Adult-onset Leigh Syndrome: An analysis of the North American Mitochondrial Disease Consortium Database
Emanuele Barca1, Adam Kroopnick1, Alexander Houck1, Kiran Thakur1, Rachelle Dugue2, Zarazuela Zolkipli-Cunningham3, Marni Falk3, Amy Goldstein3, Matthew Demczko3, Ralitza Gavrilova4, Austin Larson5, Johan Van Hove5, Russell Saneto6, Richard Buchsbaum7, John Thompson7, Michio Hirano1
1Columbia University Irving Medical Center, 2Stanford University, 3The Children's Hospital of Philadelphia, 4Mayo Clinic, 5Children`s Hospital Colorado, 6Seattle Childrens Hospital, 7Columbia Univ School of Public Health
Objective:
This analysis of Adult-Onset Leigh Syndrome (LS) patients from the North American Mitochondrial Disease Consortium (NAMDC) Registry aims to enhance clinical insights, improve diagnoses, and uncover potential modifiers
Background:
LS is a rare syndrome linked to defects in more than one hundred genes. Most LS patients develop subacute neurological deterioration or regression before age two years. The pathological and radiological hallmarks are the subacute necrotizing degeneration of basal ganglia, cerebellum, brainstem, and/or cervical spinal cord, frequently triggered by metabolic stress. A small group of patients develop central nervous system involvement later in life.
Design/Methods:
This retrospective study stemmed from a case of a twenty-five-year-old man with mild developmental delay and sensory-motor neuropathy admitted for worsening weakness. During his hospital stay, he developed a rapidly progressive encephalopathy and classic LS radiological findings. Intrigued by this observation, we interrogated the NAMDC registry to retrieve data from other adult-onset LS individuals. The registry contains demographic, manifestation, genetic, imaging, and biochemistry data from more than 2100 subjects enrolled from 17 centers in North America and Canada.
Results:
We identified six subjects with onset of CNS manifestations after age 18. Most of the subjects had been involved of other organ systems preceding the CNS lesions. Four probands had pathogenic variants in nuclear-encoded mitochondria metabolism genes, one in mitochondrial DNA-encoded ATP synthase subunit gene, and one patient remained genetically undefined. The disease progression varied among the cohort, with probands harboring nuclear variants experiencing a slower course compared to the individual with a mitochondrial DNA defect, who suffered a rapid, progressive, and fatal deterioration.
Conclusions:
Our data show that mitochondrial patients with LS experience evolving and progressive phenotypes, and the presence of manifestations in other organs often precedes LS in adults, suggesting that clinicians should carefully avoid metabolic stressors known to precipitate neurodegeneration in subjects with the observed genetic variants.