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PubMed1987

Glutaric aciduria type I: clinical heterogeneity and neuroradiologic features.

We present four patients, two pairs of siblings, with glutaric aciduria type I (GA I). All four had undetectable glutaryl-CoA dehydrogenase activity on fibroblast culture and massive urinary excretion of glutaric acid. All had serum carnitine deficiency at time of diagnosis except one patient who was diagnosed neonatally. All had a unique pattern of frontotemporal atrophy on CT. Remarkably, in both sibling pairs, one child was asymptomatic. This suggests that the biochemical markers hitherto identified with GA I do not encompass the entire scope of the metabolic or enzymatic abnormalities. Alternatively, as yet unidentified mechanisms might spare or delay the destructive process.

Atrophy↗
PubMed1998

[Glutaric aciduria type 1: phenotypic variability. Report of 6 patients].

We report six patients with glutaric aciduria type 1 in four families. The patients had marked clinical variability, even within families. Three of the patients studied were normal until the onset of neurologic abnormalities, that presented as an encephalitis-like illness in the first year of age. One patient had an early and important developmental delay, but never suffered an encephalopathic crisis. Two patients have intellectual preservation; one of them has a mild tremor and choreoathetosis since the first year of age, and the other had only two afebrile seizures in infancy and no other neurologic signs. Three patients are severely handicapped, with a severe dystonic-dyskinetic disorder and unable to even sit. All the six patients have macrocephaly and in all the computed tomography showed enlarged CSF spaces and sulcal separation over the frontal and temporal lobes. Urine organic acids study of all patients showed large quantities of glutaric acid.

Adult↗
PubMed1987

A case of glutaric aciduria type I with unique abnormalities in the cerebral CT findings.

A first Japanese case of glutaric aciduria type I (GA-I) was described. She was a 7-month-old girl presenting with poor head control, irritability and sleeplessness. The profile of urinary organic acids by gas chromatography mass spectrometry (GC/MS) suggesting GA-I were confirmed by no activity of glutaryl-CoA dehydrogenase in the fibroblasts. The cerebral computer tomography (CT) showed marked changes such as large fluid collections on bilateral frontotemporal regions and a slight enlargement of bilateral ventricles. The amounts of urinary glutarate excretion decreased after restriction of lysine and tryptophan in her diet and administration of carnitine improved the carnitine levels in blood and urine, while these were less effective for the neurological symptoms. On the other hand, oral administration of lioresal, an analogue of gamma-aminobutyrate (GABA), cleared her symptoms such as ill temper, irritability and sleeplessness dramatically, and the abnormalities of the CT examinations were not more deteriorative until 2 years of her age at least. The neurological manifestations of GA-I seemed to be affected by the unusual metabolism of GABA in the central nervous system.

Baclofen↗
PubMed2001

Biochemical and molecular diagnosis of glutaric aciduria type 1 in a black South African male child: case report.

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.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Prenatal molecular diagnosis of glutaric aciduria type I by direct mutation analysis.

Various biochemical strategies are followed for the prenatal diagnosis of glutaric aciduria type I (GA I). However, since the description of patients with normal excretion of glutarate and significant residual activity, the difficulties of prenatal biochemical diagnosis are obvious. The characterization of the glutaryl-CoA dehydrogenase (GCDH) gene has allowed us to develop a single strand conformation polymorphism (SSCP) screening method, followed by direct sequencing, to identify the disease causing mutations in patients with GA I. Here we report the first prenatal diagnoses based on DNA analysis in chorionic villi biopsy or cultured amniotic fluid cells in three families at risk for GA I. Our results show that this strategy provides a fast and reliable method for prenatal diagnosis. In addition we report two new mutations (1209-1210ins G and R161W) in the GCDH gene that occurred at hypermutable loci.

Child, Preschool↗
PubMedDate not supplied

Ocular findings in glutaric aciduria type 1.

