scholarly journals Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica’s experience

2022 ◽  
Vol 17 (1) ◽  
Author(s):  
R. Badilla-Porras ◽  
A. Echeverri-McCandless ◽  
J. M. Weimer ◽  
A. Ulate-Campos ◽  
A. Soto-Rodríguez ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Clinical Characteristics ◽  
Clinical Manifestations ◽  
Cerebellar Atrophy ◽  
Batten Disease ◽  
Costa Rican ◽  
Common Element ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Molecular Testing ◽  
Homozygous Mutation

Abstract Background Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G > T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population. Objective To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to characterize via molecular testing their causative mutations. Methods DNA extracted from buccal swabs was used for CLN6 gene sequencing. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records. Results Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens. Conclusions This investigation supports that the previously characterized c.214G > T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

scholarly journals Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) Clinical Findings and Molecular Diagnosis: Costa Rica´s Experience

2021 ◽  
Author(s):  
Ramses Badilla-Porras ◽  
Ann Echeverri-McCandless ◽  
Jill Weiner ◽  
Adriana Ulate-Campos ◽  
Andrés Soto-Rodríguez ◽  
...  
Keyword(s):  
Costa Rica ◽  
Clinical Diagnosis ◽  
Clinical Characteristics ◽  
Clinical Manifestations ◽  
Cerebellar Atrophy ◽  
Batten Disease ◽  
Costa Rican ◽  
Common Element ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Homozygous Mutation

Abstract Background: Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G>T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population.Objective: To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to genetically characterize their causative mutations.Methods: CLN6 gene sequences were determined from DNA extracted from patient buccal swabs. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records.Results: Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously-described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens.Conclusions: This investigation supports that the previously characterized c.214G>T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

scholarly journals Modelling of Neuronal Ceroid Lipofuscinosis Type 2 in Dictyostelium discoideum Suggests That Cytopathological Outcomes Result from Altered TOR Signalling

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 469 ◽  
Author(s):  
Paige K. Smith ◽  
Melodi G. Sen ◽  
Paul R. Fisher ◽  
Sarah J. Annesley
Keyword(s):  
Dictyostelium Discoideum ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Clinical Manifestations ◽  
Batten Disease ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Antisense Inhibition ◽  
Phenotypic Characterisation ◽  
Cellular Slime ◽  
Multiple Cell

The neuronal ceroid lipofuscinoses comprise a group of neurodegenerative disorders with similar clinical manifestations whose precise mechanisms of disease are presently unknown. We created multiple cell lines each with different levels of reduction of expression of the gene coding for the type 2 variant of the disease, Tripeptidyl peptidase (Tpp1), in the cellular slime mould Dictyostelium discoideum. Knocking down Tpp1 in Dictyostelium resulted in the accumulation of autofluorescent material, a characteristic trait of Batten disease. Phenotypic characterisation of the mutants revealed phenotypic deficiencies in growth and development, whilst endocytic uptake of nutrients was enhanced. Furthermore, the severity of the phenotypes correlated with the expression levels of Tpp1. We propose that the phenotypic defects are due to altered Target of Rapamycin (TOR) signalling. We show that treatment of wild type Dictyostelium cells with rapamycin (a specific TOR complex inhibitor) or antisense inhibition of expression of Rheb (Ras homologue enriched in the brain) (an upstream TOR complex activator) phenocopied the Tpp1 mutants. We also show that overexpression of Rheb rescued the defects caused by antisense inhibition of Tpp1. These results suggest that the TOR signalling pathway is responsible for the cytopathological outcomes in the Dictyostelium Tpp1 model of Batten disease.

scholarly journals Genetic, structural and clinical analysis of spastic paraplegia 4

2021 ◽  
Author(s):  
Parizad Varghaei ◽  
Mehrdad A Estiar ◽  
Setareh Ashtiani ◽  
Simon Veyron ◽  
Kheireddin Mufti ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
De Novo ◽  
Clinical Manifestations ◽  
Signs And Symptoms ◽  
Clinical Analysis ◽  
Copy Number Variations ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Spastic Paraplegia ◽  
Synonymous Mutations

