Publications by authors named "Rita Guerreiro"

152 Publications

A Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

Clin Pharmacol Ther 2021 Oct 17. Epub 2021 Oct 17.

Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (C ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.
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http://dx.doi.org/10.1002/cpt.2451DOI Listing
October 2021

A comprehensive analysis of copy number variation in a Turkish dementia cohort.

Hum Genomics 2021 07 28;15(1):48. Epub 2021 Jul 28.

Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, USA.

Background: Copy number variants (CNVs) include deletions or multiplications spanning genomic regions. These regions vary in size and may span genes known to play a role in human diseases. As examples, duplications and triplications of SNCA have been shown to cause forms of Parkinson's disease, while duplications of APP cause early onset Alzheimer's disease (AD).

Results: Here, we performed a systematic analysis of CNVs in a Turkish dementia cohort in order to further characterize the genetic causes of dementia in this population. One hundred twenty-four Turkish individuals, either at risk of dementia due to family history, diagnosed with mild cognitive impairment, AD, or frontotemporal dementia, were whole-genome genotyped and CNVs were detected. We integrated family analysis with a comprehensive assessment of potentially disease-associated CNVs in this Turkish dementia cohort. We also utilized both dementia and non-dementia individuals from the UK Biobank in order to further elucidate the potential role of the identified CNVs in neurodegenerative diseases. We report CNVs overlapping the previously implicated genes ZNF804A, SNORA70B, USP34, XPO1, and a locus on chromosome 9 which includes a cluster of olfactory receptors and ABCA1. Additionally, we also describe novel CNVs potentially associated with dementia, overlapping the genes AFG1L, SNX3, VWDE, and BC039545.

Conclusions: Genotyping data from understudied populations can be utilized to identify copy number variation which may contribute to dementia.
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http://dx.doi.org/10.1186/s40246-021-00346-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317312PMC
July 2021

Vasculitic peripheral neuropathy in deficiency of adenosine deaminase 2.

Neuromuscul Disord 2021 09 14;31(9):891-895. Epub 2021 May 14.

Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory vasculopathy characterized by systemic vasculitis, early-onset stroke and livedo racemosa. We report a family cohort of 3 patients with ADA2 compound heterozygous mutation p.[Thr360Ala] and [Gly383Ser]. Two of them had progressive involvement of the peripheral nervous system in the fourth decade, both after stroke. In one patient, clinical and neurophysiological studies showed progression of mononeuritis multiplex to chronic axonal sensorimotor polyneuropathy, nerve biopsy had features of small vessel vasculitic neuropathy, and muscle biopsy disclosed neurogenic atrophy with reinnervation. The second patient presented with progressive sensory symptoms of the lower limbs and chronic axonal sensorimotor polyneuropathy in nerve conduction studies. These two patients had absent plasma ADA2 activity. The third patient had no neurological affection despite low, but not absent, plasma ADA2 activity. Patients were started on a tumor necrosis factor (TNF) inhibitor, which has presumed benefits for the vasculitic phenotype of DADA2.
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http://dx.doi.org/10.1016/j.nmd.2021.05.001DOI Listing
September 2021

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features.

Eur J Neurol 2021 08 1;28(8):2603-2613. Epub 2021 Jun 1.

Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Background And Purpose: Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD.

Method: Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed.

Results: The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1 ± 4.97 years and the mean duration of the disease was 8.9 ± 3.51 years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients.

Conclusion: A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.
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http://dx.doi.org/10.1111/ene.14908DOI Listing
August 2021

How understudied populations have contributed to our understanding of Alzheimer's disease genetics.

Brain 2021 05;144(4):1067-1081

Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, USA.

The majority of genome-wide association studies have been conducted using samples with a broadly European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this review, we aimed to illustrate the benefits to genetic characterization of Alzheimer's disease, in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we conducted a literature search to understand the contributions of studies, on different populations, to Alzheimer's disease genetics. Using both PubMed and Alzforum Mutation Database, we systematically quantified the number of studies reporting variants in known disease-causing genes, in a worldwide manner, and discuss the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant single nucleotide polymorphisms across populations by focusing on loci that show different association profiles between populations (a key example being APOE). Reports of variants in APP, PSEN1 and PSEN2 can initially determine whether patients from a country have been studied for Alzheimer's disease genetics. Most genome-wide significant associations in non-Hispanic white genome-wide association studies do not reach genome-wide significance in such studies of other populations, with some suggesting an opposite effect direction; this is likely due to much smaller sample sizes attained. There are, however, genome-wide significant associations first identified in understudied populations which have yet to be replicated. Familial studies in understudied populations have identified rare, high effect variants, which have been replicated in other populations. This work functions to both highlight how understudied populations have furthered our understanding of Alzheimer's disease genetics, and to help us gauge our progress in understanding the genetic architecture of this disease in all populations.
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http://dx.doi.org/10.1093/brain/awab028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105043PMC
May 2021

PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice.

