scholarly journals Mutational Analysis and mtDNA Haplogroup Characterization in Three Serbian Cases of Mitochondrial Encephalomyopathies and Literature Review

Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1969
Author(s):  
Phepy G. A. Dawod ◽  
Jasna Jancic ◽  
Ana Marjanovic ◽  
Marija Brankovic ◽  
Milena Jankovic ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Age Of Onset ◽  
Single Case ◽  
Phenotypic Variability ◽  
Leigh Syndrome ◽  
Clinical Severity ◽  
Sequencing Analysis ◽  
Clinical Genetic ◽  
Mitochondrial Encephalomyopathies ◽  
Mtdna Mutations

Mitochondrial encephalomyopathies (MEMP) are heterogeneous multisystem disorders frequently associated with mitochondrial DNA (mtDNA) mutations. Clinical presentation varies considerably in age of onset, course, and severity up to death in early childhood. In this study, we performed molecular genetic analysis for mtDNA pathogenic mutation detection in Serbian children, preliminary diagnosed clinically, biochemically and by brain imaging for mitochondrial encephalomyopathies disorders. Sanger sequencing analysis in three Serbian probands revealed two known pathogenic mutations. Two probands had a heteroplasmic point mutation m.3243A>G in the MT-TL1 gene, which confirmed mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome (MELAS), while a single case clinically manifested for Leigh syndrome had an almost homoplasmic (close to 100%) m.8993T>G mutation in the MT-ATP6 gene. After full mtDNA MITOMASTER analysis and PhyloTree build 17, we report MELAS’ association with haplogroups U and H (U2e and H15 subclades); likewise, the mtDNA-associated Leigh syndrome proband shows a preference for haplogroup H (H34 subclade). Based on clinical–genetic correlation, we suggest that haplogroup H may contribute to the mitochondrial encephalomyopathies’ phenotypic variability of the patients in our study. We conclude that genetic studies for the distinctive mitochondrial encephalomyopathies should be well-considered for realizing clinical severity and possible outcomes.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Madison E. Hoes ◽  
Anastazja M. Gorecki ◽  
Frances Theunissen ◽  
Abigail L. Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

scholarly journals Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cristina Grippaudo ◽  
Isabella D’Apolito ◽  
Concetta Cafiero ◽  
Agnese Re ◽  
Pietro Chiurazzi ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Mutational Analysis ◽  
Clinical Signs ◽  
Open Bite ◽  
Clinical Severity ◽  
Mixed Dentition ◽  
Phenotype Correlation ◽  
Posterior Teeth ◽  
Primary Failure Of Eruption ◽  
Genotype Phenotype Correlation

Abstract Background Primary failure of eruption (PFE) is a hereditary condition, and linkage with variants in the PTH1R gene has been demonstrated in many cases. The clinical severity and expression of PFE is variable, and the genotype–phenotype correlation remains elusive. Further, the similarity between some eruption disorders that are not associated with PTH1R alterations is striking. To better understand the genotype–phenotype correlation, we examined the relationship between the eruption phenotype and PTH1R genotype in 44 patients with suspected PFE and 27 unaffected relatives. Sanger sequencing was employed to analyze carefully selected PFE patients. Potential pathogenicity of variants was evaluated against multiple genetic databases for function prediction and frequency information. Results Mutational analysis of the PTH1R coding sequence revealed 14 different variants in 38 individuals (30 patients and 8 first-degree relatives), 9 exonic and 5 intronic. Their pathogenicity has been reported and compared with the number and severity of clinical signs. In 72.7% of patients with pathogenic variants, five clinical and radiographic criteria have been found: involvement of posterior teeth, involvement of the distal teeth to the most mesial affected, supracrestal presentation, altered vertical growth of the alveolar process and posterior open-bite. In cases with mixed dentition (3), the deciduous molars of the affected quadrant were infraoccluded. Discussion The probability of an affected patient having a PTH1R variant is greater when five specific clinical characteristics are present. The likelihood of an eruption defect in the absence of specific clinical characteristics is rarely associated with a PTH1R mutation. Conclusions We report here that systematic clinical and radiographic observation using a diagnostic rubric is highly valuable in confirming PFE and offers a reliable alternative for accurate diagnosis.