Background: Spastic paraplegia type 4 (SPG4), resulting from heterozygous mutations in the SPAST gene, is the most common form among the heterogeneous group of hereditary spastic paraplegias (HSPs). Objective: To study genetic and clinical characteristics of SPG4 across Canada. Methods: The SPAST gene was analyzed in a total of 696 HSP patients from 431 families by either HSP-gene panel sequencing or whole exome sequencing (WES). We used Multiplex ligation-dependent probe amplification to analyze copy number variations (CNVs), and performed in silico structural analysis of selected mutations. Clinical characteristics of patients were assessed, and long-term follow-up was done to study genotype-phenotype correlations. Results: We identified 157 SPG4 patients from 65 families who carried 41 different SPAST mutations, six of which are novel and six are CNVs. We report novel aspects of mutations occurring in Arg499, a case with homozygous mutation, a family with probable compound heterozygous mutations, three patients with de novo mutations, three cases with pathogenic synonymous mutation, co-occurrence of SPG4 and multiple sclerosis, and novel or rarely reported signs and symptoms seen in SPG4 patients. Conclusion: Our study demonstrates that SPG4 is a heterogeneous type of HSP, with diverse genetic features and clinical manifestations. In rare cases, biallelic inheritance, de novo mutation, pathogenic synonymous mutations and CNVs should be considered.

scholarly journals Intracranial Calcification Associated with 3-Methylcrotonyl-CoA Carboxylase Deficiency

2021 ◽  
pp. 1-6
Author(s):  
Süleyman Şahin ◽  
Miraç Yıldırım ◽  
Ömer Bektaş ◽  
İlknur Sürücü Kara ◽  
Ahmet Cevdet Ceylan ◽  
...  
Keyword(s):  
Clinical Manifestations ◽  
Cerebellar Atrophy ◽  
Clinical Findings ◽  
Organic Aciduria ◽  
Intracranial Calcification ◽  
Cranial Computed Tomography ◽  
Global Developmental Delay ◽  
Homozygous Mutation ◽  
Screening Programs ◽  
Intracranial Calcifications

3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency is the most frequent organic aciduria detected in newborn screening programs. It demonstrates a variable heterogeneous clinical phenotype, ranging from neonatal onset with severe neurological disorders to asymptomatic adult forms. Herein, we report the first 2 related cases of 3-MCC deficiency presenting with intracranial calcification in the literature. A girl and a boy aged 3 years, 9 months and 4 years were included in the study. The main clinical manifestations were acquired microcephaly, global developmental delay, intractable seizures, mild feeding difficulty, and intermittent dystonic contractions. On physical and neurological examinations, their weights, heights, and head circumferences were below the 3rd percentile, they had acquired microcephaly, truncal hypotonia, upper and lower limb spasticity, hyperreflexia, positive bilateral Babinski signs, and clonus. The detailed biochemical and metabolic tests were unremarkable, except blood 3-hydroxyisovalerylcarnitine (C5OH) was slightly increased in case 1. Cranial computed tomography demonstrated mild cerebral and cerebellar atrophy as well as bilateral periventricular and thalamic calcifications in both cases. We identified a homozygous mutation of c.1015G&#x3e;A (p.V339M) in the <i>MCCC2</i>gene, and the mutation was confirmed by Sanger sequencing. To the best of our knowledge, our cases are the first reported describing intracranial calcification in cases with 3-MCC deficiency. This report expands on the underlying causes of intracranial calcifications and suggests that 3-MCC deficiency may have intracranial calcifications on bilateral thalamus and periventricular white matters. If clinical findings show intracranial calcification, 3-MCC deficiency should also be kept in mind.