Sci Rep 2021 03 16;11(1):6072. Epub 2021 Mar 16.

Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.

Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.
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http://dx.doi.org/10.1038/s41598-021-84919-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966789PMC
March 2021

Congenital ataxia due to novel variant in ATP8A2.

Clin Genet 2021 07 22;100(1):79-83. Epub 2021 Apr 22.

UnIGENe/CGPP - Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.

Congenital ataxias are a heterogeneous group of disorders characterized by congenital or early-onset ataxia. Here, we describe two siblings with congenital ataxia, who acquired independent gait by age 4 years. After 16 years of follow-up they presented near normal cognition, cerebellar ataxia, mild pyramidal signs, and dystonia. On exome sequencing, a novel homozygous variant (c.1580-18C > G - intron 17) in ATP8A2 was identified. A new acceptor splice site was predicted by bioinformatics tools, and functionally characterized through a minigene assay. Minigene constructs were generated by PCR-amplification of genomic sequences surrounding the variant of interest and cloning into the pCMVdi vector. Altered splicing was evaluated by expressing these constructs in HEK293T cells. The construct with the c.1580-18C > G homozygous variant produced an aberrant transcript, leading to retention of 17 bp of intron 17, by the use of an alternative acceptor splice site, resulting in a premature stop codon by insertion of four amino acids. These results allowed us to establish this as a disease-causing variant and expand ATP8A2-related disorders to include less severe forms of congenital ataxia.
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http://dx.doi.org/10.1111/cge.13954DOI Listing
July 2021

Polygenic risk scores for Alzheimer's disease are related to dementia risk in APOE ɛ4 negatives.

Alzheimers Dement (Amst) 2021 22;13(1):e12142. Epub 2021 Jan 22.

Department of Psychiatry and Neurochemistry Neuropsychiatric Epidemiology Unit Institute of Neuroscience and Physiology the Sahlgrenska Academy Centre for Ageing and Health (AGECAP) at the University of Gothenburg Mölndal Sweden.

Introduction: Studies examining the effect of polygenic risk scores (PRS) for Alzheimer's disease (AD) and apolipoprotein E () genotype on incident dementia in very old individuals are lacking.

Methods: A population-based sample of 2052 individuals ages 70 to 111, from Sweden, was followed in relation to dementia. AD-PRSs including 39, 57, 1333, and 13,942 single nucleotide polymorphisms (SNPs) were used.

Results: AD-PRSs (including 39 or 57 SNPs) were associated with dementia (57-SNPs AD-PRS: hazard ratio 1.09, confidence interval 1.01-1.19, = .03), particularly in ɛ4 non-carriers (57-SNPs AD-PRS: 1.15, 1.05-1.27, 4 × 10, 39-SNPs AD-PRS: 1.22, 1.10-1.35, 2 × 10). No association was found with the other AD-PRSs. Further, ɛ4 was associated with increased risk of dementia (1.60, 1.35-1.92, = 1 × 10). In those aged ≥95 years, the results were similar for the AD-PRSs, while ɛ4 only predicted dementia in the low-risk tertile of AD-PRSs.

Discussion: These results provide information to identify individuals at increased risk of dementia.
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http://dx.doi.org/10.1002/dad2.12142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821873PMC
January 2021

The association of circulating amylin with β-amyloid in familial Alzheimer's disease.

Alzheimers Dement (N Y) 2021 20;7(1):e12130. Epub 2021 Jan 20.

Department of Pharmacology and Nutritional Sciences University of Kentucky Lexington Kentucky USA.

Introduction: This study assessed the hypothesis that circulating human amylin (amyloid-forming) cross-seeds with amyloid beta (Aβ) in early Alzheimer's disease (AD).

Methods: Evidence of amylin-AD pathology interaction was tested in brains of 31 familial AD mutation carriers and 20 cognitively unaffected individuals, in cerebrospinal fluid (CSF) (98 diseased and 117 control samples) and in genetic databases. For functional testing, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats.

