Materiały źródłowe

• #1 Diagnosis and management of glutaric aciduria type I – revised recommendations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3109243/

  Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. […] 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 L-tryptophan. […] Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. […] Early clinical diagnosis is hampered by the lack of characteristic or even pathognomonic signs and symptoms before an encephalopathic crisis. […] Therefore GA-I has been included in the disease panel of newborn screening in some countries. […] The aim of newborn and high-risk screening is to reduce the incidence of neurological disease. […] For mass newborn screening for glutaric aciduria type I determination of C5DC in DBS by MS/MS should be used.

• #2

  https://link.springer.com/article/10.1007/s10545-011-9289-5

  Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. […] 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 L-tryptophan. […] Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. […] Early clinical diagnosis is hampered by the lack of characteristic or even pathognomonic signs and symptoms before an encephalopathic crisis. […] Therefore GA-I has been included in the disease panel of newborn screening in some countries. […] The aim of newborn and high-risk screening is to reduce the incidence of neurological disease. […] The accurate diagnosis of GA-I has important practical implications when devising treatment plans and giving appropriate information to children and their families.

• #3 Glutaric Aciduria Type I Diagnosis Case with Normal Glutaryl Carnitine and Urine Organic Acid Analysis – The Journal of Pediatric Research

  https://jpedres.org/articles/glutaric-aciduria-type-i-diagnosis-case-with-normal-glutaryl-carnitine-and-urine-organic-acid-analysis/doi/jpr.85530

  Glutaric aciduria Type I (GA-I) is a rare inherited metabolic disease, deficiency of glutaryl-CoA dehydrogenase results in accumulation of the putatively neurotoxic metabolites glutaric and 3-hydroxyglutaric acid (GA, 3-OH-GA) in body tissues, particularly within the brain. […] Here we presented a 3-year-old girl with hypotonia and dystonia diagnosed with GA-I although the repeated analysis of the carnitine profile and organic acid analyses were normal. […] In the presence of bilateral striatal involvement and cortical atrophy and dystonia, GA-I should be kept in mind. Blood carnitine profile and urine organic acid analyses may not be consistent. It is important to evaluate the cases for genetic investigation. […] In GA-I; brain GA has been found to exceed plasma and CSF levels even in patients with normal or low GA levels in urine, best explained by Klker et al.

• #4 Glutaric aciduria type 1 (GA-1)

  https://www.nutricia.com/specialize/iem/ga1.html

  GA1 can be diagnosed in the first few days of life. […] GA1 can be screened at birth through a simple heel-prick blood spot test (GA1 test). […] Upon diagnosis, people should be referred to a metabolic specialist for ongoing supervision of their management.

• #5 Glutaric aciduria type 1

  https://www.nhs.uk/conditions/glutaric-aciduria/

  At around 5 days old, babies are now offered newborn blood spot screening to check if they have GA1. This involves pricking your baby’s heel to collect drops of blood to test. […] If GA1 is diagnosed, treatment can be given straight away to reduce the risk of serious complications. […] With early diagnosis and the correct treatment, the majority of children with GA1 are able to live normal, healthy lives. However, treatment for GA1 must be continued for life. […] It’s important to get medical help immediately if your baby develops symptoms of a metabolic crisis. Your doctor will give you advice to help recognise the signs. […] Children diagnosed with GA1 are referred to a specialist metabolic dietitian and given a low-protein diet. This is tailored to reduce the amount of amino acids your baby receives, especially lysine and tryptophan.

• #6 Glutaric acidemia type I | Newborn Screening

  https://newbornscreening.hrsa.gov/conditions/glutaric-acidemia-type-i

  Glutaric acidemia type I is an inherited (genetic) condition that prevents the body from breaking down certain proteins properly. […] Newborn screening for glutaric acidemia type I is done using a small amount of blood collected from your baby’s heel. […] If your baby’s blood spot screening result for glutaric acidemia type I is out-of-range, your baby’s health care provider will contact you. […] Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly. […] False-positive newborn screening results for this condition are rare. […] Your baby may need the following tests after an out-of-range screening result: Blood and/or urine tests, Genetic testing using a blood sample, Small skin sample. […] Glutaric acidemia type I is a genetic condition. […] It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to prevent the health problems caused by this condition.

• #7

  https://www.gov.uk/government/publications/ga1-suspected-description-in-brief/ga1-suspected

  Glutaric aciduria type 1 (pronounced glue-ta-ric acid-ur-ee-a), or GA1, is a rare but treatable inherited metabolic disorder that prevents the normal breakdown of protein. […] When your baby was about 5 days old, your midwife took some blood from your babys heel for their newborn blood spot screening test (the heel prick test). The newborn blood spot screening test measures the amount of a substance called acylcarnitine (C5-DC) in the blood. A high level of acylcarnitine (C5-DC) suggests your baby may have GA1. This is called a screen positive result. […] If your baby has a screen positive result, you will be seen by a metabolic doctor, dietitian and nurse specialist (the metabolic team). The team will provide advice and support. Blood and urine tests will be carried out to confirm if your baby has GA1.