Postoperative cognitive dysfunction: progress mechanisms and clinical characteristics

2019 ◽  
Vol 2 (19) ◽  
pp. 29-33
Author(s):  
K. B. Manysheva ◽  
M. A. Akhmedov ◽  
A. A. Rakhmanova ◽  
S. M. Khutalieva
Keyword(s):  
Cognitive Dysfunction ◽  
Clinical Characteristics ◽  
Cognitive Deficit ◽  
Neuropsychological Testing ◽  
Postoperative Cognitive Dysfunction ◽  
Clinical Manifestations ◽  
Postoperative Recovery ◽  
Neuropsychological Rehabilitation ◽  
Brain Barrier Permeability ◽  
The Central Nervous System

The article is devoted to the study of postoperative cognitive dysfunction — a syndrome that is often found in the postoperative period and does not depend on the volume of surgeon. Based on the analysis of the results of modern studies, the authors cite the most likely etiological causes of the syndrome, grouped according to different categories of risk factors. The pathogenetic algorithm for cognitive dysfunction includes the appearance of systemic inflammation, improving blood-brain barrier permeability with the endothelial dysfunction, the migration of inflammatory agents into the central nervous system, and the formation of oxidative stress. The clinical manifestations of cognitive deficit in the outcome of surgeon performed under general anesthesia, the authors illustrate with their own observations of patients with a neurosurgical profile with spinal pathology operated on with the use of propofol anesthesia, comparing the results of neuropsychological testing with an assessment of the level of anxiety. In conclusion, the authors outline a strategy for the prevention of postoperative cognitive dysfunction and recommend conducting neuropsychological rehabilitation as an important component of postoperative recovery for all patients with a diagnosed cognitive deficit that occurred after surgery.

Clinical Characteristics and Outcomes of Influenza in Hospitalized Pediatric Patients in King Chulalongkorn Memorial Hospital

2020 ◽  
Vol 103 (11) ◽  
pp. 1220-1229
Keyword(s):  
Lung Disease ◽  
Chronic Lung Disease ◽  
Associated Factors ◽  
Clinical Characteristics ◽  
Care Center ◽  
Tertiary Care ◽  
Memorial Hospital ◽  
Molecular Testing ◽  
Duration Of Hospitalization ◽  
Severity Of The Disease

Objective: To describe clinical characteristics and outcomes of laboratory-confirmed influenza in hospitalized children in a tertiary care center and to identify factors associated with the severity. Materials and Methods: The present study was a retrospective medical chart review study conducted at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Data were extracted from children aged under 15 years old hospitalized between January 2014 and December 2018. Patients who had laboratory-confirmed influenza by rapid antigen detection or molecular testing were included. Severe influenza was defined as patients who developed influenza complications or duration of hospitalization for more than three days. Multivariate logistic regression was used to identify the associated factors with the severity of the disease. Results: Three hundred fifty-seven influenza patients were included with median age of 43 months (IQR 19 to 81), of which 63.3% were aged under 60 months. There were 174 patients (48.7%) with comorbidities, most common were immunosuppression (18.2%), chronic pulmonary disease (12.2%), and congenital heart disease (11.5%). Fifty-seven out of 183 patients (31.1%) had history of influenza vaccination in the medical records. One hundred sixty-one patients (45.1%) had 212 influenza complications including influenza-related pneumonia (89, 24.9%), secondary bacterial infection (53, 14.8%), and neurologic complications (47, 13.2%), in which 27 cases (7.6%) were transferred to intensive care unit (ICU). Four cases (1.1%) died but not directly related to influenza. Associated factors with complicated influenza were aged less than 24 months [aOR 2.67 (95% CI 1.68 to 4.26)] and presence of chronic lung disease [aOR 4.34 [95% CI 2.01 to 9.35)]. Conclusion: Two-third of the children hospitalized with influenza were younger than 60 months. Nearly half developed complications most associated with the age of less than two years old and patients with chronic lung disease. Low rates of vaccination were demonstrated. Keywords: Influenza, Pediatrics, Complications, Pneumonia, Hospitalization

scholarly journals 369. Clinical Characteristics of the First 177 Patients Admitted with COVID-19 at a Bronx Community Hospital

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S254-S254
Author(s):  
Victoria Bengualid ◽  
Maria Martinez ◽  
Zhenisa Hysenaj ◽  
Debra M Willner ◽  
Judith Berger
Keyword(s):  
Oxygen Saturation ◽  
Clinical Characteristics ◽  
Clinical Manifestations ◽  
Gastrointestinal Symptoms ◽  
Retrospective Chart Review ◽  
Patient Characteristics ◽  
Altered Mental Status ◽  
Channel Blockers ◽  
First Case ◽  
Overall Mortality

