, intake of some drugs or fava beans [12]	Fluorescent spot test [13]	Kernicterus [14], rhabdomyolysis [15]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactosemia is quite widespread among different countries of the world with significant demographic differences with race and ethnicity. In spite of that, typical symptoms and clinical signs are manifested in most of the patients.

• Classic galactosemia affects approximately 1/50,000 live births in the USA. ^[1]. It is around 1 in 47000 among the White Americans. ^[2].1% of the North American people are carriers. ^[3]
• Incidence in UK is 1 in 70000, in Ireland 1 in 23000. ^[2]
• Incidence in the traveller community is notably high as 1 in 480. ^[2]
• In western Europe the percentage of galactosemia ranges from 1: 23000 to 1: 44000. ^[4]

• The incidence seems to be rather lower among people of African and Asian descent.^[3]
• The disorder is apparently less prevalent among Asians. Galactosemia is seen in all races; however, its variants are classified genetically, being most notable among African–Americans.^[5]
• Symptoms mostly develop in a few days to two weeks after initiating feeding in an apparently normal infant leading often to discharge from the hospital prior to the onset of the illness.
• The other important clinical finding in these patients is cataract.^[6]
• Cognitive impairment is present in the majority of patients.^[7]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujaya Chattopadhyay, M.D.[2]

Galactosemia satisfies the criteria for newborn screening successfully. Since most babies are born apparently healthy, there is a considerable window for prompt detection of the disease and appropriate intervention.

Galactosemia despite being incurable, qualifies for screening as early detection can prevent complications. ^[1] . Neonatal blood samples should be collected within 48 hours of birth, reach the laboratory within another 24 hours for the most accurate results.

• RBC Galactose level : Total blood galactose measurement alone or in combination with GALT activity in a dried blood sample is used for primary screening. Galactose-1-phosphate more than 10mg% is highly suggestive of galactosemia. ^[2]
• Reducing substances in urine: Presence of reducing sugars in urine other than glucose is highly suggestive of galactosemia. But, this test is highly non-specific as it is positive in various other clinical conditions (prematurity ^[3], proximal renal tubular acidosis ^[4] etc.)
• Galactitol excretion in urine: Boronic acid-based methods and multi-well-based arrays help in detection of galactitol in urine, a potent neurotoxin^[5]. This test also plays an important role in checking adherence to galactose restricted diet and projecting cataract development in babies born to galactosemic expectant mothers ^[6].
• Hypoglycemia, lactic acidosis, ketonuria: This triad is present in neonates challenged with galactose, but is seen in a wide range of clinical conditions, thus being extremely non-specific. ^[7]
• RBC Enzyme Activity: GALT activity assessment, combined with galactose-1-phosphate in a dried blood spot, can directly detect disorders associated with GALT and indirectly those associated with GALK and GALE and Duarte galactosemia. ^[8]
• Genetic testing: DNA testing for GALT, GALK and GALE mutations are also available in resourceful healthcare systems ^[9].

Thus, screening for galactosemia is primarily based on estimation of galactose, galactose-1-phosphate and GALT in RBCs. Elevated galactose with absent GALT activity indicates classic galactosemia, some GALT activity points towards Duarte variant, while raised sugar with normal GALT suggests deficiency of galactokinase or epimerase.

Template:WH Template:WS

The major risk factor for galactosemia is the presence of the defective gene(s).

Galactosemia is an inherited autosomal recessive disorder of galactose metabolism. Two defective alleles are necessary to manifest the condition.^[1]

• Children born to carrier parents harboring the gene(s) run the risk of developing galactosemia.
• Therefore, every child born to carrier parents has a 25% chance of developing the disorder.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dayana Davidis, M.D. [2]

Galactosemia is an inherited metabolic disorder with a variable natural history. It can lead to severe systemic complications if neglected. The prognosis depends on various factors.

Acute neonatal illness is experienced by most patients. A reported lower enzyme activity leads to more severe presentation while newborn screening results in detection at more favorable stages of the disease. Clinical features include ^[1] having one or more of:

• Elevated liver enzymes
• Hypoglycemia
• Encephalopathy
• Sepsis
• Bleeding diathesis
• Cataract

A younger age of diagnosis and early introduction of dietary changes exert a positive effect on the natural history of galactosemia ^{[2] [3]}.

Despite dietary modifications, most of the galactosemic patients develop neurological and/or gonadal complications and are at risk of bone damage ^[1].

• Tremor: Most often seen in the second decade of life ^[1]
• General motor abnormality ataxia
• Seizures
• Dystonia
• Anxiety disorder: It is the most frequently reported mental problem and common in all age categories, usually after the second decade.
• ADHD, ASD: More likely before the second decade

• Premature ovarian insufficiency and subfertility ^[5]
• Cryptorchidism ^[6]
• Delayed psychosexual development ^[7]

Reduced bone mineral density ^[8]

The prognostic outcome of galactosemia depends on a number of factors ^[1]:

• Newborn screening: Associated with lower rates of neurological symptoms
• Enzyme activity: Enzyme acitivity <1% correlates with more severe mental and behavioral symptoms.
• Diet: Onset of diet in the first week of life is associated with a more favorable prognosis. Moreover, a relaxed diet (lactose free without any further restrictions) has been proven to be more beneficial than a strict diet for long-term clinical outcomes ^[9].

Template:WH Template:WS