Results: Amylin-Aβ cross-seeding was identified in AD brains. High CSF amylin levels were associated with decreased CSF Aβ concentrations. AD risk and amylin gene are not correlated. Suppressed amylin secretion protected APP/PS1 rats against AD-associated effects. In contrast, hypersecretion or intravenous injection of human amylin in APP/PS1 rats exacerbated AD-like pathology through disruption of CSF-brain Aβ exchange and amylin-Aβ cross-seeding.

Discussion: These findings strengthened the hypothesis of circulating amylin-AD interaction and suggest that modulation of blood amylin levels may alter Aβ-related pathology/symptoms.
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http://dx.doi.org/10.1002/trc2.12130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816817PMC
January 2021

A Non-APOE Polygenic Risk Score for Alzheimer's Disease Is Associated With Cerebrospinal Fluid Neurofilament Light in a Representative Sample of Cognitively Unimpaired 70-Year Olds.

J Gerontol A Biol Sci Med Sci 2021 05;76(6):983-990

Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP), University of Gothenburg, Sweden.

The effect of Alzheimer's disease (AD) polygenic risk scores (PRS) on amyloid and tau pathophysiology and neurodegeneration in cognitively unimpaired older adults is not known in detail. This study aims to investigate non-APOE AD-PRS and APOE ε4 in relation to AD pathophysiology evaluated by cerebrospinal fluid (CSF) biomarkers in a population-based sample of 70-year olds. A total of 303 dementia-free individuals from the Gothenburg H70 Birth Cohort Studies were included. Genotyping was performed using the NeuroChip, and AD-PRS were calculated. CSF levels of amyloid-β (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), neurogranin (Ng), and neurofilament light (NfL) were measured with enzyme-linked immunosorbent assay. Associations were found between non-APOE PRS and both NfL (p = .001) and Aβ42 (p = .02), and between APOE ε4 and Aβ42 (p = 1e-10), t-tau (p = 5e-4), and p-tau (p = .002). Similar results were observed when only including individuals with CDR = 0, except for no evidence of an association between non-APOE PRS and Aβ42. There was an interaction between non-APOE PRS and Aβ42 pathology status in relation to NfL (p = .005); association was only present in individuals without Aβ42 pathology (p = 3e-4). In relation to Aβ42, there was a borderline interaction (p = .06) between non-APOE PRS and APOE ε4; association was present in ε4 carriers only (p = .03). Similar results were observed in individuals with CDR = 0 (n = 246). In conclusion, among cognitively healthy 70-year olds from the general population, genetic risk of AD beyond the APOE locus was associated with NfL in individuals without Aβ42 pathology, and with Aβ42 in APOE ε4 carriers, suggesting these associations are driven by different mechanisms.
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http://dx.doi.org/10.1093/gerona/glab030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140047PMC
May 2021

Genetic variants in glutamate-, Aβ-, and tau-related pathways determine polygenic risk for Alzheimer's disease.

Neurobiol Aging 2021 05 12;101:299.e13-299.e21. Epub 2020 Nov 12.

Human Genetics Group, School of Life Sciences, University of Nottingham, Nottingham, UK. Electronic address:

Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.009DOI Listing
May 2021

Whole-exome sequencing of Finnish patients with vascular cognitive impairment.

Eur J Hum Genet 2021 04 2;29(4):663-671. Epub 2020 Dec 2.

Department of Pathology, University of Helsinki, Helsinki, Finland.

Cerebral small vessel disease (CSVD) is the most important cause of vascular cognitive impairment (VCI). Most CSVD cases are sporadic but familial monogenic forms of the disorder have also been described. Despite the variants identified, many CSVD cases remain unexplained genetically. We used whole-exome sequencing in an attempt to identify novel gene variants underlying CSVD. A cohort of 35 Finnish patients with suspected CSVD was analyzed. Patients were screened negative for the most common variants affecting function in NOTCH3 in Finland (p.Arg133Cys and p.Arg182Cys). Whole-exome sequencing was performed to search for a genetic cause of CSVD. Our study resulted in the detection of possibly pathogenic variants or variants of unknown significance in genes known to associate with CSVD in six patients, accounting for 17% of cases. Those genes included NOTCH3, HTRA1, COL4A1, and COL4A2. We also identified variants with predicted pathogenic effect in genes associated with other neurological or stroke-related conditions in seven patients, accounting for 20% of cases. This study supports pathogenic roles of variants in COL4A1, COL4A2, and HTRA1 in CSVD and VCI. Our results also suggest that vascular pathogenic mechanisms are linked to neurodegenerative conditions and provide novel insights into the molecular basis of VCI.
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http://dx.doi.org/10.1038/s41431-020-00775-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115269PMC
April 2021

Psychiatric Manifestations of Mutations.

