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![A general negative exponential model of development. The model [42, 43] describes development of performance (Y) as an exponential function of age (a). b represents the asymptote to which the performance converges, c is the difference between maximum of Y and asymptote. d indicates how quickly performance changes from maximum to asymptote](profile/Gisela-Haege/publication/278406004/figure/fig4/AS:309876686376968@1450891767282/A-general-negative-exponential-model-of-development-The-model-42-43-describes.png)
A general negative exponential model of development. The model [42, 43] describes development of performance (Y) as an exponential function of age (a). b represents the asymptote to which the performance converges, c is the difference between maximum of Y and asymptote. d indicates how quickly performance changes from maximum to asymptote
Source publication
Background: Glutaric aciduria type I (GA-I) is an inherited metabolic disease due to
deficiency of glutaryl-CoA dehydrogenase (GCDH). Cognitive functions are generally
thought to be spared, but have not yet been studied in detail.
Methods: Thirty patients detected by newborn screening (n=13), high-risk screening
(n=3) or targeted metabolic testing...
Contexts in source publication
Context 1
... of a mathematical model of developmental [42,43] (Fig. 1) were calculated for the cross-sectional results of GA-I patients and controls separately. The model describes developmental change by a negative exponential function of performance Y by age (a) as Y = b + ce -da . Parameter b represents the asymptote to which performance converges over time, c is the differ- ence between the maximum of ...
Context 2
... test whether the exponential functions of the three groups show different gradients (Fig. 1, parameter d, i.e. how fast the asymptotic performance is achieved), patient and control data were aggregated into three different age groups: a starting period (5-8 years) with a relatively low level of performance, followed by a period of rapid im- provement (9-12 years), and a period of relatively stable performance without further improvement ...
Context 3
... the three groups do not develop on the same Mead and Cournow 1983. Data of all psychological test scores show good fits to the model (R 2 adj ≥ 0.442), both for GA-I patients (n = 30; asymptomatic: n = 17; dystonic: n = 13) and controls (n = 196), with the exception of VS3 for dystonic patients. For definition of model parameters b,c and d see Fig. 1. R 2 adj : adjusted explanatory power of the regression model. SE: standard error level, the form of their development is the same (in analogy to growth development on different percentiles). (5) Per- formance of asymptomatic patients did not significantly dif- fer from controls, except for visual motor coordination, where asymptomatic ...
Similar publications
Biallelic mutations of the GCDH gene result in Glutaric Aciduria type 1 (GA1; OMIM #231670), an uncommon autosomal recessive inborn error caused by the deficiency of glutaryl-CoA dehydrogenase (CCDH), a mitochondrial matrix protein involved in the degradation of l-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic deficiency leads to the accu...
Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a s...
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl‐CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively...
Citations
... Nesse contexto, sabe-se que um diagnóstico neonatal precoce permite um tratamento adequado dessa patologia, modificando a evolução e melhorando prognóstico do paciente. (Beauchamp, et al. 2009;Boy, et al. 2015;Brown, et al. 2015;Lobo, 2012). ...
Objetivo: Analisar o diagnóstico, a evolução e tratamento da acidemia glutárica tipo I em paciente pediátrico. Metodologia: A presente pesquisa foi elaborada por meio de um estudo de caso, de caráter descritivo, na qual se avaliou a referida patologia e suas interfaces em paciente pediátrico de modo a analisar cada fase e suas intercorrências mais importantes durante o período de tratamento no HUMAP. Resultados: Paciente realizou exames de imagem, laboratoriais e genéticos, na busca de um diagnóstico etiológico conclusivo, além disso, as características mais marcantes da patologia AG-I, foram os sintomas neurológicos, como a alteração de tônus, hipotonia axial, alteração de força, irritabilidade e as crises epiléticas. Conclusão: Paciente ainda em tratamento nessa instituição, mantendo quadro com melhora da irritabilidade e controle das crises epiléticas com o uso da oxicarbazepima, uso de fórmula específica com restrição de lisina enriquecido com vitamina e minerais, com evolução de melhora importante do quadro, após aproximadamente 30 dias.
... Evaluation of dystonic MD should comprise clinical localisation and severity. The Barry-Albright Dystonia Rating Scale 165,166 has been used in some studies, 28,167 but may be of limited use in infants and young children since it likely underestimates the severity of MD in this age group due to severe truncal hypotonia. 28 The Fahn-Marsden Dystonia Rating Scale (FMDRS) has been used in hyperkinetic MD including cerebral palsy and is recommended for assessment of generalised dystonia, but does not assess individual body areas and has not been evaluated for GA1. ...
