Clinicoradiological Spectrum of L-2-Hydroxy Glutaric Aciduria: Typical and Atypical Findings in an Indian Cohort

Abstract

Context: Neurometabolic disorders form an important group of potentially treatable diseases. It is important to recognize the clinical phenotype and characteristic imaging patterns to make an early diagnosis and initiate appropriate treatment. L-2-hydroxy glutaric aciduria (L2HGA) is a rare organic aciduria with a consistent and highly characteristic imaging pattern, which clinches the diagnosis in most cases. Aims: The study aims to describe the clinical profile, magnetic resonance imaging (MRI) patterns, and outcome in a cohort of children with L2HGA and to assess the clinicoradiological correlation. Materials and Methods: This is a retrospective descriptive study done at the Department of Radiodiagnosis and Neurological Sciences of our institution. Clinical and radiological findings of children diagnosed with L2HGA over an 8-year period (2010–2017) were collected and analyzed. Descriptive statistical analysis of clinical and imaging data was performed. Results: There were six girls and four boys. A total of 14 MRI brain studies in 10 patients with the diagnosis were analyzed. MRI of all patients showed a similar pattern with extensive confluent subcortical white-matter signal changes with symmetrical involvement of dentate nuclei and basal ganglia. In two children who presented with acute decompensation, there was asymmetric cortical involvement and restricted diffusion, which are previously unreported. There was no significant correlation between the radiological pattern with the disease duration, clinical features, or course of the disease. Conclusion: MRI findings in L2HGA are highly consistent and diagnostic, which helps in early diagnosis, particularly in resource-constraint settings, where detailed metabolic workup is not possible. The article also describes novel clinical radiological profile of acute encephalopathic clinical presentation.

Screening for Inherited Metabolic Disorders by Tandem Mass Spectrometry May Miss L-2 Hydroxy Glutaric Aciduria: A Report of Two Cases

“…12 The mildly raised serum ceruloplasmin levels may be attributed to acute-phase reaction and raised urine copper due to renal derangement. Unlike previous case series in which all patients have been diagnosed with increased serum or urinary excretion of L-2HG, 4 8 9 our patients did not show abnormalities in the metabolic screening. Urinary excretion of L-2HG can be lower in patients with homozygous or compound heterozygous pathogenic missense variants than null variants, possibly due to residual enzyme activity.…”

“…Imaging shows signal abnormalities in the dentate nucleus and cerebral white matter with characteristic sparing of subcortical white matter. 9 In this report, we present two patients with similar features of intellectual disability and seizures. Patients presented to us in the adolescent age.…”

“…Imaging shows signal abnormalities in the dentate nucleus and cerebral white matter with characteristic sparing of subcortical white matter. 9…”

“…The mean age at diagnosis in the previous case series was in childhood between 1 and 10 years. 8 9 Patients described by Fujitake et al 10 and Goffette et al 11 were diagnosed in the adult age group. However, all of them had an insidious onset of developmental delay in childhood, similar to our patients.…”

In Silico Analysis of the L-2-Hydroxyglutarate Dehydrogenase Gene Mutations and Their Biological Impact on Disease Etiology

“…The inception of L2HGA is also different, e.g., it might be either congenital with severe seizures and intellectual disability or might occur in middle age with mild features, which is an issue that may result in a delayed diagnosis of L2HGA [9][10][11]. Many studies have reported that elevated levels of L-2-hydroxyglutaric acid in the brain, probably linked with higher levels of lysine in the blood, may cause brain tumors [3,12,13].…”