scholarly journals Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India

2021 ◽  
Author(s):  
Valakunja H. Ganaraja ◽  
Kiran Polavarapu ◽  
Mainak Bardhan ◽  
Veeramani Preethish-Kumar ◽  
Shingavi Leena ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Positive Family History ◽  
Disease Onset ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Limb Weakness ◽  
Duration Of Symptoms ◽  
Large Deletions ◽  
Scapular Winging ◽  
Initial Symptoms

AbstractCalpainopathy is caused by mutations in the CAPN3. There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.

scholarly journals Familial Aggregation in Idiopathic Subglottic Stenosis

2020 ◽  
Vol 163 (5) ◽  
pp. 1011-1017
Author(s):  
Virginia E. Drake ◽  
Alexander Gelbard ◽  
Nara Sobriera ◽  
Elizabeth Wohler ◽  
Lynne L. Berry ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Familial Aggregation ◽  
Tertiary Care ◽  
Positive Family History ◽  
Disease Onset ◽  
Subglottic Stenosis ◽  
Patient Demographics ◽  
The North ◽  
Familial Clustering ◽  
Tertiary Care Centers

Objective To evaluate inheritance patterns and define the familial clustering rate of idiopathic subglottic stenosis (iSGS). Study Design Retrospective observational study. Setting International multicenter collaborative of >30 tertiary care centers. Methods Patients with a clinically confirmed iSGS diagnosis within the North American Airway Collaborative’s iSGS1000 cohort consented between 2014 and 2018 were eligible for enrollment. Patient demographics and disease severity were abstracted from the collaborative’s iSGS longitudinal registry. Pedigrees of affected families were created. Results A total of 810 patients with iSGS were identified. Positive family history for iSGS was reported in 44 patients in 20 families. The rate of familial clustering in iSGS is 2.5%. Mean age of disease onset is 42.6 years. Of the 44 patients with familial aggregation of iSGS, 42 were female and 2 were male; 13 were mother-daughter pairs and 2 were father-daughter pairs. There were 3 sister-sister pairs. There was 1 niece-aunt pair and 2 groups of 3 family members. One pedigree demonstrated 2 affected mother-daughter pairs, with the mothers being first-degree paternal cousins. Inheritance is non-Mendelian, and anticipation is present in 11 of 13 (84%) parent-offspring pairs. The mean age of onset between parents (48.4 years) and offspring (36.1 years) was significantly different ( P = .016). Conclusion This study quantifies the rate of familial clustering of iSGS at 2.5%. Inheritance is non-Mendelian, and disease demonstrates anticipation. These data suggest that there may be a genetic contribution in iSGS.

scholarly journals Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Wo-Tu Tian ◽  
Fei-Xia Zhan ◽  
Qing Liu ◽  
Xing-Hua Luan ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Western Blotting ◽  
Age Of Onset ◽  
Neuropsychiatric Symptoms ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Brain Biopsy ◽  
Loss Of Function ◽  
Wild Type ◽  
Axonal Spheroids ◽  
Initial Symptoms

Abstract Background CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. Methods In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. Results Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. Conclusions Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. Trial registration ChiCTR, ChiCTR1800015295. Registered 21 March 2018.

Retrospective evaluation of patients with X-linked adrenoleukodystrophy with a wide range of clinical presentations: a single center experience

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Asburce Olgac ◽  
Çiğdem Seher Kasapkara ◽  
Betül Derinkuyu ◽  
Deniz Yüksel ◽  
Semra Çetinkaya ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Neurological Deterioration ◽  
Loss Of Function ◽  
Single Center ◽  
Hematopoietic Stem ◽  
Initial Symptoms ◽  
Wide Range ◽  
Neurological System

