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1362 J Neurol Neurosurg Psychiatry 2004;75:1362–1366 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from more dystonia in his hands while on his have been identified and hydroxygluaric LETTERS medications. aciduria has been proposed to have an His previous diagnostic evaluation autosomal recessive inheritence, occurring Dystonia, tremor, and included serological testing that had revealed in both D and L isoforms. Most of the cases a normal thyroid stimulating hormone con- reported in the literature are identified in parkinsonism in a 54 year old centration, normal liver function tests, nor- early childhood. The D isoform usually man with 2-hydroxyglutaric mal ammonia concentration, and normal presents with neonatal or early infantile aciduria reactive plasma reagent. Head magnetic encephalopathy, seizures, extrapyramidal resonance imaging (MRI) had been per- symptoms, and cardiomyopathy.34 In con- Glutaric aciduria is often considered to be a formed one year before presentation and the trast, the L isoform may present within the rapidly progressing dementing illness with flair images revealed prominent white matter 1st years of life with non-specific motor only occasional extrapyramidal symptoms, 1–7 hyperintensities in the frontal and parietal delay, and later cognitive and motor devel- usually described as dystonia. We present regions, with posterior ex vacuo dilatation of opmental delay. Gait ataxia may occur as a case of late onset 2-hydroxygluaric aciduria his lateral ventricles (fig 1), and mild early as the 2nd year.5 Additional findings and slowly progressive dystonia and parkin- cerebellar atrophy. Urine organic acids were sonism. include occasional pyramidal and extrapy- sent and revealed 2-hydroxyglutaric aciduria. ramidal features and dystonia, with a pre- dilection for the hands. Progressive mental Case report retardation is common in these patients. A 54 year old man was referred to the Discussion Most cases are diagnosed in childhood but University of Florida movement disorders This case demonstrates that older patients Clerc et al,6 in 2000, reported an adult patient center for management of ‘‘end stage with parkinsonism may have inborn errors of with tremor and excessive urinary excretion Parkinson’s disease’’. He was diagnosed with metabolism. Our patient was unique in that of L-2-hydroxyglutaric aciduria. Our case also developmental delay and mild cerebral palsy until his mid-20s and later when he lost his highlights the possibility of this disorder by his paediatrician, for a failure to meet job in his mid-30s, he was assumed to have presenting later in life with dystonia, tremor, mild cerebral palsy, and only after developing motor milestones. He had below average and parkinsonism. other parkinsonian features was he later grades in school and graduated high school Imaging and urine samples are very helpful misdiagnosed as having Parkinson’s disease. two years behind his age matched peers. At in making this diagnosis. Neuroimaging The important clues that were missed in this age 26, he noticed a mild intention tremor in findings in L-2-hydroxyglutaric aciduria patient were the developmental delay, the his right hand, a mild head tremor, and mild reveal subcortical leucoencephalopathy (as progression of symptoms leading to a mental unsteadiness in walking. These were seen in our case), and may also show atrophy assumed to be potentially parkinsonian fea- incapacity to hold his job, and the parkinso- 25 7 nian features that were unresponsive to of the cerebellum. Larnaout and colleagues tures, and later in his 30s he was given the performed a necropsy on a patient with assumed diagnosis of Parkinson’s disease. He levodopa and other agents. In addition, his MRI, which was carried with him to the childhood onset of cognitive and motor delay was treated with levodopa, dopamine ago- and epilepsy whose brother was diagnosed nists, a monoamine oxidase inhibitor, and appointment, had changes indicative of glutaric aciduria. A differential diagnosis in with L-2-hydroxyglutaric aciduria and they anticholinergics, which all failed to help his described the diffuse white matter changes as symptoms. He was gainfully employed by the this case should have included other non- levodopa responsive disorders that can pre- demyelination with spongiform, cavitating city in a maintenance department until being cystic lesions and cerebellar white matter fired in his mid-30s for incompetence. At the sent with movement disorders, such as copyright. proprionic acidaemia, methylmalonic acid- gliosis. This pattern of involvement was time of his clinic appointment, his mother consistent with the MRI results and was noted progressive difficulty with swallowing, uria, glutaric