scholarly journals Neurodegenerative Disease Risk in Carriers of Autosomal Recessive Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Sophia R. L. Vieira ◽  
Huw R. Morris
Keyword(s):  
Genetic Risk ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Disease Risk ◽  
Late Onset ◽  
Gene Mutations ◽  
Carrier Status ◽  
Lysosomal Storage ◽  
Increased Risk ◽  
Distinct Allele

Genetics has driven significant discoveries in the field of neurodegenerative diseases (NDDs). An emerging theme in neurodegeneration warrants an urgent and comprehensive update: that carrier status of early-onset autosomal recessive (AR) disease, typically considered benign, is associated with an increased risk of a spectrum of late-onset NDDs. Glucosylceramidase beta (GBA1) gene mutations, responsible for the AR lysosomal storage disorder Gaucher disease, are a prominent example of this principle, having been identified as an important genetic risk factor for Parkinson disease. Genetic analyses have revealed further examples, notably GRN, TREM2, EIF2AK3, and several other LSD and mitochondria function genes. In this Review, we discuss the evidence supporting the strikingly distinct allele-dependent clinical phenotypes observed in carriers of such gene mutations and its impact on the wider field of neurodegeneration.

scholarly journals Diagnostic exome-based preconception carrier testing in consanguineous couples: results from the first 100 couples in clinical practice

2021 ◽  
Author(s):  
Suzanne C. E. H. Sallevelt ◽  
Alexander P. A. Stegmann ◽  
Bart de Koning ◽  
Crool Velter ◽  
Anja Steyls ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Rare Variants ◽  
Clinical Care ◽  
Carrier Testing ◽  
Carrier Status ◽  
Routine Diagnostics ◽  
Affected Offspring ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Genetics And Genomics

Abstract Purpose Consanguineous couples are at increased risk of being heterozygous for the same autosomal recessive (AR) disorder(s), with a 25% risk of affected offspring as a consequence. Until recently, comprehensive preconception carrier testing (PCT) for AR disorders was unavailable in routine diagnostics. Here we developed and implemented such a test in routine clinical care. Methods We performed exome sequencing (ES) for 100 consanguineous couples. For each couple, rare variants that could give rise to biallelic variants in offspring were selected. These variants were subsequently filtered against a gene panel consisting of ~2,000 genes associated with known AR disorders (OMIM-based). Remaining variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, after which only likely pathogenic and pathogenic (class IV/V) variants, present in both partners, were reported. Results In 28 of 100 tested consanguineous couples (28%), likely pathogenic and pathogenic variants not previously known in the couple or their family were reported conferring 25% risk of affected offspring. Conclusion ES-based PCT provides a powerful diagnostic tool to identify AR disease carrier status in consanguineous couples. Outcomes provided significant reproductive choices for a higher proportion of these couples than previous tests.

scholarly journals Aerobic exercise improves hippocampal blood flow for hypertensive Apolipoprotein E4 carriers

2021 ◽  
pp. 0271678X2199034
Author(s):  
Carolyn S Kaufman ◽  
Robyn A Honea ◽  
Joseph Pleen ◽  
Rebecca J Lepping ◽  
Amber Watts ◽  
...  
Keyword(s):  
Blood Flow ◽  
Aerobic Exercise ◽  
Genetic Risk ◽  
Exercise Intervention ◽  
Late Onset ◽  
Control Group ◽  
Carrier Status ◽  
Or Education ◽  
Exercise Interventions ◽  
Apolipoprotein E4

Cerebrovascular dysfunction likely contributes causally to Alzheimer’s disease (AD). The strongest genetic risk factor for late-onset AD, Apolipoprotein E4 ( APOE4), may act synergistically with vascular risk to cause dementia. Therefore, interventions that improve vascular health, such as exercise, may be particularly beneficial for APOE4 carriers. We assigned cognitively normal adults (65–87 years) to an aerobic exercise intervention or education only. Arterial spin labeling MRI measured hippocampal blood flow (HBF) before and after the 52-week intervention. We selected participants with hypertension at enrollment (n = 44). For APOE4 carriers, change in HBF (ΔHBF) was significantly ( p = 0.006) higher for participants in the exercise intervention (4.09 mL/100g/min) than the control group (−2.08 mL/100g/min). There was no difference in ΔHBF between the control (−0.32 mL/100g/min) and exercise (−0.54 mL/100g/min) groups for non-carriers (p = 0.918). Additionally, a multiple regression showed an interaction between change in systolic blood pressure (ΔSBP) and APOE4 carrier status on ΔHBF ( p = 0.035), with reductions in SBP increasing HBF for APOE4 carriers only. Aerobic exercise improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between ΔSBP and ΔHBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD. ClinicalTrials.gov Identifier: NCT02000583

