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.

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.

S-Adenosylhomocysteine hydrolase deficiency, also known as AdoHcy hydrolase deficiency or adenosylhomocysteinase (AHCY) deficiency, is an autosomal recessive disorder characterized by a defective AHCY gene. AHCY codes for the enzyme S-adenosylhomocysteine hydrolase (AdoHcyase) which efficiently eliminates S-adenosylhomocysteine (SAH) by catalyzing its hydrolysis into adenosine and homocysteine. SAH is both a byproduct of S-adenosylmethionine-dependent methyltransferases and a powerful methyltransferase inhibitor. For these reasons, AdoHcyase is thought to play an essential role in regulating methylations. AdoHcyase deficiency causes a buildup of homocysteine which may be then converted into methionine or cysteine. The accumulation of methionine as a result of AHCY deficiency may lead to signs and symptoms associated with hypermethioninemia, including mental and motor retardation, dysmorphism (unusual facial features), and abnormalities in liver function.

Pyruvate dehydrogenase complex deficiency results from a mutation in the E1-alpha polypeptide gene (PDHA1). PDHA1 encodes the pyruvate dehydrogenase complex (PDC) a critical complex that converts pyruvate from glycolysis to acetyl CoA for the citric acid cycle. This conversion step links glycolysis and the citric acid cycle. A defect in this complex causes accumulation of lactate and pyruvate in the blood; lactate and pyruvic acid in the spinal fluid; and lactate in the urine. Symptoms include lactic and metabolic acidosis, motor retardation, dystonia, growth and mental retardation, and respiratory distress.

Purine nucleoside phosphorylase deficiency (Nucleoside phosphorylase; Immunodeficiency) is a rare disease causing severe immunodeficiency. The disease is caused by a mutation in the enzyme purine nucleoside phosphorylase. The enzyme is necessary for purine breakdown. The mutation causes deoxy-GTP (dGTP) to accumulate which causes T-cell toxicity. The disease results in accumulation of guanosine, inosine, and uric acid in serum; and orotic acid in some cases in the urine. Symptoms include anemia, ataxia, hypotonia, lymphopenia, mental retardation, and tremor or twitching.

Hypercholesterolemia, also called elevated cholesterol, is an autosomal dominant disorder caused by a defective LDLR gene. The LDLR gene codes for a receptor that binds to low-density lipoprotein which are carriers of cholesterol in the blood. The mutation on the LDLR gene causes the removal of cholesterol from the bloodstream to be limited, resulting in a buildup of cholesterol in the blood. This disorder is characterized by a large accumulation of cholesterol in the blood. Symptoms of the disorder include angina, tendon xanthomas increased risk of cardiac arrest. Treatment with atorvastatin, simvastatin or rosuvastatin, in combination with a heart healthy diet and regular exercise is very effective. It is estimated that hypercholesterolemia affects 1 in 500 individuals in most countries.

Prolinemia Type II is caused by mutation in the pyrroline-5-carboxylate dehydrogenase gene (P5CDH) mitochondrial matrix NAD-dependent dehydrogenase. This dehydrogenase is a catalyst for converting pyrroline-5-carboxylate to glutamate in the proline degradation pathway. An enzyme defect causes accumulation of glycine, hydroxyproline and proline in the urine, ornithine in the serum and proline in plasma. Symptoms include mental retardation, acute and chronic renal failure, and seizures.

Prolidase deficiency is an autosomal recessive disorder. The enzyme prolidase cleaves iminodipeptides with N-terminal proline or hydroxyproline. Collagen has high levels of iminoacids therefore, these dipeptidases are important for collagen metabolism. A defect in this enzyme causes accumulation of imidodipeptides in urine. Symptoms include skin lesions, anemia, dysmorphism, mental retardation, and ptosis (drooping eyelid).

Phenylketonuria, also called Folling disease, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder that affects the proper processing of phenylalanine caused by a defective phenylalanine hydroxylase. Phenylalanine hydroxylase breaks down phenylalanine from the diet. This disorder is characterized by a large accumulation of phenylalanine in the blood and other tissues. Symptoms of the disorder include behavioural problems, psychiatric disorders and seizures. Treatment eating a diet limiting the intake of phenylalanine is very effective. It is estimated that phenylketonuria affects 1 in 15,000 individuals in the United States.

Ornithine transcarbamylase deficiency (OTC deficiency), is a rare inborn error of metabolism (IEM) and X-linked disorder of the urea cycle caused by a deficiency of ornithine transcarbamylase. Ornithine transcarbamylase is responsible for processing nitrogen produced by the urea cycle. This disorder is characterized by a large accumulation of ammonia in the bloodstream. Symptoms of the disorder include lethargy, seizures, or coma. Treatment with hemodialysis is very effective in patients with high ammonia blood levels. It is estimated that ornithine transcarbamylase deficiency affects 1 in 14,000 to 1 in 77,000 individuals. These estimates are very different because adults with the late-onset form of ornithine transcarbamylase deficiency are less likely to come to medical attention.