• #8 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  With more than 15 years experience in newborn screening for GA-I, it has become evident that this diagnostic intervention is a powerful tool to prevent the manifestation of movement disorders in the majority of early diagnosed patients. […] The major limitation in evaluating the clinical benefit of newborn screening for GA-I patients is the current knowledge on the long-term disease course. […] The diagnostic test is the determination of glutarylcarnitine (C5DC) concentration in dried blood spots. […] C5DC can be detected in dried blood spot samples by its ion pair m/z 388 → m/z 85 using tandem mass spectrometry. […] Therefore, C5DC can be included in tandem mass-spectrometry based newborn screening. […] The overall sensitivity of C5DC screening in a mixed population is about 95%.

• #9

  https://omim.org/entry/231670

  Boy et al. (2018) evaluated the clinical history in 94 individuals from Germany who were identified between 1999 and 2016 with GA1, including 87 patients who were identified by newborn screening, 4 patients missed by newborn screening, and 3 women identified with GA1 because of a positive newborn screen of their unaffected child. Overall, newborn screening with C5DC had an estimated sensitivity of 95.6%, but the sensitivity was lower for patients with a low excreter phenotype (84%). Available molecular genetic results were as follows: 35 patients were homozygous and 38 patients were compound heterozygous for mutations in the GCDH gene; in 2 patients with a high excreter phenotype and 1 patient with a low-excreter phenotype only 1 mutation in GCDH was found; and in 1 patient, 3 mutations in GCDH were identified.

• #9

  https://omim.org/entry/231670

  A number sign (#) is used with this entry because glutaric acidemia I (GA1) is caused by homozygous or compound heterozygous mutation in the gene encoding glutaryl-CoA dehydrogenase (GCDH; 608801) on chromosome 19p13. […] Glutaric acidemia I (GA1) is an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (Goodman et al., 1995). […] Kyllerman et al. (1994) noted that glutaric aciduria may go undetected in patients with cerebral palsy and mental retardation. In patients suspected of having the disorder, repeated examinations of organic acids in the urine and enzyme assay may be necessary to confirm the diagnosis. […] Tortorelli et al. (2005) found that the urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia I in patients with inconclusive biochemical findings.

• #10 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  False positive screening results may be due to glutaric aciduria type II, pseudoglutarylcarnitinemia in patients with medium chain acyl-CoA dehydrogenase deficiency, newborns with renal failure, and maternal GA-I. […] The prospective follow-up study in Germany showed that the absolute risk reduction for an acute encephalopathic crisis was 0.67 in the newborn screening group compared to symptomatic patients and that the number needed to treat to prevent one acute encephalopathic crisis was 1.50. […] This huge effect was confirmed in a second evaluation of the same cohort three years later. […] The beneficial effect of newborn screening and combined metabolic treatment has been confirmed independently by other groups in different countries and national healthcare systems. […] Cost-effectiveness of tandem mass spectrometry-based newborn screening for GA-I was recently assessed in Germany based on the results of the prospective follow-up study.

• #11 Diagnosis and management of glutaric aciduria type I – revised recommendations

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3109243/

  A positive MS/MS screening result should be confirmed by one or more alternative techniques, including a sensitive method for quantitative determination of GA and 3-OH-GA in urine or blood such as GC/MS, mutation analysis of the GCDH gene, and/or GCDH enzyme analysis. […] If an infant or child presents with clinical signs or symptoms, or neuroradiologic findings of GA-I, a diagnostic evaluation should be undertaken regardless of whether the child was previously evaluated in a newborn screening programme. […] The accurate diagnosis of GA-I has important practical implications when devising treatment plans and giving appropriate information to children and their families. […] In patients with signs and symptoms of glutaric aciduria type I, a specific diagnostic work-up should include quantitative analysis of GA and 3-OH-GA in urine or blood, GCDH gene mutation analysis, and/or enzyme analysis. […] Diagnosis, choice of antiepileptic drug therapy and management of seizures in GA-I should follow existing guidelines except for the use of valproate which should be avoided in this condition.

• #12

  https://link.springer.com/article/10.1007/s10545-011-9289-5

  Significant differences still exist in the approaches used to diagnose and manage affected patients, and there is a wide variation in the outcome, particularly in patients diagnosed presymptomatically. […] The major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GA-I based on the best evidence available. […] A positive MS/MS screening result should be confirmed by one or more alternative techniques, including a sensitive method for quantitative determination of GA and 3-OH-GA in urine or blood such as GC/MS, mutation analysis of the GCDH gene, and/or GCDH enzyme analysis. […] If an infant or child presents with clinical signs or symptoms, or neuroradiologic findings of GA-I, a diagnostic evaluation should be undertaken regardless of whether the child was previously evaluated in a newborn screening programme.

