Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric aciduria type I (GA I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia and pathologically by neural degeneration of the caudate and putamen. Studies of metabolite excretion allowed us to categorize 43 GA I Spanish patients into two groups: group 1 (26 patients), those presenting with high excretion of both glutarate and 3-hydroxyglutarate, and group 2 (17 patients), those who might not be detected by routine urine organic acid analysis because glutarate might be normal and 3-hydroxyglutarate only slightly higher than controls. Single-strand conformation polymorphism (SSCP) screening and sequence analysis of the 11 exons and the corresponding intron boundaries of the GCDH gene allowed us to identify 13 novel and 10 previously described mutations. The most frequent mutations in group 1 were A293T and R402W with an allele frequency of 30% and 28%, respectively. These two mutations were also found in group 2, but always in heterozygosity, in particular in combination with mutations V400M or R227P. Interestingly, mutations V400M and R227P were only found in group 2, and at least one of these mutations was found in 11 of 15 unrelated alleles, accounting together for 53% of the mutant alleles in group 2. Therefore, it seems clear that two genetically and biochemically distinct groups of patients exist. The severity of the clinical phenotype seems to be closely linked to the development of encephalopathic crises rather than to residual enzyme activity or genotype. Comparison of GCDH protein with other acyl-CoA dehydrogenases (whose x-ray crystal structure has been determined) reveals that most of the mutations identified in GCDH protein seem to affect folding and tetramerization, as has been described for a number of mutations affecting mitochondrial beta-oxidation acyl-CoA dehydrogenases.
 ...
PMID:Glutaryl-CoA dehydrogenase deficiency in Spain: evidence of two groups of patients, genetically, and biochemically distinct. 1096 Apr 96

Glutaric aciduria typo I (GA I) is an uncommon metabolic disease with autosomal recessive inheritance. It usually presents in the first years of life and frequently causes movement disorders. Only a few cases have been diagnosed in adulthood. Two siblings who were diagnosed of GA I after a course of more than 20 years are reported here. The elder brother, after 9 months of normal psychomotor development, suffered from an acute encephalopathy with generalized hypotonia and, later on, dyskinetic movements. Throughout the following years severe generalized dystonia developed. The younger brother presented at 16 months with acute encephalopathy, hypotonia and generalized choreoathetoid movements. Cranial computed tomography showed in both patients an slight enlargement of Silvian cisures and diffuse white matter hypodensities. Magnetic resonance imaging performed in the second case disclosed in addition bilateral hyperintensities in putamen and caudate nucleous. At 29 and 24 years of age, respectively, an increased urinary excretion of glutaric and 3-hydroxiglutaric acids was detected in both patients. Glutaryl-CoA deshidrogenase activity in fibroblasts was absent in both. The patients were treated with carnitine and riboflavine, with no response. The present report shows that diagnosis of GA I should be considered in adults presenting a range of movement disorders from childhood.
 ...
PMID:[Glutaric aciduria type I: diagnosis in adulthood and phenotypic variability]. 1173 16

Glutaric aciduria type 1 (GA-1) is an inborn error of metabolism caused by a deficiency of the mitochondrial enzyme glutaryl-Co enzyme A dehydrogenase. GA-1 is not uncommon amongst Caucasians but to the best of our knowledge, it has previously not been reported in black African children. We present a case of GA-1 in a black South African boy who was referred to hospital at the age of five years and ten 10 months with dyskinesia and dystonia accompanied by chorea and athetosis. Radiological examination revealed enlarged basal cisterns with bilateral fluid collection around the sylvian fissures suggestive of GA-1. Analysis of urine showed raised levels of glutaric acid at 520 micromol/mmol creatinine (normal <2.0), 3-hydroxyglutaric acid at 113 micromol/mmol creatinine (normal <3.0) and a low blood carnitine level of 31.5 micromol/l (normal 35-84). A definitive diagnosis was reached through DNA analysis which revealed homozygosity for an A293T mutation in the glutaryl-Co-enzyme A dehydrogenase (GCDH) gene.
 ...
PMID:Biochemical and molecular diagnosis of glutaric aciduria type 1 in a black South African male child: case report. 1219 54

