Outcome of the glutaric aciduria type 1 (GA1) newborn screening program in Manitoba: 1980–2020 (original) (raw)
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Promising outcomes in glutaric aciduria type I patients detected by newborn screening
Metabolic Brain Disease, 2013
Glutaric aciduria type I (GA-I) is an inborn error of lysine and tryptophan metabolism. Clinical manifestations of GA-I include dystonic or dyskinetic cerebral palsy, but when the symptoms occur, treatment is not effective. In Taiwan, newborn screening for GA-I started in 2001; we wish to evaluate the outcomes of patients detected through newborn screening. Newborns diagnosed with GA-I by abnormal dried blood spot glutarylcarnitine (C5DC) levels followed in our hospital were included in this study. They were treated with special diets, carnitine supplements, and immediate stress avoidance. Six patients were included in this study. All patients were treated prior to reaching 1 month of age. They were followed up with for 4 to 9 years. One patient had encephalopathic crisis episodes prior to turning 1 year old that caused pallidal lesions. Another patient had a chronic progressive disease during infancy that caused bilateral putamen lesions. These two patients had delayed development, but their brain lesions were resolved. The other four patients ran uneventful courses. They had normal intelligenece, ranged between average to low average level and their brain magnetic resonance imaging showed only high intensity over deep white matter. Patients with GA-I diagnosed by newborn screening have promising outcomes, though the risks of disease progression prior to 1 year of age remain significant.
Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families
International Journal of Neonatal Screening
Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1,...
Genetics in Medicine, 2020
Purpose Glutaric aciduria type 1 (GA1), a rare inherited neurometabolic disorder, results in a complex movement disorder (MD) with predominant dystonia if untreated. Implementation into newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the neurological outcome. Methods Systematic literature search for articles published from 2000 to 2019 was performed using the PRISMA protocol. Studies reporting on more than one individual identified by NBS were included. We investigated effects of interventional and noninterventional variables on neurological outcome. Results Fifteen publications reporting on 647 GA1 patients were included. In the NBS group (n = 261 patients), 195 patients remained asymptomatic (74.7%), while 66 patients (25.3%) developed a MD. Compared with the NBS group, a much higher proportion of patients (349/386; 90.4%; p
Molecular Genetics and Metabolism, 2002
Glutaric acidemia type 1 (GA1) is overrepresented in the aboriginal population of Island Lake, Manitoba, and northwestern Ontario who speak the Ojibway-Cree (Oji-Cree) dialect. The carrier frequency in these communities has been predicted to be as high as 1 in 10 individuals. Prior to beginning newborn screening for GA1 in May 1998, 18 of 20 affected patients diagnosed at this center have been from these high-risk communities. Most have followed an acute encephalopathic course with permanent neurologic sequelae and high mortality. They excrete small amounts of glutaric acid and 3-hydroxyglutaric acid and have significant residual enzyme activity. A single homozygous mutation in glutaryl-CoA-dehydrogenase (GCDH IVS-1 ؉ 5g 3 t) has been identified in this population. DNA-based newborn screening targeted to our high-risk communities was begun in order to provide presymptomatic detection and treatment of affected patients. Of the first 1176 newborns screened, 4 affected infants were identified and treated with a low-protein diet, carnitine, and riboflavin. All 4 infants have required numerous hospitalizations for treatment of intercurrent illnesses. Eventually, 3 infants presented with acute dystonic encephalopathy and seizures along with permanent neurological sequelae. One of these infants died unexpect-edly at home at 18 months of age. The fourth, now 9 months old, has had a gastrostomy tube placed to facilitate fluid replacement in addition to a standard treatment protocol and is doing well. The reasons for our initial disappointing outcomes in the first 3 of 4 affected babies are likely multiple. Based on our early experience and that of other centers screening newborns for GA1, current therapeutic strategies may be insufficient in preventing the occurrence of neurologic sequelae in some children. An incomplete understanding of the neurotoxic mechanisms underlying this devastating disorder hampers effective management. © 2002 Elsevier Science (USA)
Diagnosis and management of glutaric aciduria type I – revised recommendations
Journal of Inherited Metabolic Disease, 2011
Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalo-pathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and Ltryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the Communicated by: Ertan Mayatepek References to electronic databases: Glutaric aciduria type I: OMIM # 231670. Glutaryl-CoA dehydrogenase: EC 1.3.99.7. Competing interest: None declared. Electronic supplementary material The online version of this article (
Journal of Clinical Images and Medical Case Reports, 2021
Glutaric acidemia type 1 (GA1) is an inborn error of metabolism caused by the deficiency of the enzyme glutaryl-CoA dehydrogenase, with consequent accumulation of the aminoacids lysine, hydroxylsine and tryptophan. About 1 in every 100,000 individuals are affected by the disease. Neurological manifestations are variable and include acute and chronic encephalopathic crises, dystonia, motor and cognitive deficits, as well as neuroimaging findings such as brain hypoplasia, striatal, white matter and subdural effusions. Early diagnosis is crucial for specific therapy, which includes a diet with restricted amino acids and carnitine replacement. The present work describes the variability of neurological manifestations in four patients with glutaric acidemia type 1, diagnosed in different age groups, through mass spectrometry, technology of the expanded neonatal screening available in the Ministry of Health program in Federal District, Brazil. Complications of GA1 were more severe in cases...
Simplified Approach to Glutaric Acidurias: A Mini-Review
Journal of Rare Diseases Research & Treatment
Inherited metabolic diseases (IMDs), comprise a large class of genetic diseases affecting the metabolism. Expanded newborn screening from dried dried blood spot (DBS) samples for inborn errors of metabolism has increased the detection of metabolic disorders in asymptomatic newborns and reduced the morbidity and mortality by early interventions. Organic acidurias (OADs) arise from the defects in the intermediary metabolic pathways of carbohydrate, amino acid and fatty acid oxidation, leading to the accumulation of organic acids in tissues and their subsequent excretion in urine. Glutaric acidurias are a group of OADs which have three major types with different genetic mutations affecting different metabolic enzymes. In this mini-review we will compare three types of GA and their genotypes, symptoms, diagnosis, and treatments will be discussed briefly.