Dear Sirs,A13 -year-old girl was seen at the Neurology and Med-ical Genetics Clinics with delayed milestones, macro-cephaly and developmental regression. She had no historyof perinatal complications other than delivery via cesareansection because of breech presentation. Over the preceding2 years she had developed nystagmus, occurring 4–5 timesa week. She had staring spells but had a normal EEG. Hermilestones, which included standing at 18 months of age,first words at 2 years of age, walking at 2 years of age,and writing letters at 6–7 years of age, were delayed. Herdevelopmental regression included enuresis, day time lossof bladder control and use of incorrect words for identifi-cation. Her gait had become unsteady, speech less under-standable because of mumbling, and she experiencedintermittent difficulty in recognizing her mother. Herfamily history was unremarkable with no consanguinity.On examination she had macrocephaly, mild facial coars-ening, thick eye brows, dark coarse hair, mild synophrys,thick lips, high arched palate, low anterior and posteriorhairline, intermittent tonic up gaze, nystagmus, and hypo-tonia with normal muscle bulk. MRI of the brain (Fig. 1)showed enlarged extra-axial spaces, hypoplastic temporallobes, open Sylvian fissures, mild ventriculomegaly andenlarged perivascular spaces. Skeletal survey was normal.Additional laboratory work up including lactic acid,pyruvic acid, mitochondrial respiratory enzyme analysis,CoQ10 levels, neurotransmitter profile (5-methyltetrahy-drofolate, 5-hydroxyindoleacetic acid, homovanillic acid,3-O-methyldopa, neopterin, tetrahydrobiopterin, succinyl-adenosine and pyridoxal 5 phosphate), karyotype, chro-mosomal microarray (44K custom Agilent platform),plasma amino acids and acylcarnitine profile was normal.Urine organic acid analysis revealed significant 2-hydrox-yglutaric aciduria, which was confirmed to be the