Mov Disord Clin Pract 2020 Oct 4;7(7):838-841. Epub 2020 Sep 4.

Department of Clinical and Movement Neurosciences Queen Square London United Kingdom.

Background: Biallelic mutations in were identified as the cause of Kufor-Rakeb disease, a pallido-pyramidal syndrome characterized by young-onset dystonia-parkinsonism with vertical supranuclear gaze palsy, spasticity, and cognitive decline. The phenotypic spectrum has broadened since, but predominantly psychiatric or behavioral manifestations have not been highlighted.

Cases: Here we report the clinical, radiological, and genetic findings in 2 unrelated patients with mutations. One patient had a prominent behavioral (autistic spectrum) presentation and the other a psychiatric (paranoid psychosis) presentation. Both had additional features, such as delayed milestones, ataxia, pyramidal signs, upgaze restriction, or impaired cognition to varying extent, but these were partly subtle or developed later in the disease course.

Conclusion: Prominent behavioral or psychiatric features can be the first or most prominent manifestation of -related disease. They may be a diagnostic clue in patients with ataxia, spasticity, or parkinsonism and may require an interdisciplinary neurological and psychiatric treatment approach.
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http://dx.doi.org/10.1002/mdc3.13034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533993PMC
October 2020

A deletion of IDUA exon 10 in a family of Golden Retriever dogs with an attenuated form of mucopolysaccharidosis type I.

J Vet Intern Med 2020 Sep 12;34(5):1813-1824. Epub 2020 Aug 12.

Department of Neurodegenerative Diseases, Institute of Neurology, University College London, London, United Kingdom.

Background: Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder caused by a deficiency of the enzyme α-l-iduronidase, leading to accumulation of undegraded dermatan and heparan sulfates in the cells and secondary multiorgan dysfunction. In humans, depending upon the nature of the underlying mutation(s) in the IDUA gene, the condition presents with a spectrum of clinical severity.

Objectives: To characterize the clinical and biochemical phenotypes, and the genotype of a family of Golden Retriever dogs.

Animals: Two affected siblings and 11 related dogs.

Methods: Family study. Urine metabolic screening and leucocyte lysosomal enzyme activity assays were performed for biochemical characterization. Whole genome sequencing was used to identify the causal mutation.

Results: The clinical signs shown by the proband resemble the human attenuated form of the disease, with a dysmorphic appearance, musculoskeletal, ocular and cardiac defects, and survival to adulthood. Urinary metabolic studies identified high levels of dermatan sulfate, heparan sulfate, and heparin. Lysosomal enzyme activities demonstrated deficiency in α-l-iduronidase activity in leucocytes. Genome sequencing revealed a novel homozygous deletion of 287 bp resulting in full deletion of exon 10 of the IDUA gene (NC_006585.3(NM_001313883.1):c.1400-76_1521+89del). Treatment with pentosan polyphosphate improved the clinical signs until euthanasia at 4.5 years.

Conclusion And Clinical Importance: Analysis of the genotype/phenotype correlation in this dog family suggests that dogs with MPS-I could have a less severe phenotype than humans, even in the presence of severe mutations. Treatment with pentosan polyphosphate should be considered in dogs with MPS-I.
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http://dx.doi.org/10.1111/jvim.15868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517864PMC
September 2020

Genetics of synucleins in neurodegenerative diseases.

Acta Neuropathol 2021 04 1;141(4):471-490. Epub 2020 Aug 1.

Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. N.E., Grand Rapids, MI, 49503-2518, USA.

The SNCA locus currently has an indisputable role in Parkinson's disease and other synucleinopathies. The role of genetic variability in the other members of the synuclein family (SNCB and SNCG) in disease is far less clear. In this review, we critically assess the pathogenicity, main characteristics, and roles of genetic variants in these genes reported to be causative of synucleinopathies. We also summarize the different association signals identified in the SNCA locus that have been associated with risk for disease. We take a bird's eye view of the variability currently reported in the general population for the three genes and use these data to infer on the potential relationship between each of the genes and human disease.
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http://dx.doi.org/10.1007/s00401-020-02202-1DOI Listing
April 2021

CYLD variants in frontotemporal dementia associated with severe memory impairment in a Portuguese cohort.

