Acquisition of Developmental Milestones in Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum and Other TUBB4A-Related Leukoencephalopathy

2021 ◽  
Vol 36 (10) ◽  
pp. 805-811 ◽  
Author(s):  
Francesco Gavazzi ◽  
Brittany A. Charsar ◽  
Catherine Williams ◽  
Justine Shults ◽  
Cesar A. Alves ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Late Onset ◽  
Developmental Trajectories ◽  
Disease Onset ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
Developmental Milestones ◽  
Clinical Endpoints ◽  
Neurologic Disorders ◽  
The Common

Mutations in TUBB4A are associated with a spectrum of neurologic disorders categorized as TUBB4A-related leukoencephalopathy. Affected children can present with global developmental delay or normal early development, followed by a variable loss of skills over time. Further research is needed to characterize the factors associated with the divergent developmental trajectories in this rare monogenic disorder because this phenotypic spectrum is not fully explained by genotype alone. To characterize early psychomotor features, developmental milestones and age of disease onset were collected from medical records (n=54 individuals). Three subcohorts were identified: individuals with the common p.Asp249Asn variant vs all other genotypes with either early (<12 months of age) or late onset of presentation. Individuals with the p.Asp249Asn variant or those with non-p.Asp249Asn genotypes with later disease onset attained key milestones, including head control, sitting, and independent walking. Subjects with early-onset, non-p.Asp249Asn–associated disease were less likely to achieve developmental milestones. Next, we defined the developmental severity as the percentage of milestones attained by age 2 years. The mild form was defined as attaining at least 75% of key developmental milestones. Among cohort categorized as mild, individuals with p.Asp249Asn variant were more likely to lose acquired abilities when compared with non-p.Asp249Asn individuals. Our results suggest multiple influences on developmental trajectory, including a strong contribution from genotype and age of onset. Further studies are needed to identify additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

Acquisition of Developmental Milestones in Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum and Other TUBB4A-Related Leukoencephalopathy

2021 ◽  
pp. 088307382100097
Author(s):  
Francesco Gavazzi ◽  
Brittany A. Charsar ◽  
Catherine Williams ◽  
Justine Shults ◽  
Cesar A. Alves ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Late Onset ◽  
Developmental Trajectories ◽  
Disease Onset ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
Developmental Milestones ◽  
Clinical Endpoints ◽  
Neurologic Disorders ◽  
The Common

Mutations in TUBB4A are associated with a spectrum of neurologic disorders categorized as TUBB4A-related leukoencephalopathy. Affected children can present with global developmental delay or normal early development, followed by a variable loss of skills over time. Further research is needed to characterize the factors associated with the divergent developmental trajectories in this rare monogenic disorder because this phenotypic spectrum is not fully explained by genotype alone. To characterize early psychomotor features, developmental milestones and age of disease onset were collected from medical records (n=54 individuals). Three subcohorts were identified: individuals with the common p.Asp249Asn variant vs all other genotypes with either early (<12 months of age) or late onset of presentation. Individuals with the p.Asp249Asn variant or those with non-p.Asp249Asn genotypes with later disease onset attained key milestones, including head control, sitting, and independent walking. Subjects with early-onset, non-p.Asp249Asn–associated disease were less likely to achieve developmental milestones. Next, we defined the developmental severity as the percentage of milestones attained by age 2 years. The mild form was defined as attaining at least 75% of key developmental milestones. Among cohort categorized as mild, individuals with p.Asp249Asn variant were more likely to lose acquired abilities when compared with non-p.Asp249Asn individuals. Our results suggest multiple influences on developmental trajectory, including a strong contribution from genotype and age of onset. Further studies are needed to identify additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

scholarly journals 3279 First in Man

2019 ◽  
Vol 3 (s1) ◽  
pp. 45-45
Author(s):  
Laura Adang ◽  
Francesco Gavazzi ◽  
Valentina De Giorgis ◽  
Micaela De Simone ◽  
Elisa Fazzi ◽  
...  
Keyword(s):  
Skill Acquisition ◽  
Classification System ◽  
Developmental Trajectories ◽  
Spastic Paraparesis ◽  
Altered Mental Status ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
P Value ◽  
Kaplan Meier ◽  
Neurologic Disability

