Compound Heterozygous DARS2 Mutations as a Mimic of Hereditary Spastic Paraplegia
2021-05-17

Compound heterozygous and sometimes homozygous mutations in the DARS2 gene have been described as a cause of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL; Online Mendelian Inheritance in Man: 611105).1, 2 LBSL is characterized by progressive spasticity, ataxia, and dorsal column dysfunction usually starting during childhood or adolescence combined with distinct leukoencephalopathy of the brainstem and spinal cord.3 Here we describe 2 brothers with isolated, slowly progressive spastic paraparesis, proprioceptive dysfunction, and an onset in adulthood mimicking hereditary spastic paraplegia (HSP). Patient L-15088 (Fig. 1D), a 44-year-old man, had noticed leg weakness when playing soccer at aged 18 years. His walking distance decreased gradually, and he described muscle cramps after extensive exercise. In the neurological examination, he presented with spastic paraparesis (4/5 on the Medical Research Council scale), brisk muscle tendon reflexes of the lower extremities, bilateral Babinski signs, and spastic-ataxic gait (modified Ashworth scale, 2). Vibration sensation was absent in the lower extremities, and positional sense was impaired. Walking distance was 20 m without and 500 m with walking aids (see Video 1). The 50-year-old brother L-15089 noticed reduced leg strength during marches in military training at the age of 19 years. He additionally described urinal urge symptoms. On examination, L-15089 was slightly less affected than L-15088 with an unaided walking distance of 200 m. Symptoms and leg spasticity were more pronounced on the left body side (modified Ashworth scale, 2; see Video 2). In both brothers, there was no cognitive dysfunction nor brainstem or cranial nerve involvement. In 2007, diagnostic workup in both brothers identified T2*-signal alterations in the cervical spine and white matter gliosis in the brain. Review of the previous cranial and spinal cord magnetic resonance imaging (MRI) in 2020 revealed T2 and fluid-attenuated inversion recovery signal alterations typical and highly specific for LBSL4 in both patients (Fig. 1A–C). Cerebrospinal fluid analysis in L-15088 showed no abnormalities including normal lactate levels. Notably, blood lactate levels were mildly elevated (Table 1). Electrophysiological examinations revealed an axonal polyneuropathy in both brothers. Furthermore, genetic testing in L-15088 was negative for Friedreich ataxia and several forms of HSP (hereditary spastic paraplegia 3, 4, 5, 7). Exome sequencing identified compound heterozygous variants in the DARS2 gene in both brothers including a paternally inherited, novel intronic variant (c.228-21T>C) and a maternally inherited missense variant (c.536G>A; p.Arg179His), previously reported in 6 patients with LBSL3-5 (Fig. 1E). Notably, the intronic variant is located in a mutational hotspot, and almost all patients (n = 113/120) carry a base pair substitution in this specific region.1, 3 Supporting previous reports,1, 6 we demonstrated altered splicing (skipping of exon 3) in the 3 carriers of c.228-21T>C (both patients and the father). Notably, the splice alteration affects only a minority of transcripts as indicated by low abundance of the corresponding alternative sequence (Fig. 1E). In contrast to previous reports of other intronic changes in this region, we do not see major indication of nonsense-mediated mRNA decay of the allele with the intronic c.228-21T>C variant because both the maternal and paternal alleles that can be differentiated at the position of the missense variant (c.536) are present at comparable levels (Fig. 1E). Based on the clinical presentation (Table 1), the typical MRI changes (Fig. 1A–C), and the genotype (Fig. 1D), a diagnosis of LBSL was made in both brothers. Here we report 2 brothers suffering from LBSL attributed to compound-heterozygous DARS2 mutations. Although a few previously reported patients had isolated spastic paraparesis7-9 and polyneuropathy10 as in our brothers, most other patients presented with additional cerebellar ataxia and oculomotor abnormalities including nystagmus. However, clinical information in Table 1 also highlights the importance of missing data (e.g. information on Babinski sign available in only 7/134 patients) in publications, which sometimes hinders valid phenotype–genotype correlations. Importantly, based on the variable phenotypic expressivity, the term LBSL seems no longer appropriate because the increase of lactate is only present in a minority of cases and a presentation as a HSP is part of the phenotypic DARS2 spectrum. Furthermore, this case underlines the importance of a re-review of MRIs. T1-hypointensities and T2-hyperintensities are typically present in the corticospinal tract, medial lemniscus, and dorsal columns as well as the cerebral white matter. In the latter, signal abnormalities are either spotty or if confluent, spare the subcortical white matter.11 This specific pattern or others of rare diseases can be missed or misinterpreted by nonexperts, leading to delay or even prevention of the correct diagnosis. The authors thank the patients and the family for the participation in this study as well as the Damp Foundation and the Clinician Scientist School Lübeck for their support. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. M.G.P.: 1A, 1B, 1C, 3A Y.H.: 1C, 3B K.G.-H.: 1C, 3B F.H.: 1C, 3B K.L.: 1A, 1B, 1C, 3B N.B.: 1A, 1B, 1C, 3B Approval of an institutional review board was not required for this work. The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Written consent for participation and publication was obtained from the patients. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The study was supported by the German Research Foundation (FOR2488), the German Research Foundation via the Clinician Scientist School Lübeck (DFG-GEPRIS 413535489), and the Damp Foundation. The authors do not declare any conflicts of interest or competing interests. Martje G. Pauly is funded by the Clinician Scientist School Lübeck. Yorck Hellenbroich has nothing to report. Kathrin Grundmann-Hauser has nothing to report. Frauke Hinrichs has nothing to report. Katja Lohmann received research funding from the German Research Foundation, the Damp-Stiftung and the Movement Disorders Society and is member of the GP2 initiative within ASAP (https://parkinsonsroadmap.org/gp2/). Norbert Brüggemann served as a consultant for Censa Pharmaceuticals, Centogene, and Bridgebio and is funded by the German Research Foundation (BR4328.2-1, GRK1957).