ABSTRACT
BACKGROUND: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset, autosomal dominant disease involving microvessels of the brain and eye resulting in central nervous system degeneration with visual disturbances, stroke, motor impairment, and cognitive decline. Frameshift mutations at the C-terminus of TREX1 gene are the molecular cause of this disorder. OBJECTIVES: The objective of this study is to present the different clinical manifestations of RVCL in three-related patients and to investigate the presence of TREX1 mutation in the extended genealogy. METHODS: Multidisciplinary testing was performed in three related patients. Based on their family history, the study was extended to 34 relatives from the same small community. Neurological evaluation, sequencing of TREX1, and presymptomatic diagnosis were offered to all participants. RESULTS: The patients exhibited the heterozygous TREX1 mutation p.V235Gfs*6, but with phenotypic variability. In addition, 15 relatives were identified as pre-manifest mutation carriers. The remaining participants did not carry the mutation. CONCLUSIONS: This is the figrst report of a large Mexican genealogy with RVCL, where the same TREX1 mutation causes a variation in organ involvement and clinical progression. The early identification and follow-up of individuals at risk may help provide insights into the basis for this variability in presentation.
Subject(s)
Biological Variation, Population , Exodeoxyribonucleases/genetics , Hereditary Central Nervous System Demyelinating Diseases/physiopathology , Phosphoproteins/genetics , Retinal Diseases/physiopathology , Vascular Diseases/physiopathology , Female , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Hereditary Central Nervous System Demyelinating Diseases/genetics , Heterozygote , Humans , Male , Mexico , Middle Aged , Mutation , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Vascular Diseases/diagnosis , Vascular Diseases/geneticsABSTRACT
In 1989, we described a new autosomic-recessive myelin-mutant rat that develops a progressive motor syndrome characterized by tremor, ataxia, immobility episodes (IEs), epilepsy, and paralysis. taiep is the acronym of these symptoms. The rat developed a hypomyelination, followed by demyelination. At an age of 7-8 months, taiep rats developed IEs, characterized electroencephalographically by REM sleep-like cortical activity. In our study, we analyzed the ontogeny of gripping-induced IEs between 5 and 18 months, their dependence to light-dark changes, sexual dimorphism, and susceptibility to mild stress. Our results showed that IEs start at an age of 6.5 months, with a peak frequency between 8.5 and 9.5 months. IEs have two peaks, one in the morning (0800-1000 h) and a second peak in the middle of the night (2300-0100 h). Spontaneous IEs showed an even distribution with a mean of 3 IEs every 2 h. IEs are sexually dimorphic being more common in male rats. The IEs can be induced by gripping the rat by the tail or the thorax, but most of the IEs were produced by gripping the tail. Mild stress produced by i.p. injection of physiological saline significantly decreased IEs. These results suggested that IEs are dependent on several biological variables, which are caused by hypomyelination, followed by demyelization, which causes alterations in the brainstem and hypothalamic mechanisms responsible for the sleep-wake cycle regulation, producing emergence of REM sleep-like behavior during awake periods.