• #13 Glutaric Acidemia Type 1 – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546575/

  The diagnosis of GA-1 in a proband with a positive NBS result or suggestive biochemical and/or clinical findings is confirmed by identification of biallelic pathogenic variants in GCDH or, when molecular genetic test results are uncertain, by detection of significantly reduced activity of the enzyme glutaryl-CoA dehydrogenase (GCDH) in cultured fibroblasts or leukocytes. […] Guidelines for diagnosis and management of glutaric acidemia type 1 (GA-1) due to deficiency or absence of functional glutaryl-CoA dehydrogenase were developed in 2007 and recently revised. […] GA-1 should be suspected in infants with a positive NBS result. NBS for GA-1 primarily relies on measuring glutarylcarnitine (C5DC) in dried blood spots, which has been shown to have 96% sensitivity. Positive C5DC values (i.e., those above the cutoff reported by the screening laboratory) require follow-up biochemical testing with either urine organic analysis or quantitative glutaric and 3-hydroxyglutaric acid, with preference for quantitative studies if available. If either is abnormal, treatment and testing to establish a definitive diagnosis should be initiated concurrently.

• #14

  https://www.gov.uk/government/publications/ga1-suspected-description-in-brief/glutaric-aciduria-type-1-ga1-detailed-information

  Glutaric aciduria type 1 (pronounced glue-ta-ric acid-ur-ee-a), or GA1, is a rare but treatable inherited metabolic disorder that prevents the normal breakdown of protein. […] When your baby was about 5 days old, your midwife took some blood from your baby’s heel for their newborn blood spot screening test (the heel prick test). The newborn blood spot screening test measures the amount of a substance called acylcarnitine (C5-DC) in the blood. A high level of acylcarnitine (C5-DC) suggests your baby may have GA1. This is called a screen positive result. […] If your baby has a screen positive result, you will be seen by a metabolic doctor, dietitian and nurse specialist (the metabolic team). The team will provide advice and support. Blood and urine tests will be carried out to confirm if your baby has GA1.

• #15 What is glutaric aciduria type 1?

  https://www.medicalnewstoday.com/articles/glutaric-aciduria-type-1

  Nearly all babies will have a simple blood test, known as a heel-prick test, to check for conditions that may not be immediately apparent. This screening method can help identify metabolic disorders such as GA1. […] If the test shows unusual results, a metabolic team will conduct further testing to help confirm a diagnosis. A metabolic team may consist of a metabolic doctor, dietitian, and nurse specialist. Typically, a diagnostic workup will involve blood and urine tests to measure the levels of glutaric acid and related compounds. […] To confirm a diagnosis, healthcare professionals may conduct GCDH enzyme analysis or genetic testing for a GCDH gene variant.

• #16 Glutaric Acidemia Type 1 – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK546575/

  The diagnosis of GA-1 in a proband with suggestive biochemical and/or clinical findings is confirmed by identification of biallelic pathogenic variants in GCDH or, when molecular genetic test results are uncertain, by detection of significantly reduced activity of the enzyme glutaryl-CoA dehydrogenase in cultured fibroblasts or leukocytes.

• #17

  https://link.springer.com/article/10.1007/s10545-011-9289-5

  In patients with signs and symptoms of glutaric aciduria type I, a specific diagnostic work-up should include quantitative analysis of GA and 3-OH-GA in urine or blood, GCDH gene mutation analysis, and/or enzyme analysis. […] For mass newborn screening for glutaric aciduria type I determination of C5DC in DBS by MS/MS should be used. […] Diagnosis, choice of antiepileptic drug therapy and management of seizures in GA-I should follow existing guidelines except for the use of valproate which should be avoided in this condition.

• #18 Simplified Approach to Glutaric Acidurias: A Mini-Review

  https://www.rarediseasesjournal.com/articles/simplified-approach-to-glutaric-acidurias-a-minireview.html

  Inherited metabolic diseases (IMDs), often referred to as inborn errors of the metabolism (IEM), comprise a large class of genetic diseases affecting the metabolism. […] The definite diagnosis of such patients is achieved through genetic analysis. […] Glutaric acidurias are a group of OADs which have three major types with different genetic mutations affecting different metabolic enzymes and all three having an autosomal recessive inheritance. […] Increased urinary concentrations of 3-OH-GA is the most sensitive biochemical marker for diagnosis and the diagnostically relevant metabolite is elevated C5DC in dried blood spot (DBS) screening. […] For further diagnosis, glutaryl-CoA dehydrogenase activity in cultured fibroblasts can be measured and mutation analysis carried out on genomic DNA.