Abstract Background The first case of COVID-19 was admitted on March 15th 2020 to our community based hospital in the Bronx, NY. The aim of this study is to describe the clinical characteristics and outcome of these first COVID-19 patients. Patient Characteristics and Outcome Methods IRB approved retrospective chart review study of all COVID-19 patients admitted during March 2020 focusing on patient characteristics, co-morbidities, clinical manifestations and outcome. Results A total of 177 patients were admitted during March 2020: 57% African American 23.1% Hispanic and 16.9% White. 44.9% female, average age 60 years, and 90% had at least one comorbidity. Outcome was available on all patients except for one who was transferred to another institution for ECMO. Overall mortality was 33%. Clinical presentation: 69.4% presented with cough or shortness of breath, 15.8% with diarrhea, nausea, vomiting or abdominal pain, and 14.6% with myalgia, dizziness or altered mental status. 6.2% presented only with fever. However 59.8% of patients presented with fever and respiratory or gastrointestinal symptoms. Mortality The table compares patients who died vs discharged (either home or to a short term facility). Those that were 65 years or older, hypertensive or presented to the ER with an oxygen saturation of 94% or lower, were more likely to die. Ventilated patients: 31.6% of patients were intubated with a mortality rate of 77%. 22% of these patients were intubated in the first 24 hours. Compared to non-intubated patients, there was no difference in BMI, diabetes, hypertension, COPD/Asthma, use of statins, aspirin or calcium channel blockers. Intubated patients older than 64 years had significantly higher mortality rates (p=0.0001). Conclusion This cohort of COVID-19 patients is unique as almost all received Hydroxychloroquine and Azithromycin. Only 9% received steroids and even fewer received an interleukin-6 inhibitor, convalescent plasma or Remdesivir. African Americans and Hispanics accounted for 80% of patients. Greater than 90% received Medicaid. Overall mortality was 33%. The most common presentation was respiratory followed by gastrointestinal symptoms. The overall mortality was 33% but increased to 77% in intubated patients. Age, hypertension, and ER oxygen saturation correlated with mortality. Disclosures All Authors: No reported disclosures

scholarly journals SAT0507 CLINICAL CHARACTERISTICS AND TREATMENT RESPONSE IN JUVENILE GOUT PATIENTS: A SINGLE CENTER EXPERIENCE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1210.2-1210
Author(s):  
S. Zheng ◽  
P. Y. Lee ◽  
Y. Huang ◽  
Q. Huang ◽  
S. Chen ◽  
...  
Keyword(s):  
Renal Function ◽  
Uric Acid ◽  
Treatment Response ◽  
Serum Uric Acid ◽  
Clinical Characteristics ◽  
Disease Onset ◽  
Clinical Manifestations ◽  
Joint Involvement ◽  
Normal Body Mass Index ◽  
Finger Joints

