L-2-Hydroxyglutaric aciduria diagnosed in an adult presenting with acute deterioration

Abstract

Sirs, A 31-year-old male with childhood diagnosis of undefined mild learning disability presented to the neurological services with a 3-week history of rapid cognitive decline, functional decompensation and progressive ataxia following a single, brief (\30 s), witnessed, generalised tonic– clonic seizure. Epilepsy was diagnosed 5-years prior to presentation following two generalised tonic–clonic seizures, after which he had remained seizure free with carbamazepine therapy. He was born after an uncomplicated full-term pregnancy and delivery. His parents were healthy and non-consanguineous. Speech and motor milestones were normal. Mild intellectual delay became apparent at 6 years of age when difficulty with schoolwork and inability to keep up with peers was noticed. He completed schooling thereafter in a special needs school. From 18 years of age he was in permanent employment and fully independent in activities of daily living (ADLs). In the 3-week period preceding presentation, he was unable to continue working or function independently, needing new assistance with most ADLs, e.g. dressing, bathing, etc. Throughout childhood he was noted to be clumsy, mildly unsteady and have difficulty playing sport. Preceding admission unsteadiness markedly deteriorated and slurring of speech developed, together with new tendency for repetitive speech. Short-term memory impairment also developed. Clinical examination revealed dysarthria, cerebellar ataxia, bilateral dysmetria, lower limb hypertonia, pathological hyper-reflexia with extensor plantar responses, sustained ankle clonus and frontal release signs. Muscle strength testing was normal. He had preserved registration but impaired 5-min recall (1/3), echolalia, perseveration and impaired Luria 3 step command testing. There was no dysmorphism or macrocephaly. MRI brain revealed marked subcortical leukoencephalopathy, subcortical white matter loss and cerebellar atrophy (Fig. 1). EEGs demonstrated symmetrical delta activity without epileptiform discharge, consistent with an encephalopathic/neurodegenerative process. Urinary organic acid testing demonstrated a marked increase in 2-hydroxyglutarate excretion. CSF organic acid testing revealed a 2-hydroxyglutarate peak. CSF amino acid analysis showed elevated lysine titres (82 lmol/L: Normal range 6–32 lmol/L), consistent with 2-hydroxyglutaric aciduria (2HGA). Urinary and CSF enantiomeric analysis showed an L-isomer of 2-hydroxyglutarate, confirming a diagnosis of L-2-hydroxyglutaric aciduria (L2HGA). Treatment administered included riboflavin 150 mg twice daily and carnitine 1 g twice daily. Thereafter clinical status stabilized and no further deterioration occurred. Clinical examination 1 year later remains unchanged. 2-Hydroxyglutaric aciduria is a rare, neurometabolic, autosomal recessive disorder of lysine metabolism. There are less than 20 adult reports of L2HGA (average age at time S. Saidha (&) S. Murphy M. Hennessy Department of Neurology, University College Hospital, Galway, Ireland e-mail: shivsaidha@hotmail.com