• #19 Glutaric aciduria type 1 – Wikipedia

  https://en.wikipedia.org/wiki/Glutaric_aciduria_type_1

  GA1 is included in newborn screening panels. Elevated glutarylcarnitine can be detected by mass spectrometry in a dried blood spot collected shortly after birth. After a positive screening result, confirmatory testing is performed. This includes urine organic acid analysis, looking for glutaric acid and 3-hydroxyglutaric acid. Plasma and urine acylcarnitine analysis can also be informative. Molecular analysis, including gene sequencing and copy number analysis of GCDH, can be performed to confirm the diagnosis. Molecular testing can also provide information for family planning and prenatal testing, if desired. […] Normally, magnetic resonance imaging shows the Sylvian fissure to be operculated, but in GA1-associated encephalopathy, operculation is absent.

• #20 Indian Pediatrics – Brief Reports

  https://www.indianpediatrics.net/oct2001/oct-1148-1154.htm

  Glutaric aciduria Type I (GA-I) is a recessively inherited inborn error of metabolism characterized by the deficiency of the mitochondrial enzyme Glutaryl CoA dehydrogenase (GCDH) which catalyzes the dehydrogenation – decarboxylation of Glutaric acid, an intermediary metabolite in the degradation pathway of lysine, hydroxy-lysine and tryptophan. […] The diagnosis of GA-I rests on the demonstration of urinary excretion of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid by GC-MS. […] The detection of glutaric acid alone is insufficient for the diagnosis of this disorder. […] For this reason detection of 3-hydroxyglutarate is considered the most specific. […] Neuroimaging serves as a useful tool, many a times providing the first clue to the diagnosis. […] MRI is the imaging modality of choice.

• #21 Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families

  https://www.mdpi.com/2409-515X/7/2/32

  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). […] Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1, by adjusting cut-offs and introducing various ratios, the biological diversity still leads to false-negative NBS results for GA-1. […] Normal C5DC in NBS cannot completely exclude GA-1. […] In case of a positive first NBS result or a clinical suspicion of GA-1 even if the child had a normal NBS result, a complete workup including molecular genetic testing is necessary.

• #22 Glutaric Aciduria Type I Diagnosis Case with Normal Glutaryl Carnitine and Urine Organic Acid Analysis – The Journal of Pediatric Research

  https://jpedres.org/articles/glutaric-aciduria-type-i-diagnosis-case-with-normal-glutaryl-carnitine-and-urine-organic-acid-analysis/doi/jpr.85530

  It has been shown that urine C5DC, GA and 3-OH-GA did not show any correlation with the patients clinics. […] We want to mention that normal blood carnitine and urine organic acid analysis can be found in patients with GA-I. […] Cranial MRI plays an important role in the diagnostic work-up in GA-I patients. […] The diagnosis should be suspected on the combination of clinical and neuroradiological findings of the patient and GCDH gene analysis should be performed in such cases.

• #23 Glutaric aciduria type I (GA-I)

  https://healthywa.wa.gov.au/sitecore/content/Corporate/Articles/U_Z/WA-Newborn-Bloodspot-Screening-Program/Conditions-screened-for-in-WA/Glutaric-aciduria-type-I

  GA-I is an organic acid disorder. […] There is specific damage to the basal ganglia in the brain. […] Deficiency of the enzyme glutaryl-CoA dehydrogenase, which metabolises lysine, hydroxylysine and tryptophan. […] Metabolites on bloodspot screening: Increased glutarylcarnitine (C5DC), Increased C5DC/C5OH ratio. […] Diagnostic tests: Plasma acylcarnitine profile, Plasma amino acids, Urine organic acids, GCDH gene analysis. […] A proportion of patients are „low excretors” and biochemical detection may not be reliable.

• #24 Simplified Approach to Glutaric Acidurias: A Mini-Review

  https://www.rarediseasesjournal.com/articles/simplified-approach-to-glutaric-acidurias-a-minireview.html

  The early diagnosis of GA-I is essential, since the metabolic symptoms can be usually prevented by carnitine supplementation and a diet that is low in lysine and tryptophan to reduce glutaric acid production, and also may include supplementation with L-carnitine, riboflavin. […] Acylcarnitine analysis in tandem mass spectrometry is a preferred diagnostic tool for GA-II cases. […] In late-onset cases, the elevation of acylcarnitine levels may be mild and atypical, or detectable only during an acute episode. Under these circumstances, genetic screening is the key to establish a definitive diagnosis. […] With no known biomarker other than notable glutaric aciduria without elevation of any other markers of GA-I or GA-II, and an increased glutaric acid excretion following lysine loading, GA-III is thought to be a diagnosis of exclusion, following suspicion based on clinical manifestations or metabolite profiles.

