A novel splice GCDH variant and analysis of splicing variants in glutaric aciduria type I

Glutaric aciduria and L-2-hydroxyglutaric aciduria: Clinical and molecular findings of 35 patients from Turkey

Elevated glutaric acid levels in Dhtkd1-/Gcdh- double knockout mice challenge our current understanding of lysine metabolism

The clinical, biochemical and genetic findings in two Slovak patients with glutaric aciduria type I (GAI) are presented. 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. 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. We found the presence of typical metabolic profile and novel causal pathogenic variants in both GAI patients. 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 clinical and biochemical findings in three patients with glutaric aciduria Type 1 (GAT1) are presented. They had a normal postnatal period of three to 14 months. They developed sudden and severe encephalopathy following an infection or trauma (patient 3) that gradually progressed to severe dystonia, choreoathetosis, spastic quadriplegia and mental retardation. Neuroradiologic studies of the brain revealed white matter disease and frontotemporal lobe hypoplasia. The urine findings by gas chromatography/mass spectrometry (GC)/(MS) were characteristic of GAT1. Since GAT1 is an organic acidemia without intermittent acidotic attacks, but primarily manifests with progressive encephalopathy, it is important to recognize the potential of its existence among handicapped children in chronic care facilities. The good clinical response in two of the patients urges early diagnosis in subsequent newborn siblings of the families with the disease. The diagnosis of three patients in less than two years indicates the need for neonatal screening for the recognition of this disease, among other treatable metabolic diseases, in Saudi Arabia.

To the Editor. I have read with great interest the recent paper of Morris and co-workers on the evaluation of infants with subdural hematoma and suspected child abuse.1 Under these circumstances one important differential diagnosis may be missed without the appropriate diagnostic tests. Glutaric aciduria type I (GA-I) secondary to deficiency of glutaryl CoA dehydrogenase is an inborn error of lysine, hydroxylysine, and tryptophan metabolism that may occur as frequently as 1:30,000 newborns.2 Infants and children with GA-I may present with subdural effusions and/or subdural hematoma, which may be accompanied by retinal hemorrhages.2–5 Macrocephaly is either present at birth or may develop during the first months of life. Early development in most children with GA-I is completely unremarkable before their initial encephalopathic episode occurs on average at 12 months of life.2The presence of GA-I warrants diagnostic consideration in cases with subdural hematoma with no additional physical findings suggestive of child abuse.6 The diagnostic workup should include urine analysis of organic acids, plasma carnitine/acylcarnitine analysis, measurement of enzyme activity in fibroblasts or leukocytes, and/or mutation analysis.In Reply. Dr Bodamer raises an important point in the evaluation of infants for possible child abuse. There have been instances in which infants with GA-I have had subdural collections mistaken for abusive injuries.In our series, GA-I was part of the differential especially in the oldest infant, who presented with a dystonic movement disorder. Urine organic acid analysis was normal in this patient. His subsequent lack of neurologic problems after social intervention made fibroblast or leukocyte culture or other testing unnecessary.None of the other patients in the series had clinical presentations suggesting GA-I nor did they have computed tomography or magnetic resonance imaging changes associated with that diagnosis apart from the subdural hematomas. All have been followed for a lengthy period since the initial diagnosis without subsequent neurologic episodes.Trauma is the primary cause of most infant subdural hematomas. Defining the nature of the trauma can be difficult for a single physician, but a specialized team investigation can help define the nature of the trauma, preventing recurrence and its attendant brain injury and even death. We thank Dr Bodamer for his reminder about a more rare cause of this condition.

Ammonium accumulation and chemokine decrease in culture media of Gcdh−/− 3D reaggregated brain cell cultures

Clinical and molecular investigation in Chinese patients with glutaric aciduria type I

Glutaric Aciduria type I and acute renal failure — Coincidence or causality?

To investigate if expanded newborn screening using tandem mass spectroscopy (TMS) is adequate to detect low excretor phenotype in Indian Glutaric aciduria type I (GA-I) patients. Ten GA-I patients were investigated for blood glutaryl carnitine (C5DC) levels on dried blood spot (DBS) by tandem mass spectroscopy and urine glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) by gas chromatography-mass spectroscopy. The student's T test and Pearson's correlation were applied to draw a relationship between various biochemical parameters. Further confirmation of low excretors by DNA mutation analysis in the glutaryl CoA dehydrogenase (GCDH) gene was performed by polymerase chain reaction and Sangers sequencing. Among 10 GA-I patients, 7 patients were found to have high excretor, and 3 were found to have low excretor phenotype. The low excretors were found to have GCDH gene mutations. The mean C5DC levels in high and low excretors were 2.61 ± 2.02μmol/L and 2.31 ± 1.00μmol/L, respectively. In high excretors, C5DC levels correlated with GA (r = 0.95). In low excretors, C5DC levels correlated with 3-OH-GA (r = 0.99). No significant difference was found between C5DC levels of high and low excretors (p = 0.82). The MS/MS, C5DC screening is a sensitive technique and detected 10 GA-I patients. Irrespective of the urine organic acid levels, Indian GA-I patients including low excretors seem to have a significantly elevated C5DC level and well above the stipulated cut-off values and therefore, expanded newborn screening is probably adequate to diagnose them.

