Catecholamine excretion profiles identify clinical subgroups of neuroblastoma patients.

INTRODUCTION: Analysis of urinary catecholamine metabolites is one of the primary modalities to diagnose patients with neuroblastoma. Although catecholamine excretion patterns have been recognised in the past, their biological rationale and clinical relevance remain largely unknown. Therefore, this study was designed to identify unique catecholamine excretion patterns and elucidate their underlying biology and clinical relevance. PATIENTS AND METHODS: A panel of 25 neuroblastoma cell lines was screened for catecholamine excretion. Detection of the catecholamine enzymes was performed using Western blot. Based on catecholamine enzymes presence and excreted catecholamine metabolites, excretion profiles were defined. The prevalence of these profiles was investigated in vivo using diagnostic urines from 301 patients with neuroblastoma and immunohistochemistry on primary tumours. The clinical relevance of the profiles was determined by linking the profiles to clinical characteristics and outcome of patients with neuroblastoma. RESULTS: Four excretion profiles (A-D) were identified in vitro, which correlated with the relative protein expression of the catecholamine enzymes. These profiles were also identified in urine samples from patients with neuroblastoma and correlated with the presence of the catecholamine enzymes in the tumour. Strikingly, in 66% of the patients, homovanillic acid and vanillylmandelic acid excretions were discordant with the catecholamine profiles. Clinical characteristics and outcome gradually improved from patients with profile A (predominantly high risk) towards profile D (predominantly observation), with 5-years overall survival of 35% and 93%, respectively. CONCLUSIONS: Catecholamine profiles in vitro and in vivo reflect, to a large extent, the presence of the individual catecholamine enzymes and represent distinct subgroups of patients with neuroblastoma.

Advances in methods for characterization of hepatic urea cycle enzymatic activity in HepaRG cells using UPLC-MS/MS.

Current methodologies for the assessment of urea cycle (UC) enzymatic activity are insufficient to accurately evaluate this pathway in biological specimens where lower UC is expected. Liver cell lines, including HepaRG, have been described to have limited nitrogen fixation through the UC, limiting their applicability as biocomponents for Bioartificial Livers (BAL). This work aims to develop novel and sensitive analytical solutions using Mass Spectrometry-based methodology to measure the activity of four UC enzymes in human liver and HepaRG cells. Activity of carbamoyl-phosphate synthetase I (CPS I), ornithine transcarbamylase (OTC), argininosuccinate lyase (ASL) and arginase (ARG I and II) was determined on homogenates from normal human liver and HepaRG cells cultured in monolayer or in the AMC-BAL. Enzyme products were determined by stable-isotope dilution UPLC-MS/MS. Activity of CPS I, OTC and ARG I/II enzymes in HepaRG monolayer cultures was considerably lower than in human control livers albeit an increase was achieved in HepaRG-BAL cultures. Improved analytical assays developed for the study of UC enzyme activity, contributed to gain understanding of UC function in the HepaRG cell line. The decreased activity of CPS I suggests that it may be a potential rate-limiting factor underlying the low UC activity in this cell line.

Dimensional and discrete variations on the psychosis continuum in a Dutch crowd-sourcing population sample.

BACKGROUND: Mild psychotic experiences are common in the general population. Although transient and benign in most cases, these experiences are predictive of later mental health problems for a significant minority. The goal of the present study was to perform examinations of the dimensional and discrete variations in individuals' reporting of subclinical positive and negative psychotic experiences in a unique Dutch internet-based sample from the general population. METHODS: Positive and negative subclinical psychotic experiences were measured with the Community Assessment of Psychic Experiences in 2870 individuals. First, the prevalence of these experiences and their associations with demographics, affect, psychopathology and quality of life were investigated. Next, latent class analysis was used to identify data-driven subgroups with different symptom patterns, which were subsequently compared on aforementioned variables. RESULTS: Subclinical psychotic experiences were commonly reported. Both positive and negative psychotic experiences were associated with younger age, more negative affect, anxiety and depression as well as less positive affect and poorer quality of life. Seven latent classes ('Low psychotic experiences', 'Lethargic', 'Blunted', 'Distressed', 'Paranormal', 'Distressed/grandiose' and 'Distressed/positive psychotic experiences') were identified that demonstrated both dimensional differences in the number/severity of psychotic experiences and discrete differences in the patterns of reported experiences. CONCLUSION: Subclinical psychotic experiences show both dimensional severity variations and discrete symptom-pattern variations across individuals. To understand and capture all interindividual variations in subclinical psychotic experiences, their number, nature and context (co-occurrence patterns) should be considered at the same time. Only some psychotic experiences may lay on a true psychopathological psychosis continuum.