• #25 Glutaric aciduria type 1 | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/glutaric-aciduria-type-1?embed_domain=external.radpair.com

  Glutaric aciduria type 1 is a leukodystrophy that can be subclassified as an organic acidopathy. It has a highly variable clinical presentation, and laboratory investigations are not always diagnostic. Imaging, therefore, has an important role to play as the MRI features can be characteristic. […] Definitive diagnosis of glutaric aciduria type 1 can be established by DNA-based analysis, looking for mutations in the GCDH gene on chromosome 19. […] MRI is the modality of choice in the assessment of glutaric aciduria type 1. In clinically severely affected children, bilateral basal ganglia abnormalities are seen with initial swelling that subsequently progresses to atrophy and necrosis. […] The findings described above are not specific in isolation, but a combination of them in a macrocephalic child with extrapyramidal symptoms highly suggestive, if not pathognomonic. […] Early post-natal diagnosis should be sought as an early treatment prior to metabolic decompensation has the best chance of preventing neurological deterioration.

• #26 Glutaric Acidemia Type I (GA1) – Rare Disease Diagnostics

  https://diagnostics.protheragen.us/glutaric-acidemia-type-i-ga1.html

  The genetic markers for GA1 consist of detection of mutations in the GCDH gene which encodes the enzyme glutaryl-CoA dehydrogenase. More than 200 pathogenic variants in the GCDH gene are known, and their diagnosis through next generation sequencing (NGS) is confirmatory for GA1. […] The non-invasive, handy, and easy to use in vitro diagnostic (IVD) kits allow effective diagnosis of glutaric acidemia type I (GA1). These kits capture diagnostic information with great accuracy through the measurement of metabolic and genetic biomarkers, making it possible to clinically differentiate GA1 from other metabolic disorders. […] Protheragen appreciates the role of IVDs in the diagnosis and management of GA1. Our scientists aim at the creation of IVD solutions, developing and deploying test kits for genetic and metabolic biomarker diagnostics, as well as supporting advanced diagnostic device development for the rare metabolic disease GA1.

• #27 Invitae Elevated C5-DC (Glutaric Aciduria Type I) Test | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06195

  The Invitae Elevated C5-DC (Glutaric Aciduria Type I) Test analyzes the GCDH gene, which is associated with glutaric acidemia type 1 (GA1). Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants would also guide testing and diagnosis of at-risk relatives. […] Based on validation study results, this assay achieves 99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions 15bp in length, and exon-level deletions and duplications. Invitae’s methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. […] Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test.

• #28 GA2P – Overview: Glutaric Aciduria Type II Gene Panel, Varies

  https://www.mayocliniclabs.com/test-catalog/Overview/608029

  Follow up for abnormal biochemical results suggestive of glutaric acidemia type II […] Establishing a molecular diagnosis for patients with glutaric acidemia type II […] Identification of variants within genes known to be associated with glutaric acidemia, allowing for predictive testing of at-risk family members […] This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 8 genes associated with glutaric aciduria: ETFA, ETFB, ETFDH, FLAD1, SLC52A1, SLC52A2, SLC52A3, TANGO2. […] Identification of a pathogenic variant may assist with diagnosis, prognosis, clinical management, familial screening, and genetic counseling for glutaric aciduria type II. […] The recommended first-tier tests to screen for glutaric acidemia Type II (GA II) are a combination of biochemical tests including acylcarnitine profile in plasma and urine organic acids.

• #29 Glutaric Acidemia Type I (GA I) | Revvity

  https://www.revvity.com/disorders/glutaric-acidemia-type-i-ga-i

  Glutaric acidemia, type I (GA I), was first described in 1975. […] GA I is frequently undiagnosed until an acute metabolic crisis occurs. […] Newborn screening using tandem mass spectrometry of the heel stick dried blood spot identifies patients with GA I by the presence of glutaric acid covalently bound to carnitine (C5-dicarboxylic acylcarnitine, C5-DC). […] This permits the earliest possible diagnosis and initiation of treatment for presymptomatic patients. […] In acutely ill patients, large amounts of glutaric acid can be detected in blood and urine by organic acid analysis. […] Analysis of the urine for abnormal organic acids in a suspected patient may reveal glutaric acid, 3-hydroxyglutaric acid (which is pathognomonic for GA I), and possibly glutaconic acid. […] GCD enzyme activity can be assayed in cultured fibroblasts, cultured amniocytes and chorionic villus (direct or cultured). […] Prenatal diagnosis has also been accomplished by finding elevated glutaric acid in amniotic fluid. […] Free carnitine levels are often low and acylated carnitine levels are high at diagnosis. […] Plasma amino acids are usually normal and not helpful in diagnosis.

