Browsing Pathways

Metachromatic leukodystrophy also known as MLD, is a rare inborn error of metabolism (IEM) which arises from a defective gene called ARSA. The ARSA gene which codes for arylsulfatase. An improperly function arylsulfatase enzyme can lead to the build up of 3-O-sulfogalactosylceramide in urine, neural and non neural tissues like kidney and gallbladder. MLD like many conditions comes in a slew of different shapes and sizes. The most common these is known as the late infantile form. This form affects children after their first year of age and manifests itself with children having difficulty walking. Of the many other symptoms which present themselves some of them include developmental delays, muscle weakness, rigidity and wasting, convulsions, and dementia, just to name a few. In extreme cases a comatose state may arise in affected children and without treatment, the majority of those affected by late infantile MLD will perish by/or before the age of 5. Another form of MLD is juvenile MLD. Characterized by an age of onset between 3 and 10. It is typically discovered when affected children start to show detiorating school performance, and mental faculties, as well as with the onset of dementia. Progression is slower though very much the same as in the former form of MLD discussed above. Most individuals die 10 to 15 years after the first symptoms manifest. The final form of MLD is adult onset MLD. Defined as occurring after the age of 16 and characterized by progressive dementia or by some psychiatric disorder. The progression of this form is the slowest of the three, and affected individuals may survive a decade or more.

Metachromatic leukodystrophy also known as MLD, is a rare inborn error of metabolism (IEM) which arises from a defective gene called ARSA. The ARSA gene which codes for arylsulfatase. An improperly function arylsulfatase enzyme can lead to the build up of 3-O-sulfogalactosylceramide in urine, neural and non neural tissues like kidney and gallbladder. MLD like many conditions comes in a slew of different shapes and sizes. The most common these is known as the late infantile form. This form affects children after their first year of age and manifests itself with children having difficulty walking. Of the many other symptoms which present themselves some of them include developmental delays, muscle weakness, rigidity and wasting, convulsions, and dementia, just to name a few. In extreme cases a comatose state may arise in affected children and without treatment, the majority of those affected by late infantile MLD will perish by/or before the age of 5. Another form of MLD is juvenile MLD. Characterized by an age of onset between 3 and 10. It is typically discovered when affected children start to show detiorating school performance, and mental faculties, as well as with the onset of dementia. Progression is slower though very much the same as in the former form of MLD discussed above. Most individuals die 10 to 15 years after the first symptoms manifest. The final form of MLD is adult onset MLD. Defined as occurring after the age of 16 and characterized by progressive dementia or by some psychiatric disorder. The progression of this form is the slowest of the three, and affected individuals may survive a decade or more.

Methionine adenosyltransferase (MAT; Hypermethioninemia; MAT I/III deficiency) deficiency is caused by mutations in the MAT1A gene which causes isolated hypermethioninemia. MAT catalyzes the formation of adenosylmethionine from methionine and ATP. Adenosylmethionine is an important methyl donor in most transmethylation reactions. MAT dificiency is characterized by increased homocysteine and methionine levels in plasma; and accumulation of methionine in urine. Symptoms include dystonia, mental retardation and unusual odor.

Methionine adenosyltransferase (MAT; Hypermethioninemia; MAT I/III deficiency) deficiency is caused by mutations in the MAT1A gene which causes isolated hypermethioninemia. MAT catalyzes the formation of adenosylmethionine from methionine and ATP. Adenosylmethionine is an important methyl donor in most transmethylation reactions. MAT dificiency is characterized by increased homocysteine and methionine levels in plasma; and accumulation of methionine in urine. Symptoms include dystonia, mental retardation and unusual odor.

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.

Methylenetetrahydrofolate reductase deficiency (MTHFRD; Homocystinuria due to defect of n(5,10)-methylene THF deficiency) is caused by a defect in the MTHFR gene which codes for methylenetetrahydrofolate reductase. Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. A defect in this enzyme results in accumulation of homocysteine and methionine in both plasma and urine. Some of the symptoms and signs include mental retardation, withdrawal, hallucinations, delusions, muscle weakness. Some patients remain asymptomatic until adulthood.

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDH Deficiency; Aldehyde Dehydrogenase 6 Family, Member A1; ALDH6A1 Deficiency)is caused by a defect in methylmalonate semialdehyde dehydrogenase, which catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. A defect in methylmalonate semialdehyde dehydrogenase causes accumulation of 3-Aminoisobutyric acid, 3-Hydroxyisobutyric acid, 3-hydroxypropionic acid, beta-Alanine, lactate, and methylmalonic acid in urine. Symptoms inclue failure to thrive, large liver, mental and motor retardation and vomiting.

Methylmalonate Semialdehyde Dehydrogenase Deficiency (MMSDH Deficiency; Aldehyde Dehydrogenase 6 Family, Member A1; ALDH6A1 Deficiency)is caused by a defect in methylmalonate semialdehyde dehydrogenase, which catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA, respectively. A defect in methylmalonate semialdehyde dehydrogenase causes accumulation of 3-Aminoisobutyric acid, 3-Hydroxyisobutyric acid, 3-hydroxypropionic acid, beta-Alanine, lactate, and methylmalonic acid in urine. Symptoms include failure to thrive, large liver, mental and motor retardation and vomiting.

Methylmalonic acidemia cause defects (Methylmalonaciduria due to methylmalonic CoA mutase; Acidemia, methylmalonic; MMA) in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase. Defects in the enzyme Methylmalonyl-CoA mutase causes accumulation of ammonia in blood; methylmalonic acid in plasma; creatinine and uric acid in serum; 3-Aminoisobutyric acid, 3-Hydroxypropionic acid, 3-Hydroxyvaleric acid, glycine, methylcitric acid and methylmalonic acid in urine; and methylmalonic acid in spinal fluid. Symptoms include anemia, dehydration, growth retardation, nephrosis, respiratory distress and metabolic acidosis.