Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report
Ashraf Yahia1,9,12, Liena Elsayed1*, Arwa Babai2, Mustafa A. Salih3, Sarah Misbah El-Sadig4,8, Mutaz Amin1, Mahmoud Koko5, Rayan Abubakr2, Razaz Idris2, Shaimaa Omer M.A. Taha6, Salah A. Elmalik13, Alexis Brice11,12, Ammar Eltahir Ahmed7,8, Giovanni Stevanin10,12
1Department of Biochemistry, Faculty of Medicine, University of Khartoum, Sudan.
2Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
3Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
4Department of Medicine, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
5Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany.
6Department of Radiology, Dar Al Elaj specialized hospital, Khartoum, Sudan.
7Department of Physiology, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.
8Department of Neurology, Soba University Hospital, Khartoum, Sudan.
9Department of Biochemistry, Faculty of Medicine, National University, Sudan.
10Ecole Pratique des Hautes Etudes, EPHE, PSL Research University, Paris, France.
11APHP Pitié-Salpêtrière Hospital, Department of genetics, Paris, France.
12Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne
13Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
* Corresponding author
Background: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL, OMIM # 611105) is a genetic disease of the central nervous system characterized by lower limbs spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in DARS2 gene but has never been reported in Sub-Saharan Africa so far.
Case presentation: Two siblings, currently aged 18 years and 15 years, from a consanguineous family presented with pyramidal signs and symptoms since infancy and developmental delay. Whole exome sequencing of a proband patient identified two compound heterozygous variants (NM_018122.4:c.1762C>G and c.563G>A) in DARS2 gene. Sanger sequencing confirmed the segregation of these variants in trans in both patients and further identified one asymptomatic patient (aged 20 years) who showed only brisk reflexes and mild lower limb spasticity. In contradistinction to the subtle clinical presentation, the latter had an abnormal MRI features and serum lactate levels comparable to her symptomatic siblings.
Conclusion: This report illustrates intra-familial phenotypic variation in LBSL and provides an example of a marked dissociation between the clinical and radiological phenotypes of the disease. Screening relatives of LBSL patients can detect asymptomatic cases and might have implications for counseling.