Clinical, Biochemical, and Genetic Heterogeneity in Glutaric Aciduria Type II Patients.
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SUBMITTER: Ali A
PROVIDER: S-EPMC8466204 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposeTo characterize the phenotypic and genotypic variations associated with Glutaric aciduria type 1 (GA1) in Chinese patients.MethodsWe analyzed the clinical, neuroradiological, biochemical, and genetic information from 101 GA1 patients in mainland China.Results20 patients were diagnosed by newborn screening and the remaining 81 cases were identified following clinical intervention. Macrocephaly was the most common presentation, followed by movement disorders and seizures. A total of 59 patients were evaluated by brain MRI and 58 patients presented with abnormalities, with widening of the sylvian fissures being the most common symptom. The concentration of glutarylcarnitine in the blood, glutarylcarnitine/capryloylcarnitine ratio, and urine levels of glutaric acid were increased in GA1 patients and were shown to decrease following intervention. A total of 88 patient samples were available for genotyping and 74 variants within the GCDH gene, including 23 novel variants, were identified. The most common variant was c.1244-2A > C (18.4%) and there were no significant differences in the biochemical or clinical phenotypes described for patients with the four most common variants: c.1244-2A > C, c.1064G > A, c.533G > A, and c.1147C > T. Patients identified by newborn screening had better outcomes than clinical patients.ConclusionOur findings expand the spectrum of phenotypes and genotypes for GA1 in Chinese populations and suggest that an expanded newborn screening program using tandem mass spectrometry may facilitate the early diagnosis and treatment of this disease, improving clinical outcomes for patients in China.
| S-EPMC8293753 | biostudies-literature
Project description:Glutaric aciduria type 1 is a rare autosomal recessive disorder. GCDH gene mutations cause glutaryl-CoA dehydrogenase deficiency and accumulation of glutaric acid and 3-hydroxyglutaric acid, resulting in damage of striatum and other brain nucleus and neurodegeneration. Patients with glutaric aciduria type 1 present with complex heterogeneous phenotypes and genotypes. The symptoms are extremely variable. The ages of the clinical onset of the patients range from the fetus period to adulthood. The patients with mild glutaric aciduria type 1 are almost asymptomatic before onset, however, severe glutaric aciduria type 1 may cause death or disability due to acute encephalopathy. Acute metabolic crisis in patients with underlying glutaric aciduria type 1 is often triggered by febrile illnesses, trauma, hunger, high-protein foods and vaccination during a vulnerable period of brain development in infancy or early childhood. The early-onset patients usually have a poor prognosis. Urinary organic acids analysis, blood acylcarnitines analysis and GCDH study are important for the diagnosis of this disorder. Neonatal screening is essential for the early diagnosis and the improvement of prognosis.
| S-EPMC7390359 | biostudies-literature
Project description:Glutaric acidemia type 1 (GA-1, OMIM 231670) is an autosomal recessive inborn error of metabolism caused by the deficiency of glutaryl-coenzyme A (CoA) dehydrogenase with most children presenting in infancy with encephalopathy, dystonia, and macrocephaly. In this article, we presented the clinical characteristics, molecular profile, and outcomes in 29 unrelated families with affected children (30 cases total). The mean age at onset of illness was 10 months (±14.58), whereas the mean age at referral for molecular diagnosis was 29.44 months (±28.11). Patients were residents of nine different states of India. Clinical presentation varied from acute encephalitis followed by neuroregression and chronic/insidious developmental delay. Neurological sequelae varied from asymptomatic (no sequelae, 2 patients) to moderate (5 patients) and severe (23 patients) sequelae. All patients underwent blood tandem mass spectrometry (TMS on dried blood spots) and/or urine gas chromatography mass spectrometry (GCMS). Neuroimaging demonstrated batwing appearance in 95% cases. Sanger's sequencing of GCDH , covering all exons and exon-intron boundaries, was performed for all patients. Variants identified include 15 novel coding variants: p.Met100Thr, p.Gly107Ser, p.Leu179Val, p.Pro217Ser, p. Phe236Leufs*107, p.Ser255Pro, p.Met266Leufs*2, p.Gln330Ter, p.Thr344Ile, p.Leu345Pro, p.Lys377Arg, p.Leu424Pro, p.Asn373Lys, p.Lys377Arg, p.Asn392Metfs*9, and nine known genetic variants such as p.Arg128Gln, p.Leu179Arg, p.Trp225Ter, p.Met339Val, p.Gly354Ser, p.Arg402Gln, p.Arg402Trp, p.His403Tyr, and p.Ala433Val (Ensembl transcript ID: ENST00000222214). Using in silico analysis, genetic variants were shown to be affecting the residues responsible for homotetramer formation of the glutaryl-CoA dehydrogenase protein. Treatment included oral carnitine, riboflavin, protein-restricted diet, lysine-deficient special formulae, and management of acute crises with intravenous glucose and hydration. However, the mortality (9/30, 27.58%) and morbidity was high in our cohort with only two patients affording the diet. Our study is the largest multicentric, genetic variant-proven series of glutaric aciduria type 1 from India till date.