CYP46A1 variants influence Alzheimer’s disease risk and brain cholesterol metabolism

2009 ◽  
Vol 24 (3) ◽  
pp. 183-190 ◽  
Author(s):  
Heike Kölsch ◽  
Dieter Lütjohann ◽  
Frank Jessen ◽  
Julius Popp ◽  
Frank Hentschel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Risk ◽  
Cholesterol Metabolism ◽  
Disease Risk ◽  
Brain Cholesterol ◽  
Increased Risk ◽  
Csf Levels ◽  
Interaction Term ◽  
Gene Variability

AbstractBackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.MethodsWe performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p = 0.016; rs4900442: p = 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p = 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p = 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p = 0.001) and cholesterol (p < 0.001).ConclusionOur results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

scholarly journals M Mode Ultrasound and Tissue Doppler Imaging to Assess Diaphragm Feature in Late Onset Pompe Disease

2020 ◽  
Vol 12 (3) ◽  
pp. 55-58
Author(s):  
Paris Meng ◽  
Adam Ogna ◽  
Abdallah Fayssoil
Keyword(s):  
Tissue Doppler Imaging ◽  
Pompe Disease ◽  
Autosomal Recessive ◽  
Storage Disease ◽  
Late Onset ◽  
Tissue Doppler ◽  
Doppler Imaging ◽  
Supportive Treatment ◽  
Lysosomal Storage ◽  
Diaphragm Weakness

Late-onset Pompe disease (LOPD) is an autosomal recessive lysosomal storage disease. Clinical features include skeletal muscle deficiency and diaphragm weakness. Clinical management relies on supportive treatment and mechanical ventilation in patients with chronic respiratory failure. M mode ultrasound and sniff tissue Doppler imaging can be used to assess and follow diaphragm function.

Bovine β-mannosidosis: Pathologic and Genetic Findings in Salers Calves

1993 ◽  
Vol 30 (2) ◽  
pp. 130-139 ◽  
Author(s):  
L. Bryan ◽  
S. Schmutz ◽  
S. D. Hodges ◽  
F. F. Snyder
Keyword(s):  
Autosomal Recessive ◽  
Storage Disease ◽  
Autosomal Recessive Disease ◽  
Pedigree Analysis ◽  
Lymphoid Tissues ◽  
Lysosomal Storage ◽  
Gestational Weight ◽  
Head Tremor ◽  
Renal Enlargement ◽  
The Brain

β-mannosidosis is a recently recognized lysosomal storage disease in newborn Salers calves. Fourteen calves with β-mannosidase deficiency were examined. Twelve calves were from routine laboratory submissions, and two calves were the result of a breeding trial. Salers calves with β-mannosidase deficiency were of normal gestational weight, 36 ± 6 kg, but were affected at birth. The head was moderately domed, and there was mild superior brachygnathism. The calves were recumbent and had a head tremor. There was bilateral renal enlargement, severe hypomyelination in the brain and variable thyroid gland enlargement. Severe cytoplasmic vacuolation was present within neurons, tubule epithelial cells, follicular cells and macrophages of the nervous, renal, thyroid and lymphoid tissues, respectively. Pedigree analysis and breeding trial results were consistent with an autosomal recessive disease. An initial biochemical survey of 1,494 Salers cattle indicated a carrier frequency of 23%.

