Original Communication

Journal of Neurology

, Volume 258, Issue 3, pp 440-448

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Heterogeneous patterns of tissue injury in NARP syndrome

  • Jeffrey M. GelfandAffiliated withDepartment of Neurology, University of California
  • , Jacque L. DuncanAffiliated withDepartment of Ophthalmology, University of California
  • , Caroline A. RacineAffiliated withDepartment of Neurology, University of California
  • , Leslie A. GillumAffiliated withDepartment of Neurology, University of California
  • , Cynthia T. ChinAffiliated withDepartment of Radiology, University of California
  • , Yuhua ZhangAffiliated withSchool of Optometry, University of California
  • , Qing ZhangAffiliated withDepartment of Medical and Molecular Genetics, School of Medicine, Indiana University
  • , Lee-Jun C. WongAffiliated withDepartment of Molecular and Human Genetics, Baylor College of Medicine
  • , Austin RoordaAffiliated withSchool of Optometry, University of California

Abstract

Point mutations at m.8993T>C and m.8993T>G of the mtDNA ATPase 6 gene cause the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome, a mitochondrial disorder characterized by retinal, central and peripheral neurodegeneration. We performed detailed neurological, neuropsychological and ophthalmological phenotyping of a mother and four daughters with NARP syndrome from the mtDNA m.8993T>C ATPase 6 mutation, including 3-T brain MRI, spectral domain optical coherence tomography (SD-OCT), adaptive optics scanning laser ophthalmoscopy (AOSLO), electromyography and nerve conduction studies (EMG-NCS) and formal neuropsychological testing. The degree of mutant heteroplasmy for the m.8993T>C mutation was evaluated by real-time allele refractory mutation system quantitative PCR of mtDNA from hair bulbs (ectoderm) and blood leukocytes (mesoderm). There were marked phenotypic differences between family members, even between individuals with the greatest degrees of ectodermal and mesodermal heteroplasmy. 3-T MRI revealed cerebellar atrophy and cystic and cavitary T2 hyperintensities in the basal ganglia. SD-OCT demonstrated similarly heterogeneous areas of neuronal and axonal loss in inner and outer retinal layers. AOSLO showed increased cone spacing due to photoreceptor loss. EMG-NCS revealed varying degrees of length-dependent sensorimotor axonal polyneuropathy. On formal neuropsychological testing, there were varying deficits in processing speed, visual–spatial functioning and verbal fluency and high rates of severe depression. Many of these cognitive deficits likely localize to cerebellar and/or basal ganglia dysfunction. High-resolution retinal and brain imaging in NARP syndrome revealed analogous patterns of tissue injury characterized by heterogeneous areas of neuronal loss.

Keywords

Mitochondrial disorders Neuroophthalmology Neuropsychology Cerebellar disease Neuropathy