• #30

  https://omim.org/entry/231670

  Goodman et al. (1980) monitored 2 pregnancies at risk for glutaric acidemia I. In 1 case in which the fetus was unaffected, glutaric acid was not detected in the amniotic fluid at amniocentesis (15 weeks) and the glutaryl-CoA dehydrogenase activity of cultured amniotic cells was normal. In the other case, there was a marked increase of glutaric acid in the amniotic fluid as well as a deficiency of glutaryl-CoA dehydrogenase in cultured amniotic cells. The pregnancy was terminated, and postmortem studies confirmed the diagnosis of glutaric acidemia. […] Christensen (1994) described experience with chorionic villus sampling for first-trimester diagnosis of glutaric acidemia I. Among 16 pregnancies, 4 were predicted to represent an affected fetus; in 3 of the affected cases, GCDH activity was measured in both uncultured and cultured chorionic cells and the correct diagnosis was established by both measurements.

• #31 A Case of Mistaken Identity: Glutaric Aciduria Type I Masquerading as Postmeningitic Hydrocephalus – Journal of Clinical Imaging Science

  https://clinicalimagingscience.org/a-case-of-mistaken-identity-glutaric-aciduria-type-i-masquerading-as-postmeningitic-hydrocephalus/

  We report the characteristic neuroimaging features of a rare metabolic leukodystrophy in an 8-year-old boy, born of consanguineous parenthood. […] These imaging features were signatory to arrive at a diagnosis of glutaric aciduria type 1. […] However, classical imaging features lead to the accurate diagnosis of this condition, which is confirmed by biochemical examination of blood and urine. […] Presently, MR brain study was performed which revealed diffuse brain atrophy. […] These MR features led to the diagnosis of GAT 1, which also explained the appearances on the previous CT studies. […] The imaging features described for GAT 1 are a characteristic combination of macrocrania, diffuse cerebral atrophy, widened or open Sylvian fissures due to lack of operculation (with temporal lobe hypoplasia), diffuse hemispheric white-matter abnormalities, and bilaterally symmetric basal ganglia lesions.

• #32 Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging | American Journal of Neuroradiology

  http://www.ajnr.org/content/early/2023/07/20/ajnr.A7928

  BACKGROUND AND PURPOSE: Routine MR imaging has limited use in evaluating the severity of glutaric aciduria type 1. To better understand the mechanisms of brain injury in glutaric aciduria type 1, we explored the value of diffusional kurtosis imaging in detecting microstructural injury of the gray and white matter. […] The diagnosis of GA-1 was established by brain MR imaging and biochemical (urine organic acids and plasma acylcarnitines) and GCDH gene mutation analyses. […] MR imaging findings are an important tool for the diagnosis of GA-1, which include characteristic cyst-like bilateral enlargement of the Sylvian fissures, signal abnormalities, and atrophy of the supratentorial WM and the deep GM structures. […] Therefore, conventional imaging examinations are insufficient to accurately assess brain damage in patients with GA-1.

• #33 Glutaric Aciduria Type 1: Comparison between Diffusional Kurtosis Imaging and Conventional MR Imaging | American Journal of Neuroradiology

  http://www.ajnr.org/content/early/2023/07/20/ajnr.A7928

  In our study, the significant correlation between the BAD score and DKI metrics, including the MK, AK, and RK in the putamen, caudate head, and pallidum, supported the hypothesis that striatum microstructural changes may contribute to a permanent motor decline and dystonia. […] Our results indicate that DKI enables the timely detection of changes in the brain tissue microstructure of patients with GA-1, which is more beneficial for the assessment of the disease severity compared with routine brain MR imaging scores.

• #34 HGEMS – Overview: Hydroxyglutaric Acids, Glutaric Acid, Ethylmalonic Acid, and Methylsuccinic Acid, Serum

  https://www.mayocliniclabs.com/test-catalog/overview/62231

  Evaluation of patients with an abnormal newborn screen showing elevations of glutarylcarnitine (C5-DC) using serum specimens […] Diagnosis of glutaric acidemia type 1 […] Differentiating diagnoses of glutaric acidemia type I (GA1) and glutaric acidemia type II (GA2) […] Elevation of glutaric acid (GA) and 3-hydroxyglutaric acid (3OH-GA) are consistent with a diagnosis of glutaric acidemia type I (GA1).

• #35 Glutaric aciduria type 1 (GA1)

  https://www2.hse.ie/conditions/heel-prick-screening/conditions/glutaric-aciduria/

  Glutaric aciduria type 1 (GA1) is an inherited condition. […] If GA1 is not detected and treated early, it can be life threatening. […] Babies with GA1 benefit from early diagnosis and treatment. […] If the heel prick suggests your baby may have GA1, they will be referred to a specialist.