Novel PEX3 Gene Mutations Resulting in a Moderate Zellweger Spectrum Disorder.

BACKGROUND: Peroxisome biogenesis disorders (PBDs) may have a variable clinical expression, ranging from severe, lethal to mild phenotypes with progressive evolution. PBDs are autosomal recessive disorders caused by mutations in PEX genes, which encode proteins called peroxins, involved in the assembly of the peroxisome. Patient Description: We herein report a patient who is currently 9 years old and who is compound heterozygous for two novel mutations in the PEX3 gene. RESULTS: Mild biochemical abnormalities of the peroxisomal parameters suggested a Zellweger spectrum defect in the patient. Sequence analysis of the PEX3 gene identified two novel heterozygous, pathogenic mutations. CONCLUSION: Mutations in PEX3 usually result in a severe, early lethal phenotype. We report a patient compound heterozygous for two novel mutations in the PEX3 gene, who is less affected than previously reported patients with a defect in the PEX3 gene. Our findings indicate that PEX3 defects may cause a disease spectrum similar as previously observed for other PEX gene defects.

Casting wider nets for anxiety and depression: disability-driven cross-diagnostic subtypes in a large cohort.

BACKGROUND: In search of empirical classifications of depression and anxiety, most subtyping studies focus solely on symptoms and do so within a single disorder. This study aimed to identify and validate cross-diagnostic subtypes by simultaneously considering symptoms of depression and anxiety, and disability measures. METHOD: A large cohort of adults (Lifelines, n = 73 403) had a full assessment of 16 symptoms of mood and anxiety disorders, and measurement of physical, social and occupational disability. The best-fitting subtyping model was identified by comparing different hybrid mixture models with and without disability covariates on fit criteria in an independent test sample. The best model's classes were compared across a range of external variables. RESULTS: The best-fitting Mixed Measurement Item Response Theory model with disability covariates identified five classes. Accounting for disability improved differentiation between people reporting isolated non-specific symptoms ['Somatic' (13.0%), and 'Worried' (14.0%)] and psychopathological symptoms ['Subclinical' (8.8%), and 'Clinical' (3.3%)]. Classes showed distinct associations with clinically relevant external variables [e.g. somatization: odds ratio (OR) 8.1-12.3, and chronic stress: OR 3.7-4.4]. The Subclinical class reported symptomatology at subthreshold levels while experiencing disability. No pure depression or anxiety, but only mixed classes were found. CONCLUSIONS: An empirical classification model, incorporating both symptoms and disability identified clearly distinct cross-diagnostic subtypes, indicating that diagnostic nets should be cast wider than current phenomenology-based categorical systems.

Polyunsaturated fatty acid status in treated isovaleric acidemia patients.

BACKGROUND/OBJECTIVES: Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with isovaleric acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. SUBJECTS/METHODS: We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. RESULTS: The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P<0.001) and omega-6 (in particular 20:3n-6 P<0.0001 and 20:4n-6 P=0.0005) fatty acids. In addition, an elevation in omega-9 fatty acids, with the exception of 20:3n-9 and C22:1n-9, was not suggestive of complete essential fatty acid deficiency but rather indicative of isolated and/or combined omega-3 and omega-6 fatty acid depletion. CONCLUSIONS: This study emphasizes the potential nutritional insufficiencies that may occur because of therapeutic intervention in IVA.

Two Novel Mutations in the SLC25A4 Gene in a Patient with Mitochondrial Myopathy.