Severe cardiac involvement in Gaucher type IIIC: a case report and review of the literature

2017 ◽  
Vol 27 (7) ◽  
pp. 1426-1429 ◽  
Author(s):  
Yılmaz Kör ◽  
Mehmet Keskin ◽  
Osman Başpınar
Keyword(s):  
Gaucher Disease ◽  
Autosomal Recessive ◽  
Cardiac Involvement ◽  
Late Onset ◽  
Neurological Symptoms ◽  
Type I ◽  
Lysosomal Storage ◽  
Cardiovascular Involvement ◽  
Eye Movement Disorders ◽  
Type Iiic

AbstractGaucher disease is an autosomal-recessive lysosomal storage disease characterised by the accumulation of glucocerebroside in macrophages; it is caused by mutations in glucocerebrosidase gene-1 in many organ tissues such as the liver, spleen, and bone marrow. Its different clinical subtypes, according to the presence and severity of neurological symptoms, are as follows: type I, non-neuronopathic (95%); type II, acute neuronopathic; and type III, chronic neuronopathic. Type IIIC is a rare subgroup characterised by cardiovascular involvement as well as eye-movement disorders and late-onset neurological symptoms. In such cases, homozygous D409H is the most frequently detected mutation. In this article, we report the case of a patient, aged 15 years and 8 months, with complaints of syncope and a diagnosis of type IIIC Gaucher disease.

scholarly journals Oral care precautions for patients with cystic fibrosis

2021 ◽  
Vol 3 (2) ◽  
pp. 073-079
Author(s):  
H. Goumghar ◽  
M. Sidqui
Keyword(s):  
Cystic Fibrosis ◽  
Oral Hygiene ◽  
Autosomal Recessive ◽  
Autosomal Recessive Disease ◽  
Oral Care ◽  
Poor Oral Hygiene ◽  
Optimal Care ◽  
Hygiene Practices ◽  
Medical Issues ◽  
Increased Risk

Cystic fibrosis (CF) is the most common severe autosomal recessive disease in the Caucasian population. Although it remains incurable, it is currently possible to extend the life expectancy of patients with modern therapeutic possibilities. Given the medical issues that a child with CF faces, oral health may be perceived as being of lesser importance. Thus, the establishment of good dietary and oral hygiene practices may not take place, leading to an increased risk of caries and gingivitis due to poor oral hygiene. A change in patient management may be necessary to ensure optimal care.

scholarly journals Apolipoprotein E genotype and MRI-detected brain alterations pertaining to neurodegeneration: A systematic review

2021 ◽  
Author(s):  
Albert Dayor Piersson ◽  
Mazlyfarina Mohamad ◽  
Subapriya Suppiah ◽  
Nor Fadilah Rajab
Keyword(s):  
Systematic Review ◽  
Apolipoprotein E ◽  
Temporal Lobe ◽  
Late Onset ◽  
Apoe Genotype ◽  
Posterior Cingulate Cortex ◽  
Parahippocampal Gyrus ◽  
Carrier Status ◽  
Apoe Ε4 ◽  
Increased Risk

AbstractIntroductionThe effect of apolipoprotein E (APOE) genotype, particularly APOE ε4, the main genetic risk factor for late-onset Alzheimer’s disease (LOAD), has been widely explored in neuroimaging studies pertaining to older adults. The goal of this systematic review was to review the literature on the relationship between carriage of the APOE ε4 allele and grey matter (GM) changes across various age groups and its influence on neurodegeneration as evidenced by structural magnetic resonance imaging (MRI).MethodsA search of the electronic databases Pubmed, Scopus, Ovid and Cochrane was carried out till March 2020. Only studies published in English were included. Risk of bias of each study was assessed using the modified Newcastle-Ottawa Scale.ResultsA total of 115 articles met the inclusion criteria. Methodological quality varied from poor to good. There is moderate evidence of reduced GM volume in the middle frontal gyrus, precuneus, hippocampus, hippocampal subfields, amygdala, parahippocampal gyrus, middle temporal lobe, whole temporal lobe, temporal pole, and posterior cingulate cortex in APOE ε4 carriers.ConclusionThe present data supports the utility of the hippocampal GM volume to evaluate early structural neurodegenerative changes that occurs in APOE ε4 positive elderly individuals who are at increased risk of developing LOAD. Furthermore, the evidence supports serial measurements and comparison of hippocampal volume based on age group, to track the progression of neurodegeneration in APOE ε4 carriers. Additional longitudinal studies are necessary to confirm whether the combination of MRI-detected hippocampal atrophy with APOE ε4 carrier status, can better predict the development of LOAD in cognitively normal individuals.

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