Intra-familial phenotypic heterogeneity in a Sudanese family with DARS2-related leukoencephalopathy, brainstem and spinal cord involvement and lactate elevation: a case report
Ashraf Yahia,
Liena Elsayed,
Arwa Babai,
Mustafa A. Salih,
Sarah Misbah El-Sadig,
Mutaz Amin,
Mahmoud Koko,
Rayan Abubakr,
Razaz Idris,
Shaimaa Omer M.A. Taha,
Salah A. Elmalik,
Alexis Brice,
Ammar Eltahir Ahmed,
Giovanni Stevanin
Affiliations
Ashraf Yahia
Department of Biochemistry, Faculty of Medicine, University of Khartoum
Liena Elsayed
Department of Biochemistry, Faculty of Medicine, University of Khartoum
Arwa Babai
Institute of Endemic Diseases, University of Khartoum
Mustafa A. Salih
Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University
Sarah Misbah El-Sadig
Department of Medicine, Faculty of Medicine, University of Khartoum
Mutaz Amin
Department of Biochemistry, Faculty of Medicine, University of Khartoum
Mahmoud Koko
Department of Neurology & Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen
Rayan Abubakr
Institute of Endemic Diseases, University of Khartoum
Razaz Idris
Institute of Endemic Diseases, University of Khartoum
Shaimaa Omer M.A. Taha
Department of Radiology, Dar Al Elaj specialized hospital
Salah A. Elmalik
Department of Physiology, College of Medicine, King Saud University
Alexis Brice
Department of Genetics, APHP, Pitié-Salpêtrière Hospital
Ammar Eltahir Ahmed
Department of Physiology, Faculty of Medicine, University of Khartoum
Giovanni Stevanin
Ecole Pratique des Hautes Etudes, EPHE, PSL Research University
Abstract 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 limb spasticity, cerebellar ataxia and involvement of the dorsal column. The disease is caused by mutations in the DARS2 gene but has never been reported in sub-Saharan Africa so far. Case presentation Two siblings, 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 the proband identified two compound heterozygous variants (NM_018122.4:c.1762C > G and c.563G > A) in DARS2. Sanger sequencing confirmed the presence of the mutations and their segregation in trans in both patients and in their elder sister (aged 20 years), who showed only brisk reflexes and mild lower limb spasticity. Surprisingly, in contrast to her subtle clinical presentation, the elder sister had abnormal MRI features and serum lactate levels comparable to her ill sisters. 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. This may have implications for the detection of mutation carriers in LBSL.
