Abstract：
:Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by acute encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. We investigated the efficacy of substrate reduction through inhibition of 2-aminoadipic semialdehyde synthase (AASS), an enzyme upstream of the defective glutaryl-CoA dehydrogenase (GCDH), in a cell line and mouse model of GA1. We show that loss of AASS function in GCDH-deficient HEK-293 cells leads to an approximately fivefold reduction in the established GA1 clinical biomarker glutarylcarnitine. In the GA1 mouse model, deletion of Aass leads to a 4.3-, 3.8-, and 3.2-fold decrease in the glutaric acid levels in urine, brain, and liver, respectively. Parallel decreases were observed in urine and brain 3-hydroxyglutaric acid levels, and plasma, urine, and brain glutarylcarnitine levels. These in vivo data demonstrate that the saccharopine pathway is the main source of glutaric acid production in the brain and periphery of a mouse model for GA1, and support the notion that pharmacological inhibition of AASS may represent an attractive strategy to treat GA1.
journal_name
J Inherit Metab Disjournal_title
Journal of inherited metabolic diseaseauthors
Leandro J,Dodatko T,DeVita RJ,Chen H,Stauffer B,Yu C,Houten SMdoi
10.1002/jimd.12276subject
Has Abstractpub_date
2020-11-01 00:00:00pages
1154-1164issue
6eissn
0141-8955issn
1573-2665journal_volume
43pub_type
杂志文章abstract：:Glutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs b...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1023/a:1005390105171
更新日期：1998-06-01 00:00:00
abstract：:Glycogen storage disease type V (GSDV) is a rare inborn error of carbohydrate metabolism. Patients present with exercise intolerance due to blocked glycogen breakdown in skeletal muscle. Introducing alternative fuel substrates, such as ketone bodies (KBs), could potentially alleviate muscle symptoms. This pilot study ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1002/jimd.12223
更新日期：2020-07-01 00:00:00
abstract：:Congenital disorders of glycosylation (CDG) are a rapidly growing family comprising >100 genetic diseases. Some 25 CDG are pure O-glycosylation defects. Even among this CDG subgroup, phenotypic diversity is broad, ranging from mild to severe poly-organ/system dysfunction. Ophthalmic manifestations are present in 60% o...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1002/jimd.12025
更新日期：2019-01-01 00:00:00
abstract：:Glycogen storage disease type 1a (von Gierke disease, GSD1a) is caused by the deficiency of microsomal glucose-6-phosphatase (G6Pase) activity. The cloning of G6Pase cDNA and characterization of the human G6Pase gene enabled the identification of the mutations causing GSD1a. Here we report on the clinical and biochemi...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1005445802822
更新日期：1999-04-01 00:00:00
abstract：:Dopa decarboxylase (DDC or AADC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-aromatic amino acids into the corresponding aromatic amines. AADC deficiency is an inborn error of neurotransmitters biosynthesis with an autosomal recessive inheritance. About 30 pathogenic muta...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-011-9340-6
更新日期：2011-12-01 00:00:00
abstract：:Until recently, there have not been any confirmed reports of beta-mannosidase deficiency in man. We have now analysed urine from two patients with confirmed beta-mannosidase deficiency and have found Man-beta(1-4)GlcNAc concentrations of 65 and 73 mg/mmol creatinine. These levels are at least 12 times higher than thos...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01799685
更新日期：1990-01-01 00:00:00
abstract：:Deficiency of lysosomal α-L-iduronidase results in systemic accumulation of glycosaminoglycans (GAGs). Cardiac lesions due to accumulation of GAGs include hypertrophic cardiomyopathy, valvular insufficiency/stenosis, and coronary artery stenosis due to intimal proliferation. Cardiac dysfunction is one of the most comm...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-009-1057-4
更新日期：2009-12-01 00:00:00
abstract：:Mixed hyperlipidaemia is a common finding in glycogen storage disease type Ia (GSD Ia). Although cross-sectional studies have demonstrated increases in intermediate-density lipoproteins (IDLs) and reductions in lipoprotein lipase activity, no studies have investigated the dynamics of apolipoprotein B-100 (apo B) metab...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1012407609063
更新日期：2001-10-01 00:00:00
abstract：:N-Acetylaspartate (NAA) is an important osmolyte in the vertebrate brain that participates in an intercompartmental metabolic cycle. It is synthesized primarily in neurons from L-aspartate (Asp) and acetyl-CoA and, after its regulated release, it is hydrolysed by aspartoacylase in an oligodendrocyte compartment to pro...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1005618526988
更新日期：2000-11-01 00:00:00
abstract：:In a few rare diseases, specialised studies in cerebrospinal fluid (CSF) are required to identify the underlying metabolic disorder. We aimed to explore the possibility of detecting key synaptic proteins in the CSF, in particular dopaminergic and gabaergic, as new procedures that could be useful for both pathophysiolo...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-010-9256-6
更新日期：2011-04-01 00:00:00
abstract：:This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for α-mannosidosis. The older brother, the index case, was diagnosed at the age of 3 years and underwent transplantation at 13 years for the treatment of increasing som...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-009-9035-4
更新日期：2010-12-01 00:00:00
abstract：:Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an immunoreactive trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integr...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-010-9117-3
更新日期：2010-10-01 00:00:00
abstract：OBJECTIVE:To analyse diagnostic value of somato-sensory evoked potentials (SEP), magnetic resonance imaging (MRI), and clinical neurological examination in the decision for decompression surgery in mucopolysaccharidosis (MPS) VI patients with craniocervical cord compression (CCJ). METHODS:We retrospectively analysed n...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-013-9591-5
更新日期：2013-11-01 00:00:00
abstract：:The purpose of this review is to describe neurological phenotypes associated with lysosomal storage diseases (LSDs), focusing on features arising from primary neuronal involvement. Clinical presentation, progression and genetic data, are discussed in detail in Part 2, the electronic material. Main features are summari...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/s10545-010-9079-5