In a 28-year-old male with a mild mitochondrial myopathy manifesting as exercise intolerance and early signs of cardiomyopathy without muscle weakness or ophthalmoplegia, we identified two novel mutations in the SLC25A4 gene: c.707G>C in exon 3 (p.(R236P)) and c.116_137del in exon 2 (p.(Q39Lfs*14)). Serum lactate levels at rest were elevated (12.7 mM). Both the patient's father and brother were heterozygous carriers of the c.707G>C mutation and were asymptomatic. The second mutation causes a 22 bp deletion leading to a frame shift likely giving rise to a premature stop codon and nonsense-mediated decay (NMD). The segregation of the mutations could not be tested directly as the mother had died before. However, indirect evidence from NMD experiments showed that the two mutations were situated on two different alleles in the patient. This case is unique compared to other previously reported patients with either progressive external ophthalmoplegia (PEO) or clear hypertrophic cardiomyopathy with exercise intolerance and/or muscle weakness carrying recessive mutations leading to a complete absence of the SLC25A4 protein. Most likely in our patient, although severely reduced, SLC25A4 is still partially present and functional.

Rhabdomyolysis: review of the literature.

Rhabdomyolysis is a serious and potentially life threatening condition. Although consensus criteria for rhabdomyolysis is lacking, a reasonable definition is elevation of serum creatine kinase activity of at least 10 times the upper limit of normal followed by a rapid decrease of the sCK level to (near) normal values. The clinical presentation can vary widely, classical features are myalgia, weakness and pigmenturia. However, this classic triad is seen in less than 10% of patients. Acute renal failure due to acute tubular necrosis as a result of mechanical obstruction by myoglobin is the most common complication, in particular if sCK is >16.000 IU/l, which may be as high as 100,000 IU/l. Mortality rate is approximately 10% and significantly higher in patients with acute renal failure. Timely recognition of rhabdomyolysis is key for treatment. In the acute phase, treatment should be aimed at preserving renal function, resolving compartment syndrome, restoring metabolic derangements, and volume replacement. Most patients experience only one episode of rhabdomyolysis, mostly by substance abuse, medication, trauma or epileptic seizures. In case of recurrent rhabdomyolysis, a history of exercise intolerance or a positive family history for neuromuscular disorders, further investigations are needed to identify the underlying, often genetic, disorder. We propose a diagnostic algorithm for use in clinical practice.

Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters.

Hyperammonemia is a frequent finding in various organic acidemias. One possible mechanism involves the inhibition of the enzyme N-acetylglutamate synthase (NAGS), by short-chain acyl-CoAs which accumulate due to defective catabolism of amino acids and/or fatty acids in the cell. The aim of this study was to investigate the effect of various acyl-CoAs on the activity of NAGS in conjunction with the formation of glutamate esters. NAGS activity was measured in vitro using a sensitive enzyme assay with ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) product analysis. Propionyl-CoA and butyryl-CoA proved to be the most powerful inhibitors of N-acetylglutamate (NAG) formation. Branched-chain amino acid related CoAs (isovaleryl-CoA, 3-methylcrotonyl-CoA, isobutyryl-CoA) showed less pronounced inhibition of NAGS whereas the dicarboxylic short-chain acyl-CoAs (methylmalonyl-CoA, succinyl-CoA, glutaryl-CoA) had the least inhibitory effect. Subsequent work showed that the most powerful inhibitors also proved to be the best substrates in the formation of N-acylglutamates. Furthermore, we identified N-isovalerylglutamate, N-3-methylcrotonylglutamate and N-isobutyrylglutamate (the latter two in trace amounts), in the urines of patients with different organic acidemias. Collectively, these findings explain one of the contributing factors to secondary hyperammonemia, which lead to the reduced in vivo flux through the urea cycle in organic acidemias and result in the inadequate elimination of ammonia.

Radiation-induced oesophagitis in lung cancer patients. Is susceptibility for neutropenia a risk factor?