OBJECTIVES/SPECIFIC AIMS: A mimic of congenital infections and a rare genetic cause of interferon overproduction, Aicardi Goutières Syndrome (AGS) results in significant neurologic disability. AGS is caused by pathogenic changes in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1). All affected individuals exhibit neurologic impairment: from mild spastic paraparesis to severe tetraparesis and global developmental delay. We hypothesize that genotype influences the heterogeneous developmental trajectory found in AGS. METHODS/STUDY POPULATION: To characterize this spectrum, age and symptoms at presentation and longitudinal developmental skill acquisition was collected from an international cohort of children (n=88) with genetically confirmed AGS. RESULTS/ANTICIPATED RESULTS: We found that individuals present at variable ages, with the largest range in SAMHD1, ADAR, and IFIH1. There are 3 clusters of symptoms at presentation: altered mental status (irritability or lethargy), systemic inflammatory symptoms, and acute neurologic symptoms, with variability across all genotypes. By creating Kaplan-Meier curves for developmental milestones, we were able to create genotype-based developmental trajectories for the children affected by the 5 most common genotypes: TREX1, IFIH1, SAMHD1, ADAR, and RNASEH2B. Individuals with AGS secondary to TREX1 were the most severely affected, significantly less likely to reach milestones compared to the other genotypes, including head control, sitting, and nonspecific mama/dada (p-value <0.005). Individuals affected by SAMHD1, IFIH1, and ADAR collectively attained the most advanced milestones, with 44% of the population achieving a minimum of a single word and 31% able to walk independently. Three retrospective scales were also applied: Gross Motor Function Classification System, Manual Ability Classification Scale, and Communication Function Classification System. Within each genotypic cohort, there was pronounced heterogeneity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results demonstrate the influence of genotype on early development, but also suggest the importance of other unidentified variables. These results underscore the need for deep phenotyping to better characterize subcohorts within the AGS population.

scholarly journals Progressive supranuclear palsy in a sample of brazilian population: clinical features of 16 patients

2002 ◽  
Vol 60 (4) ◽  
pp. 917-922 ◽  
Author(s):  
Paulo Eduardo Mestrinelli Carrilho ◽  
Egberto Reis Barbosa
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Clinical Features ◽  
Age Of Onset ◽  
Disease Onset ◽  
Final Diagnosis ◽  
Postural Instability ◽  
Chronic Dacryocystitis ◽  
Neurologic Disorders ◽  
The Mean ◽  
Vertical Gaze

Progressive supranuclear palsy (PSP) is an uncommon disorder characterized by marked postural instability, vertical gaze abnormalities and axial rigidity. The purpose of this study is to report the clinical features of 16 consecutive subjects seen over a 10-year period at a Movement Disorders Clinic. These subjects fulfilled criteria for probable PSP namely those of the National Institute of Neurologic Disorders and Stroke (NINDS) and the Society for PSP (SPSP). This patient-group represented 2.1% of all degenerative parkinsonians observed and the mean age of onset of the disease was 64.7 years (sd = ± 7.2). Postural instability with falls was the most frequent initial feature presented in PSP patients (62.5%). The hallmark of the disease, the supranuclear vertical gaze palsy, appeared after 2.3 years of disease onset, and only 12.5% had such manifestation at the first evaluation. Transient tremor was observed with a relatively high frequency in this group (44%), but only 19% had rest tremor. Chronic dacryocystitis, probably related to a paucity of blinking, was observed in two patients as an inaugural manifestation. In the first evaluation, only 19% of the 16 patients were diagnosed as probable PSP. The mean interval prior to the final diagnosis was 2.4 years.

scholarly journals Outcomes of ADHD Symptoms in Late Adolescence: Are Developmental Subtypes Important?