... 55 Another study with 30 patients using computer-based test battery for information processing showed similar neuropsychological functions in asymptomatic patients compared to a healthy control group, whereas dystonia primarily influenced performance in tests measuring motor speed but not tests with higher cognitive demand. 167 A recent US study reported on normal psychomotor development in 60 patients identified by NBS and normal cognitive functions in 10 of them. 30 In contrast, IQ and cognitive dysfunction may also be impaired in early and late-treated children. ...
Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age three (to six) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, i.e. age 6 years. However, impact of dietary relaxation on long-term outcome is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations 1-3 and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes. This article is protected by copyright. All rights reserved.
... Earlier case reports and small case series supported the notion of unaffected cognitive functions in NBS www.nature.com/scientificreports/ patients [28][29][30][31] , and cross-sectional analysis of computer-based testing of developmental functions and cognitive performances showed similar results in GA1 patients and healthy controls while dystonic patients showed impairment in tests measuring motor speed, but not in tests with higher cognitive load 28 . In contrast, cognitive decline was described in adult patients 32 , and deficits in short-and long-term memory were recently demonstrated in Gcdh-deficient mice, an animal model for GA1 with complete loss of enzymatic GCDH activity 33 . ...
... Earlier case reports and small case series supported the notion of unaffected cognitive functions in NBS www.nature.com/scientificreports/ patients [28][29][30][31] , and cross-sectional analysis of computer-based testing of developmental functions and cognitive performances showed similar results in GA1 patients and healthy controls while dystonic patients showed impairment in tests measuring motor speed, but not in tests with higher cognitive load 28 . In contrast, cognitive decline was described in adult patients 32 , and deficits in short-and long-term memory were recently demonstrated in Gcdh-deficient mice, an animal model for GA1 with complete loss of enzymatic GCDH activity 33 . ...
... Earlier case reports and small case series supported the notion of unaffected cognitive functions in NBS www.nature.com/scientificreports/ patients [28][29][30][31] , and cross-sectional analysis of computer-based testing of developmental functions and cognitive performances showed similar results in GA1 patients and healthy controls while dystonic patients showed impairment in tests measuring motor speed, but not in tests with higher cognitive load 28 . In contrast, cognitive decline was described in adult patients 32 , and deficits in short-and long-term memory were recently demonstrated in Gcdh-deficient mice, an animal model for GA1 with complete loss of enzymatic GCDH activity 33 . ...
... Earlier case reports and small case series supported the notion of unaffected cognitive functions in NBS www.nature.com/scientificreports/ patients [28][29][30][31] , and cross-sectional analysis of computer-based testing of developmental functions and cognitive performances showed similar results in GA1 patients and healthy controls while dystonic patients showed impairment in tests measuring motor speed, but not in tests with higher cognitive load 28 . In contrast, cognitive decline was described in adult patients 32 , and deficits in short-and long-term memory were recently demonstrated in Gcdh-deficient mice, an animal model for GA1 with complete loss of enzymatic GCDH activity 33 . ...
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. This national, prospective, observational, multi-centre study includes 107 individuals with confirmed GA1 identified by newborn screening between 1999 and 2020 in Germany. Clinical status, development, and IQ were assessed using standardized tests. Impact of interventional and non-interventional parameters on cognitive outcome was evaluated. The majority of tested individuals (n = 72) showed stable IQ values with age (n = 56 with IQ test; median test age 11 years) but a significantly lower performance (median [IQR] IQ 87 [78–98]) than in general population, particularly in individuals with a biochemical high excreter phenotype (84 [75–96]) compared to the low excreter group (98 [92–105]; p = 0.0164). For all patients, IQ results were homogenous on subscale levels. Sex, clinical motor phenotype and quality of metabolic treatment had no impact on cognitive functions. Long-term neurologic outcome in GA1 involves both motor and cognitive functions. 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. These findings implicate the necessity of new treatment concepts.
... Damage to the fornix has not been reported in association with GA-1 so farthis is the first case -and cognitive function seems to be preserved in these patients [18]. Boy et al. were the first to investigate as many as 30 patients with confirmed diagnosis of GA-1 in order to analyze their neuropsychological functions (in general, the biggest described group of GA-1 patients that we found in the literature included 77 individuals [19]). ...
... Boy et al. were the first to investigate as many as 30 patients with confirmed diagnosis of GA-1 in order to analyze their neuropsychological functions (in general, the biggest described group of GA-1 patients that we found in the literature included 77 individuals [19]). They also reviewed the literature for cognitive research and stated that memory deficits had not been reported in GA-1 patientsexcept for 2 cases [18]. ...