BACKGROUND: Radiation-induced oesophagitis is a major side effect of concurrent chemotherapy and radiotherapy. A strong association between neutropenia and oesophagitis was previously shown, but external validation and further elucidation of the possible mechanisms are lacking. METHODS AND PATIENTS: A total of 119 patients were included at two institutions. The concurrent group comprised 34 SCLC patients treated with concurrent carboplatin and etoposide, and concurrent chest irradiation, and 36 NSCLC patients with concurrent cisplatin and etoposide, and concurrent radiotherapy, while the sequential group comprised 49 NSCLC patients received sequential cisplatin and gemcitabine, and radiotherapy. RESULTS: Severe neutropenia was very frequent during concurrent chemoradiation (grade: 4 41.4%) and during induction chemotherapy in sequentially treated patients (grade 4: 30.6%), but not during radiotherapy (only 4% grade 1). In the concurrent group, the odds ratios of grade 3 oesophagitis vs. neutropenia were the following: grade 2 vs. grade 0/1: 5.60 (95% CI 1.55-20.26), p = 0.009; grade 3 vs. grade 0/1: 10.40 (95% CI 3.19-33.95); p = 0.0001; grade 4 vs. grade 0/1: 12.60 (95% CI 4.36-36.43); p < 0.00001. There was no correlation between the occurrence of neutropenia during induction chemotherapy and acute oesophagitis during or after radiotherapy alone. In the univariate analysis, total radiation dose (p < 0.001), overall treatment time of radiotherapy (p < 0.001), mean oesophageal dose (p = 0.038) and neutropenia (p < 0.001) were significantly associated with the development of oesophagitis. In a multivariate analysis, only neutropenia remained significant (p = 0.023). CONCLUSION: We confirm that neutropenia is independently correlated with oesophagitis in concurrent chemoradiation, but that the susceptibility for chemotherapy-induced neutropenia is not associated with radiation-induced oesophagitis. Further studies focusing on the underlying mechanisms are thus warranted.

The inflammatory response in acyl-CoA oxidase 1 deficiency (pseudoneonatal adrenoleukodystrophy).

Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids exhibited increased mRNA expression of IL-1α and IL-1ß cytokines. Furthermore, expression of IL-6 and IL-8 cytokines in patient fibroblasts was down-regulated by MAPK, p38MAPK, and Jun N-terminal kinase inhibitors. Thus, the absence of acyl-coenzyme A oxidase 1 activity in P-NALD fibroblasts triggers an inflammatory process, in which the IL-1 pathway seems to be central. The use of specific kinase inhibitors may permit the modulation of the enhanced inflammatory status.

MRI as diagnostic tool in early-onset peroxisomal disorders.

OBJECTIVE: Peroxisomal blood tests are generally considered to be conclusive. We observed several patients with a clinical and MRI phenotype suggestive of an infantile onset peroxisomal defect, but no convincing abnormalities in initial peroxisomal blood tests. Brain MRI showed typical abnormalities as observed in the neonatal adrenoleukodystrophy variant of infantile peroxisomal disorders. Our aim was to evaluate the accuracy of this MRI diagnosis with further peroxisomal testing. METHODS: We searched our database of unclassified leukoencephalopathies and found 6 such patients. We collected clinical data and scored available MRIs of these patients. We performed further peroxisomal studies in fibroblasts, including immunofluorescence microscopy analysis with antibodies against catalase, a peroxisomal matrix enzyme. We performed complementation analysis and analyzed the suspected genes. RESULTS: We confirmed the diagnosis of Zellweger spectrum disorder in 3 patients and D-bifunctional protein deficiency in the others. The clinical findings were within the spectrum known for these diagnoses. Sequential MRIs showed that the abnormalities started in the hilus of the dentate nucleus and superior cerebellar peduncles. Subsequently, the cerebellar white matter and brainstem tracts were affected, followed by the parieto-occipital white matter, splenium of the corpus callosum, and posterior limb of the internal capsule. Eventually, all cerebral white matter became abnormal. The thalamus was typically affected as well. CONCLUSIONS: If MRI reveals abnormalities suggestive of infantile onset peroxisomal defects, negative peroxisomal blood tests do not exclude the diagnosis. Further tests in fibroblasts should be performed, most importantly immunofluorescence microscopy analysis with antibodies against catalase to stain peroxisomes.

Clinical variability of isovaleric acidemia in a genetically homogeneous population.

Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.

[Sjögren-Larsson syndrome: 2 case reports]. / Le syndrôme de Sjögren-Larsson: à propos de 2 cas.

