Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.
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PMID:Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy. 1040 75

A 55-year-old female presented with a 6-year history of paresthesias, incontinence, spasticity, and gait abnormalities. Neuroimaging revealed white matter abnormalities associated with subependymal nodules. Biochemical evaluation noted increased serum C5-DC glutarylcarnitines and urine glutaric and 3-hydroxyglutaric acids. Evaluation of the glutaryl-CoA dehydrogenase (GCDH) gene revealed compound heterozygosity consisting of a novel variant (c.1219C>G; p.Leu407Val) and pathogenic mutation (c.848delT; p.L283fs). Together, these results were consistent with a diagnosis of adult-onset type I glutaric aciduria.
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PMID:Adult-onset glutaric aciduria type I presenting with white matter abnormalities and subependymal nodules. 2631 1

Glutaric aciduria type 1 (GA-1) is an autosomal-recessive disorder caused by the deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase. A 13-month-old boy presented with microcephaly, developmental delay, and progressive spasticity and was being treated as spastic cerebral palsy, later on had loss of developmental milestones after acute episode of illness at 12 months of age. The magnetic resonance imaging of brain revealed widened Sylvian fissure, hyperintensities in bilateral globus pallidus, and bilateral frontoparietal atrophy along with white matter loss. The urine examination by gas chromatography-mass spectroscopy revealed a marked excretion of glutaric acid and 3-hydroxyglutaric acid. The diagnosis of GA-1 was confirmed on the basis of characteristic neuroimaging, biochemical, and mutation studies. There are rare reports in the literature about association of GA-1 with microcephaly. The child was started on trihexyphenidyl, l -carnitine, and high-dose riboflavin, and dietary therapy in the form of low-protein diet was advised.
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PMID:Glutaric Aciduria Type 1 with Microcephaly: Masquerading as Spastic Cerebral Palsy. 3027 73

Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.
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PMID:Elevated levels of BDNF and cathepsin-d as possible peripheral markers of neurodegeneration in plasma of patients with glutaric acidemia type I. 3191 Feb 96