Writer’s cramp as a presentation of L-2-hydroxyglutaric aciduria
© Termsarasab and Frucht.; licensee BioMed Central Ltd. 2014
Received: 3 July 2014
Accepted: 26 September 2014
Published: 11 December 2014
L-2-hydroxyglutaric aciduria (L2HGA) is a neurometabolic disorder characterized by macrocephaly, seizures, progressive mental retardation, pyramidal signs, ataxia and tremor. Dystonia is an under-recognized feature of this entity in the literature. We report two siblings with L2HGA, one of whom presented with writer’s cramp followed by dystonia of the other hand. An elevated plasma lysine, highly elevated urine 2-hydroxyglutaric acid, and MRI with characteristic findings (leukoencephalopathy of bilateral subcortical white matter sparing central white matter) suggested the diagnosis, which was confirmed by genetic testing.
L-2-hydroxyglutatric aciduria (L2HGA) is a neurometabolic disorder in the family of cerebral organic acid disorders, examples of which include glutaric aciduria type I, saccharopinuria, 2-amino-/2-oxo-adipic aciduria, D-2-hydroxyglutaric aciduria and Canavan’s disease (N-acetylaspartic aciduria) . L2HGA is an autosomal recessive disorder with the defective gene encoding a Flavin Adenine Dinucleotide (FAD)-dependent L-2-hydroxyglutarate dehydrogenase. The typical clinical presentation includes macrocephaly and progressive neurologic signs such as febrile and afebrile seizures, cerebellar deficits (gait and limb ataxia), speech problems, learning disabilities and developmental delay, and pyramidal signs . Movement disorders described in the literature in these patients include tremor, dystonia and ataxia -. We present two siblings with L2HGA, one of whom presented with focal hand dystonia, to call attention to this unusual condition.
The proband is a 15-year-old Egyptian girl. She developed difficulty writing with her right hand at age 8. The problem started selectively with writing but soon spread to involve other tasks. She switched to writing with her left hand, and developed writing problem two years later. Subsequently she developed problems with other tasks including holding utensils and using a computer for school. She had slow developmental milestones and some cognitive impairment but no history of seizures. Her ethnic background is Egyptian/Turkish and Egyptian/Syrian on maternal and paternal sides respectively, with no known consanguinity.
The sister of patient one is sixteen. She had delayed developmental milestones starting in early childhood, but was not tested until her younger sister manifested the symptoms. On examination, she had mild kinetic tremor of both hands, and finger-to-nose test showed mild past-pointing. Her speech was mildly scanning with no dysarthria. She could not perform tandem walking. There was no evidence of dystonia.
MRI of the brain showed findings similar to the proband, and genetic testing also revealed the same mutation as the proband. She is also on riboflavin but on no medication for tremor.
The diagnosis of L2HGA is usually considered when plasma amino acid and urine organic screening tests show elevated lysine and 2-hydroxyglutaric acid, respectively. We suspect that few movement disorder neurologists would consider L2HGA in a young patient with writer’s cramp. Indeed, lists of causes of secondary dystonia in major movement disorder textbooks do not even include this condition.
The phenomenology of movement disorders in L2HGA reported in the literature includes dystonia, tremor, ataxia and rarely myoclonus. Dystonia has been described affecting the hands and upper limbs . Tremor described in the literature is mostly intention tremor, similar to the intention tremor of case 2. Ataxia can affect either the trunk or limbs , and mild myoclonus in the upper extremity has been reported in one patient .
Although the most common initial presentation reported by Barth and colleagues were walking delay and gait abnormality (6 out of 8 patients), movement disorders may be under-recognized . Balaji et al. recently described 2 siblings with L2HGA, one of which with dystonia of the head, trunk and upper extremities, the other with dystonia of distal upper and lower extremities . In our patient (proband), the initial presentation that prompted her parents to bring her to medical attention was writer’s cramp. Focal task-specific dystonia of the arm is unusual in childhood outside of the setting of DYT-1 dystonia. It has also been reported in myoclonus-dystonia syndrome (DYT-11) , and X-linked dystonia-parkinsonism (DYT-3). Writer’s cramp has been reported as a presentation in a limited number of secondary dystonias in children such as basal ganglia arteriovenous malformations , basal ganglia infarction , Wilson’s disease, Huntington’s disease, pantothenate kinase-associated neurodegenration (PKAN), glutaric aciduria, GM1 gangliosidosis, and Leigh’s disease. L2HGA should be added to the list of secondary dystonias of childhood.
In the Krebs cycle, 2-ketoglutaric acid is usually catalyzed by the enzyme L-malate dehydrogenase to L-2-hydroxyglutaric acid. It has been proposed that L-2-hydroxyglutaric acid is an unwanted substrate which then requires a “repair” enzyme, L-2-hydroxyglutaric acid dehydrogenase, to shift it back to 2-ketoglutaric acid in the Krebs cycle . This “repair” enzyme is deficient in L2HGA. MRI findings in this disorder are unique, and once seen, are pathognomonic. The neuroradiologic differential diagnoses of leukoencephalopathy with grey matter signal abnormalities (with neuroanatomical structures involved in parenthesis) include Canavan’s disease (globus pallidi, dentate nuclei), L2HGA (basal ganglia, dentate nuclei), Alexander’s disease (deep grey matter, dentate hilum), GM1/GM2 gangliosidoses (basal ganglia), Krabbe’s disease (thalami, dentate nuclei), and maple syrup urine disease (thalami, globus pallidi) .
Although treatment options are limited in L2HGA, it is important to recognize this disorder as it is associated with malignant brain tumors such as glioblastoma and primitive neuroectodermal tumor , requiring close surveillance. Riboflavin treatment  and protein restriction may have a role, but data is limited. FAD and levocarnitine chloride were also reported as treatment options .
It is important to have a high index of suspicion of secondary dystonia when evaluating pediatric patients who initially present with upper extremity dystonia or writer’s cramp. We illustrate the example of this phenotype as an initial presentation of L2HGA.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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