Hyperlysinemias
Identification of the alpha-aminoadipic semialdehyde synthase gene, which is defective in familial hyperlysinemia. (1/3)
The first two steps in the mammalian lysine-degradation pathway are catalyzed by lysine-ketoglutarate reductase and saccharopine dehydrogenase, respectively, resulting in the conversion of lysine to alpha-aminoadipic semialdehyde. Defects in one or both of these activities result in familial hyperlysinemia, an autosomal recessive condition characterized by hyperlysinemia, lysinuria, and variable saccharopinuria. In yeast, lysine-ketoglutarate reductase and saccharopine dehydrogenase are encoded by the LYS1 and LYS9 genes, respectively, and we searched the available sequence databases for their human homologues. We identified a single cDNA that encoded an apparently bifunctional protein, with the N-terminal half similar to that of yeast LYS1 and with the C-terminal half similar to that of yeast LYS9. This bifunctional protein has previously been referred to as "alpha-aminoadipic semialdehyde synthase," and we have tentatively designated this gene "AASS." The AASS cDNA contains an open reading frame of 2,781 bp predicted to encode a 927-amino-acid-long protein. The gene has been sequenced and contains 24 exons scattered over 68 kb and maps to chromosome 7q31.3. Northern blot analysis revealed the presence of several transcripts in all tissues examined, with the highest expression occurring in the liver. We sequenced the genomic DNA from a single patient with hyperlysinemia (JJa). The patient is the product of a consanguineous mating and is homozygous for an out-of-frame 9-bp deletion in exon 15, which results in a premature stop codon at position 534 of the protein. On the basis of these and other results, we propose that AASS catalyzes the first two steps of the major lysine-degradation pathway in human cells and that inactivating mutations in the AASS gene are a cause of hyperlysinemia. (+info)Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. (2/3)
BACKGROUND: Pyridoxine-dependent seizures (PDS) is a rare, autosomal recessively inherited disorder. Recently alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency was identified as a major cause of PDS, which causes accumulation of both alpha-AASA and pipecolic acid (PA) in body fluids. METHODS: We studied urinary and plasma alpha-AASA and PA levels in 12 Dutch clinically diagnosed patients with PDS. RESULTS: Alpha-AASA was elevated in both urine and plasma in 10 patients. In these patients plasma PA levels were also elevated but urinary PA levels were normal. DISCUSSION: In all patients with clinically definite PDS, and in most patients with probable or possible PDS, the clinical diagnosis of PDS could be confirmed at the metabolite level. Non-invasive urinary screening for alpha-AASA accumulation provides a reliable tool to diagnose PDS and can save these patients from the classical and potentially dangerous pyridoxine withdrawal test to prove PDS. (+info)Genetic basis of hyperlysinemia. (3/3)
(+info)Hyperlysinemias are inherited metabolic disorders characterized by an elevated level of the amino acid lysine in the blood. There are two major types: primary hyperlysinemia (also known as Lysinuric protein intolerance) and secondary hyperlysinemia.
Primary hyperlysinemia is caused by a deficiency of the enzyme responsible for breaking down lysine, arginine, and ornithine in the body. This leads to an accumulation of these amino acids in the blood and can cause various symptoms such as vomiting, seizures, developmental delay, and kidney problems.
Secondary hyperlysinemia, on the other hand, is not a result of a specific enzyme deficiency but rather due to an excess intake of lysine or a disorder that affects lysine metabolism. Symptoms may vary depending on the underlying cause and can range from mild to severe.
It's important to note that hyperlysinemias are rare disorders, and their diagnosis typically requires specialized testing. Treatment may involve dietary modifications, supplementation of missing enzymes or cofactors, and management of symptoms as they arise.