• #36 Glutaric acidemia type I: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/glutaric-acidemia-type-i/

  Glutaric acidemia type I (also called glutaric aciduria type I) is an inherited disorder in which the body is unable to process certain proteins properly. […] The severity of glutaric acidemia type I varies widely; some individuals are only mildly affected, while others have severe problems. […] Strict dietary control may help limit progression of the neurological damage. […] Glutaric acidemia type I occurs in approximately 1 in 100,000 individuals. […] Mutations in the GCDH gene cause glutaric acidemia type I. […] This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. […] Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision.

• #37 A review of patients with glutaric aciduria type 1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa

  http://www.scielo.org.za/scielo.php?script=sci_arttext&pid=S0256-95742017000300017

  Glutaric aciduria type 1 (GA1) is an organic acidaemia. […] The objective of this study was to describe the profile of patients diagnosed with GA1 at Inkosi Albert Luthuli Central Hospital, Durban, South Africa from 2007 to 2015. […] Diagnosis was based on clinical suspicion, followed by the detection of GA in the urine, and confirmed on genetic screening for the mutations. […] The diagnosis can be confirmed by testing for the A293T mutation of the GCDH gene, which can be done at the National Health Laboratory Service. […] Early diagnosis and implementation of appropriate therapy result in better neurological outcomes.

• #38 Impact of newborn screening and quality of therapy on the neurological outcome in glutaric aciduria type 1: a meta-analysis | Genetics in Medicine

  https://www.nature.com/articles/s41436-020-00971-4

  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. […] This meta-analysis demonstrates that NBS programs for GA1 have an overall positive effect on the neurological outcome of affected individuals but their success critically depends on the quality of therapy. […] The aim of this meta-analysis of worldwide NBS studies is to evaluate the benefit of NBS programs for individuals with GA1 and to elucidate whether adherence to recommended therapies positively affects the neurologic outcome. […] Patients identified by NBS show a superior neurologic outcome with a higher rate of normal motor development and a lower rate of acute or insidious onset of MD compared with patients identified by TMS. […] Quality of therapy becomes the major predictor of neurological outcome in a screened population of GA1. […] Nonadherence to MT increases the risk of insidious onset MD. […] Nonadherence to ET increases the risk of acute onset MD.

• #39 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20201014/Study-summarizes-treatment-and-management-of-glutaric-acidemia-type-1.aspx

  A new study summarizes over 30 years of clinical experience in the treatment and management of glutaric acidemia type 1 (GA1), a rare and potentially devastating metabolic disorder caused by variants in the GCDH gene. […] Today, with the benefit of early diagnosis, dietary therapy, and an effective hospital protocol, only 7% of children born with GA1 suffer brain injury. […] Overall, early diagnosis of GA1 with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective – preventing over 90% of brain injuries.

• #40 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  It was clearly shown using a Markov model that newborn screening for GA-I significantly reduced the number of disability adjusted life years (DALYs) by 3.7 and that it helped to save about 31,000 Euro per 100,000 screened newborns within a 20 year time horizon. […] More than 15 years after the start of first newborn screening pilot projects for GA-I, there is now convincing evidence from different countries and health systems that combination of early diagnosis via newborn screening and an early start of metabolic treatment has dramatically improved the neurological outcome and survival of patients with this disease.

• #41 Newborn screening by tandem mass spectrometry for glutaric aciduria type 1: a cost-effectiveness analysis | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-167

  Glutaric aciduria type I (GA-I) is a rare metabolic disorder caused by inherited deficiency of glutaryl-CoA dehydrogenase. […] The aim of our study was therefore to assess the cost-effectiveness of newborn screening for GA-I by tandem mass spectrometry (MS/MS) compared to a scenario where GA-I is not included in the MS/MS screening panel. […] Newborn screening for GA-I can be efficiently based on the identification of elevated glutarylcarnitine (C5DC) concentrations in dried blood spots by tandem mass spectrometry (MS/MS). […] Hence, GA-I fulfills major criteria for the inclusion into newborn screening programmes. […] A previous review on the cost-effectiveness of neonatal screening concluded that screening for GA-I was likely to be highly cost-effective. […] The purpose of our analysis is therefore, to determine the cost-effectiveness of including GA-I into MS/MS newborn screening in comparison to the alternative of not including GA-I into the screening panel.

• #42 Newborn screening by tandem mass spectrometry for glutaric aciduria type 1: a cost-effectiveness analysis | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-8-167

  In the scenario without newborn screening for GA-I, we assumed that diagnosis based on high-risk screening of macrocephaly is established in 15% of cases, while the other 85% of cases will be diagnosed after clinical presentation. […] If newborn screening for GA-I is not established, GA-I patients can be diagnosed either early due to clinical signs like macrocephaly, a known index case in an affected family, or after the manifestation of irreversible neurologic symptoms (e.g. complex movement disorder). […] The scenario presenting a universal neonatal screening for GA-I includes 11.5% of the diagnosed cases to suffer from sMD. […] Following a positive screening result, the diagnosis of GA-I is confirmed by metabolite, mutation analysis and/or enzyme activity. […] In line with current evidence, our findings indicate that the morbidity resulting from GA-I can be considerably reduced by early diagnosis and treatment. […] Moreover, the long-term costs of screening for GA-I were shown to be lower than excluding GA-I from a MS/MS screening panel. […] To extend a pre-existing MS/MS screening by GA-I is a cost saving health intervention under conditions comparable to the German health system.