UNLABELLED: Sjögren-Larsson syndrome (SLS) is a neurocutaneous autosomal recessive disease caused by fatty aldehyde dehydrogenase (FADH) deficiency. This enzyme is involved in the biosynthesis pathways of some fatty acids, phytanic acid, and leukotrienes. The main features of the disease are its association with congenital ichthyosis, mental retardation, and spastic tetraplegia. METHODS: We report on the diagnostic and therapeutic management of 2 cases of SLS. RESULTS: The diagnosis of SLS was suspected in the first patient at 2 years of age before the clinical triad appeared and confirmed at 4 years of age by the culture of fibroblasts and the peak of lipids on 1.3 ppm spectroscopy. After 3 months of treatment with zileuton, an inhibitor of leukotriene synthesis, moderate clinical efficacy for pruritus and ichthyosis was observed. The second patient was diagnosed at 1 year of age with the association of psychomotor retardation and congenital ichthyosis, in accordance with acute Guillain-Barré syndrome. Diagnosis was confirmed with enzymology, and cerebral spectro-MRI featured an abnormal lipidic peak. Zileuton therapy was initiated at the time of diagnosis and was effective for pruritus after 6 months of treatment. CONCLUSION: We report 2 cases of SLS with delayed diagnosis, due to non neonatal symptoms. Treatment with zileuton shows partial efficacy especially in pruritus. The uncommon association of this rare dysmyelinating disease with Guillain-Barré syndrome in the second patient is discussed.

High prevalence of short-chain acyl-CoA dehydrogenase deficiency in the Netherlands, but no association with epilepsy of unknown origin in childhood.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.

Preadipocytes of type 2 diabetes subjects display an intrinsic gene expression profile of decreased differentiation capacity.

OBJECTIVE: Insulin resistance and type 2 diabetes mellitus (T2DM) are associated with increased adipocyte size, altered secretory pattern and decreased differentiation of preadipocytes. In this study, we identified the underlying molecular processes in preadipocytes of T2DM patients, a characteristic for the development of T2DM. DESIGN AND PARTICIPANTS: Preadipocyte cell cultures were prepared from subcutaneous fat biopsies of seven T2DM patients (age 53 ± 12 years; body mass index (BMI) 34 ± 5 kg m(-2)) and nine control subjects (age 51 ± 12 years; BMI 30 ± 3 kg m(-2)). Microarray analysis was used to identify altered processes between the T2DM and control preadipocytes. RESULTS: Gene expression profiling showed changed expression of transcription regulators involved in adipogenesis and in extracellular matrix remodeling, actin cytoskeleton and integrin signaling genes, which indicated decreased capacity to differentiate. Additionally, genes involved in insulin signaling and lipid metabolism were downregulated, and inflammation/apoptosis was upregulated in T2DM preadipocytes. CONCLUSION: Decreased expression of genes involved in differentiation can provide a molecular basis for the reduced adipogenesis of preadipocytes of T2DM subjects, leading to reduced formation of adipocytes in subcutaneous fat depots, and ultimately leading to ectopic fat storage.

Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01).

BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL). PATIENTS AND METHODS: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC-Radiation Therapy Oncology Group Late Effects Normal Tissue-Subjective, Objective, Management, Analytic scale was used for clinicians' assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose. RESULTS: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005). CONCLUSION: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.

3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy.

OBJECTIVE: 3-Methylglutaconic aciduria type I is a rare inborn error of leucine catabolism. It is thought to present in childhood with nonspecific symptoms; it was even speculated to be a nondisease. The natural course of disease is unknown. METHODS: This is a study on 10 patients with 3-methylglutaconic aciduria type I. We present the clinical, neuroradiologic, biochemical, and genetic details on 2 new adult-onset patients and follow-up data on 2 patients from the literature. RESULTS: Two unrelated patients with the characteristic biochemical findings of 3- methylglutaconic aciduria type I presented in adulthood with progressive ataxia. One patient additionally had optic atrophy, the other spasticity and dementia. Three novel mutations were found in conserved regions of the AUH gene. In both patients, MRI revealed extensive white matter disease. Follow-up MRI in a 10-year-old boy, who presented earlier with isolated febrile seizures, showed mild abnormalities in deep white matter. CONCLUSION: We define 3-methylglutaconic aciduria type I as an inborn error of metabolism with slowly progressive leukoencephalopathy clinically presenting in adulthood. In contrast to the nonspecific findings in pediatric cases, the clinical and neuroradiologic pattern in adult patients is highly characteristic. White matter abnormalities may already develop in the first decades of life. The variable features found in affected children may be coincidental. Long-term follow-up in children is essential to learn more about the natural course of this presumably slowly progressive disease. Dietary treatment with leucine restriction may be considered.