Abstract Objectives X-linked adrenoleukodystrophy (X-ALD), is a peroxisomal inborn error of metabolism caused due to the loss of function variants of ABCD1 gene that leads to accumulation of very long chain fatty acids (VLCFAs) in several tissues including the neurological system. Childhood cerebral X-ALD (CCALD) is the most common and severe form of X-ALD, if left untreated. Allogenic hematopoietic stem cell transplantation (HSCT) is the only available therapy that halts neurological deterioration in CCALD. We present 12 patients with several subtypes of X-ALD that were followed-up in a single center. Methods Data of 12 patients diagnosed with X-ALD were documented retrospectively. Demographics, age of onset, initial symptoms, endocrine and neurological findings, VLCFA levels, neuroimaging data, molecular genetic analysis of ABCD1 gene, and disease progress were documented. Results Mean age of initiation of symptoms was 7.9 years and mean age of diagnosis was 10.45 years. Eight patients had the CCALD subtype, while two had the cerebral form of AMN, one had the adult form of cerebral ALD, and one patient had the Addison only phenotype. The most common initial symptoms involved the neurological system. Loes scores varied between 0 and 12. Seven patients with CCALD underwent HSCT, among them three patients died. The overall mortality rate was 25%. Conclusions Patients with X-ALD should be carefully followed up for cerebral findings and progression, since there is no genotype–phenotype correlation, and the clinical course cannot be predicted by family history. HSCT is the only available treatment option for patients with neurological deterioration.

Folnegović & Folnevogić-Šmalc's “Schizophrenia in Croatia: Inter-regional Differences in Prevalence and a Comment on Constant Incidence”

1994 ◽  
Vol 164 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Brian Cooper ◽  
John M. Eagles
Keyword(s):  
Age Of Onset ◽  
Positive Family History ◽  
Disease Onset ◽  
Incidence Rates ◽  
Population Characteristics ◽  
Reproduction Rate ◽  
Study Objective ◽  
Admission Rates ◽  
Manic Depressive ◽  
Economic Migration

“Study objective - The aim was to examine why differences exist in schizophrenia prevalence and risk in some areas of Croatia, when schizophrenia incidence rates do not appear to vary. Design - Areas differing by schizophrenia admission rates in patients born in 1953 and admitted by the age of 31 years are compared using a number of indicators relating both to general population characteristics and to those of schizophrenic cases in these populations. Setting - The study covers the whole of Croatia (4 601 469 inhabitants, 1981 census). Subjects - By the age of 31 years, out of 80 445 individuals born in Croatia in 1953, 464 were admitted for and diagnosed as having schizophrenia. Main results - Admission risk rates are higher in those parts of Croatia where emigration rates are high and lower where immigration rates are high. There is also a positive correlation with schizophrenia prevalence and manic depressive psychosis rates. There is a negative correlation with age of onset of schizophrenia and with schizophrenic reproduction rates. In the study areas, hospital incidence rates are not significantly different. Conclusions - Economic migration and negative selection in the domestic population are likely to be the most significant factors leading to differences in schizophrenia prevalence. The approximately equal incidence rates in the population, with different prevalence and admission risks, are linked to differences in the disease onset among schizophrenics with a positive family history for this condition. In other words, these patients, when part of the population with a greater prevalence and a greater hereditary loading, experience the onset more often at an earlier age. Thus they have a lower reproduction rate than in a population with a lower prevalence and a lower hereditary loading. Thus incidence rates in populations with different prevalences and different hereditary loads are maintained roughly equal over generations.”

scholarly journals Pediatric multiple sclerosis: analysis of clinical and epidemiological aspects according to National MS Society Consensus 2007

2008 ◽  
Vol 66 (3b) ◽  
pp. 665-670 ◽  
Author(s):  
Maria Lúcia Brito Ferreira ◽  
Maria Íris Morais Machado ◽  
Maria José Guedes Dantas ◽  
Álvaro José Porto Moreira ◽  
Adélia Maria de Miranda Henriques Souza
Keyword(s):  
Multiple Sclerosis ◽  
Early Childhood ◽  
Age Of Onset ◽  
Disease Onset ◽  
Demyelinating Diseases ◽  
Childhood And Adolescence ◽  
Significance Level ◽  
Initial Symptoms ◽  
Relapsing Remitting ◽  
Different Characteristics

OBJECTIVE: To describe the epidemiological and clinical characteristics of child/adolescence multiple sclerosis (MS). METHOD: According to a descriptive, cohort study, with comparison of groups, data of 31 cases of child/adolescent MS, diagnosed at State Reference Center for Demyelinating Diseases - Hospital da Restauração, Recife, Pernambuco, Brazil, from 1987 to July 2007, were analyzed. The variables were: sex, initial symptoms, time for diagnosis, time of disease onset (early childhood, later childhood and adolescence), time of follow-up, number of relapses, relapses index and disability. Using SPSS software, version 13.0, t Student and Mann-Whitney tests were performed, with significance level of 0.05. RESULTS: There were 3 (9.7%) cases of early childhood MS, 9 (29%), of late childhood MS, and 19 (61.3%), of adolescence MS. The general sex rate female: male was 1.8:1, varying according to age of onset. The predominant deficits were motor (12; 38.7%) and brainstem/cerebellum (7; 22.5%) especially on subsequent relapses of relapsing/remitting form. Time for diagnosis and average relapses index were higher in early childhood than in adolescence class (p=0.049 and p=0.028, respectively). Disability was higher for primary and secondary MS, as well as for early childhood. CONCLUSION: Early childhood MS presents proper and different characteristics from adults, consisting in a difficult diagnosis that demands aid of expert neurologist on MS.