scholarly journals Mitochondrial tRNA mutations in Chinese children with tic disorders

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Peifang Jiang ◽  
Yinjie Ling ◽  
Tao Zhu ◽  
Xiaoying Luo ◽  
Yilin Tao ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Phenotypic Variability ◽  
Han Chinese ◽  
Tic Disorders ◽  
Trna Genes ◽  
Incomplete Penetrance ◽  
Mitochondrial Trna ◽  
Pathogenic Potential ◽  
Total Prevalence ◽  
Chinese Subjects

Abstract Aim: To conduct the clinical, genetic, and molecular characterization of 494 Han Chinese subjects with tic disorders (TD). Methods: In the present study, we performed the mutational analysis of 22 mitochondrial tRNA genes in a large cohort of 494 Han Chinese subjects with TD via Sanger sequencing. These variants were then assessed for their pathogenic potential via phylogenetic, functional, and structural analyses. Results: A total of 73 tRNA gene variants (49 known and 24 novel) on 22 tRNA genes were identified. Among these, 18 tRNA variants that were absent or present in <1% of 485 Chinese control patient samples were localized to highly conserved nucleotides, or changed the modified nucleotides, and had the potential structural to alter tRNA structure and function. These variants were thus considered to be TD-associated mutations. In total, 25 subjects carried one of these 18 putative TD-associated tRNA variants with the total prevalence of 4.96%. Limitations: The phenotypic variability and incomplete penetrance of tic disorders in pedigrees carrying these tRNA mutations suggested the involvement of modifier factors, such as nuclear encoded genes associated mitochondrion, mitochondrial haplotypes, epigenetic, and environmental factors. Conclusion: Our data provide the evidence that mitochondrial tRNA mutations are the important causes of tic disorders among Chinese population. These findings also advance current understanding regarding the clinical relevance of tRNA mutations, and will guide future studies aimed at elucidating the pathophysiology of maternal tic disorders.

Novel combined insulin-like 3 variations of a single nucleotide in cryptorchidism

2019 ◽  
Vol 32 (9) ◽  
pp. 987-994 ◽  
Author(s):  
Xenophon Sinopidis ◽  
Roza Mourelatou ◽  
Eirini Kostopoulou ◽  
Alexia Karvela ◽  
Andrea-Paola Rojas-Gil ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Testicular Descent ◽  
Sequencing Analysis ◽  
Single Nucleotide ◽  
Allelic Variants ◽  
Exon 2 ◽  
Pcr Products ◽  
Exon 1 ◽  
Male Patients ◽  
Allelic Variations

Abstract Background Insulin-like 3 hormone (INSL3) is involved in the process of testicular descent, and has been thoroughly studied in cryptorchidism. However, INSL3 allelic variations found in the human genome were heterozygous and only a few of them were found exclusively in patients with cryptorchidism. Under this perspective, we aimed to study the presence of INSL3 allelic variations in a cohort of patients with cryptorchidism and to estimate their potential consequences. Methods Blood samples were collected from 46 male patients with non-syndromic cryptorchidism and from 43 age-matched controls. DNA extraction and polymerase chain reaction (PCR) were performed for exons 1 and 2 of the INSL3 gene in all subjects. Sequencing analysis was carried out on the PCR products. All data were grouped according to testicular location. Results Seven variations of a single nucleotide (SNVs) were identified both in patients with cryptorchidism and in controls: rs2286663 (c.27G > A), rs1047233 (c.126A > G) and rs6523 (c.178A > G) at exon 1, rs74531687 (c.191-30C > T) at the intron, rs121912556 (c.305G > A) at exon 2 and rs17750642 (c.*101C > A) and rs1003887 (c.*263G > A) at the untranslated region (UTR). The allelic variants rs74531687 and rs121912556 were found for the first time in the Greek population. The novel homozygotic combination of the three allelic variants rs1047233-rs6523-rs1003887 seemed to present a stronger correlation with more severe forms of cryptorchidism. Conclusions The combination of specific INSL3 SNVs rather than the existence of each one of them alone may offer a new insight into the involvement of allelic variants in phenotypic variability and severity.

