PSEN2 Mutations May Mimic Frontotemporal Dementia: Two New Case Reports and a Review.

BACKGROUND: Monogenic Alzheimer's disease (AD) has severe health and socioeconomic repercussions. Its rarest cause is presenilin 2 (PSEN2) gene mutations. We present two new cases with presumed PSEN2-AD with unusual clinical and neuroimaging findings in order to provide more information on the pathophysiology and semiology of these patients. METHODS: Women aged 69 and 62 years at clinical onset, marked by prominent behavioral and language dysfunction, progressing to severe dementia within three years were included. The complete study is depicted. In addition, a systematic review of the PSEN2-AD was performed. RESULTS: Neuroimaging revealed pronounced frontal white matter hyperintensities (WMH) and frontotemporal atrophy/hypometabolism. The genetic study unveiled PSEN2 variants: c.772G>A (p.Ala258Thr) and c.1073-2_1073-1del. Both cerebrospinal fluid (CSF) and experimental blood biomarkers shouldered AD etiology. CONCLUSIONS: Prominent behavioral and language dysfunction suggesting frontotemporal dementia (FTD) may be underestimated in the literature as a clinical picture in PSEN2 mutations. Thus, it may be reasonable to include PSEN2 in genetic panels when suspecting FTDL. PSEN2 mutations may cause striking WMH, arguably related to myelin disruption induced by amyloid accumulation.

Circular statistics for analyzing changes in retinal nerve fiber layer.

OBJECTIVE: To evaluate the use of circular statistics to analyze retinal nerve fibre layer (RNFL) thickness in eyes with and without a prior history of optic neuritis (ON). DESIGN: Single-centre consecutive study. PARTICIPANTS: Twenty-two multiple sclerosis patients and 20 healthy control subjects. METHODS: Data on 28 eyes with a history of ON of 22 multiple sclerosis patients and 40 eyes of 20 healthy control subjects collected in 2010 and 2015. RNFL thickness was measured separately in 12 sectors around the optic nerve head. We used circular statistics to calculate the mean weighted vector of RNFL thickness for each sector and eye in 2 measurements made 5 years apart (2010 and 2015). Comparisons of weighted mean vectors between groups were made using a paired Mardia-Watson-Wheeler test. RESULTS: The directions of the mean weighted vectors for ON eyes were 45.8º in 2010 and 56.0º in 2015, whereas in control eyes the directions were 319.4º in 2010 and 188.9º in 2015. No significant differences were found between 2010 and 2015 in any of the 2 groups. However, significant differences were found between ON and control eyes in 2010 and 2015. CONCLUSIONS: This paper provides an example of how to use circular statistics in cases of directional data in ophthalmology and demonstrates that circular statistics are a suitable tool for this purpose.

A family-based study to identify genetic biomarkers of fibromyalgia: consideration of patients' subgroups.

OBJECTIVES: Evidence from genome-wide and candidate gene association studies, familial aggregation and linkage analyses demonstrate the genetic contribution to fibromyalgia (FM) disease. This study aimed to identify genetic biomarkers of FM and its related comorbid disorders, by exploring 41 polymorphisms potentially involved in FM pathogenesis in families with at least one patient with FM. METHODS: Core symptoms were assessed, and blood samples collected from 556 patients with FM and 395 healthy relatives. For the genetic study, a final sample of 401 FM patients and 232 healthy controls was selected, discarding patients with concomitant pathologies and controls with chronic pain. A family-based approach using DFAM test (Plink) and SNPs (single nucleotide polymorphisms) combination analyses to compare FM patients vs. controls were first applied. Second, the genotypic distribution of subgroups of FM patients, stratified by severe vs. mild symptoms of pain, depression and sleep impairment, was considered. RESULTS: No evidence of associations with FM per se were detected, using either a family-based approach or SNPs combination analyses. However, considering the subgroups of FM patients, the SNP rs6454674 (CNR1, cannabinoid receptor 1 gene) was found as a potential genetic marker of FM correlated with depression (p<.001). CONCLUSIONS: No significant associations using either the family-based analysis or the SNPs combination tests dissociated FM patients and their healthy relatives. FM patients with and without depression showed a significant difference in the genotypic distribution related to the SNP rs6454674 in the cannabinoid receptor 1 gene (CNR1) indicating that FM is not a homogenous disorder.

Unilateral calf atrophy secondary to a de novo mutation of the caveolin-3 gene.

A 23-year-old man was evaluated for atrophy of the left calf. He had a myopathic pattern on electromyography. Light microscopy showed dystrophic changes and reduced immunostaining for dysferlin and caveolin-3. The subsarcolemmal space was enlarged, and abnormal vesicles were visible with electron microscopy. A genetic study showed a heterozygous A45T mutation at exon 2 of the caveolin-3 gene. Such a mutation has been reported previously with limb-girdle muscular dystrophy type 1C and rippling muscle disease phenotypes.