Heterogeneous patterns of tissue injury in NARP syndrome

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-010-5775-1) contains supplementary material, which is available to authorized users.

Inherited mitochondrial neuropathies

“…PNP is usually sensori-motor and often more motor than sensory. Nerve conduction studies may show length-dependent sensori-motor, axonal PNP [15]. Sural nerve biopsy may show reduced number of predominantly myelinated fibers.…”

Neuroimaging in Mitochondrial Disorders

“…Each modality can be combined to gain complementary information regarding the brain's structural, functional, and metabolic dimensions, and how these may be altered in pathologic states (Table 3). With newer DTI 0 diffusion-tensor imaging; DWI 0 diffusion-weighted imaging; FLAIR 0 fluid attenuation inversion recovery; fMRI 0 functional magnetic resonance imaging; MR 0 magnetic resonance; MRI 0 magnetic resonance imaging; MRS 0 magnetic resonance spectroscopy modalities, such as DTI, MRS, and fMRI, mechanisms of injury are starting to be understood in mitochondrial and other metabolic disorders [12,13].…”

“…The chemical also has to be present in a detectable concentration on the order of milligrams and should produce an acceptable signal-to-noise ratio. These conditions are met by 31 P, 1 H, 19 F, 13 C, 7 Li, and 23 Na.…”

Vi-2 : Apport De l'ÉLECTROPHYSIOLOGIE Chez l'ADULTE : Exemples

“…Dans ce syndrome, l'OCT montre des zones hétérogènes en pertes neuronales et axonales de la rétine externe et interne et l'optique adaptative met en évidence un espacement des photorécepteurs lié à la perte des photorécepteurs [Gelfand et al, 2011]. …”