Background
Most white matter diseases present on magnetic resonance imaging as focal or diffuse T2-hyperintensities. However, in a few of them, radially oriented stripes of low (relatively normal) signal intensity are observed within diffusely affected T2-hyperintense cerebral white matter and are called “tigroid pattern” in the literature. The fornix is a tiny white matter fibers bundle playing crucial role in cognitive functioning, easily overlooked on magnetic resonance imaging and not described in inborn errors of metabolism.
Case presentation
We present a case of glutaric aciduria type 1 with a follow-up of over nine years. The course of the disease is presented in three magnetic resonance scans at the age of 8 and 21 months, and 10 years, with diffusion restriction in the fornix in scan 1 and 2 and with tigroid pattern in scan 3. Despite appropriate diet and supplementation, injury of white matter progressed achieving diffuse stage with tigroid pattern. Psychological tests revealed deficits in patient’s specific cognitive skills, most likely related to damage to the fornix.
Conclusions
To our knowledge, this is the first report of tigroid pattern of white matter involvement in glutaric aciduria type 1 and the first report of forniceal injury in this disease which seems to be correlated with patient’s low functioning in all kinds of memory skills, previously not reported in glutaric aciduria type 1.
... Interestingly, GA administration did not modify the number of working memory errors in RAM task (Table 1). In agreement with this result, a recent developmental study of neuropsychological functions, specifically in relation to WM, revealed that patients with GA-I did not exhibit impaired performance in visual working memory task [56], suggesting that WM may be preserved in GA-I, even in patients with striatal degeneration. Then, our result suggests that animals injected with GA are able to have memory acquisition; however, learning process is slower due to PM impairment. ...
Dysfunction of basal ganglia neurons is a characteristic of glutaric acidemia type I (GA-I), an autosomal recessive inherited neurometabolic disease characterized by deficiency of glutaryl-CoA dehydrogenase (GCDH) and accumulation of glutaric acid (GA). The affected patients present clinical manifestations such as motor dysfunction and memory impairment followed by extensive striatal neurodegeneration. Knowing that there is relevant striatal dysfunction in GA-I, the purpose of the present study was to verify the performance of young rats chronically injected with GA in working and procedural memory test, and whether N-acetylcysteine (NAC) would protect against impairment induced by GA. Rat pups were injected with GA (5 μmol g body weight⁻¹, subcutaneously; twice per day; from the 5th to the 28th day of life) and were supplemented with NAC (150 mg/kg/day; intragastric gavage; for the same period). We found that GA injection caused delay procedural learning; increase of cytokine concentration, oxidative markers, and caspase levels; decrease of antioxidant defenses; and alteration of acetylcholinesterase (AChE) activity. Interestingly, we found an increase in glial cell immunoreactivity and decrease in the immunoreactivity of nuclear factor-erythroid 2-related factor 2 (Nrf2), nicotinic acetylcholine receptor subunit alpha 7 (α7nAChR), and neuronal nuclei (NeuN) in the striatum. Indeed, NAC administration improved the cognitive performance, ROS production, neuroinflammation, and caspase activation induced by GA. NAC did not prevent neuronal death, however protected against alterations induced by GA on Iba-1 and GFAP immunoreactivities and AChE activity. Then, this study suggests possible therapeutic strategies that could help in GA-I treatment and the importance of the striatum in the learning tasks.
... Boy et al. 27 investigated information processing of 30 children and young adults with glutaric aciduria type I (mean age=unknown, range 5-29y; 18 males) in comparison to a healthy control group (n=196, age range 5-28y, 103 males) in a prospective case-control study. In the patient group, 13 children were diagnosed with dystonia secondary to glutaric aciduria type I but the paper does not specify the results for this subgroup, therefore no conclusion can be drawn here. ...
Aim:
Cognitive impairments have been established as part of the non-motor phenomenology of adult dystonia. In childhood dystonia, the extent of cognitive impairments is less clear. This systematic review aims to present an overview of the existing literature to elucidate the cognitive profile of primary and secondary childhood dystonia.
Method:
Studies focusing on cognition in childhood dystonia were searched in MEDLINE and PsychInfo up to October 2017. We included studies on idiopathic and genetic forms of dystonia as well as dystonia secondary to cerebral palsy and inborn errors of metabolism.
Results:
Thirty-four studies of the initial 527 were included. Studies for primary dystonia showed intact cognition and IQ, but mild working memory and processing speed deficits. Studies on secondary dystonia showed more pronounced cognitive deficits and lower IQ scores with frequent intellectual disability. Data are missing for attention, language, and executive functioning.
