Browsing Pathways

Momoamine oxidase A (MAO-A) deficiency, or Brunner syndrome, is an X-linked recessive genetic disorder caused by a mutation in the MAOA gene that encodes for monoamine oxidase A. As such it is almost exclusively found in men. MAO-A is an enzyme that catalyzes the deamination of amines such as epinephrine, dopamine and tyramine, as part of the tyrosine metabolism pathway. In this disorder, some neurotransmitters such as serotonin and dopamine build up in the brain due to their inability to be properly metabolized. Since serotonin helps to regulate emotions and mood, with epinephrine and norepinephrine regulating stress, the unnecessary presence of the chemicals in the brain can lead to poor impulse control, aggression and other effects. The buildup of chemicals may also damage the brain, leading to a lower IQ in individuals with this disorder. In addition, foods containing the compounds that cannot be broken down, such as tyramine, can cause episodes of increased symptoms in the patients. In the subpathway that converts dopamine to homovanillic acid, there are two instances of MAO-A that are inactivated in this disorder, both in different branches. The first reaction converts dopamine to 3,4-dihydroxyphenylacetaldehyde, while the second converts 3-methoxytyramine to homovanillin. With the inactivation of MAO-A, 3-methoxytyramine builds up as there are no reactions that use it, and both of these paths lead to a decrease in the concentration of homovanillic acid, as there are no other reactions present that produce it. Another reaction, this time converting tyramine to homovanillin, is also prevented by the lack of MAO-A, which leads to an accumulation of tyramine in the body. In another branch of tyrosine metabolism, the absence of MAO-A prevents the oxidation of norepinephrine and epinephrine into 3,4-dihydroxymandelaldehyde. Its absence also prevents the oxidative deamination of metanephrine and normetanephrine into 3-methoxy-4-hydroxyphenylglycolaldehyde. As this is no longer produced, it leads to a decrease in the concentration of vanillylmandelic acid, which is produced from 3-methoxy-4-hydroxyphenylglycolaldehyde in a reaction catalyzed by aldehyde dehydrogenase.

GM2 gangliosidosis varient B or Tay-Sachs disease(TSD) is a neurodegenerative disorder which causes death in infantiles by age 5. Symptoms of TSD are present within 6 months of birth and include lack of motor development, mental retardation, seizures, and ultimately death. TSD is caused by the accumulation of GM2 gangliosides. Hexosaminadase A is the enzyme responsible for the degradation of GM2 gangliosides. It is a heterodimer made an alpha and beta subunit. The deficiency of this enzyme leads to the accumulation of GM2 gangliosides in neuronal lysosomes, eventually leading to cell death

Adenine phosphoribosyltransferase deficiency, which is also known as APRTD or APRT deficiency, is a rare inherited inborn error of metabolism (IEM) leading to the recurrent formation of kidney stones. It is an autosomal recessive disorder associated with a mutation in the enzyme adenine phosphoribosyltransferase (APRT). APRT is involved in the nucleotide salvage pathway, which provides an alternative, and energetically more efficient route to nucleotide biosynthesis in humans and most other animals. A defect in this enzyme can lead to the accumulation of the insoluble purine known as 2,8-dihydroxyadenine. In particular, when APRT has reduced or nonexistent activity, adenine accumulates which is then degraded by xanthine dehydrogenase to 2,8-dihydroxyadenine (DHA). 2,8-Dihydroxyadenine is a derivative of adenine which accumulates in 2,8 dihydroxyadenine urolithiasis (kidney stones). Kidney and urinary tract stones can obstruct the urinary tract, resulting in pain and difficulty urinating. If left untreated, the condition can eventually produce kidney failure. APRTD was first diagnosed in 1976. There are two categories of APRTD: type I involves a complete loss of the APRT function while type II involves a partial loss and is mostly found in Japan. APRT deficiency is estimated to affect 1 in 27 000 people in Japan. APRTD is rarer in Europe, where it affects 1 in 50 000 to 100 000 people. A diagnosis of APRTD can be made by analyzing kidney stones or measuring DHA concentrations in urine. APRTD is treatable with regular doses of allopurinol, which inhibits xanthine dehydrogenase activity. APRTD can also be treated with a low-purine diet and a high fluid intake.

Mitochondrial DNA depletion syndromes are a group of autosomal recessive disorders. They are characterized by decreased levels of mitochondrial DNA (mtDNA), resulting in decreased energy production. Mitochondrial DNA depletion syndrome-3 is caused by a mutation in the gene coding for deoxyguanosine kinase (DGUOK). DGUOK aids in maintaining the levels of available deoxyguanosine triphosphate (dGTP), thus the deficiency of DGUOK impairs the synthesis of dGTP. Symptoms of DGUOK deficiency can arise in the form of a multi-system disease in neonates or an isolated hepatic disease in infancy, with the former being more common. The most common cause of death in both forms is progressive hepative disease.

Myoadenylate deaminase deficiency, also called adenosine monophosphate (AMP) deaminase deficiency, is an common autosomal recessive disorder caused by a defective AMP deaminase 1. AMP deaminase 1 catalyzes the conversion of inosinic acid into adenosine monophosphate or other way around. Symptoms of the disorder is not common but could include fatigue, myalgia (i.e. muscle pain) and cramps after exercise. Treatment with methotrexate is very effective. It is estimated that affects 1 in 50 to 100 people in white population and affecting African American 1 in 40,000 people.

