Browsing Pathways

Tyrosinemia type I, also known as fumarylacetoacetase or FAH deficiency, is the most severe type of tyrosinemia, a buildup of tyrosine in the body. It is caused by an autosomal recessive mutation in the the FAH gene that encodes for fumarylacetoacetase, an enzyme that is responsible for the last of five steps that are involved in the metabolic breakdown of tyrosine in the liver and kidneys. The lack of this enzyme's function leads to a buildup of 4-fumarylacetoacetic acid as it couldn't be broken down to fumaric acid and acetoacetic acid. This also leads to an increased concentration of maleylacetoacetic acid. This eventually leads to the increased concentration of L-tyrosine in the body. Symptoms of tyrosinemia type I include jaundice and an enlarged liver, kidney dysfunction, as well as a failure to grow, as foods with high protein and amino acids lead to increased symptoms. Additionally, individuals are more at risk for future liver cancer.

Leukotriene C4 synthetase deficiency is caused by a defect in the enzyme leukotriene C4 synthetase (LTC4S). This enzyme catalyzes the synthesis of leukotriene C4 (LTC4) through conjugation of LTA4 with reduced glutathione (GSH), which is synthesized by glutathione synthetase. Leukotriene C4 and its receptor-binding metabolites LTD4 and LTE4 are cysteinyl leukotrienes that are potent lipid mediators of tissue inflammation. In general, leukotrienes are potent proinflammatory mediators synthesized from membrane-derived arachidonic acid after activation of certain granulocytes. A defect in LTC4 results in decreased concentrations of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in plasma, spinal fluid and urine. Symptoms include early death, failure to thrive, motor retardation, microcephaly, and progressive neurological defect.

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).

Lysosomal Acid Lipase Deficiency, also known as Wolman disease, is predictably enough the result of a specific defect in lysosomal acid lipase. The defect results from a mutation on the 10th chromosome to the LIPA gene. Of interest is that the nature of the particular defect to the LIPA gene can result in two major, and distinct disorders. The first and more severe is the infantile-onset Wolman disease, whereas the other less severe disorder is late-onset cholesteryl ester storage diseas, also known as CESD. These two disorders are the product of mutations to different regions of the LIPA gene. Wolman disease is characterized by increased transaminases in serum, and increased cholesteryl esters and triglycerides in various tissues. Symptoms include anemia, diarrhea, failure to thrive, enlarged liver, malabsorption, steatorrhea and abdominal pain.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Malonyl-CoA decarboxylase deficiency, also called malonic aciduria, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective MLYCD gene. The MLYCD gene codes for the protein malonyl-CoA decarboxylase which regulates the creation and degradation of fatty acids. This disorder is characterized by a large accumulation of fatty acid byproducts in the tissues. Symptoms of the disorder include delayed development, hypotonia, seizures, vomiting, diarrhea and cardiomyopathy. Treatment with L-carnitine is very effective, as it encourages beta-oxidation of fatty acids. Less than 30 cases globally have ever been reported, making this disorder extremely rare.

The autosomal recessive disorder Smith-Lemli-Opitz Syndrome (SLOS; SLO Syndrome; RSH; Rutledge Lethal Multiple Congenital Anomaly, Syndrome; Polydactyly, Sex Reversal, Renal Hypoplasia, and Unilobar Lung; Lethal Acrodysgenital Syndrome) is characterized by disordered steroid biosynthesis. It results from a mutation in the DHCR7 gene coding for the enzyme sterol delta-7-reducatase. This enzyme catalyzes the production of cholesterol by reducing the C7-C8 double bond of 7-dehydrocholesterol (7-DHC). SLOS causes the accumulation of 7-dehydrocholesterol and 8-dehydrocholesterol, and a decrease of cholesterol in plasma; and 3-methylglutaconic acid in urine. All patients with SLOS have mental retardation, and symptoms include ambiguous genitalia, hypotonia, microcephaly, syndactyly, limb abnormalities and deformities and polydactyly.

Maple syrup urine disease, also called BCKD deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective BCKDHA, BKCDHB or DBT gene. These genes code for a protein which is vital in the breakdown of amino acids, specifically the amino acids leucine, isoleucine and valine. This disorder is characterized by a large accumulation of these amino acids in the body. Symptoms of the disorder include a distinct maple syrup smell of the urine, vomiting, lethargy, abnormal movements and delayed development. Treatment includes long-term dietary management which aims to restrict the consumption of branched-chain amino acids. It is estimated that maple syrup urine disorder affects 1 in 185,000 infants globally. This number increases significantly when looking specifically at Old World Order Mennonites, where the prevalence is 1 in 380 infants.

Sialuria is caused by mutation in the gene encoding uridinediphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase, which causes an excessive synthesis of sialic acid (N-acetylneuraminic acid, NeuAc). This causes accumulation of sialic acid in the urine. Symptoms of sialuria include hepatosplenomegaly, hypotonia, frequent upper respiratory infections, gastroenteritis and seizures.

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.