• #43 Glutaric aciduria type I – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/glutaric-aciduria-type-i/

  Biochemical diagnosis involves the analysis of urine organic acids and acylcarnitines to detect the characteristic elevations in 3-OH glutaric acid, glutaric acid and glutarylcarnitine (C5DC). […] Screening for GA-I is part of the NHS newborn blood spot screening (NBS) programme in England. […] C5DC acylcarnitine in dried blood spots is used as the initial diagnostic metabolite in NBS. However, this does not reliably detect low excreters that may only exhibit slightly increased C5DC levels. […] Genetic testing of the GCDH gene or GCDH enzyme analysis in fibroblasts/leucocytes may be used to confirm the diagnosis.

• #44 The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study | Scientific Reports

  https://www.nature.com/articles/s41598-021-98809-9

  The aim of the study was a systematic evaluation of cognitive development in individuals with glutaric aciduria type 1 (GA1), a rare neurometabolic disorder, identified by newborn screening in Germany. […] The biochemical high excreter phenotype is the major risk factor for cognitive impairment while cognitive functions do not appear to be impacted by current therapy and striatal damage. […] This study aims at prospectively investigating long-term cognitive development and functions of early diagnosed and treated individuals with GA1 in Germany over a period of over 20 years. […] According to a previous definition based on residual enzymatic GCDH activity and urinary GA concentrations, the biochemical subtype was arbitrarily classified as HE if GA concentration in urine was higher than 100 mmol/mol creatinine, or as LE if GA was equal to or below 100 mmol/mol creatinine.

• #45 The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study | Scientific Reports

  https://www.nature.com/articles/s41598-021-98809-9

  The biochemical subtype had an impact on full scale IQ with LE patients showing superior results compared to HE patients at last visit. […] The study clearly demonstrates poorer cognitive outcome of individuals with HE phenotype compared to LE patients and the general population and thus, a first significant impact of the biochemical subtype on the clinical course. […] In summary, this study shows that neurologic impairment in GA1 is not only limited to motor deficits but is also related to cognitive functions.

• #46 Audiological and otologic manifestations of glutaric aciduria type I | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01571-w

  Hearing loss was found in 76.9% (10/13) of GA-1 patients, including slight hearing loss in 46.1% (6/13) of patients, mild hearing loss in 15.4% (2/13) of patients, and moderate hearing loss in 7.7% (1/13) of patients. […] A high prevalence of hearing impairment is found in GA-1 patients. Adequate audiological evaluation is essential for these patients, especially for those after encephalopathic crises or with ICU admission history. […] The diagnosis of GA-1 is made based on analyzing the C5DC concentration in dried blood spots during newborn screening and confirmed by mutations in the GCDH gene. […] To date, no study has explored otologic and audiological profiles in patients with GA-1. […] We found that a high percent of patients with GA-1 encountered slight to moderate sensorineural hearing loss in this study.

• #47 Audiological and otologic manifestations of glutaric aciduria type I | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-020-01571-w

  The presence of 3-OH-GA in GA-1 patients may lead to increased vulnerability of endothelial structures and subsequent vascular dysfunction. […] We found that 75% of GA-1 patients had varying degrees of hearing loss in our study. […] Hearing loss is a common issue in patients with GA-1. Clinicians should consider the high prevalence of hearing loss in these patients, especially in patients with encephalopathic crisis or ICU admittance. Further studies are needed to investigate the nature of hearing impairment in GA-1.

• #48 Newborn Screening for Glutaric Aciduria Type I: Benefits and limitations

  https://www.mdpi.com/2409-515X/1/2/57

  More than 15 years ago glutaric aciduria type I has been included in newborn screening programmes and pilot studies evaluating the potential benefit of early diagnosis and start of metabolic treatment for patients with this disease have been initiated. […] After implementation of glutaric aciduria type I in an increasing number of countries, and with careful evaluation of disease course and impact of early treatment, there is now solid evidence that affected individuals do have substantial benefit and that newborn screening for this disease is a cost-effective diagnostic intervention. […] Despite this success, there are still limitations concerning diagnostic sensitivity for patients with a low excreting phenotype and knowledge on long-term disease outcome. […] In conclusion, it has become evident that tandem mass spectrometry-based newborn screening for glutaric aciduria type I is a powerful and cost-effective tool to prevent the manifestation of prognostically-relevant movement disorders in the majority of early diagnosed patients.

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