2018 ◽  
Vol 24 (1) ◽  
pp. 113-125 ◽  
Author(s):  
Aja Louise Murray ◽  
Tom Booth ◽  
Bonnie Auyeung ◽  
Manuel Eisner ◽  
Denis Ribeaud ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Late Onset ◽  
Developmental Trajectories ◽  
Behavioral Outcomes ◽  
Growth Mixture Modeling ◽  
Late Adolescence ◽  
Adhd Symptoms ◽  
Community Based ◽  
Symptom Trajectories ◽  
Growth Mixture

Objective: Substantial individual variation exists in the age of onset and course of ADHD symptoms over development. We evaluated whether, within this variation, meaningful developmental subtypes can be defined. Method: Using growth mixture modeling in a community-based sample ( N = 1,571), we analyzed ADHD symptom trajectories based on measures taken at ages 7, 8, 9, 10, 11, 13, and 15 years. We evaluated whether those showing developmental trajectories characterized by later onsets versus early onsets differed in terms of mental health and behavioral outcomes in late adolescence (age 17 years). Result: The late onset category was best conceptualized as a milder subtype than early onset. The former was, however, more similar in outcomes to the latter than to the unaffected category, suggesting that later onsets are still associated with impairment. Conclusion: Considering diagnoses for those affected by ADHD symptoms but who do not meet current age of onset criteria may be important for ensuring that they receive appropriate support.

scholarly journals Clinical Analysis of Algerian Patients with Pompe Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Y. Sifi ◽  
M. Medjroubi ◽  
R. Froissart ◽  
N. Taghane ◽  
K. Sifi ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Pompe Disease ◽  
Clinical Presentation ◽  
Age Of Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Dried Blood Spots ◽  
Clinical Analysis ◽  
Pompe’S Disease ◽  
Pompe's Disease

Pompe’s disease is a metabolic myopathy caused by a deficiency of acid alpha-glucosidase (GAA), also called acid maltase, an enzyme that degrades lysosomal glycogen. The clinical presentation of Pompe’s disease is variable with respect to the age of onset and rate of disease progression. Patients with onset of symptoms in early infancy (infantile-onset Pompe disease (IOPD)) typically exhibit rapidly progressive hypertrophic cardiomyopathy and marked muscle weakness. Most of them die within the first year of life from cardiac and/or respiratory failure. In the majority of cases of Pompe’s disease, onset of symptoms occurs after infancy, ranging widely from the first to sixth decade of life (late-onset Pompe’s disease or LOPD). Progression of the disease is relentless and patients eventually progress to loss of ambulation and death due to respiratory failure. The objective of this study was to characterize the clinical presentation of 6 patients (3 with EOPD and the other 3 with LOPD) of 5 families from the East of Algeria. All our patients were diagnosed as having Pompe’s disease based on biochemical confirmations of GAA deficiency by dried blood spots (DBS) and GAA gene mutations were analyzed in all patients who consented (n=4). Our results are similar to other ethnic groups.

scholarly journals A clinico-pathological and molecular analysis reveals differences between solitary (early and late-onset) and synchronous rectal cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
José Perea ◽  
Juan L. García ◽  
Luis Corchete ◽  
Sandra Tapial ◽  
Susana Olmedillas-López ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Age Of Onset ◽  
Late Onset ◽  
Cpg Island ◽  
Familial Cancer ◽  
Disease Onset ◽  
Comparative Genomic ◽  
Malignant Neoplasms ◽  
Genomic Alterations ◽  
Molecular Features

AbstractRectal cancer (RC) appears to behave differently compared with colon cancer. We aimed to analyze existence of different subtypes of RC depending on distinct features (age of onset and the presence of synchronous primary malignant neoplasms). We compared the clinicopathological, familial and molecular features of three different populations diagnosed with RC (early-onset RC [EORC], late-onset RC, and synchronous RC [SRC]). Eighty-five RCs were identified and were evaluated according to their microsatellite instability, CpG Island Methylator Phenotype (CIMP) and chromosomal instability, as assessed by Next Generation Sequencing and microarray-based comparative genomic hybridization approaches. The results were subjected to cluster analysis. SRCs displayed the most specific characteristics including a trend for the development of multiple malignant neoplasms, a greater proportion of CIMP-High tumors (75%) and more frequent genomic alterations. These findings were confirmed by a clustering analysis that stratified RCs according to their genomic alterations. We also found that EORCs exhibited their own features including an important familial cancer component and a remarkable rate of mutations in TP53 (53%). Together, heterogeneity in RC characteristics by age of disease-onset and SRC warrants further study to optimize tailored prevention, detection and intervention strategies—particularly among young adults.

