Clinically asymptomatic adult patient with extensive LBSL MRI pattern and DARS2 mutations

Abstract

Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL) is defined by (a) a recessive inheritance, (b) a slowly progressive spinocerebellar syndrome, and (c) signal abnormalities of various tracts on magnetic resonance imaging (MRI) involving the corpus callosum, the pyramidal tracts, the brainstem, the cerebellar peduncles, the mesencephalic trigeminal tract, the cerebellar white matter, and the dorsal columns of the spinal cord [1–3]. LBSL is associated with mutation in the DARS2 gene, encoding for mitochondrial aspartyl-tRNA synthetase (mtAspRS) [4]. We report the first asymptomatic adult patient with a typical MRI aspect of LBSL associated with a new DARS2 mutation. The index case, a 23-year-old French Caucasian woman, without medical or family history, had progressive walking difficulties since the age of four. Clinical examination showed spastic paraparesis, mixed proprioceptive and cerebellar ataxia, and intention tremor in both upper limbs. She was able to walk 500 m without help. Brain and spinal MRI revealed a typical aspect of LBSL (Fig. 1a), and the presence of high lactate levels in the abnormal cerebral white matter on magnetic resonance spectroscopy (MRS). Sequence analysis of the DARS2 gene [4] revealed compound heterozygous mutations, i.e. a 228-16C[G mutation located in the stretch of C residues just upstream of exon 3 and a second novel missense mutation c.745C[A in exon 8 (Fig. 2). To study the deleterious effect of the mutations, we further analysed the first degree relatives of the index case (parents, two brothers of age 30 and 36, and one sister of age 28), after the patient’s written consent was obtained. Clinical examination was strictly normal in all relatives including vibration sense in the lower limbs. Direct genomic sequencing of exons 3 and 8 showed a heterozygote state in the father (c.745C[A mutation), the mother (228-16C[G mutation), and the two brothers (c.745C[A mutation). The 28-year-old asymptomatic sister had heterozygote composite mutations (228-16C[G P. Labauge (&) Department of Neurology, CHU Nimes, Hopital Caremeau, 2 Avenue du Pr Debre, 30029 Nimes Cedex 4, France e-mail: labauge@yahoo.fr