Writer’s cramp as a presentation of L-2-hydroxyglutaric aciduria
Journal of Clinical Movement Disorders volume 1, Article number: 9 (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.
Physical examination revealed no macrocephaly. Eye movements were normal, and her speech was slightly scanning but not dysarthric. As soon as she picked up a pen to write, there was moderate to severe action dystonia in both arms, more prominent on the left. There was no null point or geste antagoniste (Figure 1 and Additional file 1). There was no rest or action tremor. There was mild dysmetria on finger-to-nose testing. Gait was normal.
Biochemical testing revealed elevated plasma lysine and highly elevated urine 2-hydroxyglutaric acid. Molecular genetic testing showed a heterozygous mutation in the L2HGDH gene – c.584A>G and c.1115delT. MRI of the brain revealed marked diffuse subcortical white matter abnormalities with hypointense and hyperintense signals on T1 and T2 images, and relative sparing of central white matter. There were also hyperintense signals in both dentate nuclei on T2 images (Figure 1A-E). MR spectroscopy revealed a high lactate peak and reduced N-acetylaspartate to creatine ratio (Figure 1F). She was treated with trihexyphenidyl up to 6 mg/day, but could not tolerate it due to the side effect of worsening cognition. The dose was reduced to 2 mg/day (Figure 2). She also takes riboflavin.
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.
Hoffmann GF, Kölker S: Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism. In Inborn Metabolic Diseases. 5th edition. Edited by: Saudubray J, Berghe G, Walter JH. Springer, Germany; 2012:333–347. 10.1007/978-3-642-15720-2_23
Barth PG, Hoffmann GF, Jaeken J, Lehnert W, Hanefeld F, van Gennip AH, Duran M, Valk J, Schutgens RB, Trefz FK, Reimann G, Hartung H-P: L-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992, 32: 66–71. 10.1002/ana.410320111
Moroni I, D’Incerti L, Farina L, Rimoldi M, Uziel G: Clinical, biochemical and neuroradiological findings in L-2-hydroxyglutaric aciduria. Neurol Sci 2000, 21: 103–108. 10.1007/s100720070104
Topcu M, Aydin OF, Yalcinkaya C, Haliloglu G, Aysun S, Anlar B, Topaloglu H, Turanli G, Yalnizoglu D, Kesimer M, Coskun T: L-2-hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr 2005, 47: 1–7.
Balaji P, Viswanathan V, Chellathurai A, Panigrahi D: An interesting case of metabolic dystonia: L-2 hydroxyglutaric aciduria. Ann Indian Acad Neurol 2014, 17: 97–99. 10.4103/0972-2327.128565
Gerrits MC, Foncke EM, de Haan R, Hedrich K, van de Leemput YL, Baas F, Ozelius LJ, Speelman JD, Klein C, Tijssen MA: Phenotype-genotype correlation in Dutch patients with myoclonus-dystonia. Neurology 2006, 66: 759–761. 10.1212/01.wnl.0000201192.66467.a3
Gerrits MC, Foncke EM, Koelman JH, Tijssen MA: Pediatric writer’s cramp in myoclonus-dystonia: maternal imprinting hides positive family history. Eur J Paediatr Neurol 2009, 13: 178–180. 10.1016/j.ejpn.2008.03.007
Kurita H, Sasaki T, Suzuki I, Kirino T: Basal ganglia arteriovenous malformation presenting as “writer’s cramp”. Childs Nerv Syst 1998, 14: 285–287. 10.1007/s003810050227
Liu GT, Carrazana EJ, Macklis JD, Mikati MA: Delayed oculogyric crises associated with striatocapsular infarction. J Clin Neuroophthalmol 1991, 11: 198–201.
Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C: Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis 2012, 35: 571–587. 10.1007/s10545-012-9462-5
Yang E, Prabhu SP: Imaging manifestations of the leukodystrophies, inherited disorders of white matter. Radiol Clin North Am 2014, 52: 279–319. 10.1016/j.rcl.2013.11.008
Moroni I, Bugiani M, D’Incerti L, Maccagnano C, Rimoldi M, Bissola L, Pollo B, Finocchiaro G, Uziel G: L-2-hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology 2004, 62: 1882–1884. 10.1212/01.WNL.0000125335.21381.87
Yilmaz K: Riboflavin treatment in a case with l-2-hydroxyglutaric aciduria. Eur J Paediatr Neurol 2009, 13: 57–60. 10.1016/j.ejpn.2008.01.003
Samuraki M, Komai K, Hasegawa Y, Kimura M, Yamaguchi S, Terada N, Yamada M: A successfully treated adult patient with L-2-hydroxyglutaric aciduria. Neurology 2008, 70: 1051–1052. 10.1212/01.wnl.0000287141.90944.95
Abramson C, Platt S, Garosi L, Penderis J: L-2-hydroxyglutaric aciduria in Staffordshire bull terriers. Vet Rec 2003, 153: 95–96.
Scurrell E, Davies E, Baines E, Cherubini GB, Platt S, Blakemore W, Williams A, Schoniger S: Neuropathological findings in a Staffordshire bull terrier with l-2-hydroxyglutaric aciduria. J Comp Pathol 2008, 138: 160–164. 10.1016/j.jcpa.2007.11.005
The authors declare that they have no competing interests.
PT participated in patient evaluation, drafting/revising the manuscript, video editing. SJF participated in patient evaluation, drafting/revising the manuscript, video editing and study concept. Both authors read and approved the final manuscript.
Electronic supplementary material
Additional file 1: Video 1. The speech of patient 1 was normal. There was dystonia of bilateral hands, left greater than right, with spooning of the fingers. She did not have tremor or ataxia. During writing, there was moderate extension of the right wrist and abduction of the right elbow. There was no mirror dystonia when she wrote with the left hand. There was excessive bilateral arm swing during walking. The latter segment of the video shows examination 3 months after she was treated with trihexyphenidyl 6 mg/day. She preferred to write with both hands. Writer’s cramp was slightly improved from the previous examination when she was allowed to write with only the right hand. Right focal hand dystonia was also mildly better when she held the pen between her right index and middle fingers. There was mild flexion of the left wrist when she wrote with her left hand. The dose of trihexyphenidyl was subsequently reduced due to cognitive side effects. (ZIP 11 MB)
About this article
Cite this article
Termsarasab, P., Frucht, S.J. Writer’s cramp as a presentation of L-2-hydroxyglutaric aciduria. J Clin Mov Disord 1, 9 (2014). https://doi.org/10.1186/s40734-014-0009-9