scholarly journals Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

2019 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Population Genetics ◽  
Disease Risk ◽  
Age Of Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Lifetime Risk ◽  
Significant Heterogeneity ◽  
Population Admixture ◽  
Gene Therapies ◽  
Polygenic Diseases

AbstractWith the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk, however the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If gene therapies that prevent heritable diseases were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.

scholarly journals Developmental Outcomes of Aicardi Goutières Syndrome

2019 ◽  
Vol 35 (1) ◽  
pp. 7-16 ◽  
Author(s):  
Laura Adang ◽  
Francesco Gavazzi ◽  
Micaela De Simone ◽  
Elisa Fazzi ◽  
Jessica Galli ◽  
...  
Keyword(s):  
Classification System ◽  
Age Of Onset ◽  
Spastic Paraparesis ◽  
Altered Mental Status ◽  
Developmental Trajectory ◽  
Clinical Endpoints ◽  
Presenting Symptoms ◽  
Severe Intellectual Disability ◽  
Neurologic Disability ◽  
Early Features

Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery ( TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or TREX1-related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by SAMHD1, IFIH1, and ADAR attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.

scholarly journals Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective

2019 ◽  
Vol 20 (20) ◽  
pp. 5013 ◽  
Author(s):  
Roman Teo Oliynyk
Keyword(s):  
Population Genetics ◽  
Disease Risk ◽  
Age Of Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Lifetime Risk ◽  
Significant Heterogeneity ◽  
Population Admixture ◽  
Gene Therapies ◽  
Polygenic Diseases

With the accumulation of scientific knowledge of the genetic causes of common diseases and continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This study endeavored to assess population genetics consequences of such therapies. Computer simulations were used to evaluate the heterogeneity in causal alleles for polygenic diseases that could exist among geographically distinct populations. The results show that although heterogeneity would not be easily detectable by epidemiological studies following population admixture, even significant heterogeneity would not impede the outcomes of preventive gene therapies. Preventive gene therapies designed to correct causal alleles to a naturally-occurring neutral state of nucleotides would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome would manifest differently for late-onset diseases, for which the therapies would result in a delayed disease onset and decreased lifetime risk; however, the lifetime risk would increase again with prolonging population life expectancy, which is a likely consequence of such therapies. If the preventive heritable gene therapies were to be applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even with a fraction of the population receiving such therapies. With ongoing population admixture, all groups would benefit over generations.

From a molar to a molecular approach to the developmental trajectory of syntax comprehension by persons with intellectual disability

2020 ◽  
Author(s):  
Bruno Facon
Keyword(s):  
Developmental Trajectories ◽  
Developmental Trajectory ◽  
Typically Developing ◽  
Cognitive Level ◽  
Cross Sectional ◽  
Test Items ◽  
Complex Sentences ◽  
Regression Curves ◽  
Cognitive Measure ◽  
Syntactic Skills

The aim was to investigate whether a progressive dissociation between the cognitive level and syntax comprehension occurs during the development of persons with intellectual disabilities (ID). Two cross-sectional developmental trajectory analyses were successively conducted. Study 1 comprised 615 typically developing participants and 615 participants with ID. Their total scores on a syntax comprehension test were regressed on a nonverbal cognitive measure and the slopes of the two groups’ regression lines were compared. In Study 2, logistic regression curves of the two groups for each of the 92 test items were compared. Results showed only negligible between-groups differences of developmental trajectories, whatever the level of analysis. The idea of a progressive dissociation between cognitive level and receptive syntactic skills of people with ID is not confirmed. However, a syntax test evaluating more complex sentences than those used in this study might show such a dissociation.

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