SHORT COMMUNICATION A homozygous mutation in the NDUFS1 gene presents with a mild cavitating leukoencephalopathy Alireza Kashani & Isabelle Thiffault & Marie-Emmanuelle Dilenge & Christine Saint-Martin & Kether Guerrero & Luan T. Tran & Eric Shoubridge & Marjo S. van der Knaap & Nancy Braverman & Geneviève Bernard Received: 20 May 2014 /Accepted: 9 June 2014 # Springer-Verlag Berlin Heidelberg 2014 Abstract We report a case of mild cavitating leukoencephalopathy associated with a homozygous c.755A > G (p.Asp252Gly) NDUFS1 mutation in a 7-year old boy. Biochemical analysis confirmed an isolated reduc- tion in complex I activity. Magnetic resonance imaging of the brain showed a diffuse cystic leukoencephalopathy with the involvement of the corpus callosum and sparing of the gray matter. The clinical course was marked by an acute presentation of neurological deficits at 24 months followed by recurrent episodes of mild neurological deterioration, subsequent remissions, and prolonged periods of stability. This is one of the mildest known clinical presentations of complex I deficiency secondary to mutations in NDUFS1, expanding the clinical spectrum and natural history of this disorder. Consideration of clinical variability needs to be taken into account in patient management and family counseling. Keywords Complex I deficiency . NDUFS1 . Progressive cavitating encephalopathy . Leukodystrophy Introduction Respiratory chain complex I deficiency is the most frequently observed defect in childhood onset mitochondrial diseases. Defects in complex I are genetically heterogeneous and clin- ically associated with a wide range of presentations, including marked and often fatal lactic acidosis with cardiomyopathy, Leigh syndrome, myopathy, hepatopathy, renal tubular dys- function, stroke-like episodes (MELAS), and leukodystrophy [1, 2]. The majority of affected individuals present during the first year of life and have a rapidly progressive and fatal course [1, 3, 2]. NDUFS1 encodes one of the 14 highly conserved core subunits of complex I. Seven of these core subunits are encoded by mitochondrial DNA, while the other seven, in- cluding NDUFS1, are encoded by nuclear DNA. NDUFS1 mutations are the most common nuclear DNA abnormality reported in patients with complex I deficiency [1]. Up to now, 13 NDUFS1 mutations have been identified [1, 4, 5, 2, 6, 7]. Although NDUFS1 mutations most com- monly present with a severe and rapidly progressive leukoencephalopathy, milder presentations have also been reported, and no genotype–phenotype correlation has been identified [5, 3, 2, 6, 8, 7]. Here, we present a 7-year old boy with a homozygous missense c.755A > G (p.Asp252Gly) mutation in NDUFS1 , a mild clinical course, and a A. Kashani (*) : I. Thiffault : M.<E. Dilenge : K. Guerrero : L. T. Tran : G. Bernard Departments of Pediatrics, Neurology and Neurosurgery, Montreal Children’ s Hospital, McGill University Health Center, 2300 Tupper Street, Montreal, QC H3H 1P3, Canada e-mail: ali.kashani@mail.mcgill.ca I. Thiffault Department of Genetics, CHU-Sainte-Justine, Université de Montréal, Montreal, Canada C. Saint-Martin Department of Radiology, Montreal Children’ s Hospital, McGill University Health Center, Montreal, Canada E. Shoubridge Department of Genetics, McGill University and Montreal Neurological Institute, Montreal, Canada M. S. van der Knaap Department of Child Neurology, VU University Medical Center, and Neuroscience Campus, Amsterdam, The Netherlands N. Braverman Department of Genetics, McGill University, Montreal, Canada N. Braverman Department of Pediatrics, Montreal Children’ s Hospital, Montreal, Canada Neurogenetics DOI 10.1007/s10048-014-0412-2