scholarly journals Loss-of-function mutations inRAB39Bare associated with typical early-onset Parkinson disease

2015 ◽  
Vol 1 (1) ◽  
pp. e9 ◽  
Author(s):  
Suzanne Lesage ◽  
Jose Bras ◽  
Florence Cormier-Dequaire ◽  
Christel Condroyer ◽  
Aude Nicolas ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Early Onset ◽  
Loss Of Function

scholarly journals Early-Onset Parkinson Disease Screening in Patients From Nigeria

2021 ◽  
Vol 11 ◽  
Author(s):  
Lukasz M. Milanowski ◽  
Olajumoke Oshinaike ◽  
Benjamin J. Broadway ◽  
Jennifer A. Lindemann ◽  
Alexandra I. Soto-Beasley ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Parkinson Disease ◽  
Neurodegenerative Diseases ◽  
Early Onset ◽  
Local Population ◽  
Age At Onset ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
African Countries ◽  
Age Related

Introduction: Nigeria is one of the most populated countries in the world; however, there is a scarcity of studies in patients with age-related neurodegenerative diseases, such as Parkinson disease (PD). The aim of this study was to screen patients with PD including a small cohort of early-onset PD (EOPD) cases from Nigeria for PRKN, PINK1, DJ1, SNCA multiplication, and LRRK2 p.G2019S.Methods: We assembled a cohort of 109 Nigerian patients with PD from the four main Nigerian tribes: Yoruba, Igbo, Edo, and Hausa. Fifteen cases [14 from the Yoruba tribe (93.3%)] had EOPD (defined as age-at-onset <50 years). All patients with EOPD were sequenced for the coding regions of PRKN, PINK1, and DJ1. Exon dosage analysis was performed with a multiplex ligation-dependent probe amplification assay, which also included a SNCA probe and LRRK2 p.G2019S. We screened for LRRK2 p.G2019S in the entire PD cohort using a genotyping assay. The PINK1 p.R501Q functional analysis was conducted.Results: In 15 patients with EOPD, 22 variants were observed [PRKN, 9 (40.9%); PINK1, 10 (45.5%); and DJ1, 3 (13.6%)]. Three (13.6%) rare, nonsynonymous variants were identified, but no homozygous or compound heterozygous carriers were found. No exonic rearrangements were present in the three genes, and no carriers of SNCA genomic multiplications or LRRK2 p.G2019S were identified. The PINK1 p.R501Q functional analysis revealed pathogenic loss of function.Conclusion: More studies on age-related neurodegenerative diseases are needed in sub-Saharan African countries, including Nigeria. Population-specific variation may provide insight into the genes involved in PD in the local population but may also contribute to larger studiesperformed in White and Asian populations.

scholarly journals Early-Onset Osteoporosis

2021 ◽  
Author(s):  
Outi Mäkitie ◽  
M. Carola Zillikens
Keyword(s):  
Young Adults ◽  
Early Onset ◽  
Type I Collagen ◽  
Young Patients ◽  
Fragility Fractures ◽  
Underlying Disease ◽  
Bone Fragility ◽  
Sphingolipid Metabolism ◽  
Type I ◽  
Loss Of Function

AbstractOsteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

scholarly journals The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Maria A. Gandini ◽  
Ivana A. Souza ◽  
Laurent Ferron ◽  
A. Micheil Innes ◽  
Gerald W. Zamponi
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
Structural Damage ◽  
De Novo ◽  
Splice Variants ◽  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Significant Loss ◽  
Loss Of Function ◽  
Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

scholarly journals Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

2021 ◽  
Author(s):  
Andreas R. Janecke ◽  
Xiaoqin Liu ◽  
Rüdiger Adam ◽  
Sumanth Punuru ◽  
Arne Viestenz ◽  
...  
Keyword(s):  
Early Onset ◽  
Single Nucleotide Polymorphism Array ◽  
Outer Nuclear Layer ◽  
Retinal Dystrophy ◽  
Geographic Origin ◽  
Retinal Disease ◽  
Homozygosity Mapping ◽  
Rod Photoreceptor ◽  
Loss Of Function ◽  
Knockout Mouse Model

