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Consequências a curto e a longo prazo de alterações no metabolismo da galactose
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Abstract(s)
A galactose é um monossacárido vital para o ser humano, com diversas funções no organismo, em particular enquanto fonte de energia primordial em lactentes e pelo papel estrutural crucial, particularmente importante no desenvolvimento inicial. A principal fonte de galactose é a lactose presente no leite e produtos lácteos. Após ingestão, a lactose é hidrolisada no lúmen intestinal pela lactase em glicose e galactose. A galactose é transportada através da membrana da borda em escova do enterócito pelo co-transportador ativo de sódio/glicose SGLT1 e, através de difusão facilitada pelo transportador de glucose GLUT2, através da membrana baso lateral do enterócito. Ao entrar na corrente sanguínea, entra no fígado através da veia porta, o principal local do metabolismo da galactose, onde é internalizado pelo GLUT5.
A galactosemia é uma doença hereditária do metabolismo que resulta de mutações nos quatro genes que codificam as enzimas envolvidas no metabolismo da galactose. Estas mutações afetam as enzimas responsáveis pela metabolização da galactose que estão presentes na via de Leloir (galactocinase, galactose-1-fosfato uridiltransferase e difosfato de uridina UDP-galactose 4-epimerase), com a consequente acumulação de galactose no sangue. A galactosemia clássica caracteriza-se pela diminuição de atividade da GALT, devido à ocorrência de uma das mais de 250 mutações no gene que a codifica, e apresenta-se inicialmente, no período neonatal, com sinais clínicos subtis e inespecíficos, como intolerância alimentar, icterícia, letargia, hipotonia, vómitos, diarreia e má evolução estaturo-ponderal. Se não for diagnosticada e tratada, evolui para várias complicações com elevado risco de vida como, hepatomegalia, insuficiência hepática, diáteses hemorrágicas, disfunção renal, encefalopatia, sépsis por E coli, choque e, por fim, morte. Estudos a nível celular demonstraram que a atividade reduzida da GALT ou GALE resulta num aumento do stress oxidativo. Tendo isso em conta, após um século da descoberta da doença, é possível conceber melhores opções terapêuticas como sejam fármacos que reduzem os metabolitos potencialmente tóxicos, antioxidantes para reduzir o stress oxidativo das células ou chaperones farmacológicos para estabilizar as proteínas afetadas.
As guidelines de tratamento da galactosemia preconizam uma dieta restritiva em lactose e galactose, bem como o rastreio bioquímico periódico. Adicionalmente, são recomendados diversos outros rastreios, incluindo o desenvolvimento cognitivo, neurológico, oftalmológico, entre outros, uma vez que, apesar das restrições alimentares, os doentes apresentam complicações a longo prazo, como cataratas, baixo coeficiente de inteligência e perdas de densidade óssea, que serão abordadas mais a fundo durante a realização da tese.
Galactose is a vital monosaccharide for humans, with various functions in the body, as a primary energy source in infants and for its crucial structural role, particularly important in early development. The main source of galactose is the lactose present in milk and dairy products. After ingestion, lactose is hydrolyzed in the intestinal lumen by lactase into glucose and galactose. Galactose is transported across the brush border membrane of the enterocyte by the active sodium/glucose co-transporter SGLT1 and, through diffusion facilitated by the glucose transporter GLUT2, across the lateral basement membrane of the enterocyte. On entering the bloodstream, it enters the liver via the portal vein, the main site of galactose metabolism, where it is internalized by GLUT5. Galactosemia is an inherited metabolic disease that results from mutations in the four genes that code for the enzymes involved in galactose metabolism. These mutations affect the enzymes responsible for metabolizing galactose that are present in the Leloir pathway (galactokinase (GALK), galactose-1-phosphate uridyl transferase (GALT) and uridine diphosphate (UDP)-galactose 4-epimerase (GALE), with the consequent accumulation of galactose in the blood. Classical galactosemia is characterized by a decrease in GALT activity, due to one of the more than 250 mutations in the gene that codes for GALT, and initially presents itself, in the neonatal period, with subtle and non-specific clinical signs, such as food intolerance, jaundice, lethargy, hypotonia, vomiting, diarrhea and failure to thrive. If left undiagnosed and untreated, it progresses to several life-threatening complications such as hepatomegaly, liver failure, bleeding diathesis, kidney dysfunction, encephalopathy, E coli sepsis, shock and ultimately death. Studies at the cellular level have shown that reduced GALT or GALE activity results in increased oxidative stress. Taking this into account, a century after the discovery of the disease, it is possible to design better therapeutic options such as drugs that reduce potentially toxic metabolites, antioxidants to reduce oxidative stress in cells or pharmacological chaperones to stabilize the affected proteins. According to the galactosemia treatment guidelines, treatment consists of a lactose- and galactose-restricted diet and periodic biochemical screening. In addition, various screenings are recommended, including cognitive, neurological and ophthalmological development, among others, since, despite dietary restrictions, patients have long-term complications, such as cataracts, low intelligence and loss of bone density, which will be discussed in more depth during the thesis.
Galactose is a vital monosaccharide for humans, with various functions in the body, as a primary energy source in infants and for its crucial structural role, particularly important in early development. The main source of galactose is the lactose present in milk and dairy products. After ingestion, lactose is hydrolyzed in the intestinal lumen by lactase into glucose and galactose. Galactose is transported across the brush border membrane of the enterocyte by the active sodium/glucose co-transporter SGLT1 and, through diffusion facilitated by the glucose transporter GLUT2, across the lateral basement membrane of the enterocyte. On entering the bloodstream, it enters the liver via the portal vein, the main site of galactose metabolism, where it is internalized by GLUT5. Galactosemia is an inherited metabolic disease that results from mutations in the four genes that code for the enzymes involved in galactose metabolism. These mutations affect the enzymes responsible for metabolizing galactose that are present in the Leloir pathway (galactokinase (GALK), galactose-1-phosphate uridyl transferase (GALT) and uridine diphosphate (UDP)-galactose 4-epimerase (GALE), with the consequent accumulation of galactose in the blood. Classical galactosemia is characterized by a decrease in GALT activity, due to one of the more than 250 mutations in the gene that codes for GALT, and initially presents itself, in the neonatal period, with subtle and non-specific clinical signs, such as food intolerance, jaundice, lethargy, hypotonia, vomiting, diarrhea and failure to thrive. If left undiagnosed and untreated, it progresses to several life-threatening complications such as hepatomegaly, liver failure, bleeding diathesis, kidney dysfunction, encephalopathy, E coli sepsis, shock and ultimately death. Studies at the cellular level have shown that reduced GALT or GALE activity results in increased oxidative stress. Taking this into account, a century after the discovery of the disease, it is possible to design better therapeutic options such as drugs that reduce potentially toxic metabolites, antioxidants to reduce oxidative stress in cells or pharmacological chaperones to stabilize the affected proteins. According to the galactosemia treatment guidelines, treatment consists of a lactose- and galactose-restricted diet and periodic biochemical screening. In addition, various screenings are recommended, including cognitive, neurological and ophthalmological development, among others, since, despite dietary restrictions, patients have long-term complications, such as cataracts, low intelligence and loss of bone density, which will be discussed in more depth during the thesis.
Description
Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz
Keywords
Galactosemia GALT GALE GALK 1 Metabolic