Outcome of three cases of untreated maternal glutaric aciduria type I

Garcia, Paula; Martins, Esmeralda; Diogo, Luísa; Rocha, Hugo; Marcão, Ana; Gaspar, Eurico; Almeida, Margarida; Vaz, Catarina; Soares, Isabel; Barbot, Clara; Vilarinho, Laura

doi:10.1007/s00431-007-0556-2

Cited by 32 publications

(34 citation statements)

References 20 publications

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“…One patient diagnosed by genetic family counselling was asymptomatic [23]. In three reported patients macrocephaly and developmental delay/learning disability without motor symptoms had already been noticed during infancy and childhood [11, 15] suggesting late diagnosis rather than late onset in some patients. As in patients with acute and insidious onset , macrocephaly was not a reliable clinical indicator, being present in only 50% of our late-onset patients.…”

Section: Discussionmentioning

confidence: 99%

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Boy

Heringer

Brackmann

et al. 2017

Orphanet J Rare Dis

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BackgroundWithout neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment.ResultsNo late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients.ConclusionsWhile clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Boy

Heringer

Brackmann

et al. 2017

Orphanet J Rare Dis

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“…To date, over 80 mutations, including missense, nonsense and intronic variations, have been associated with GA1 in patients (Keyser et al, 2008;Westover et al, 2003;Goodman et al, 1998). However, controversy persists concerning attempts to connect phenotype to specific genotypic markers of the disease, as patients symptomatic for GA1 sometimes do not present with GCDH deficiency (Westover et al, 2003;Christensen et al, 2004;Garcia et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening

Begley

Davies

Hartley

et al. 2011

Acta Crystallogr F Struct Biol Cryst Commun

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Glutaric acidemia type 1 is an inherited metabolic disorder which can cause macrocephaly, muscular rigidity, spastic paralysis and other progressive movement disorders in humans. The defects in glutaryl-CoA dehydrogenase (GCDH) associated with this disease are thought to increase holoenzyme instability and reduce cofactor binding. Here, the first structural analysis of a GCDH enzyme in the absence of the cofactor flavin adenine dinucleotide (FAD) is reported. The apo structure of GCDH from Burkholderia pseudomallei reveals a loss of secondary structure and increased disorder in the FAD-binding pocket relative to the ternary complex of the highly homologous human GCDH. After conducting a fragment-based screen, four small molecules were identified which bind to GCDH from B. pseudomallei. Complex structures were determined for these fragments, which cause backbone and side-chain perturbations to key active-site residues. Structural insights from this investigation highlight differences from apo GCDH and the utility of small-molecular fragments as chemical probes for capturing alternative conformational states of preformed protein crystals.

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“…Therefore, GA-1 has been included in the disease panel of newborn screening in some countries 5,7,23,24 . The Portuguese Neonatal Screening Programme, which was expanded to other disorders besides phenylketonuria and hypothyroidism in 2005, includes GA-1 29,30 . The cases presented were diagnosed before that date.…”

Section: Casementioning

confidence: 99%