Type I glutaric aciduria (GA1) results from mitochondrial matrix flavoprotein glutaryl-CoA dehydrogenase deficiency and is a cause of acute striatal necrosis in infancy. We present detailed clinical, neuroradiologic, molecular, biochemical, and functional data on 77 patients with GA1 representative of a 14-year clinical experience. Microencephalic macrocephaly at birth is the earliest sign of GA1 and is associated with stretched bridging veins that can be a cause of subdural hematoma and acute retinal hemorrhage. Acute striatal necrosis during infancy is the principal cause of morbidity and mortality and leads to chronic oromotor, gastroesophageal, skeletal, and respiratory complications of dystonia. Injury to the putamen is heralded by abrupt-onset behavioral arrest. Tissue degeneration is stroke-like in pace, radiologic appearance, and irreversibility. It is uniformly symmetric, regionally selective, confined to children under 18 months of age, and occurs almost always during an infectious illness. Our knowledge of disease mechanisms, though incomplete, is sufficient to allow a rational approach to management of encephalopathic crises. Screening of asymptomatic newborns with GA1 followed by thoughtful prospective care reduces the incidence of radiologically and clinically evident basal ganglia injury from approximately 90% to 35%. Uninjured children have good developmental outcomes and thrive within Amish and non-Amish communities.
 ...
PMID:Type I glutaric aciduria, part 1: natural history of 77 patients. 1288 85

All 28 patients, 13 females and 15 males, with glutaric aciduria type 1 diagnosed between 1975 and 2001 in Denmark, Finland, Norway and Sweden were identified and studied retrospectively until 2001. Mass screening was not performed. Three were sibling cases. Prenatal enzymatic diagnosis performed in 11 pregnancies led to termination in one. The median follow-up time was 14 years. Six patients had died. At 10 years of age the cumulative survival rate was 89% and at 35 years 44%. The dominating neurological sign was dystonia in 20 and dyskinesia in 4. Three had only slight spastic signs and information was missing in one. The head circumference at birth was significantly larger than normal and increased significantly until 6 months of age. The onset was acute encephalopathic in 24 patients and insidious in 3. From the time of diagnosis, all patients but one were prescribed protein restriction and/or a diet low in lysine and tryptophan. Riboflavine and/or carnitine supplementation were given to 25. Neurological deficits did not improve on the offered treatment. Deterioration may have been averted by intense acute metabolic treatment in a few patients. Dystonia correlated significantly to absence of speech but not to cognitive function. Severe disability, including motor, cognitive and speech functions, correlated significantly with acute onset, dystonia and mortality, and weakly with a deteriorating course, but not with age at onset, diagnosis, or follow-up, nor to head size. Results from future population studies derived from mass screening will have to relate to clinical diagnostic series of the kind presented here.
 ...
PMID:Long-term follow-up, neurological outcome and survival rate in 28 Nordic patients with glutaric aciduria type 1. 1512 Jun 83

Glutaric aciduria type 1 is an inborn error of metabolism due to deficiency of glutaryl-CoA dehydrogenase. This disorder mainly affects children. The majority of patients develop a dystonic-dyskinetic syndrome. The dystonia is painful and can cause significant disability. This report documents an 18-month-old child, the youngest reported, who underwent pallidotomy for disabling dystonia. The surgery improved dystonic symptoms, especially pain in this child with minor complications related to the procedure. Pallidotomy is a reasonable option for children with dystonic symptoms secondary to glutaric aciduria.
 ...
PMID:Bilateral pallidotomy for severe dystonia in an 18-month-old child with glutaric aciduria. 1530 79

