Long Survival in Leigh Syndrome: New Cases and Review of Literature

Abstract

Leigh syndrome (MIM 25600), also known as infantile subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder with characteristic bilateral symmetric lesions in basal ganglia and subcortical brain regions. It is commonly associated with systemic cytochrome c oxidase (COX) deficiency and mutations in the SURF1 gene (MIM 185620), encoding a putative assembly or maintenance factor of COX. The clinical course is dominated by neurodevelopmental regression, brain stem, and basal ganglia involvement (e.g., dystonia, apnea) with death often occurring before the age of 10 years. Herein, we present three sisters carrying a previously reported homozygous SURF1 mutation (c.868_869insT) that is predicted to result in a truncated protein with loss of function. Our patients show heterogeneous clinical findings with different distribution patterns of metabolic lesions in brain magnetic resonance imaging (MRI) as well as a Chiari malformation with hydrocephalus in one patient. However, all three siblings show an unusual long survival (12 years and>16 years). COX activity was not detectable in one patient and strongly reduced in the other two. We discuss these findings with respect to a review of the literature. A total of 15 additional patients with survival>14 years have been reported so far. Overall, no clear genotype-phenotype correlations are detectable among these patients.

Mitochondrial Fatty Acid Oxidation Disorders Associated with Short-Chain Enoyl-CoA Hydratase (ECHS1) Deficiency

“…The clinical presentation of ECHS1D is typified by Leigh syndrome (subacute necrotizing encephalomyelopathy) or Leigh-like syndrome, with symptoms including (but not limited to) developmental delay, dystonia, metabolic acidosis, cardiomyopathy and apnea. Leigh syndrome is a progressive neurodegenerative disease characterized by bilateral symmetric brain lesions and psychomotor regression [ 36 ], and is not typically observed in other FAO disorders [ 37 ]. Leigh syndrome has been associated with more than 75 genes, mostly involved in OXPHOS complex I structure and assembly [ 38 ].…”

Human diseases associated with defects in assembly of OXPHOS complexes

“…Very few missense mutations have been detected [ 90 ], sometimes in association with less severe phenotypes [ 91 ]. Nevertheless, no clear genotype–phenotype correlations are detectable amongst these patients [ 92 ]. Even amongst subjects who showed an unusual long survival, COX activity was not detectable or strongly reduced, including cases harboring a SURF1 variant that abolish the initiation codon [ 93 ].…”

Profiling and identification of new proteins involved in brain ischemia using MALDI-imaging-mass-spectrometry

“…These controversies may reflect the dependence of the process on the time of ischemia and reperfusion [66]. Deficiencies in COX function, expression or assembly have been related with other diseases such as the mitochondrial disorders Leigh Syndrome [67], neonatal hypertrophic cardiomyopathy [68] or early-onset leukodystrophic encephalopathy [69].…”