scholarly journals Characterization and treatment of congenital thrombotic thrombocytopenic purpura

Blood ◽  
2019 ◽  
Vol 133 (15) ◽  
pp. 1644-1651 ◽  
Author(s):  
Ferras Alwan ◽  
Chiara Vendramin ◽  
Ri Liesner ◽  
Amanda Clark ◽  
William Lester ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Age Of Onset ◽  
Organ Damage ◽  
Compound Heterozygous ◽  
Prophylactic Therapy ◽  
Thrombocytopenic Purpura ◽  
Stroke Incidence ◽  
End Organ Damage ◽  
Congenital Thrombotic Thrombocytopenic Purpura ◽  
Diagnosis Age

Abstract Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.

scholarly journals A Mild Phenotype Caused by Two Novel Compound Heterozygous Mutations in CEP290

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1240
Author(s):  
Agnieszka Rafalska ◽  
Anna M. Tracewska ◽  
Anna Turno-Kręcicka ◽  
Milena J. Szafraniec ◽  
Marta Misiuk-Hojło
Keyword(s):  
Vision Loss ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Mild Phenotype ◽  
Cone Function ◽  
Retinal Disorders ◽  
Molecular Inversion Probes ◽  
Disease Experience ◽  
The Individual ◽  
Inherited Retinal Disorders

CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss due to cone-rod dystrophy, as in Leber congenital amaurosis. In this case report, we describe two novel loss-of-function heterozygous alterations in the CEP290 gene, discovered in a patient suffering from retinitis pigmentosa using massive parallel sequencing of a molecular inversion probes library constructed for 108 genes involved in IRDs. A milder phenotype than expected was found in the individual, which serves to prove that some CEP290-associated disorders may display preserved cone function.

Adult systemic lupus erythematosus in Egypt: The nation-wide spectrum of 3661 patients and world-wide standpoint

Lupus ◽  
2021 ◽  
pp. 096120332110142
Author(s):  
Tamer A Gheita ◽  
Rasha Abdel Noor ◽  
Esam Abualfadl ◽  
Osama S Abousehly ◽  
Iman I El-Gazzar ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Age Of Onset ◽  
Wide Spectrum ◽  
Age At Onset ◽  
Disease Onset ◽  
Clinical Manifestations ◽  
Population Based ◽  
Systemic Lupus ◽  
Cross Sectional

Objective The aim of this study was to present the epidemiology, clinical manifestations and treatment pattern of systemic lupus erythematosus (SLE) in Egyptian patients over the country and compare the findings to large cohorts worldwide. Objectives were extended to focus on the age at onset and gender driven influence on the disease characteristics. Patients and method This population-based, multicenter, cross-sectional study included 3661 adult SLE patients from Egyptian rheumatology departments across the nation. Demographic, clinical, and therapeutic data were assessed for all patients. Results The study included 3661 patients; 3296 females and 365 males (9.03:1) and the median age was 30 years (17–79 years), disease duration 4 years (0–75 years) while the median age at disease onset was 25 years (4–75 years). The overall estimated prevalence of adult SLE in Egypt was 6.1/100,000 population (1.2/100,000 males and 11.3/100,000 females).There were 316 (8.6%) juvenile-onset (Jo-SLE) and 3345 adult-onset (Ao-SLE). Age at onset was highest in South and lowest in Cairo (p < 0.0001). Conclusion SLE in Egypt had a wide variety of clinical and immunological manifestations, with some similarities with that in other nations and differences within the same country. The clinical characteristics, autoantibodies and comorbidities are comparable between Ao-SLE and Jo-SLE. The frequency of various clinical and immunological manifestations varied between gender. Additional studies are needed to determine the underlying factors contributing to gender and age of onset differences.

scholarly journals Multivariate ordered logistic regression analysis of the postoperative effect of symptomatic discoid lateral meniscus