aciduria, and leucodystrophy. considered to be the typical spongiosis balance difficulties, and aggressive beha- Given his relatively benign course, he prob- encountered in disorders of amino acid viour. There was no history of exposure to ably has L-2-hydroxyglutaric aciduria and not metabolism. neuroleptics, and he did not smoke or drink D-2-hydroxyglutaric aciduria. Our patient The diagnosis of hydroxyglutaric aciduria is alcohol. His brother also had a tremor. unfortunately died as a result of an accident made by analysing urine samples with gas On neurological examination he was alert shortly after his evaluation, making confir- and oriented to person and place. His mation of the L isoform impossible. chromatography. The L isomer reveals a memory was tested (3/3 registration and 1/3 2-Hydroxyglutaric aciduria is a rare inborn solitary peak of 2-hydroxyglutaric acid, recall after five minutes). He had a hypo- error of metabolism that was first recognised whereas the D isomer may have other citric 1 phonic dysarthria with pallilalia. Gerstmann in the L isoform by Duran and colleagues acid cycle intermediates present in addition 2 3 features (right/left confusion, finger anomia, and later defined clinically by Barth et al. to D-2-hydroxyglutaric acid. In the USA, acalculia, and agraphia) were all impaired. There is less known about the molecular testing is available for the urinary detection He had frontal release signs including a root, biology and underlying biochemical defect of 2-hydroxyglutaric acid, but unfortunately http://jnnp.bmj.com/ snout, grasp, and glabellar tap. He had than in other amino acidurias. Further cases American laboratories are unable to distin- frontal lobe impairment including problems have been identified and have detailed guish between the L and the D isomer. with Luria 2 and 3 step command testing, clinical, biochemical, radiological, and patho- This case reminds us that inborn errors of anti-saccade testing, problems with crossed logical characteristics that have established a metabolism can be a cause of parkinsonism, response inhibition, and motor impersis- spectrum of the disease. Several subtypes and in selected cases an investigation should tence. Stereognosis and graphesthesia were intact. Cranial nerve examination revealed only saccadic pursuit. He had a tongue tremor. Power, reflexes, and sensory exam- on September 29, 2021 by guest. Protected ination were normal. On cerebellar examination he was hypermetric on finger to nose testing, with past pointing and ataxia. Movement disorder examination revealed prominent parkinsonian features including rigidity, bradykinesia, shuffling gait, and balance problems. His hands were mildly dystonic. He had mild bilateral postural intention tremors. His posture was stooped and he had decreased arm swing and shuffling steps. He retropulsed on a pull test and could not perform tandem gait. In addition, he had a masked face, pallilalia, and severe micrographia. His off medication Unified Parkinson’s Disease motor scale (UPDRS) examination was 55. After taking his usual medications (trihexphenidyl and selegiline) he was re-examined one hour later and his Figure 1 Flair magnetic resonance images revealed prominent white matter hyperintensites in the UPDRS score was unchanged (55). He had frontal and parietal regions with posterior ex vacuo dilatation of his lateral ventricles. www.jnnp.com J Neurol Neurosurg Psychiatry 2004;75:1362–1366 1363 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from be performed with urine organic acids so that detected on testing jaw opening against of eight seropositive subjects had a diagnosis this diagnosis can be quickly made. With the resistance, although her jaw hung slackly of ‘‘stroke’’ or ‘‘transient ischaemic attacks’’, emergence of new genetic therapies for open if not supported. Limb power and and the authors concluded that these biochemical diseases it may be important in reflexes were normal. patients might have been misdiagnosed. the future to make this diagnosis early in the Acetylcholine receptor antibodies (AchR- It is therefore possible that myasthenia course of the disease. abs) were strongly positive at 11 nmol/l gravis in the elderly is sometimes missed and (normal range 0 to 0.25 nmol/l). Other that the clinical course may in some cases be W E Owens, M S Okun autoantibodies were negative apart from a more benign than appreciated. University of Florida Movement Disorders Center, positive gastric parietal cell antibody. Department of Neurology, McKnight Brain Institute, Computed tomography of the mediastinum W W Y Wong, R J M Lane McKnight Brain Institute, PO Box 100236, Gainesville did not show any thymic abnormality.

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