scholarly journals Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

2019 ◽  
Vol 5 (2) ◽  
pp. e315 ◽  
Author(s):  
Angela J. Lee ◽  
Karra A. Jones ◽  
Russell J. Butterfield ◽  
Mary O. Cox ◽  
Chamindra G. Konersman ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Founder Mutation ◽  
Congenital Muscular Dystrophy ◽  
Clinical Severity ◽  
Muscle Pathology ◽  
Clinical Genetic ◽  
End Stage ◽  
Muscle Biopsies ◽  
Normal Cognition

ObjectiveTo characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the FKRP c.1387A>G mutation.MethodsStandardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in FKRP. Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA.ResultsWe report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in FKRP. Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous FKRP c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including FKRP. All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous FKRP c.826C>A limb-girdle muscular dystrophy.ConclusionsThe clinical features and muscle pathology in these newly reported patients homozygous for FKRP c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that FKRP c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200–1,500 years).

scholarly journals Clinical and Haplotypic Variability of Slovenian USH2A Patients Homozygous for the c. 11864G>A Nonsense Mutation

Genes ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 1015 ◽  
Author(s):  
Andrej Zupan ◽  
Ana Fakin ◽  
Saba Battelino ◽  
Martina Jarc-Vidmar ◽  
Marko Hawlina ◽  
...  
Keyword(s):  
Disease Severity ◽  
Nonsense Mutation ◽  
Age Of Onset ◽  
Phenotypic Variability ◽  
Fundus Autofluorescence ◽  
Usher Syndrome ◽  
Test Methods ◽  
Rapid Screening ◽  
Autofluorescence Imaging ◽  
Phenotype Analysis

Purpose: to determine a detailed clinical and haplotypic variability of the Slovenian USH2A patients with homozygous c.11864G>A (p.Trp3955Ter) nonsense mutation and to develop sensitive, accurate and rapid screening test. Methods: Ten unrelated homozygous patients with detailed ophthalmological exam were included in our study. The High-Resolution Melting (HRM) method was developed for fast and reliable detection of the c.11864G>A mutation. Results: The c.11864G>A mutation represents the vast majority of pathogenic alleles in Slovenian USH2A-Usher syndrome population (84%). The median age of onset of nyctalopia was 16 years and all patients younger than 40 years had hyperautofluorescent rings on fundus autofluorescence imaging. The Kaplan Meier survival analysis showed a decline of central vision after the age of 40, with 50% patients reaching visual acuity (VA) ≤ 0.05 at the average age of 66 years visual field diameter less than 20° at the average age of 59 years. There was a relatively large phenotypic variability in the retinal and audiological phenotype. Analysis of the p.Trp3955Ter-homozygous patients revealed four different haplotypes, with the frequency of the most common haplotype ~65%. Disease severity did not correlate with the haplotype. Conclusions: According to the natural history of homozygous p.Trp3955Ter patients any therapy aimed to slow disease progression in these patients would be best started before the age of 40. Phenotypic variability suggests the presence of cis and/or trans factors outside the USH2A gene that are able to affect disease severity. High frequency of p.Trp3955Ter mutation in Slovenian USH2A gene pool appears to be initiated from different unrelated founders because of migrations from neighboring populations. The mutation on haplotype 2 seems to be the major founder allele.

scholarly journals Maternally Inherited Diabetes Mellitus Associated with a Novel m.15897G>A Mutation in Mitochondrial tRNAThr Gene

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Ke Li ◽  
Lijun Wu ◽  
Jianjiang Liu ◽  
Wei Lin ◽  
Qiang Qi ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Complete Mitochondrial Genome ◽  
Mutant Cell ◽  
Atp Synthesis ◽  
Chinese Family ◽  
Molecular Characteristics ◽  
Clinical Genetic ◽  
Mitochondrial Dysfunctions ◽  
Inherited Diabetes