PURPOSE: To determine the nature and course of ocular abnormalities in glutaric aciduria (acidemia) type 1 (GA1). METHODS: Fifteen children with GA1 have been studied in the Republic of Ireland. A retrospective review of the records of the 6 children who died during their illness and prospective clinical examination of 9 survivors were performed. RESULTS: Seven of the 15 children had abnormal eye findings. Ocular complications included intraretinal hemorrhages, cataract, gaze palsy, strabismus, ametropia, and pigmentary retinopathy. CONCLUSION: Ocular involvement is common in glutaric aciduria. Complete ophthalmologic evaluation is recommended in all patients suspected to have this rare disease. Intraretinal hemorrhages due to GA1 could be misinterpreted as resulting from child abuse, and it is important to include this disorder with the differential diagnosis of child abuse.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

[Glutaric aciduria type I: diagnosis in adulthood and phenotypic variability].

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.

Adolescent↗
PubMedDate not supplied

[Glutaric aciduria type 1: an example of the importance of early detection of so-called cerebral organic aciduria].

Glutaric aciduria type 1 (GA 1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder. Typically between 6 and 18 months of age, a non-specific illness such as respiratory or gastrointestinal infection or immunization leads to encephalopathic crisis, usually resulting in degeneration of the putamen and caudate. GA 1 is an autosomal recessive disease of catabolism of amino acids lysine, hydroxylysine and tryptophane leading to accumulation of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid. Recognition of this biochemical disorder before the brain has been injured is essential to the outcome. Diagnosis depends upon the recognition of relatively non-specific physical findings such as hypotonia, tremor, irritability and macrocephaly, and on urinary organic acids analysis. The diagnosis may also be suggested by characteristic findings of neuroimaging. Specific management includes pharmacological doses of 1-carnitine and dietary protein restriction. Metabolic decompensation must be treated vigorously to avoid permanent brain damage. With this case report the authors want to contribute to the early recognition of GA1, to the prevention of the related brain damage, and to increase awareness of the existence of so-called cerebral organic acidurias.

Amino Acid Metabolism, Inborn Errors↗
PubMed2004

Genetic and biochemical study in a patient with glutaric acidemia type I.

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric academia 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 nucleus and putamen. We report a case of GA-I in a 4-year-old boy. Analysis of blood acylcarnitines by tandem mass spectrometry (MS/MS) revealed a high concentration of glutarylcarnitine in the blood (0.59 microM). Organic acid analysis of urine via gas chromatography mass spectrometry revealed glutaric acid and 3-hydroxyglutaric acids. In order to search for mutations, the GCDH gene of the patient and his parents were amplified by polymerase chain reaction and subjected to direct sequencing. Two mutations were detected in the patient's GCDH gene. One was located in exon 7 (T713C), which caused a codon 238 leucine to proline substitution; the other was located in intron 10 (IVS10-2 A-to-C), and caused a splicing variation in intron 10 and exon 11. Genetic amniocentesis was requested when the patient's mother became pregnant again, but the fetus did not carry any mutation. Tandem mass spectrometry was successfully used to make the diagnosis of GA-I in this case via identification of genetic mutation. If GA-I can be diagnosed in the early onset or presymptomatic stage, effective therapy would reduce sequelae.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

[Glutaric aciduria type I].

Glutaric aciduria type I is a congenital metabolic disease caused by an enzymatic defect in the degradation of the amino acids lysine and tryptophane. This article presents five Norwegian patients with this condition. Early clinical features may be similar to those of encephalitis. The further clinical course is dominated by choreoathetosis, hyperkinesis and spasticity. The diagnosis is made by tracing enhanced glutaric acid in the urine. The treatment is a low protein diet containing only small quantities of lysine and tryptophane. Four of our patients underwent a neuropsychological examination. Despite the fact that such patients are difficult to test, our examination indicates that the condition has a greater effect on motor than on cognitive functions.

Adolescent↗
PubMedDate not supplied

[In utero macrocephaly as clinical manifestation of glutaric aciduria type I. Report of a novel mutation].

INTRODUCTION: Macrocephaly is a pivotal clinical sign, associated with multiple neurological diseases, particularly neurometabolical ones, such as the glutaric aciduria type I (GA I). This aciduria resulting from the genetical deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH). Is a relatively common cause of acute metabolic brain damage in early childhood. We report on one case of GA I, with early manifestations since fetal period and a novel mutation. CASE REPORT: Our patient was referred due macrocephaly in utero and occipitofrontal head circumference above the 98 percentile for chronologic age during first few months of life, hypotonia and development delay. The metabolic investigations of organic acids in urine and acylcarnitine profile in blood, the brain magnetic resonance and the molecular analyses of the glutaryl-CoA deshidrogenase gene, confirm the diagnosis. The molecular analysis allowed to identify one previously described mutation A293T and a novel mutation IVS5-2 A>G. CONCLUSION: It is important the recognition of in utero macrocephaly as a sign to early diagnosis of glutaric aciduria type I to initiate specific therapy to prevent the encephalopathic crises and minimize brain damage in patients who are already neurologically impaired.