| S-EPMC8416222 | biostudies-literature
Project description:Glutaric aciduria type II (GAII) is a rare inborn error of metabolism clinically classified into a neonatal-onset form with congenital anomalies, a neonatal-onset form without congenital anomalies and a mild and/or late-onset form (MIM #231680). Here, we report on a GAII patient carrying a homozygous novel c.143_145delAGG (p.Glu48del) mutation in the ETFB gene, who presented with a neonatal-onset form with congenital anomalies and rapidly developed cardiomegaly after birth.
| S-EPMC4785565 | biostudies-literature
Project description:Patients with glutaric aciduria type 1 (GA1), a rare inherited metabolic disorder, have an increased risk for subdural hematomas (SDHs). GA1 is therefore generally included in the differential diagnosis of children presenting with SDHs. This retrospective cohort study reviews all 25 registered, in the Dutch Diagnosis Registration for Metabolic Disorders, GA1 patients in the Netherlands. This was done between May 2014 and November 2014 to determine the lifetime incidence of SDHs in this population. Seventeen patients were diagnosed either due to clinical symptoms or because of family members with GA1. One out of these 17 had a SDH. This patient showed widened Sylvian fissures on MRI, characteristic for GA1. Eight patients were diagnosed by newborn screening. Three of them had neuroimaging results, and none of them had SDHs. This study shows an overall lower incidence (4.0 %) of SDHs in patients with GA1 than reported in the literature (20-30 %).This finding, in combination with the fact that SDHs in GA1 appear to occur only in the presence of characteristic brain abnormalities on imaging, we recommend that GA1 should not routinely be a part of the differential diagnosis of children with unexplained SDHs in the absence of imaging characteristics suggestive of GA1.• Glutaric aciduria type 1 is a rare metabolic disorder predisposing children to subdural hematoma development due to brain abnormalities. • Because of these subdural hematomas, glutaric aciduria type 1 testing is part of abusive head trauma work-up. What is new: • The overall subdural hematoma incidence in glutaric aciduria type 1 patients is much lower than previously reported and only occurs in case of predisposing brain abnormalities.
| S-EPMC4908155 | biostudies-literature
Project description:UNLABELLED:Newborn screening (NBS) using tandem mass spectrometry (MS/MS) permits detection of neonates with Glutaric Aciduria-Type II (GA-II). We report follow-up of positive GA-II screens by the New England Newborn Screening Program. METHODS:1.5 million infants were screened for GA-II (Feb 1999-Dec 2012). Specialist consult was suggested for infants with two or more acylcarnitine elevations suggestive of GA-II. RESULTS:82 neonates screened positive for GA-II, 21 weighing > 1.5 kg and 61 weighing ? 1.5 kg. Seven (one weighing < 1.5 kg), were confirmed with GA-II. Four of these had the severe form (died < 1 week). The other three have a milder form and were identified because of newborn screening. Two (ages > 5 years) have a G-Tube in place, had multiple hospitalizations and are slightly hypotonic. The third infant remains asymptomatic (9 months old). Two GA-II carriers were also identified. The remaining positive screens were classified as false positives (FP). Six infants (> 1.5 kg) classified as FP had limited diagnostic work-up. Characteristics and outcomes of all specimens and neonates with a positive screen were reviewed, and marker profiles of the cases and FP were compared to identify characteristic profiles. CONCLUSION:In addition to the severe form of GA-II, milder forms of GA-II and some GA-II carriers are identified by newborn screening. Some positive screens classified as FP may be affected with a milder form of the disorder. Characteristic GA-II profiles, quantified as GA-II indexes, may be utilized to predict probability of disorder and direct urgency of intervention for positive screens.