We report here the clinical, genetic, and molecular characteristics of type 2 diabetes in a Chinese family. There are differences in the severity and age of onset in diabetes among these families. By molecular analysis of the complete mitochondrial genome in this family, we identified the homoplasmic m.15897G>A mutation underwent sequence analysis of whole mitochondrial DNA genome, which localized at conventional position ten of tRNAThr, and distinct sets of mtDNA polymorphisms belonging to haplogroup D4b1. This mutation has been implicated to be important for tRNA identity and stability. Using cybrid cell models, the decreased efficiency of mitochondrial tRNAThr levels caused by the m.15897G>A mutation results in respiratory deficiency, protein synthesis and assembly, mitochondrial ATP synthesis, and mitochondrial membrane potential. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cell lines. These data provide a direct evidence that a novel tRNA mutation was associated with T2DM. Thus, our findings provide a new insight into the understanding of pathophysiology of maternally inherited diabetes.

Phenotypic Variability in Obsessive-Compulsive Disorder and Its Relationship to Familial Risk

CNS Spectrums ◽  
1999 ◽  
Vol 4 (6) ◽  
pp. 57-61 ◽  
Author(s):  
David L. Pauls
Keyword(s):  
Cluster Analysis ◽  
Obsessive Compulsive Disorder ◽  
Segregation Analysis ◽  
Genetic Factors ◽  
Age Of Onset ◽  
Phenotypic Variability ◽  
Familial Risk ◽  
Obsessive Compulsive ◽  
Important Data ◽  
Compulsive Disorder

ABSTRACTTwin and family studies of obsessive-compulsive disorder (OCD) have gleaned important data regarding the influence of genetic factors in the development of this disorder. These studies have shown that understanding the importance of genetic factors in OCD is largely dependent upon how the phenotype is classified. The last decade of research has found that substantial variability of symptomatology exists across individuals diagnosed with OCD. Considering this, a number of analyses have been conducted to determine if possible subtypes of OCD exist, including analysis of age of onset, cluster analysis, factor analysis, and segregation analysis. These methodologies, and possibly others, could aid in identifying the genes involved in the development of OCD.

Exposure and response prevention therapy augmented with naltrexone in kleptomania: a controlled case study using galvanic skin response for monitoring

2019 ◽  
Vol 47 (5) ◽  
pp. 622-627 ◽  
Author(s):  
Sebastian Olbrich ◽  
Ina Jahn ◽  
Katarina Stengler
Keyword(s):  
Galvanic Skin Response ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Single Case ◽  
Therapy Monitoring ◽  
Response Prevention ◽  
Clinical Severity ◽  
Therapeutic Monitoring ◽  
Opioid Antagonist ◽  
Exposure And Response Prevention ◽  
Skin Response

AbstractBackground:Kleptomania is a disease that shares features with obsessive compulsive spectrum disorders (OCD) and with substance abuse disorders (SAD). This is underlined by therapeutic approaches in kleptomania ranging from cognitive behavioural therapy and selective serotonin reuptake inhibitors that are effective in OCD, and opioid antagonists that are currently being used in SAD. However, almost no literature exists about exposure and response prevention (ERP) therapy in kleptomania. Furthermore, there is a clear lack of objective markers that would allow a therapeutic monitoring.Aim:To show the effectiveness of ERP therapy in kleptomania in a single case report.Method:An ERP therapy under real-world conditions and later augmentation with the opioid antagonist naltrexone is described. Continuous measurements of galvanic skin response (GSR) before, during and after therapy sessions are reported in association with changes of the Kleptomania Symptom Assessment Scale (KSAS) self-questionnaire.Results:While KSAS scores showed a clear treatment response to ERP sessions, the GSR was significantly lower during ERP treatment in comparison with baseline measures. However, during augmentation with naltrexone, GSR measures increased again and clinical severity did not further improve.Conclusions:This case shows the possible usefulness of ERP-like approaches and therapy monitoring using electrophysiological markers of arousal for individualized treatment in kleptomania.

Sign in / Sign up

Export Citation Format

Share Document