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Dystonia, tremor, and parkinsonism in a 54 year old man with 2-hydroxyglutaric aciduria
  1. W E Owens,
  2. M S Okun
  1. University of Florida Movement Disorders Center, Department of Neurology, McKnight Brain Institute, McKnight Brain Institute, PO Box 100236, Gainesville FL 32610, USA;

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    Glutaric aciduria is often considered to be a rapidly progressing dementing illness with only occasional extrapyramidal symptoms, usually described as dystonia.1–7 We present a case of late onset 2-hydroxygluaric aciduria and slowly progressive dystonia and parkinsonism.

    Case report

    A 54 year old man was referred to the University of Florida movement disorders center for management of “end stage Parkinson’s disease”. He was diagnosed with developmental delay and mild cerebral palsy by his paediatrician, for a failure to meet motor milestones. He had below average grades in school and graduated high school two years behind his age matched peers. At age 26, he noticed a mild intention tremor in his right hand, a mild head tremor, and mild unsteadiness in walking. These were assumed to be potentially parkinsonian features, and later in his 30s he was given the assumed diagnosis of Parkinson’s disease. He was treated with levodopa, dopamine agonists, a monoamine oxidase inhibitor, and anticholinergics, which all failed to help his symptoms. He was gainfully employed by the city in a maintenance department until being fired in his mid-30s for incompetence. At the time of his clinic appointment, his mother noted progressive difficulty with swallowing, balance difficulties, and aggressive behaviour. There was no history of exposure to neuroleptics, and he did not smoke or drink alcohol. His brother also had a tremor.

    On neurological examination he was alert and oriented to person and place. His memory was tested (3/3 registration and 1/3 recall after five minutes). He had a hypophonic dysarthria with pallilalia. Gerstmann features (right/left confusion, finger anomia, acalculia, and agraphia) were all impaired. He had frontal release signs including a root, snout, grasp, and glabellar tap. He had frontal lobe impairment including problems with Luria 2 and 3 step command testing, anti-saccade testing, problems with crossed response inhibition, and motor impersistence. Stereognosis and graphesthesia were intact. Cranial nerve examination revealed only saccadic pursuit. He had a tongue tremor. Power, reflexes, and sensory examination 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 UPDRS score was unchanged (55). He had more dystonia in his hands while on his medications.

    His previous diagnostic evaluation included serological testing that had revealed a normal thyroid stimulating hormone concentration, normal liver function tests, normal ammonia concentration, and normal reactive plasma reagent. Head magnetic resonance imaging (MRI) had been performed one year before presentation and the flair images revealed prominent white matter hyperintensities in the frontal and parietal regions, with posterior ex vacuo dilatation of his lateral ventricles (fig 1), and mild cerebellar atrophy. Urine organic acids were sent and revealed 2-hydroxyglutaric aciduria.

    Figure 1

     Flair magnetic resonance images revealed prominent white matter hyperintensites in the frontal and parietal regions with posterior ex vacuo dilatation of his lateral ventricles.


    This case demonstrates that older patients with parkinsonism may have inborn errors of metabolism. Our patient was unique in that until his mid-20s and later when he lost his job in his mid-30s, he was assumed to have mild cerebral palsy, and only after developing other parkinsonian features was he later misdiagnosed as having Parkinson’s disease. The important clues that were missed in this patient were the developmental delay, the progression of symptoms leading to a mental incapacity to hold his job, and the parkinsonian features that were unresponsive to levodopa and other agents. In addition, his MRI, which was carried with him to the appointment, had changes indicative of glutaric aciduria. A differential diagnosis in this case should have included other non-levodopa responsive disorders that can present with movement disorders, such as proprionic acidaemia, methylmalonic aciduria, glutaric aciduria, and leucodystrophy. Given his relatively benign course, he probably has L-2-hydroxyglutaric aciduria and not D-2-hydroxyglutaric aciduria. Our patient unfortunately died as a result of an accident shortly after his evaluation, making confirmation of the L isoform impossible.

    2-Hydroxyglutaric aciduria is a rare inborn error of metabolism that was first recognised in the L isoform by Duran and colleagues1 and later defined clinically by Barth et al.2 There is less known about the molecular biology and underlying biochemical defect than in other amino acidurias. Further cases have been identified and have detailed clinical, biochemical, radiological, and pathological characteristics that have established a spectrum of the disease. Several subtypes have been identified and hydroxygluaric aciduria has been proposed to have an autosomal recessive inheritence, occurring in both D and L isoforms. Most of the cases reported in the literature are identified in early childhood. The D isoform usually presents with neonatal or early infantile encephalopathy, seizures, extrapyramidal symptoms, and cardiomyopathy.3,4 In contrast, the L isoform may present within the 1st years of life with non-specific motor delay, and later cognitive and motor developmental delay. Gait ataxia may occur as early as the 2nd year.5 Additional findings include occasional pyramidal and extrapyramidal features and dystonia, with a predilection for the hands. Progressive mental retardation is common in these patients. Most cases are diagnosed in childhood but Clerc et al,6 in 2000, reported an adult patient with tremor and excessive urinary excretion of L-2-hydroxyglutaric aciduria. Our case also highlights the possibility of this disorder presenting later in life with dystonia, tremor, and parkinsonism.

    Imaging and urine samples are very helpful in making this diagnosis. Neuroimaging findings in L-2-hydroxyglutaric aciduria reveal subcortical leucoencephalopathy (as seen in our case), and may also show atrophy of the cerebellum.2,5 Larnaout and colleagues7 performed a necropsy on a patient with childhood onset of cognitive and motor delay and epilepsy whose brother was diagnosed with L-2-hydroxyglutaric aciduria and they described the diffuse white matter changes as demyelination with spongiform, cavitating cystic lesions and cerebellar white matter gliosis. This pattern of involvement was consistent with the MRI results and was considered to be the typical spongiosis encountered in disorders of amino acid metabolism.

    The diagnosis of hydroxyglutaric aciduria is made by analysing urine samples with gas chromatography. The L isomer reveals a solitary peak of 2-hydroxyglutaric acid, whereas the D isomer may have other citric acid cycle intermediates present in addition to D-2-hydroxyglutaric acid.3 In the USA, testing is available for the urinary detection of 2-hydroxyglutaric acid, but unfortunately American laboratories are unable to distinguish between the L and the D isomer.

    This case reminds us that inborn errors of metabolism can be a cause of parkinsonism, and in selected cases an investigation should be performed with urine organic acids so that this diagnosis can be quickly made. With the emergence of new genetic therapies for biochemical diseases it may be important in the future to make this diagnosis early in the course of the disease.