Brain 2020 08;143(8):e67

Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.

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http://dx.doi.org/10.1093/brain/awaa183DOI Listing
August 2020

Genetic architecture of common non-Alzheimer's disease dementias.

Neurobiol Dis 2020 08 19;142:104946. Epub 2020 May 19.

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA; Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI, USA.

Frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and vascular dementia (VaD) are the most common forms of dementia after Alzheimer's disease (AD). The heterogeneity of these disorders and/or the clinical overlap with other diseases hinder the study of their genetic components. Even though Mendelian dementias are rare, the study of these forms of disease can have a significant impact in the lives of patients and families and have successfully brought to the fore many of the genes currently known to be involved in FTD and VaD, starting to give us a glimpse of the molecular mechanisms underlying these phenotypes. More recently, genome-wide association studies have also pointed to disease risk-associated loci. This has been particularly important for DLB where familial forms of disease are very rarely described. In this review we systematically describe the Mendelian and risk genes involved in these non-AD dementias in an effort to contribute to a better understanding of their genetic architecture, find differences and commonalities between different dementia phenotypes, and uncover areas that would benefit from more intense research endeavors.
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http://dx.doi.org/10.1016/j.nbd.2020.104946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207829PMC
August 2020

Novel Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype.

J Clin Med 2020 Apr 23;9(4). Epub 2020 Apr 23.

Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USA.

Homozygous variants in , encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.
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http://dx.doi.org/10.3390/jcm9041212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230264PMC
April 2020

[The Age of Multidrug Resistance: Ten Year Incidence in a Neonatal Intensive Care Unit].

Acta Med Port 2020 Mar 2;33(3):183-190. Epub 2020 Mar 2.

Unidade de Cuidados Intensivos Neonatais. Serviço de Pediatria. Hospital Garcia de Orta. Almada. Portugal.

Introduction: The emergence of multidrug-resistant bacteria is a medical challenge nowadays. The objective of the present study was to determine the incidence of multidrug-resistant bacteria infections in a neonatal Intensive Care unit.

Material And Methods: Retrospective, descriptive, incidence study of infectious episodes by multidrug-resistant bacteria from 2008 to 2017 in a differentiated perinatal support unit.

Results: Sixty-four infectious episodes included (median gestational age of 28 weeks and birth weight of 885 g). The isolated bacteria were: Enterobacteriaceae (n = 46); Methicillin-resistant Staphylococcus aureus (n = 12); Acinetobacter baumannii (n = 4); Pseudomonas aeruginosa (n = 2). A risk factor was identified in 90.6% of the episodes, with emphasis on central catheter (89%) and previous antibiotic therapy (78%). The lethality rate of these infections was 10.9% (Unit mortality rate: 4.4%). The overall incidence rate was 3.2 infectious episodes/100 hospitalizations, corresponding to 1.7 episodes/1000 days of hospitalization. There were three infectious outbreaks, with an increasing impact of Enterobacteriaceae.

Discussion: The reported incidence rate reflects a risk population, hospitalized in an Intensive Care unit, over a long period of time. The distribution of isolated bacteria, with Enterobacteriaceae predominance, is in accordance with the shift in multidrug resistance reported worldwide. The outbreaks point to the need of understanding risk factors and means of local dissemination. The relevance of these infections is evident in their lethality rate, which is higher compared to that of general hospital infections.

Conclusion: The incidence rate reflects the local dimension of the problem, representing a quality indicator which is relevant for controlling these infections.
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http://dx.doi.org/10.20344/amp.12504DOI Listing
March 2020

Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies.

Acta Neuropathol Commun 2020 01 29;8(1). Epub 2020 Jan 29.

Neurology Service, University of Coimbra Hospital, Coimbra, Portugal.

Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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http://dx.doi.org/10.1186/s40478-020-0879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990558PMC
January 2020

Cost-effectiveness of cladribine tablets versus fingolimod in patients with highly active relapsing multiple sclerosis in Portugal.

J Med Econ 2020 May 10;23(5):484-491. Epub 2020 Feb 10.

Centro de Estudos de Medicina Baseada na Evidência, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.