| S-EPMC4110341 | biostudies-literature
Project description:Glutaric aciduria type 1 (GA1) is an autosomal recessive metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase enzyme encoded by the GCDH gene. In this study, we presented the clinical and molecular findings of seven GA1 patients in Malaysia. All the patients were symptomatic from infancy and diagnosed clinically from large excretion of glutaric and 3-hydroxyglutaric acids. Bidirectional sequencing of the GCDH gene revealed ten mutations, three of which were novel (Gln76Pro, Glu131Val, and Gly390Trp). The spectrum of mutations included eight missense mutations, a nonsense mutation, and a splice site mutation. Two mutations (Gln76Pro and Arg386Gln) were homozygous in two patients with parental consanguinity. All mutations were predicted to be disease causing by MutationTaster2. In conclusion, this is the first report of both clinical and molecular aspects of GA1 in Malaysian patients. Despite the lack of genotype and phenotype correlation, early diagnosis and timely treatment remained the most important determinant of patient outcome.
| S-EPMC5031822 | biostudies-literature
Project description:Glutaric acidemia type 1 (GA1) is an inherited metabolic autosomal recessive disorder that is caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Untreated patients suffer primarily from severe striatal damage. More than 250 variants in the GCDH gene have been reported with a variable frequency among different ethnic groups. In this study, we aimed to characterize 89 Egyptian patients with GA1 and identify the variants in the 41 patients who were available for genotyping. All of our patients demonstrated clinical, neuroradiological, and biochemical characteristics that are consistent with a diagnosis of GA1. All patients presented with variable degrees of developmental delay ranging from mild to severe. Most of the 89 patients presented with acute onset type (71.9%), followed by insidious (19%) and asymptomatic (9%). A delay in diagnosis was inversely associated with macrocephaly. The prevalence rate ratio (PR) for macrocephaly that was associated with each 6-month delay was 0.95 (95%CI 0.91-0.99). However, high body weight was associated with a higher likelihood of having macrocephaly (PR 1.16, 95%CI 1.06-1.26 per 1 SD increment of Z score weight). However, body weight was inversely associated with the morbidity score. Consanguinity level was 64% among our patient's cohort and was positively associated with the C5DC level (β (95%CI) 1.06 (0.12-1.99)). Forty-one patients were available for genotyping and were sequenced for the GCDH gene. We identified a total of 25 variants, of which the following six novel variants were identified: three missense variants, c.320G > T (p.Gly107Val), c.481C > T (p.Arg161Trp) and c.572 T > G (p.Met191Arg); two deletions, c.78delG (p.Ala27Argfs34) and c.1035delG (p.Gly346Alafs*11); and one indel, c.272_331del (p.Val91_Lys111delinsGlu). All of the novel variants were absent in the 300 normal chromosomes. The most common variant, c.*165A > G, was detected in 42 alleles, and the most commonly detected missense variant, c.1204C > T (p.Arg402Trp), was identified in 29 mutated alleles in 15/41 (34.2%) of patients. Our findings suggest that GA1 is not uncommon organic acidemia disease in Egypt; therefore, there is a need for supporting neonatal screening programs in Egypt.
| S-EPMC6617250 | biostudies-literature
Project description:Classical neonatal-onset glutaric aciduria type 2 (MAD deficiency) is a severe disorder of mitochondrial fatty acid oxidation associated with poor survival. Secondary dysfunction of acyl-CoA dehydrogenases may result from deficiency for riboflavin transporters, leading to severe disorders that, nevertheless, are treatable by riboflavin supplementation. In the last 10 years, we identified nine newborns with biochemical features consistent with MAD deficiency, only four of whom survived past the neonatal period. A likely iatrogenic cause of riboflavin deficiency was found in two premature newborns having parenteral nutrition, one of whom recovered upon multivitamin supplementation, whereas the other died before diagnosis. Four other patients had demonstrated mutations involving ETF or ETF-DH flavoproteins, whereas the remaining three patients presumably had secondary deficiencies of unknown mechanism. Interestingly, six newborns among the seven tested for plasma amino acids had pronounced hyperprolinemia. In one case, because the initial diagnostic workup did not include organic acids and acylcarnitine profiling, clinical presentation and hyperprolinemia suggested the diagnosis. Analysis of our full cohort of >50,000 samples from >30,000 patients suggests that the proline/alanine ratio may be a good marker of MAD deficiency and could contribute to a more effective management of the treatable forms.
| S-EPMC4864717 | biostudies-literature
Project description: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 encephalopathic 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 L-tryptophan. 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 majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.
| S-EPMC3109243 | biostudies-literature