Neurophysiologic abnormalities are frequently seen in organic acidemias, but knowledge of the specific changes in the different types of organic acidemias is lacking. We studied electroencephalogram (EEG), visual evoked potential (VEP) and brain-stem auditory evoked response (BAER) in seven children with glutaric aciduria type I (GA1) to assess the neurophysiologic features in this rare inborn error of metabolism. Age at the time of the diagnosis ranged between 3 months and 36 months. Age at the time of neurophysiologic evaluation ranged between 11 months and 36 months. At the time of neurophysiologic evaluation, severe global developmental delay was seen in four patients, dystonia in four patients, motor delay in two patients, and axial hypotonia in two patients; macrocephaly, spasticity, moderate mental retardation and borderline intelligence were each seen in one patient. One patient had autistic features characterized by lack of language and social skills, poor eye contact and stereotypical behavior. Three of seven patients showed abnormal EEG findings. Two patients showed asymmetry with intermittent occipital delta slowing in one hemisphere. This finding probably indicates underlying cerebral dysfunction, and is not a specific feature. However, it suggests that these patients may develop abnormal EEG features during the course of the disease, and thus a baseline EEG may be useful for comparison over time. One patient showed high amplitude bursts of beta in the occipital regions with left predominance while on clonazepam and baclofen. We believe this finding was due to medication effect, and that what we observed was an exaggarated response to benzodiazepine. The clinical significance of this finding is unclear. VEP and BAER were available in four patients, and we found abnormalities in three of them. Neurophysiologic evaluation may be helpful in patients with GA1 as in other types of organic acidemias to help detect subtle changes that are not reflected by neurological examination or neuroimaging studies, and it may guide future treatment plans. Detailed neurophysiologic analysis in a large series of GA1 may yield further information regarding the extent of cerebral dysfunction.
 ...
PMID:Neurophysiologic features in glutaric aciduria type I. 1605 56

Glutaric aciduria type I is an autosomal recessive disorder of organic acid metabolism secondary to glutaryl-coenzyme A (CoA) dehydrogenase deficiency. We report a previously healthy 17-month-old girl who presented with acute dystonia. Conventional T2-weighted and fluid-attenuated inversion recovery magnetic resonance images of the brain showed hyperintensity in the caudates and putamina bilaterally with subtle involvement of the medial frontal lobes. Diffusion-weighted magnetic resonance images showed striking restricted diffusion in the caudates and putamina consistent with acute necrosis. Single-voxel hydrogen magnetic resonance spectroscopy of the involved areas was normal. The clinical diagnosis of glutaric aciduria type I was confirmed by elevation of 3-hydroxyglutaric and glutaric acids. Diffusion-weighted magnetic resonance imaging is a sensitive indicator of basal ganglia necrosis in glutaric aciduria type I.
 ...
PMID:Glutaric aciduria type I: a neuroimaging diagnosis? 1615 25

Acute encephalopathic crisis in glutaric aciduria type I results in an unfavourable disease course and poor outcome, dominated by dystonia, feeding problems, seizures and reduced life expectancy. A conditio sine qua non for the prevention of irreversible brain damage is timely diagnosis and start of therapy, i.e. before the onset of neurological disease. As there are no specific clinical signs or symptoms that allow a reliable detection of these patients before the manifestation of encephalopathic crises, neonatal screening programmes for glutaric aciduria type I have been established in some countries using analysis of glutarylcarnitine in dried blood spots by tandem mass spectrometry. This article summarizes recent strategies, pitfalls and shortcomings of mass screening for glutaric aciduria type I, focusing on the relevant risk of missing patients with a mild biochemical phenotype (i.e. low excretors). Furthermore, it evaluates a binary strategy--using glutarylcarnitine as primary variable and glutarylcarnitine/acylcarnitine ratios as secondary variable--to improve the diagnostic sensitivity and specificity of neonatal screening for glutaric aciduria type I. An optimization of diagnostic as well as therapeutic procedures must be achieved before screening for glutaric aciduria type I can be regarded as reliable and beneficial for all patients.
 ...
PMID:Neonatal screening for glutaric aciduria type I: strategies to proceed. 1676 5

Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder due to glutaryl CoA dehydrogenase deficiency. Comprehensive descriptions of GA1-associated movement disorders are rare. In order to refine the description of the motor phenotype, we prospectively studied 16 consecutive pediatric and adult GA1 patients, focusing on the movement disorders and their time course. In most patients, generalized dystonia, superimposed on baseline axial hypotonia, remained the predominant feature throughout the disease course. With aging, it tended to evolve from mobile to fixed dystonia and to be associated with akinetic-rigid parkinsonism. Prominent orofacial involvement was a consistent feature in GA1 patients with movement disorders, resulting in speech disorders with features of combined hyperkinetic dysarthria and speech apraxia. The types and outcome of movement disorders in this setting should be taken into consideration during rehabilitation and for patient selection and evaluation in therapeutic trials.
 ...
PMID:Spectrum of movement disorders associated with glutaric aciduria type 1: a study of 16 patients. 1882 14


<< Previous 1 2 3 4 5 Next >>