To assess the cost-utility of cladribine tablets fingolimod in patients with highly active relapsing-remitting multiple sclerosis (RRMS) in Portugal. A 1-year cycle cohort-based Markov state transition model was developed to simulate disease progression, measured by Kurtzke Expanded Disability Status Scale (EDSS), relapses, and conversion to secondary-progressive MS (SPMS). Patients were assumed to remain on treatment until progression to EDSS level 7, conversion to SPMS, or complete loss of efficacy due to waning effect. Natural history was based on British Columbia Multiple Sclerosis registry, London Ontario database, UK MS Trust, and cladribine tablets clinical trial (CLARITY). Portuguese all-cause mortality was adjusted for the MS associated increased mortality. Clinical inputs for active treatments (disability progression and relapse rate) were estimated on a network meta-analysis. Utility weights were derived from UK-MS Survey and published literature. Resource consumption by EDSS and due to relapses was based on published literature, National DRG microdata and expert opinion. Unit costs were obtained from official sources. The analysis was conducted from payers' perspective, time horizon of 50 years and discount rate of 5%, for both costs and benefits. Uncertainty was assessed probabilistic and deterministic sensitivity analyses. Compared to fingolimod, cladribine tablets were associated with a delay in progression, resulting in a gain of 0.85 quality adjusted life years (QALYs) and a cost decrease of 25,935 €. Probabilistic sensitivity analysis resulted in a mean ICER of -31,781 € per QALY and was dominant in 98.7% of the simulations. Cladribine tablets were dominant across the scenario analyses tested. Treatment of highly active RRMS with cladribine tablets was less costly and more effective than treatment with fingolimod. Hence, it is a dominant strategy in the Portuguese setting. No conclusions can be drawn from the present study regarding other treatment options, in particular natalizumab and alemtuzumab.
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http://dx.doi.org/10.1080/13696998.2020.1717499DOI Listing
May 2020

A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia.

FASEB J 2020 02 23;34(2):2436-2450. Epub 2019 Dec 23.

Department of Neuroinflammation, University College London Queen Square Institute of Neurology, London, UK.

Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC-derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
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http://dx.doi.org/10.1096/fj.201902447RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027848PMC
February 2020

Two pathologically confirmed cases of novel mutations in the MAPT gene causing frontotemporal dementia.

Neurobiol Aging 2020 03 20;87:141.e15-141.e20. Epub 2019 Nov 20.

Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, UK. Electronic address:

MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioral variant FTD and/or parkinsonism clinically. We describe 2 novel MAPT mutations, D252V and G389_I392del, each presenting in a patient with behavioral variant FTD and associated language and cognitive deficits. Neuroimaging revealed asymmetrical left greater than right temporal lobe atrophy in the first case, and bifrontal atrophy in the second case. Disease duration was 8 years and 5 years, respectively. Postmortem examination in both patients revealed a 3-repeat predominant tauopathy, similar in appearance to Pick's disease. These 2 mutations add to the literature on genetic FTD, both presenting with similar clinical and imaging features to previously described cases, and pathologically showing a primary tauopathy similar to a number of other MAPT mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082764PMC
March 2020

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Lancet Neurol 2020 02 3;19(2):145-156. Epub 2019 Dec 3.

Institut du Cerveau et de la Moelle épinière & Centre de Référence des Démences Rares ou précoces, Institut de la Mémoire et de la Maladie d'Alzheimer, Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France.

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.

Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.

Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.

Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.

Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
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http://dx.doi.org/10.1016/S1474-4422(19)30394-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007771PMC
February 2020

An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids.

Acta Neuropathol Commun 2019 11 27;7(1):188. Epub 2019 Nov 27.

Center for Neurodegenerative Science, Van Andel Institute, 333 Bostwick Ave. N.E, Grand Rapids, MI, 49503-2518, USA.

Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.
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http://dx.doi.org/10.1186/s40478-019-0843-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880494PMC
November 2019

Correction: Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.

Transl Psychiatry 2019 Jun 11;9(1):167. Epub 2019 Jun 11.

Human Genetics Group, University of Nottingham, Nottingham, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41398-019-0503-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559959PMC
June 2019

Alzheimer's disease polygenic risk score as a predictor of conversion from mild-cognitive impairment.

Transl Psychiatry 2019 05 24;9(1):154. Epub 2019 May 24.

Institute of Neuroscience Biomedical Research Building Campus for Ageing and Vitality Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.

Mild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer's disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer's Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.
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http://dx.doi.org/10.1038/s41398-019-0485-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534556PMC
May 2019
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