Neuroimaging supports central pathology in familial dysautonomia

Abstract

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

Familial Dysautonomia: Mechanisms and Models

“…MRI studies showed abnormalities that suggest compromised myelination as well as grey matter and white matter micro-structural damage in FD brains. Abnormal findings are more evident in optic radiation, middle cerebellar pedunculum, and frontal lobe (Axelrod et al , 2010). Significantly, analyses of FD brains showed that the levels of several transcripts and their respective proteins that are involved in myelination are severely reduced in FD brains compared to age-matched healthy individuals (Cheishvili et al , 2007).…”

The Familial Dysautonomia disease gene,Ikbkap/Elp1, is required in the developing and adult central nervous system

“…Clinical symptoms involving the CNS include visual impairment (Mendoza-Santiesteban et al, 2012, 2014; Ueki et al, 2016), high anxiety levels, learning impairments (Day, 1979; Sak et al, 1967; Welton et al, 1979; Clayson et al, 1980; Axelrod et al, 2012; Norcliffe-Kaufmann et al, 2016), seizures, decreased motor nerve conduction, deficits in brain stem reflexes (Gutiérrez et al, 2015) and abnormal electroencephalogram (EEG) activity (Niedermeyer et al, 1967; Ochoa, 2003). Neuroimaging studies [magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI)] demonstrate both white and gray matter microstructural damage in FD brains (Axelrod et al, 2010), and pathological studies have revealed enlarged 4th ventricles associated with atrophy in the medulla (Engel and Aring, 1945; Cohen and Solomon, 1955; Brown et al, 1964). Most patients die due to sudden death during sleep or respiratory failure (Axelrod, 2006).…”

Phosphatidylserine Ameliorates Neurodegenerative Symptoms and Enhances Axonal Transport in a Mouse Model of Familial Dysautonomia

“…Although the central neuropathology in FD is poorly defined, recent MRI studies indicate that FD patients have abnormal proportions of white matter, decreased optic radiation, and cerebellar microstructural alterations compared to healthy volunteers [17]. The lack of IKAP also results in reduced size and numbers of dorsal-root ganglion (DRG) and sympathetic ganglion (SG) neurons [13,18–20].…”