Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) f... more Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders. Methods: Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism. Results: The premutation ϩ gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood. Conclusion: Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.
The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR... more The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR1) and the absence of its product, fragile X mental retardation protein (FMRP), resulting from CpG island methylation associated with large CGG repeat expansions (more than 200) termed full mutation (FM). We have identified a number of novel epigenetic markers for FXS using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot (FREE1 R 5 0.97; P < 0.00001, n 5 23 and FREE2 R 5 0.93; P < 0.00001, n 5 23) and negatively correlated with lymphocyte expression of FMRP (FREE1 R 5 20.62; P 5 0.01, n 5 15 and FREE2 R 5 20.55; P 5 0.03, n 5 15) in blood of partially methylated 'high functioning' FM males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio (FREE1 R 5 20.93; P < 0.0001, n 5 12 and FREE2 R 5 20.95; P < 0.0001, n 5 9). In a sample set of 49 controls, 18 grey zone (GZ 40 -54 repeats), 22 premutation (PM 55 -170 repeats) and 22 (affected) FXS subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate FXS males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Considering its high-throughput and specificity for pathogenic FM alleles, low cost and minimal DNA requirements, FREE MALDI-TOF MS offers a unique tool in FXS diagnostics and newborn population screening.
Peduncular hallucinations are generally associated with lesions in the midbrain. They have rarely... more Peduncular hallucinations are generally associated with lesions in the midbrain. They have rarely been associated with central pontine myelinolysis, a condition associated with rapid alterations in serum sodium and chronic alcoholism. Described herein is the case of a 46-year-old man who developed typical peduncular hallucinations, whose imaging demonstrated central pontine myelinolysis. After alcohol cessation and neuroimaging resolution, the patient's hallucinatory phenomena abated.
Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) f... more Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders. Methods: Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism. Results: The premutation ϩ gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood. Conclusion: Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.
The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR... more The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR1) and the absence of its product, fragile X mental retardation protein (FMRP), resulting from CpG island methylation associated with large CGG repeat expansions (more than 200) termed full mutation (FM). We have identified a number of novel epigenetic markers for FXS using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot (FREE1 R 5 0.97; P < 0.00001, n 5 23 and FREE2 R 5 0.93; P < 0.00001, n 5 23) and negatively correlated with lymphocyte expression of FMRP (FREE1 R 5 20.62; P 5 0.01, n 5 15 and FREE2 R 5 20.55; P 5 0.03, n 5 15) in blood of partially methylated 'high functioning' FM males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio (FREE1 R 5 20.93; P < 0.0001, n 5 12 and FREE2 R 5 20.95; P < 0.0001, n 5 9). In a sample set of 49 controls, 18 grey zone (GZ 40 -54 repeats), 22 premutation (PM 55 -170 repeats) and 22 (affected) FXS subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate FXS males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Considering its high-throughput and specificity for pathogenic FM alleles, low cost and minimal DNA requirements, FREE MALDI-TOF MS offers a unique tool in FXS diagnostics and newborn population screening.
Peduncular hallucinations are generally associated with lesions in the midbrain. They have rarely... more Peduncular hallucinations are generally associated with lesions in the midbrain. They have rarely been associated with central pontine myelinolysis, a condition associated with rapid alterations in serum sodium and chronic alcoholism. Described herein is the case of a 46-year-old man who developed typical peduncular hallucinations, whose imaging demonstrated central pontine myelinolysis. After alcohol cessation and neuroimaging resolution, the patient's hallucinatory phenomena abated.
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