Interpretation:
This systematic review shows possible cognitive impairments in childhood dystonia. The severity of cognitive impairment seems to intensify with increasing neurological abnormalities. However, the available data on cognition in childhood dystonia are very limited and not all domains have been investigated yet. This underlines the need for future research using standardized neuropsychological procedures in this group.
... Although the intellect and cognitive functions are relatively well-preserved in GAI patients, the numerous structural and functional cerebral abnormalities that can begin in the last trimester of pregnancy had been found. The white matter changes seem to increase with age, both in patients with high as well as low excretion phenotypes (12). The suspicion of GAI may be often omitted in patients with cerebral palsy and mental retardation as isolated symptoms (13,14). ...
Objectives:
The clinical, biochemical and genetic findings in two Slovak patients with glutaric aciduria type I (GAI) are presented.
Background:
GAI is a rare autosomal recessive neuro-metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which is involved in the catabolic pathways of lysine, hydroxylysine and tryptophan. This enzymatic defect gives rise to elevated levels of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC) in body fluids.
Methods:
Biochemical and molecular-genetic tests were performed. Urinary organic acids were analysed by Gas Chromatography/Mass Spectrometry (GC/MS) and the entire coding region of the GCDH gene, including flanking parts, was sequenced.
Results:
We found the presence of typical metabolic profile and novel causal pathogenic variants in both GAI patients.
Conclusion:
We present the first report of two Slovak patients with GAI, which differed in the clinical and biochemical phenotype significantly. They were diagnosed by two distinct approaches - selective and newborn screening. Their diagnosis was complexly confirmed by biochemical and later on molecular-genetic examinations. Though we agreed with a thesis that early diagnostics might positively influenced patient's health outcome, contradictory facts should be considered. Supposed extremely low prevalence of GAI patients in the general population and/or the existence of asymptomatic individuals with a questionable benefit of the applied therapeutic intervention for them lead to doubts whether the inclusion of disease into the newborn screening programme is justified well enough (Tab. 1, Fig. 3, Ref. 41).
... The abnormal accumulation of metabolites would cause excitatory damage, energy metabolism damage and oxidative stress. In addition, other risk factors, such as glial activation, vascular injury, inflammatory factors and other causative factors, are involved in collaborative neurotoxic damage (18). ...
The aim of the present study was to investigate the clinical, biochemical and genetic mutation characteristics of two cases of late-onset glutaric aciduria type I (GA-I) in Uighur. The clinical data and glutaryl-CoA dehydrogenase (GCDH) genetic test results of two cases of late-onset GA-I in Uighur were collected and analyzed, and reviewed with relevant literature. One patient with late-onset GA-I primarily exhibited clinical intermittent headache, while the other patient was asymptomatic. The urinary organic acid analysis detected a large number of glutaric acid and 3-hydroxy glutaric acid, 3-hydroxy-propionic acid. One patient exhibited white matter degeneration in cranial magnetic resonance imaging (MRI) and the other patient showed no abnormality. The two patients both exhibited c. 1204C >T, p.R402W, heterozygous mutation, and c. 532G >A, p.G178R, heterozygous mutation. Besides central nervous system infectious diseases, patients with clinical headache, cranial MRI-suggested bilateral temporal lobe arachnoid cyst and abnormal signals in the basal ganglia should be highly suspected as late-onset GA-I. Early diagnosis and correct treatment are key to improve its prognosis.
... Patient has acidosis, hepatomegaly, increase liver enzyme activity, hyperammonemia, hypoketotic hypoglycemia and low HL activity. Glutaric aciduria and Reye syndrome were eliminated as possible diagnoses; Glutaric aciduria has characteristic alterations in the GC/MS profile, including elevated concentrations of glutaryl-CoA, glutaric acid, 3-hydroxyglutaric acid and glutarylcarnitine in body tissues, whereas Reye syndrome shows normal GC/MS analyses (15,16). Based on these findings, in combination with blood and urine metabolic tests, the patient was diagnosed with 3-HMG. ...
3-Hydroxy-3-methylglutaric aciduria (3-HMG, OMIN 246450) is a rare autosomal recessive metabolic disorder caused by a deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase, a key enzyme in leucine metabolism and ketone body synthesis. Acute episodes of 3-HMG may be triggered by fasting or infection, and symptoms include vomiting, diarrhea, lethargy and hypotonia. If left untreated, prolonged hypoglycemia and metabolic acidosis may cause breathing problems, seizures, and coma. In addition, 3-HMG is associated with damage to the central nervous system, and there are several reports of white matter abnormality or cerebral atrophy. The presence of bilateral basal ganglia damage in 3-HMG has been rarely reported. Here, we present a case report of a 20-month old male with severe 3-HMG and prominent bilateral lesions in the basal ganglia.