DNA Mutational Analysis↗
PubMed2005

[Glutaric aciduria type 1 with normal evolution: follow-up of one case until adult age].

We present a patient of 20 years of age with glutaric aciduria type 1 (GA1) and normal psychomotor development. Her symptoms consisted of a few convulsions between 2.5 and 4.5 years of age. She was diagnosed at 9 years of age because of the typical alterations of GA1 that appeared in computed tomography and magnetic resonance (MR) imaging studies. Enzymatic activity in fibroblasts culture was nonexistent and glutarate excretion was elevated in the annual controls where this was investigated from the diagnosis of the disease so far. MR studies showed hyposignal in T1 of the subcortical white matter, severe dilatation of the Sylvian region and temporal fossa subarachnoid spaces, and hypoplasia of the subjacent cerebral parenchyma and of both temporal lobes. The corpus callosum and the surrounding zones appeared very enlarged and with signal changes. Spectroscopic MR showed signs of membrane instability and cellular impoverishment in subcortical white matter and basal ganglia and presence of lactic acid. Macrocephaly always maintained centiles over 98. The patient has no abnormal movements or motor disturbances, her behavior and intelligence being normal and she is able to follow studies of middle level.

Basal Ganglia↗
PubMed2005

[Macrocephaly the first manifestation of glutaric aciduria type I: the importance of early diagnosis].

INTRODUCTION: The clinical manifestations of glutaric aciduria type I (GA-I) usually develop during the first two years of life as acute encephalopathic crisis leading to irreversible dystonic. Progressive macrocephaly can be an early clinical sign. We report a 9 month old patient with macrocephaly diagnosed of GA-I in the presyntomatic stage. This early diagnosis and treatment avoided the irreversible neurologic damage associated to this disease. CASE REPORT: A 9 month old male referred to the pediatrics neurology clinic because of macrocephaly with a head circumference of 51 cm (> 97th percentle). At birth this head circumference was 37.5 cm (97th percentile) and showed rapid growth during the first 4 months of life. In the physical exam there was mild hypotonia and no other neurologic alterations with normal psychomotor development. In the work up for macrocephaly urinary organic acids were determined showing a glutaric acid: 78,000 mmol/mol creatinine (normal values: 2-10); 3-hydroxyglutaric acid: 250 mmol/mol creatinine (normal values: 1-12). Cerebral magnetic resonance (MR) performed at 12 months of age showed frontotemporal atrophy with enlargement of subarachnoid spaces, a high signal in T2 in the pallidus nucleus and subdural hematomas. Genetic analysis showed a mutation S 305 L/Q 352 X in GCDH gene. L-carnitine and riboflavin supplementation and a diet with restriction of lysine and tryptophan was started. Intercurrent illnesses were treated with intravenous fluid, glucose and L-carnitine. At 3 years and 6 month of age, he had not shown any encephalopathic crisis, he had a normal psychomotor development and no dystonia. MR shows mild temporal lobe atrophy without basal ganglia alterations. CONCLUSIONS: In GA-I, macrocephaly is an early sign before other neurologic alterations. In patients with little or no neurological symptoms, early treatment may prevent the acute encephalopathic crisis and neurological deterioration, improving the prognosis and may also normalize the basal ganglia neuroradiological alterations. Urinary organic acid analysis should be performed in the work up of macrocephaly of unknown aetiology.

Brain↗
PubMed1989

Acute profound dystonia in infants with glutaric acidemia.

