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A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate.
Marjo S van der Knaap, Patrick van der Voorn, Frederik Barkhof, Rudy Van Coster, Ingeborg Krägeloh-Mann, Annette Feigenbaum, Susan Blaser, Johan S H Vles, Peter Rieckmann, Petra J W Pouwels,
We identified eight patients with a distinct magnetic resonance imaging pattern of inhomogeneous cerebral white matter abnormalities and selective involvement of brainstem and spinal tracts. Proton magnetic resonance imaging showed increased lactate in the abnormal white matter. Clinically, the patients had slowly progressive pyramidal, cerebellar, and dorsal column dysfunction. The uniform, highly characteristic magnetic resonance imaging pattern and the similarities in clinical and magnetic resonance spectroscopy findings provide evidence for a new disease entity. Autosomal recessive inheritance is likely.
Annals of neurology - Feb 2003
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.
Laura van Berge, Eline M Hamilton, Tarja Linnankivi, Graziella Uziel, Marjan E Steenweg, Pirjo Isohanni, Nicole I Wolf, Ingeborg Krägeloh-Mann, Nils J Brautaset, P Ian Andrews, Brigit A de Jong, Malak al Ghamdi, Wessel N van Wieringen, Bakhos A Tannous, Esther Hulleman, Thomas Würdinger, Carola G M van Berkel, Emiel Polder, Truus E M Abbink, Eduard A Struys, Gert C Scheper, Marjo S van der Knaap, ,
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a disorder caused by recessive mutations in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. Recent observations indicate that the phenotypic range of the disease is much wider than initially thought. Currently, no treatment is available. The aims of our study were (i) to explore a possible genotype-phenotype correlation; and (ii) to identify potential therapeutic agents that modulate the splice site mutations in intron 2 of DARS2, present in almost all patients. A cross-sectional observational study was performed in 78 patients with two DARS2 mutations in the Amsterdam and Helsinki databases up to December 2012. Clinical information was collected via questionnaires. An inventory was made of the DARS2 mutations in these patients and those previously published. An assay was developed to assess mitochondrial aspartyl-tRNA synthetase enzyme activity in cells. Using a fluorescence reporter system we screened for drugs that modulate DARS2 splicing. Clinical information of 66 patients was obtained. The clinical severity varied from infantile onset, rapidly fatal disease to adult onset, slow and mild disease. The most common phenotype was characterized by childhood onset and slow neurological deterioration. Full wheelchair dependency was rare and usually began in adulthood. In total, 60 different DARS2 mutations were identified, 13 of which have not been reported before. Except for 4 of 42 cases published by others, all patients were compound heterozygous. Ninety-four per cent of the patients had a splice site mutation in intron 2. The groups of patients sharing the same two mutations were too small for formal assessment of genotype-phenotype correlation. However, some combinations of mutations were consistently associated with a mild phenotype. The mitochondrial aspartyl-tRNA synthetase activity was strongly reduced in patient cells. Among the compounds screened, cantharidin was identified as the most potent modulator of DARS2 splicing. In conclusion, the phenotypic spectrum of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is wide, but most often the disease has a relatively slow and mild course. The available evidence suggests that the genotype influences the phenotype, but because of the high number of private mutations, larger numbers of patients are necessary to confirm this. The activity of mitochondrial aspartyl-tRNA synthetase is significantly reduced in patient cells. A compound screen established a 'proof of principle' that the splice site mutation can be influenced. This finding is promising for future therapeutic strategies.
Brain : a journal of neurology - Apr 2014