更新日期：2010-08-01 00:00:00
abstract：:Aldolase B is critical for sugar metabolism, and a catalytic deficiency due to mutations in its gene may result in hereditary fructose intolerance (HFI) syndrome, with hypoglycaemia and severe abdominal symptoms. This report describes two cases of HFI, which were identified by intravenous fructose tolerance test and a...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1022043307569
更新日期：2002-11-01 00:00:00
abstract：:Early diagnosis and improved treatment are leading to the potential for increased reproductive capability in homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency, but information about reproductive outcome and risk of thromboembolism in pregnancy is limited. To provide further information, clinical an...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1016502408305
更新日期：2002-08-01 00:00:00
abstract：:Maple syrup urine disease (MSUD), an inborn error of amino acids catabolism is characterized by accumulation of branched chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding alpha-ketoacids. Impact on the cognitive development has been reported historically, with developmental delays of varyin...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,多中心研究
doi：10.1007/s10545-017-0033-7
更新日期：2017-05-01 00:00:00
abstract：:Retinitis pigmentosa can occur as a complication of mevalonate kinase deficiency. This may be due to the unique isoprenoid metabolism in the retina. Early detection requires awareness on the part of the treating physician. ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-005-0178-7
更新日期：2005-01-01 00:00:00
abstract：:Interest in newborn screening (NBS) for lysosomal storage disorders (LSDs) has increased significantly due to newly developed enzyme replacement therapy (ERT), the need for early diagnosis, and advances in technical developments. Since the central nervous system cannot be treated by ERT, neuronopathic LSDs are general...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/s10545-010-9130-6
更新日期：2010-08-01 00:00:00
abstract：:GM2-gangliosidosis B1 variant, considered a rare disorder with a wide geographical and ethnic distribution, appears to be exceptionally frequent in Portugal. In order to establish a carrier detection method for this disease we have determined the ratio of enzymatic activities against 4MUGS and 4MUG in urine from B1 va...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF00711518
更新日期：1993-01-01 00:00:00
abstract：:Congenital lactic acidoses form a heterogeneous group of disorders: this paper considers primarily defects of the pyruvate dehydrogenase complex and the respiratory chain. Attempts to treat these disorders are hampered by uncertainty concerning the pathophysiology and by the central role of the enzymes in cellular met...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/BF01799117
更新日期：1996-01-01 00:00:00
abstract：:Direct alteration of a gene in the human genome requires an understanding of the role of the gene in metabolism. A gene may need to be introduced into a specific tissue or alternatively it may be possible to use accessible tissue such as bone marrow. The level of gene expression required also needs to be known as does...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01800862
更新日期：1986-01-01 00:00:00
abstract：:Latin America includes more than 40 countries and possessions, and its population of 570 million has an important representation of the three main human races. The area is experiencing an economic improvement, progressively bringing the inborn errors of metabolism (IEM) to a higher level among health priorities. Chall...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-010-9112-8
更新日期：2010-10-01 00:00:00
abstract：:Sandhoff disease is caused by the defective activity of the lysosomal enzyme beta-hexosaminidase, resulting in accumulation of the glycolipids, GA2 and GM2. Niemann-Pick A/B disease is caused by the defective activity of lysosomal acid sphingomyelinase resulting in sphingomyelin accumulation. Pulmonary complications h...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/b:boli.0000042958.22066.6c
更新日期：2004-01-01 00:00:00
abstract：:Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder due to deficient alpha-galactosidase A activity, which leads to accumulation of glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. The effect of this accumulation on peripheral and cardiac vascular function is poorly...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-005-0563-2
更新日期：2005-01-01 00:00:00
abstract：BACKGROUND:Fabry disease, an X-linked lysosomal storage disorder, leads to multi-organ dysfunction, including cerebrovascular disease and psychological disorders. However, the prevalence and pattern of associated cognitive dysfunction is not well understood. OBJECTIVES:To investigate whether there is reliable evidence...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,meta分析,评审
doi：10.1007/s10545-013-9643-x
更新日期：2014-03-01 00:00:00
abstract：:We have assessed very low-density lipoprotein apolipoprotein B production, using [15N]glycine as an endogenous marker in a 9-hour primed constant infusion protocol, in four adult male subjects with familial combined hyperlipidaemia and in four normolipidaemic adult male controls. The mean very low-density lipoprotein ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01800473
更新日期：1991-01-01 00:00:00
abstract：:We present a 32-year-old patient who, from age 7 months, developed photophobia, left-eye ptosis and progressive muscular weakness. At age 7 years, she showed normal psychomotor development, bilateral ptosis and exercise-induced weakness with severe acidosis. Basal blood and urine lactate were normal, increasing dramat...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-010-9169-4
更新日期：2010-12-01 00:00:00
abstract：:A 5-year-old boy, excreting large amounts of 2-hydroxyglutaric acid in the urine (3.3-7.6 mmol/l), is described. The patient presented with psychomotor retardation and dystrophy. His skeletal age was delayed. The EEG was not well differentiated; it resembled that observed in 2-year-old children. There was a severe ana...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF02312543
更新日期：1980-01-01 00:00:00
abstract：:We have identified a common novel mutation (Q354X) in the argininosuccinate lyase (ASL) gene in Saudi patients with argininosuccinic aciduria (ASAuria; McKusick 207900). The two index patients were siblings, had a neonatal onset of the disease and were diagnosed based on the clinical presentation and confirmed by anal...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-005-0081-2
更新日期：2005-01-01 00:00:00
