Fed Univ São Paulo UNIFESP, Dept Neurol & Neurosurg, Div Gen Neurol, BR-04023900 São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Neurol & Neurosurg, Div Gen Neurol, BR-04023900 São Paulo, BrazilWeb of Scienc

Pinto, Wladimir Bocca Vieira de Rezende

Souza, Paulo Victor Sgobbi de

Brain

Pinto, Wladimir Bocca Vieira de Rezende [UNIFESP]

Souza, Paulo Victor Sgobbi de [UNIFESP]

Repositório Institucional UNIFESP

BRAINA JOURNAL OF NEUROLOGYLETTER TO THE EDITORDARS2 gene clinical spectrum: new ideas regarding an underdiagnosedleukoencephalopathyWladimir Bocca Vieira de Rezende Pinto and Paulo Victor Sgobbi de SouzaDivision of General Neurology, Department of Neurology and Neurosurgery, Federal University of Sa˜o Paulo (UNIFESP), Sa˜o Paulo, SP, BrazilCorrespondence to: Wladimir Bocca Vieira de Rezende Pinto, MD,Department of Neurology and Neurosurgery,Division of General Neurology,Federal University of Sa˜o Paulo (UNIFESP),Pedro de Toledo Street,650, 04023-900.Sa˜o Paulo SP,BrazilE-mail: wladimirbvrpinto@gmail.comSir,We have read with great interest the article entitled‘Leukoencephalopathy with brainstem and spinal cord involvementand lactate elevation: clinical and genetic characterization andtarget for therapy’ in the April issue of Brain (Van Berge et al.,2014). The authors present new data regarding clinical, neuroima-ging and genetic findings linked to leukoencephalopathy withbrainstem and spinal cord involvement and lactate elevation(LBSL; MIM #611105), an autosomal recessive inherited leukoen-cephalopathy caused by compound heterozygous mutations in theDARS2 gene (1q25.1), which codes the mitochondrial aspartyl-tRNA synthetase. LBSL represents one of the typical early-onsetleukodystrophies mainly affecting children and juvenile patientswith a slow progressive cerebellar ataxia with spastic paraparesis(or sometimes only retained reflexes) and findings suggestive of aposterior cord syndrome (Van der Knaap et al., 2003). Epilepsy,learning disabilities, axonal peripheral neuropathy (Yamashitaet al., 2013) and mild cognitive compromise have also beendescribed, although asymptomatic late-onset cases and radiologic-ally diagnosed patients have also been related. Typical neuroima-ging pattern is represented by diffuse symmetric non-enhancinginhomogeneous lesions, hyperintense in T2-weighted images andhypointense in T1-weighted images, with preponderant supraten-torial periventricular and subcortical cerebellar lesions, sparing Ufibres. The lateral corticospinal tracts, the medullary pyramids, theposterior limb of internal capsule, the spinal cord dorsal columns,the medial lemniscos, the intraparenchymal trigeminal pathways,the cerebellar peduncles, the splenium of corpus callosum are alsotypically involved. The leukodystrophic lesions generally present inmagnetic resonance spectroscopy with high lactate peaks(Steenweg et al., 2011), although this finding is not pathogno-monic or required to diagnose LBSL (Sharma et al., 2011). Highlactate in CSF is rarely found.The authors made a comprehensive and expanded analysis ofclinical features in 66 patients with LBSL (Van Berge et al., 2014).They revealed that only 12% of patients start their disease afterthe age of 18 years, mainly in females. This group showed a slowprogression and most patients presented mild to moderate motorcompromise. They also showed cases of early-onset, generallywith a severe motor phenotype similar to a previous Japanesestudy (Miyake et al., 2011), but also a nearly asymptomatic nurs-ling with neuroradiological and molecular diagnosis of LBSL.Most patients had compound heterozygous mutations.Although classically thought as lethal in humans, homozygosityfor a DARS2 mutation was described in this study in severeearly-onset cases, and also in a previous study of a 25-year-oldGerman female