Acute profound dystonia developed in three previously well infants who were found to have glutaryl-CoA dehydrogenase deficiency in cultured skin fibroblasts. Two patients had excessive urinary excretion of glutaric acid, but one did not. Neuroradiologic studies performed in all three patients at the onset of their illnesses revealed large CSF-containing spaces both within the sylvian fissures and anterior to the temporal lobes. Pathologic examination of the brain of one patient demonstrated cerebral and cerebellar atrophy, shrinkage of the putamen, and white matter vacuolation. Glutaric acidemia may be a common cause of acquired persistent dystonia or choreoathetosis in infancy.

Atrophy↗
PubMed1988

[Bactericidal activity examination (MBC) of glutaric aldehyde on anaerobic non-sporing bacteria].

Sensibility (MBC) of 97 strains of non-sporing anaerobes separated from clinical materials coming from oral cavity to glutaric aldehyde (Koch Light Lab) has been examined. The experiments have been carried out by the suspension method adapting it properly to the examinations of anaerobes. 72 hours' cultures in enriched thioglycolate broth containing 10(9) of living cells of anaerobes in 1 ml have been used as inoculum. MBC results were read off after 7 days' incubation at temperature of 37 degrees C. From the total number of 97 strain 7 (7%) strains were sensible to the concentration of 156 to 311 micrograms/ml. In MBC ranges equal to 312 to 624 micrograms/ml 17 (17%) strains perished. Most of the strains namely 51 (53%) strains were damaged by the concentrations of 625 to 1249 micrograms/ml. The remaining 22 (23%) strains exacted to utilize glutaric aldehyde of the concentrations within the range of 1250 to 2500 micrograms/ml. It has been noticed that the strains from Leptotrichia buccalis species were the most sensitive ones. In the remaining of anaerobes under examinations the MBC values were similar to each other.

Aldehydes↗
PubMed1987

Postnatal and antenatal laboratory diagnosis of glutaric aciduria II in a South African family.

Glutaric aciduria type II (GA II) was proved in a neonate who presented shortly after birth with respiratory distress, metabolic acidosis, non-ketotic hypoglycaemia and a sweaty-feet-like odour. The diagnosis was based on elevated levels of glutaric and other acids in the urine and on studies on cultured skin fibroblasts where defective metabolism of fatty acids of varying chain length was demonstrated. Antenatal diagnosis was performed on a subsequent pregnancy in this family where an abnormal amniotic fluid organic acid profile together with defective fatty acid oxidation in cultured amnion cells was indicative of GA II in the fetus. This is the first report of this genetic disorder in a South African family and it should be considered in suspected organic acidaemia in the neonatal period.

Female↗
PubMed1979

[Glutaric aciduria. 1 new case].

A 4 year old girl with mild mental retardation presented with convulsions, coma and hepatomegaly. She died rapidly. The main biochemical findings were hypoglycaemia, metabolic acidosis, generalised aminoaciduria, elevation of the plasma and urine alpha-amino adipic acid, massive urine excretion of glutaric and glutaconic acids with traces of alpha-hydroxyglutaric acid. The diagnosis of glutaric aciduria was confirmed by the low activity of glutaryl CoA dehydrogenase in liver tissue. This diagnosis should be considered in children with progressive neurological disorders (dystonia, choreoathetosis) and in children with an illness similar to Reye's syndrome.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

CT and MR of the brain in glutaric acidemia type I: a review of 59 published cases and a report of 5 new patients.

PURPOSE: To identify a pattern of findings on CT or MR of the brain in glutaric acidemia type I typical enough to permit a correct diagnosis. METHODS: Clinical history and findings and brain CT and MR results in 59 previously reported patients (MR in 12) and in 5 new patients (all examined with MR and 3 also with CT) were reviewed. RESULTS: In half the patients macrocephaly was present, and in half the onset was acute, often following infection and mimicking encephalitis. Although brain atrophy or hypoplasia was found in 61% and white matter changes in 51% of the patients, open opercula (usually very widely open) and often also wide cerebrospinal fluid spaces anterior to the temporal lobes were seen in 93%. Basal ganglia lesions, presenting as volume loss and high T2 signal in the caudate head and often also the lentiform nucleus bilaterally, were found in 44% and extracerebral fluid collections in 7 of 64 patients. CONCLUSION: The finding of very widely open opercula suggests glutaric acidemia type I, and if combined with basal ganglia lesions is almost pathognomonic, especially in a child with macrocephaly.

Atrophy↗