Background:The incidence of juvenile gout is increasing in China. The clinical manifestations of juvenile gout and treatment strategies to reduce uric acid levels in children are not well described due to the limited number of cases in the past.Objectives:We aim to describe the clinical characteristic of children with gout and study the treatment response to febuxostat.Methods:These studies were approved by the Institutional Review Board of Guangdong Second provincial General Hospital. We performed a retrospective analysis on 98 juvenile gout patients (age ≤ 18 years) evaluated in our hospital from Jan 2016 to Dec 2019. We analyzed clinical parameters, laboratory data and treatment response.Results:The average age of disease onset in children with gout was 15.2 ± 2.0 years and the youngest patient was 9 years old. The majority of patients were male (94/98) and mean serum uric acid (sUA) level were 705.8 ± 145.7 μmol/L (reference range <420 μmol/L). More than half of the cohort had normal body mass index (mean 24.7 ± 4.7 kg/m2; range 14.9 to 36.1 kg/m2). Renal function was generally normal in these children (serum creatinine 96.9 ± 17.8 μmol/L). In terms of joint manifestations, juvenile gout preferentially affected finger joints (29%), ankles (28%) and metatarsal joints (MTP; 20%). The most frequent sites of initial gout attack were ankles (45%), MTP (39%) and fingers (6%). In addition, tophi can occur in pediatric patients and typically develop in the finger joints (54%). Tophi was observed in about 25% of juvenile gout patients, typically within the first two years of disease onset (mean duration 1.7 ± 0. 9 years). We have found tophi in children as young as 10 years of age.For treatment for chronic hyperuricemia, 32 patients (32.7%) were started on febuxostat and 5 patients (5.1%) received allopurinol. A decrease in sUA was observed in both groups after the first month of treatment (febuxostat: baseline 690.4 ± 99.7 μmol/L to 482.7 ± 140.8 μmol/L vs. allopurinol: baseline 728.8 ±112.8 μmol/L to 565.0 ± 116.7 μmol/L, P=0.477). Serum uric acid of 6 patients in the febuxostat group (none in the allopurinol group) dropped below 360 μmol/L. There were no statistical differences in Cr, AST and ALT between the groups. During follow-up after 3 months, further decline in sUA level were observed in patients treated with febuxostat (409.5 ± 83.4, compared with baseline P<0.001).Conclusion:Juvenile gout has a different pattern of joint involvement and is less associated with elevated BMI compared to gout in adults. We show that febuxostat is effective in reducing uric acid levels in juvenile gout. These findings will help clinicians better understand the clinical manifestations and treatment response in juvenile gout.Figure 1Compared treatment response with allopurinol and febuxostatReferences:[1]Kishimoto K, Kobayashi R, Hori D, et al. Febuxostat as a Prophylaxis for Tumor Lysis Syndrome in Children with Hematological Malignancies. Anticancer Res. 2017 Oct;37(10):5845-5849.[2]Lu, C.C., et al. Clinical characteristics of and relationship between metabolic components and renal function among patients with early-onset juvenile tophaceous gout. J Rheumatol, 2014. 41(9): p. 1878-83.Disclosure of Interests:None declared

scholarly journals Clinical manifestations of focal segmental glomerulosclerosis in Japan from the Japan Renal Biopsy Registry: age stratification and comparison with minimal change disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Takaya Ozeki ◽  
Shoichi Maruyama ◽  
Toshiyuki Imasawa ◽  
Takehiko Kawaguchi ◽  
Hiroshi Kitamura ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Renal Biopsy ◽  
Focal Segmental Glomerulosclerosis ◽  
Clinical Diagnosis ◽  
Clinical Characteristics ◽  
Minimal Change Disease ◽  
Multivariable Analysis ◽  
Laboratory Data ◽  
Minimal Change ◽  
Segmental Glomerulosclerosis

AbstractFocal segmental glomerulosclerosis (FSGS) is a serious condition leading to kidney failure. We aimed to investigate the clinical characteristics of FSGS and its differences compared with minimal change disease (MCD) using cross-sectional data from the Japan Renal Biopsy Registry. In Analysis 1, primary FSGS (n = 996) were stratified by age into three groups: pediatric (< 18 years), adult (18–64 years), and elderly (≥ 65 years), and clinical characteristics were compared. Clinical diagnosis of nephrotic syndrome (NS) was given to 73.5% (97/132) of the pediatric, 41.2% (256/622) of the adult, and 65.7% (159/242) of the elderly group. In Analysis 2, primary FSGS (n = 306) and MCD (n = 1303) whose clinical diagnosis was nephrotic syndrome (NS) and laboratory data were consistent with NS, were enrolled. Logistic regression analysis was conducted to elucidate the variables which can distinguish FSGS from MCD. On multivariable analysis, higher systolic blood pressure, higher serum albumin, lower eGFR, and presence of hematuria associated with FSGS. In Japanese nationwide registry, primary FSGS patients aged 18–64 years showed lower rate of NS than those in other ages. Among primary nephrotic cases, FSGS showed distinct clinical features from MCD.

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