AbstractBiallelic STX3 variants were previously reported in five individuals with the severe congenital enteropathy, microvillus inclusion disease (MVID). Here, we provide a significant extension of the phenotypic spectrum caused by STX3 variants. We report ten individuals of diverse geographic origin with biallelic STX3 loss-of-function variants, identified through exome sequencing, single-nucleotide polymorphism array-based homozygosity mapping, and international collaboration. The evaluated individuals all presented with MVID. Eight individuals also displayed early-onset severe retinal dystrophy, i.e., syndromic—intestinal and retinal—disease. These individuals harbored STX3 variants that affected both the retinal and intestinal STX3 transcripts, whereas STX3 variants affected only the intestinal transcript in individuals with solitary MVID. That STX3 is essential for retinal photoreceptor survival was confirmed by the creation of a rod photoreceptor-specific STX3 knockout mouse model which revealed a time-dependent reduction in the number of rod photoreceptors, thinning of the outer nuclear layer, and the eventual loss of both rod and cone photoreceptors. Together, our results provide a link between STX3 loss-of-function variants and a human retinal dystrophy. Depending on the genomic site of a human loss-of-function STX3 variant, it can cause MVID, the novel intestinal-retinal syndrome reported here or, hypothetically, an isolated retinal dystrophy.

Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients

Pancreatology ◽  
2021 ◽  
Author(s):  
Grzegorz Oracz ◽  
Michał Zaród ◽  
Maren Ewers ◽  
Helmut Laumen ◽  
Tomasz Gambin ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Early Onset ◽  
Loss Of Function

scholarly journals Association Between Titin Loss-of-Function Variants and Early-Onset Atrial Fibrillation

JAMA ◽  
2018 ◽  
Vol 320 (22) ◽  
pp. 2354 ◽  
Author(s):  
Seung Hoan Choi ◽  
Lu-Chen Weng ◽  
Carolina Roselli ◽  
Honghuang Lin ◽  
Christopher M. Haggerty ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Loss Of Function ◽  
Onset Atrial Fibrillation

scholarly journals Early-onset vs. Late-onset Parkinson’s disease: A Clinical-pathological Study

2015 ◽  
Vol 43 (1) ◽  
pp. 113-119 ◽  
Author(s):  
Leslie Wayne Ferguson ◽  
Ali H. Rajput ◽  
Alexander Rajput
Keyword(s):  
Parkinson Disease ◽  
Early Onset ◽  
Disease Duration ◽  
Late Onset ◽  
Disease Onset ◽  
Clinic Visit ◽  
Pathological Study ◽  
Younger Age ◽  
Wearing Off ◽  
Selection For

AbstractBackground:Several studies have compared early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD) but most are not based on autopsy confirmed cases.Methods:We compared clinical and pharmacological profiles, time to reach irreversible Hoehn and Yahr (H&Y) Stage 3 and levodopa motor complications in autopsy confirmed EOPD and LOPD cases.Results:At first clinic visit EOPD cases were younger but had longer disease duration and they died at a younger age (all p<0.0001). Anti-Parkinsonian drug use, including levodopa, was significantly delayed in EOPD. Lifetime use of amantadine (p<0.05) and dopamine agonists (p<0.01) were higher in EOPD. While lifetime use of levodopa was similar in the two groups, levodopa was used for a significantly longer period by EOPD (p< 0.0001). EOPD had a higher cumulative incidence of dyskinesias (p<0.01), wearing-off (p<0.01), and on-off (p<0.01). However, the time to dyskinesia onset was similar in the two groups. The threshold to wearing-off was much longer in EOPD (p<0.01). H&Y stage profile at first visit was similar in the two groups. The duration from disease onset to reach irreversible H&Y stage 3 was significantly longer in EOPD.Conclusions:Our observations indicate that progression of PD is slower in EOPD and suggest that the pre-clinical interval in this group is longer. These findings can be used for case selection for drug trials and studies of the pathogenesis of PD.

3.023 FREQUENCY OF THE MUTATIONS IN THE PARK2, PINK1 AND DJ-1 GENES IN POLISH PATIENTS WITH THE EARLY-ONSET PARKINSON DISEASE

2012 ◽  
Vol 18 ◽  
pp. S174-S175
Author(s):  
D. Koziorowski ◽  
D. Hoffman-Zacharska ◽  
J. Sławek ◽  
P. Górka ◽  
J. Bal ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Early Onset
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