Browsing Pathways

Hyperornithinemia with gyrate atrophy (HOGA), also known as gyrate atrophy of the choroid and retina, OAT deficiency, ornithine aminotransferase deficiency, ornithine keto acid aminotransferase deficiency) is an autosomal recessive disorder of ornithine metabolism caused by a defective ornithine aminotransferase (OAT). OAT catalyzes the conversion of ornithine into proline which is a conditionally essential amino acid. This disease is characterized by a very large accumulation of ornithine in the blood, urine, spinal fluid, and aqueous humour. Symptoms of the disease include early cataract formation, progressive chorioretinal degeneration, and type II muscle fiber atrophy. Some cases of HOGA are vitamin B6-responsive.

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder of the urea cycle caused by a defective SLC25A15 gene. SLC25A15 codes for the mitochondrial ornithine carrier (ORC1) which transports ornithine between the cytoplasm and the mitochondrial matrix. This disease is characterized by a large accumulation of homocitrulline in the urine. Symptoms of the disease include mental retardation, spastic paraparesis, and myoclonic seizures associated with hyperornithinemia, hyperammonemia, and homocitrullinemia. Ornithine supplementation and restricted protein intake appear to be useful in the treatment of HHH syndrome.

Arginine:glycine amidinotransferase deficiency, also called AGAT deficiency, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective arginine:glycine amidinotransferase (AGAT) gene. It manifests as a creatine deficiency disorder. Only 14 individuals with AGAT deficiency have been reported. The AGAT enzyme catalyzes the transfer of an amidino group from arginine to glycine yielding ornithine and guanidinoacetate, which is the immediate precursor of creatine. Deficiencies in the AGAT enzyme, therefore, lead to low levels of ornithine, guanidinoacetate, and creatine. People with AGAT deficiency have mild to moderate intellectual disability and delayed speech development. Some affected individuals develop autistic behaviours that affect communication and social interaction. Individuals with AGAT deficiency may experience seizures, especially when they have a fever. Children with AGAT deficiency may not gain weight and grow at the expected rate (failure to thrive) and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily due to their low creatine levels. The treatment for AGAT deficiency is creatine supplementation since the body cannot make the creatine on its own. Early-stage (fetal and early postnatal) creatine treatment has shown that those affected can develop normally and that early diagnosis and treatment can substantially improve the final prognosis of AGAT deficiency.

Lysosomal acid lipase deficiency, also called cholesteryl ester storage disease [CESD], LIPA deficiency or Wolman disease, is a rare autosomal recessive inborn error of metabolism. It's caused by not enough lysosomal acid lipase enzyme is produced at lysosome, which act to break down the fatty material. Lysosomal acid lipase enzyme catalyzes the conversion of cholesterol and fatty acid into cholesterol ester. This disorder is characterized by a large accumulation of cholesterol in the endoplasmic reticulum (ER). Symptoms of the disorder include vomiting, diarrhea, weight loss (i.e. feeding difficulties) and swelling of the abdomen. Lysosomal acid lipase deficiency can be treated with sebelipase alfa.

Hyperimmunoglobulinemia D syndrome, or HIDS, is a condition characterized by fevers that come and go, usually lasting 3-7 days, and other various symptoms such as rashes, vomiting, diarrhea and aphthous ulcers. These are usually noticed within the first year of a patient's life, and the highest frequency of HIDS usually occurs during childhood/adolescence. It occurs due to a mevalonate kinase deficiency inherited from both parents. In patients with this condition, the MVK gene is mutated, resulting in a lack of mevalonate kinase. Although globally this condition is rare, there are much higher instances in The Netherlands, about 1 in 350 Dutch nationals carry this mutation.

Mevalonic aciduria, also called MVA, is an extremely rare inherited inborn error of metabolism (IEM) and an autosomal recessive disorder caused by a defective mevalonate kinase gene. It is manifested by high levels of mevalonic acid in the urine and other body fluids. Approximately 30 patients with mevalonic aciduria (MVA) have been reported worldwide. MVA is classified as a disorder of branched-chain organic acid metabolism because the substrate for the reaction with mevalonate kinase, HMG-CoA, is a product of leucine catabolism. Mevalonate kinase is an enzyme that plays a critical role in the synthesis of cholesterol, ubiquinone for the electron transport chain, and dolichol for the synthesis of the oligosaccharides for glycoproteins. MVA is also considered a disorder of cholesterol metabolism and isoprenoid biosynthesis. Affected individuals have short stature, psychomotor retardation, progressive cerebellar ataxia, febrile crises, hepatosplenomegaly, lymphadenopathy, arthralgia, and skin rashes. Individuals also exhibit dysmorphic features and progressive visual impairment. Life expectancy with individuals with MVA is relatively short and death may occur from infancy to late childhood. MVA is one of two types of mevalonate kinase deficiency. MVA is the most severe type while the less severe type is called hyperimmunoglobulinemia D syndrome (HIDS).

In Wolman's disease excessive amounts of cholesterol ester in the liver are present mainly in the macrophages of the reticuloendo- thelial system. The livler in Wiolman's disease contains triglyceride at 10 to 20 times the normal concentratlon, most of whilch is present in hepatocytes. The first case of Wolman's disease was published in 1956 by M. Wolman, M.D., reporting a case of a 2 month old girl who had been admitted to the Hadassah University Hospital. Lysosomal acid lipase/acid cholesteryl ester hydrolase (LAL/ACEH) plays an important role in cellular processing of plasma lipoproteins and thus contributes to both the homeostatic control of plasma lipoprotein levels and the prevention of cellular lipid overload. Wolman's Disease results from severely reduced levels of the enzyme lysosomal acid lipase/acid cholesteryl ester hydrolase.

Xanthinuria Type I is a condition caused by an autosomal recessive mutation. The condition was discovered (though not diagnosed) in 1817, when stones formed of almost pure xanthine were first identified by Marcet. The symptoms arise because of a malfunction in the production of xanthine oxidase. It is a rare . It is characterized by a loss of oxidase such as in serum and the uric acid found in peepee. As a result, the opposite is true for the presence of xanthine and hypoxanthine. They will be found in the latter and former in increased quantities. Although the condition can cause a wide range of symptoms including renal xanthine stones, what occurs most of the time is that xanthinuria is asymptomatic and diagnosis is product of chance.

Xanthinuria Type II is a rare inborn error of metabolism (IEM) and autosomal recessive disorder and caused by a defective xanthine dehydrogenase. Xanthine dehydrogenase catalyzes the conversion of hypoxanthine into xanthine and conversion of xanthine into uric acid. This disorder is characterized by a large accumulation of xanthine and hypoxanthine; as well as dissipation of uric acid. Symptoms of the disorder include blood in the urine, recurrent urinary tract infections and abdominal pain. It is estimated that xanthinuria types I and II affects 1 in 69,000 individuals.

Gamma-cystathionase deficiency, also called cystathionase deficiency, is an autosomal recessive metabolic disorder caused by a defective cystathionine gamma-lyase. Cystathionine gamma-lyase catalyzes the conversion of L-Serine and homocysteine into L-Cystathionine which is the substrate of cystathionine gamma-lyase. This disorder is characterized by a large accumulation of L-Cystathionine in the cell. Symptoms of the disorder include mental deficiency and seizure. Since there is currently no cure forGamma-cystathionase deficiency, treatment involves managing the disorder's symptoms.