Glutaric aciduria type I (GA-I) is an autosomal recessive disease caused by a deficiency of the mitochondrial enzyme glutaryl CoA dehydrogenase (GCDH). This metabolic block causes increased urinary concentrations of glutaric and 3-hydroxyglutaric acids. The accumulation and excretion of glutarylcarnitine esters leads to secondary carnitine deficiency. GA-I has an incidence of 1:30,000. The clinical hallmark of GA-I is an acute encephalopathic crisis, with bilateral striatal necrosis presented by severe dystonic dyskinetic disorder. Most patients have their first symptoms during infancy, but some have a less severe form of the disease and some may even remain asymptomatic.

Treatment of glutaric aciduria type I (GA-I) via intracerebroventricular delivery of GCDH

Chapter 4 - Arachnoid Cysts in Glutaric Aciduria Type I (GA-I)

Glutaric aciduria type I (GA-I) is a rare cerebral organic acid disorder caused by inherited deficiency of glutaryl-CoA dehydrogenase (GCDH; EC 1.3.99.7), a mitochondrial flavoprotein catalysing the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA in the final catabolic pathways of the amino acids l-lysine, l-hydroxylysine and l-tryptophan (Goodman et al ., 1975). Biochemically, GA-I is characterized by an accumulation of the dicarboxylic acids glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) as well as glutarylcarnitine (Baric et al ., 1999). Clinically, the disease course is complicated by striatal injury during an acute encephalopathic crisis, which is usually precipitated by a catabolic state (e.g. infectious diseases) in infancy or early childhood (Strauss et al ., 2003; Kolker et al ., 2006). If treated before the onset of irreversible neurological symptoms, the encephalopathic crises can be prevented in the majority of children (Strauss et al ., 2003; Naughten et al ., 2004; Kolker et al ., 2006). In particular, maintenance treatment with l-carnitine supplementation and lysine restriction is beneficial for pre-symptomatically diagnosed children (Kolker et al ., 2006). An animal model of GA-I has been developed to study pathophysiology. A detailed analysis of the histopathology, biochemistry, bioenergetics and behaviour of these mice has previously been published (Koeller et al ., 2002; Sauer et al ., 2005). In spite of high levels of GA and 3-OH-GA, these Gcdh−/− mice do not develop striatal degeneration either spontaneously or following a number of triggers, inducing a catabolic state (Koeller et al ., 2002), which contrasts with the association between catabolism and encephalopathic crises in GA-I patients. Recently, Zinnanti et al . reported in Brain (2006) that excessive dietary intake of lysine or protein produced a phenotype in Gcdh−/− mice that resembled some important clinical and neuroradiological …

Glutaric aciduria type I (GA-I) is an inborn error of lysine and tryptophan metabolism. Clinical manifestations of GA-I include dystonic or dyskinetic cerebral palsy, but when the symptoms occur, treatment is not effective. In Taiwan, newborn screening for GA-I started in 2001; we wish to evaluate the outcomes of patients detected through newborn screening. Newborns diagnosed with GA-I by abnormal dried blood spot glutarylcarnitine (C5DC) levels followed in our hospital were included in this study. They were treated with special diets, carnitine supplements, and immediate stress avoidance. Six patients were included in this study. All patients were treated prior to reaching 1month of age. They were followed up with for 4 to 9years. One patient had encephalopathic crisis episodes prior to turning 1year old that caused pallidal lesions. Another patient had a chronic progressive disease during infancy that caused bilateral putamen lesions. These two patients had delayed development, but their brain lesions were resolved. The other four patients ran uneventful courses. They had normal intelligenece, ranged between average to low average level and their brain magnetic resonance imaging showed only high intensity over deep white matter. Patients with GA-I diagnosed by newborn screening have promising outcomes, though the risks of disease progression prior to 1year of age remain significant.

Molecular identification of glutaryl CoA dehydrogenase gene variations and clinical course in three glutaric aciduria type I patients