with a paroxysmal recurrent exercise-induced gaitataxia (Synofzik et al., 2011). Evaluation also disclosed mild distalposition and vibration sense deficits, hyper-reflexia and mild spas-ticity. Neuroimaging changes resembled those typical of LBSL andlaboratory evaluation showing intermittent increases in serum lac-tate. This patient also presented with an acetazolamide-responsiveepisodic ataxia phenotype, resembling the clinical phenotype ofclassical autosomal dominant episodic ataxias.Taking into account all the previous literature data and findingsof this new study, we propose the use of a new descriptivedoi:10.1093/brain/awu134 Brain 2014: 137; 1–2 | e289Advance Access publication May 24, 2014 The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.For Permissions, please email: journals.permissions@oup.com by guest on June 3, 2016http://brain.oxfordjournals.org/Downloaded from nomenclature more related to the mutated gene, so-called the‘DARS2-related conditions’ or ‘DARS2-related spectrum disorders’.We believe that the use of this broader nomenclature may repre-sent properly the clinical and neuroimaging findings of patientswith different mutations from a single gene. This approach mayalso contribute to enrich our knowledge regarding LBSLpathogenesis.The authors also started a new therapeutic approach usingdirect antisense oligonucleotide cantharidin, an important splicingmodulator, affecting the intron 2/exon 3 event splicing, the mostcommonly affected in LBSL. Despite promising results, we proposenew therapeutic approaches regarding the use of acetazolamideand other carbonic anhydrase partial inhibitors for patients whopresent with typical LBSL phenotype or with DARS2 mutationssimilarly to the episodic ataxia phenotype previously described(Synofzik et al., 2011).ReferencesMiyake N, Yamashita S, Kurosawa K, Miyatake S, Tsurusaki Y, Doi H,et al. A novel homozygous mutation of DARS2 may cause a severeLBSL variant. Clin Genet 2011; 80: 293–6.Sharma S, Sankhyan N, Kumar A, Scheper GC, van der Knaap MS,Gulati S. Leukoencephalopathy with brain stem and spinal cord in-volvement and high lactate: a genetically proven case without elevatedwhite matter lactate. J Child Neurol 2011; 26: 773–6.Steenweg ME, Pouwels PJ, Wolf NI, van Wieringen WN, Barkhof F, vander Knaap MS. Leucoencephalopathy with brainstem and spinal cordinvolvement and high lactate: quantitative magnetic resonance ima-ging. Brain 2011; 134: 3333–41.Synofzik M, Schicks J, Lindig T, Biskup S, Schmidt T, Hansel J, et al.Acetazolamide-responsive exercise-induced episodic ataxia associatedwith a novel homozygous DARS2 mutation. J Med Genet 2011; 48:713–15.Van Berge L, Hamilton EM, Linnankivi T, Uziel G, Steenweg ME,Isohanni P, et al. Leukoencephalopathy with brainstem and spinalcord involvement and lactate elevation: clinical and genetic character-ization and target for therapy. Brain 2014; 137: 1019–29.Van der Knaap MS, Van der Voorn P, Barkhof F, Van Coster R,Kra¨geloh-Mann I, Feigenbaum A, et al. A new leukoencephalopathywith brainstem and spinal cord involvement and high lactate. AnnNeurol 2003; 53: 252–8.Yamashita S, Miyake N, Matsumoto N, Osaka H, Iai M, Aida N, et al.Neuropathology of leukoencephalopathy with brainstem and spinalcord involvement and high lactate caused by a homozygous mutationof DARS2. Brain Dev 2013; 35: 312–16.e289 | Brain 2014: 137; 1–2 Letter to the Editor by guest on June 3, 2016http://brain.oxfordjournals.org/Downloaded from 

DARS2 gene clinical spectrum: new ideas regarding an underdiagnosed leukoencephalopathy

Wladimir Bocca Vieira de Rezende Pinto

Paulo Victor Sgobbi de Souza

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DARS2 gene clinical spectrum: new ideas regarding an underdiagnosed leukoencephalopathy

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