Leukoencephalopathy with brain stem and spinal cord involvement (and high lactate): raising the bar for diagnosis.

Leukoencephalopathy with brain stem and spinal cord involvement and high lactate (LBSL) is an autosomal recessive condition first recognized in 2003, characterized by progressive cerebellar ataxia, spasticity, and frequent involvement of the dorsal columns [1–7]. Decreased mitochondrial aspartyl-tRNA synthetase (mtAspRS) activity secondary to either compound heterozygosity or rarely homozygous mutations involving the DARS2 gene underlie the disease [3, 5–7]. Individuals affected by LBSL show distinctive changes on MRI including diffuse T2 hyperintensities and/or T1 hypointensities involving the cerebral white matter, corticospinal tracts and dorsal columns, variable involvement of the medial lemniscus, cerebellar peduncles, and splenium of the corpus callosum [1–7]. Though an increased lactate peak on MRS is commonly noted in the lesions many individuals with genetically confirmed LBSL fail to show this [1, 2, 4]. Though first described as a progressive disease of childhood onset, five cases with either symptom onset in adulthood or genetic and imaging diagnosis without symptoms have been published (Table 1) [1, 2, 4–6]. We present a patient with symptomatic onset at the age of 35 years, the oldest age of initial symptom manifestations yet described. A 45-year-old female presented for neurological evaluation, because of progressive difficulty walking since the age of 35 years. The patient was born to non-consanguineous parents and has three older asymptomatic siblings. Pregnancy, delivery, and early development were normal. At the age of 35 years, the patient began experiencing right lower extremity spasticity which had slowly progressed over 10 years prior to her initial evaluation. On physical examination mild weakness in the right iliopsoas was noted. There was reduced proprioceptive and vibratory sensation as well as hyperactive reflexes in the lower extremities, right greater than left. The upper extremities were normal. Plantar response was extensor on the right, flexor on the left. There was also an asymmetric spasticity in the lower extremities. An MRI of the spine showed non-enhancing linear T1 hypointensities and T2 hyperintensities involving the bilateral dorsal columns and lateral corticospinal tracts (Fig. 1 a1, b2). MRI of the head showed similar lesions throughout the centrum semiovale, splenium of the corpus callosum, and bilateral corticospinal tracts throughout their course (Fig. 1 c–f). MRS showed no lactate peak, minimal elevation of choline, and normal N-acetyl aspartate. Testing for inflammatory, demyelinating, metabolic, paraneoplastic and infectious etiologies was negative in both serum and cerebrospinal fluid. Because of the symmetry of the lesions noted on MRI a genetic cause was suspected. Mutation analysis of the DARS2 gene revealed a compound heterozygous state for two mutations. The first was a splice site mutation, c.492?2T[C, that has been shown to result in exon skipping within the DARS2 gene and has been previously associated with LBSL [3]. The second was a novel mutation in exon 5 resulting in a valine substitution for a highly conserved glutamic acid at position 158 (c.473A[T, p.Glu158Val) and was predicted by PholyPhen-2 (http:// genetics.bwh.harvard.edu/pph2/dokuwiki/downloads) to Ralitza H. Gavrilova has full access to all of the data and has the right to publish any and all data separate and apart from any sponsor.