Carnitine palmitoyltransferase I deficiency, which is also known as CPT I deficiency, is a very rare inherited inborn error of metabolism (IEM) leading to muscle weakness. Fewer than 50 people have been identified with this condition. It is an autosomal recessive disorder associated with a mutation in the enzyme carnitine palmitoyltransferase I. Carnitine palmitoyltransferase I (CPT1) is also known as carnitine acyltransferase I (CAT1), CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I. CPT I is a mitochondrial enzyme. It is responsible for the formation of acylcarnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from CoA to carnitine. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Defects in CPT I prevents the body from using certain fats for energy, particularly during periods of fasting. Affected individuals often have increased carnitine levels along with low blood sugar (hypoglycemia) and a low level of ketones (hypoketosis), which are produced during fat metabolism as an energy source. Together these signs are termed hypoketotic hypoglycemia. The condition's severity varies greatly among affected individuals and many of the signs and symptoms manifest during early childhood. People with CPT I deficiency can also have an enlarged liver (hepatomegaly) and liver malfunction. CPT I deficienct individuals are at risk for liver failure, nervous system damage, seizures, coma, and sudden death. Affected individuals should eat a high-carbohydrate, low-fat diet and avoid fasting.

Very Long Chain Acyl CoA Dehydrogenase Deficiency (VLCADD) is a rare disorder that is inherited through an autosomal recessive trait, and prevents the body from properly metabolizing very long chain fatty acids. This disorder occurs in the mitochondria, where the metabolization of fatty acids takes place. Early-onset VLCADD patients usually begin to exhibit symptoms just days or weeks after birth. Hypoglycemia, lethargy and irritability are symptoms associated with this disorder. Patients will also be at risk for hypertrophic cardiomyopathy and other heart conditions from age two months to two years. It can be diagnosed through a research of family history and generally a urine analysis will reveal that the patient has reduced of absent ketone bodies. To help control acute episodes, treatment includes maintaining a high carbohydrate and low fat diet, and avoiding fasting for more than 12 hours.

Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), also called ACADL and VLCAD, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder, which is caused by a defective very long-chain specific acyl-CoA dehydrogenase. Very long-chain specific acyl-CoA dehydrogenase breakdown certain fats to energy. This disorder is characterized by a large accumulation of fatty acids such as L-Palmitoylcarnitine in the mitochondria. Symptoms of the disorder include muscle weakness, lethargy (lack of energy) and hypoglycemia (low blood sugar). Treatment with diet modifications such as consuming supplemental calories is suggested. It is estimated that very long-chain acyl-CoA dehydrogenase deficiency affects 1 in 40,000 to 120,000 individuals.

Carnitine palmitoyltransferase II deficiency, which is also known as CPT II deficiency, is an inherited inborn error of metabolism (IEM) of fatty acid oxidation leading to muscle weakness. It is the most common inherited disorder of lipid metabolism affecting the skeletal muscle of adults. It is an autosomal recessive disorder associated with a mutation in the enzyme carnitine palmitoyltransferase II. Carnitine palmitoyltransferase II (CPT2) is a peripheral inner mitochondrial membrane protein found in all tissues that oxidize fatty acids. It catalyzes the transesterification of palmitoylcarnitine back into palmitoyl-CoA which is a substrate for beta-oxidation inside the mitochondrial matrix. CPT2 is responsible for the formation of acylcarnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from CoA to carnitine. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. Deficiencies or mutations in the CPT2 gene lead to disorders of long-chain fatty acid oxidation. There are three forms of CPT II deficiency: (1) lethal neonatal form, (2) severe infantile hepatocardiomuscular form, and (3) the myopathic form. More than 300 CPT II deficiency cases have been described with the myopathic form being the most common (myopathic form: 86%, severe infantile form: 8%, neonatal form: 6% of cases). The myopathic form is usually mild and can manifest from infancy to adulthood. The infantile and neonatal forms are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death. The adult-onset myopathic form is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The most common cause of hereditary myoglobinuria is the myopathic form of CPT II deficiency and affects men more than women.

Medium-chain acyl-CoA dehydrogenase deficiency, which is also known as MCADD, is a rare inherited inborn error of metabolism (IEM) medium-chain fatty acid metabolism. The estimated birth prevalence of MCADD is between 1 in 4 900 to 1 in 27 000 in Caucasian populations and is highest in Northern European individuals. Worldwide birth prevalence is 1 in 14 600. MCADD is an autosomal recessive disorder associated with a mutation in the enzyme medium-chain acyl-CoA dehydrogenase (MCAD). MCAD is an enzyme that catalyzes the initial step in each cycle of medium-chain fatty acid beta-oxidation in the mitochondria of cells. MCAD’s action results in the introduction of a trans-double-bond between C2 and C3 of the acyl-CoA thioester substrate. Defects in MCAD leads to the accumulation of medium-chain fatty acids in the blood, lowering the blood's pH and causing acidosis. Likewise, individuals with MCADD have difficulty metabolizing fats. As a result, MCADD is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. Intolerance to fasting and hypoglycemia result from the inability to gain energy and make sugar from fat stores, which is how most excess energy from food is stored. It is rare for the signs and symptoms of MCADD to first appear during adulthood. Typically, they manifest during infancy or early childhood and can include lethargy, hypoglycemia, and vomiting. MCAD-deficient individuals are at risk for breathing difficulties, liver problems, seizures, brain damage, coma, and sudden death. Fasting or illnesses (e.g. viral infections) can trigger related problems. Infants and young children with MCADD need to eat frequently to prevent hypoglycemia or a metabolic crisis. MCADD is occasionally mistaken for Reye syndrome, a severe disorder that may manifest in children during apparent recovery from viral infections such as flu or chickenpox. The majority of Reye syndrome cases are associated with aspirin use during these viral infections.