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Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.

ABSTRACT: Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), as well as the identification of compound-heterozygous and homozygous mutations in cytoplasmic aspartyl-tRNA synthetase (DARS). These mutations cause nonsynonymous changes to seven highly conserved amino acids, five of which are unchanged between yeast and man, in the DARS C-terminal lobe adjacent to, or within, the active-site pocket. Intriguingly, HBSL bears a striking resemblance to leukoencephalopathy with brain stem and spinal cord involvement and elevated lactate (LBSL), which is caused by mutations in the mitochondria-specific DARS2, suggesting that these two diseases might share a common underlying molecular pathology. These findings add to the growing body of evidence that mutations in tRNA synthetases can cause a broad range of neurologic disorders.

SUBMITTER: Taft RJ

PROVIDER: S-EPMC3644624 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.

Taft Ryan J RJ Vanderver Adeline A Leventer Richard J RJ Damiani Stephen A SA Simons Cas C Grimmond Sean M SM Miller David D Schmidt Johanna J Lockhart Paul J PJ Pope Kate K Ru Kelin K Crawford Joanna J Rosser Tena T de Coo Irenaeus F M IF Juneja Monica M Verma Ishwar C IC Prabhakar Prab P Blaser Susan S Raiman Julian J Pouwels Petra J W PJ Bevova Marianna R MR Abbink Truus E M TE van der Knaap Marjo S MS Wolf Nicole I NI

American journal of human genetics 20130501 5

Inherited white-matter disorders are a broad class of diseases for which treatment and classification are both challenging. Indeed, nearly half of the children presenting with a leukoencephalopathy remain without a specific diagnosis. Here, we report on the application of high-throughput genome and exome sequencing to a cohort of ten individuals with a leukoencephalopathy of unknown etiology and clinically characterized by hypomyelination with brain stem and spinal cord involvement and leg spast ...[more]

PMID: 23643384

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Project description:Key pointsDamage to corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). Here, we examined to what extent residual corticospinal connections and spasticity are present in muscles below the injury (quadriceps femoris and soleus) in humans with motor complete thoracic SCI. We found three distinct subgroups of people: participants with spasticity and corticospinal responses in the quadriceps femoris and soleus; participants with spasticity and corticospinal responses in the quadriceps femoris only; and participants with no spasticity or corticospinal responses in either muscle. Spasticity and corticospinal responses were present in the quadriceps but never only in the soleus muscle, suggesting a proximal to distal gradient of symptoms of hyperreflexia. These results suggest that concomitant patterns of residual corticospinal connectivity and spasticity exist in humans with motor complete SCI and that a clinical examination of spasticity might be a good predictor of residual descending motor pathways in people with severe paralysis.AbstractThe loss of corticospinal axons has implications for the development of spasticity following spinal cord injury (SCI). However, the extent to which residual corticospinal connections and spasticity are present across muscles below the injury remains unknown. To address this question, we tested spasticity using the Modified Ashworth Scale and transmission in the corticospinal pathway by examining motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the leg motor cortex (cortical MEPs) and by direct activation of corticospinal axons by electrical stimulation over the thoracic spine (thoracic MEPs), in the quadriceps femoris and soleus muscles, in 30 individuals with motor complete thoracic SCI. Cortical MEPs were also conditioned by thoracic electrical stimulation at intervals allowing their summation or collision. We found three distinct subgroups of participants: 47% showed spasticity in the quadriceps femoris and soleus muscles; 30% showed spasticity in the quadriceps femoris muscle only; and 23% showed no spasticity in either muscle. Although cortical MEPs were present only in the quadriceps in participants with spasticity, thoracic MEPs were present in both muscles when spasticity was present. Thoracic electrical stimulation facilitated and suppressed cortical MEPs, showing that both forms of stimulation activated similar corticospinal axons. Cortical and thoracic MEPs correlated with the degree of spasticity in both muscles. These results provide the first evidence that related patterns of residual corticospinal connectivity and spasticity exist in muscles below the injury after motor complete thoracic SCI and highlight that a clinical examination of spasticity can predict residual corticospinal connectivity after severe paralysis.

Dataset Information

Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.

Publications

Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity.

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