2021 ◽  
Author(s):  
Shun-Jie Yang ◽  
Jian Li ◽  
Yang Xue ◽  
Zhong Zhang ◽  
Gang Chen
Keyword(s):  
Logistic Regression ◽  
Age Of Onset ◽  
Univariate Analysis ◽  
Arthroscopic Surgery ◽  
Lateral Meniscus ◽  
Postoperative Outcomes ◽  
Discoid Lateral Meniscus ◽  
Work Intensity ◽  
Duration Of Symptoms ◽  
Ordered Logistic Regression

Abstract Introduction The postoperative effect of arthroscopy in the treatment of symptomatic discoid lateral meniscus (DLM) varies greatly among individuals. Therefore, this study aims to investigate the factors affecting the postoperative outcomes of symptomatic DLM. Materials and methods According to the inclusion and exclusion criteria, patients with symptomatic single-knee DLM who underwent arthroscopic surgery at our hospital from 9/2008 to 9/2015 were included. Retrospectively collected 16 factors probably affecting postoperative outcomes. The Ikeuchi grade system was used to evaluate the knee joint function. Univariate analysis was performed by Kruskal–Wallis rank-sum test or Mann–Whitney U test, and multivariate analysis by ordered logistic regression. P < 0.05 was considered statistically significant. Results A sum of 502 patients was included, including 353 females (70.3%) and 149 males (29.7%). Difference between preoperative and postoperative Ikeuchi grade was statistically significant (P < 0.001). Female was bad to obtain a good Ikeuchi grade (P = 0.009, OR 0.458). Outerbridge grade (P = 0.018, OR 0.638) was negatively correlated with Ikeuchi grade. BMI (P = 0.001, OR 0.875) and work intensity (P = 0.020, OR 0.611) were inversely correlated with Ikeuchi grade. Age of onset (P < 0.001, OR 0.956) and symptoms duration (P < 0.001, OR 0.988) were negatively correlated with Ikeuchi grade. Besides, compared to total meniscectomy, meniscoplasty with a repair was an unfavourable factor for Ikeuchi grade (P = 0.044, OR 0.245). Conclusions With the increase of BMI, work intensity, age of onset, duration of symptoms, and the severity of cartilage lesion, the postoperative results become worse. Moreover, female and meniscoplasty with repair are risk factors for the postoperative outcomes.

Effect of Marriage on Pre-existing Psychoses: A Convenient or Futile Solution for Severe Mental Disorders?

2020 ◽  
Vol 2 (3-4) ◽  
pp. 273-276
Author(s):  
Prakash B. Behere ◽  
Aniruddh P. Behere ◽  
Debolina Chowdhury ◽  
Amit B. Nagdive ◽  
Richa Yadav
Keyword(s):  
Mental Disorders ◽  
Age Of Onset ◽  
Social Stigma ◽  
Positive Family History ◽  
Mental Illnesses ◽  
Psychotic Symptoms ◽  
Antipsychotic Treatment ◽  
Contractual Relationship ◽  
History Of ◽  
Paranoid Type

Marriage can be defined as the state of being united as spouses in a consensual and contractual relationship recognized by law. The general population generally believes marriage to be a solution to mental illnesses. It can be agreed that mental disorders and marital issues have some relation. Parents of patients with psychoses expect that marriage is the solution to the illness and often approach doctors and seek validation about the success of the marriage of their mentally ill child, which is a guarantee no doctor can give in even normal circumstances. Evidence on sexual functioning in patients of psychosis is limited and needs further understanding. Studies show about 60%–70% women of the schizophrenia spectrum and illness to experience sexual difficulties. Based on available information, sexual dysfunction in population with psychosis can be attributed to a variety of psychosocial factors, ranging from the psychotic symptoms in itself to social stigma and institutionalization and also due to the antipsychotic treatment. Despite the decline in sexual activity and quality of life in general, it is very rarely addressed by both the treating doctor and by the patient themselves hence creating a lacuna in the patient’s care and availability of information regarding the illness’ pathophysiology. Patients become noncompliant with medications due to this undesirable effect and hence it requires to be given more attention during treatment. It was also found that paranoid type of schizophrenia patient had lower chances of separation than patients with other types of schizophrenia. The risk of relapse in cases with later age of onset of the disease, lower education, a positive family history of psychosis or a lower income increased more than other populations.

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