Dataset Information

Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies.

ABSTRACT:

Purpose

TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials.

Methods

Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical reports and database entries of DECIPHER and ClinVar. Main outcome measures were age at disease onset, survival, and diagnostic delay. Phenotypical, neuroradiological, and histopathological features were descriptively illustrated.

Results

Mean age at disease onset was 4 (TUBA1A) and 6 months (TUBB2B), respectively. Mortality was equally estimated with 7% at 3.2 (TUBA1A) and 8.0 years (TUBB2B). Diagnostic delay was significantly higher in TUBB2B (12.3 years) compared with TUBA1A tubulinopathy (4.2 years). We delineated the isotype-dependent clinical, neuroradiological, and histopathological phenotype of affected individuals and present brain malformations associated with epilepsy and an unfavorable course of disease.

Conclusion

The natural history of tubulinopathies is defined by the genotype and associated brain malformations. Defined data on estimated survival, diagnostic delay, and disease characteristics of TUBA1A and TUBB2B tubulinopathy will help to raise disease awareness and encourage future clinical trials to optimize genetic testing, family counseling, and supportive care.

SUBMITTER: Schroter J

PROVIDER: S-EPMC7935713 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies.

Schröter Julian J Döring Jan H JH Garbade Sven F SF Hoffmann Georg F GF Kölker Stefan S Ries Markus M Syrbe Steffen S

Genetics in medicine : official journal of the American College of Medical Genetics 20201021 3

<h4>Purpose</h4>TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials.<h4>Methods</h4>Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical reports and database entries of DECIPHER and ClinVar. Main outcome measures were ag ...[more]

PMID: 33082561

Similar Datasets

Project description:ObjectiveTo assess incidence and changes in tinnitus and bothersome tinnitus as well as associated risk factors in a large sample of UK adults.DesignProspective cohort study.SettingUK.ParticipantsFor cross-sectional analysis, a group of 168 348 participants aged between 40 and 69 years with hearing and tinnitus data from the UK Biobank resource. Longitudinal analysis included a subset of 4746 people who attended a 4-year retest assessment.Main outcome measuresPresence and bothersomeness of tinnitus.Results17.7% and 5.8% of participants reported tinnitus or bothersome tinnitus, respectively. The 4-year incidence of tinnitus was 8.7%. Multivariate logistic regression models suggested that age, hearing difficulties, work noise exposure, ototoxic medication and neuroticism were all positively associated with both tinnitus and bothersome tinnitus. Reduced odds of tinnitus, but not bothersome tinnitus, was seen in alcohol drinkers versus non-drinkers. Male gender was associated with increased odds of tinnitus, while female gender was associated with increased odds of bothersome tinnitus. At follow-up, of those originally reporting tinnitus, 18.3% reported no tinnitus. Of those still reporting tinnitus, 9% reported improvement and 9% reported tinnitus becoming more bothersome, with the rest unchanged. Male gender and alcohol consumption were associated with tinnitus being reported less bothersome, and hearing difficulties were associated with the odds of tinnitus being reported as more bothersome.ConclusionsThis study is one of the few to provide data on the natural history of tinnitus in a non-clinical population, suggesting that resolution is relatively uncommon, with improvement and worsening of symptoms equally likely. There was limited evidence for any modifiable lifestyle factors being associated with changes in tinnitus symptoms. In view of the largely persistent nature of tinnitus, public health strategies should focus on: (1) primary prevention and (2) managing symptoms in people that have tinnitus and monitoring changes in bothersomeness.

Project description:Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.

Project description:BackgroundFibrodysplasia Ossificans Progressiva (FOP; OMIM#135100) is an ultra-rare, severely disabling genetic disease characterized by congenital malformation of the great toes and progressive heterotopic ossification (HO) in muscles, tendons, ligaments, fascia, and aponeuroses often preceded by painful, recurrent soft tissue swelling (flare-ups). The formation of HO leads to progressive disability, severe functional limitations in joint mobility, and to a shortened life-span. In this prospective natural history study, we describe the baseline, cross-sectional disease phenotype of 114 individuals with FOP.MethodsAll subjects underwent protocol-specified baseline assessments to determine their disease status. Cross-sectional analyses were performed using linear regression in which functional evaluations (Cumulative Analogue Joint Involvement Scale [CAJIS] and the FOP-Physical Function Questionnaire [FOP-PFQ]) and the burden of HO as measured by low-dose whole body CT (volume of HO and number of body regions with HO) were assessed.ResultsFindings from 114 subjects (age range 4 to 56 years) were evaluated. While subject age was significantly (p < 0.0001) correlated with increased CAJIS (r = 0.66) and FOP-PFQ scores (r = 0.41), the estimated mean increases per year (based on cross-sectional average changes over time) were small (0.47 units and 1.2%, respectively). There was also a significant (p < 0.0001) correlation between baseline age and HO volume (r = 0.56), with an estimated mean increase of 25,574 mm3/year. There were significant (p < 0.0001) correlations between the objective assessment of HO volume and clinical assessments of CAJIS (r = 0.57) and FOP-PFQ (r = 0.52).ConclusionsBased on the cross-sectional analysis of the baseline data, functional and physical disability as assessed by CAJIS and the FOP-PFQ increased over time. Although longitudinal data are not yet available, the cross-sectional analyses suggest that CAJIS and FOP-PFQ are not sensitive to detect substantial progression over a 1- to 2-year period. Future evaluation of longitudinal data will test this hypothesis. The statistically significant correlations between HO volume and the functional endpoints, and the estimated average annual increase in total HO volume, suggest that the formation of new HO will be measurable over the relative short-term course of a clinical trial, and represents an endpoint that is clinically meaningful to patients.Trial registrationThis study ( NCT02322255 ) was first posted on 23 December, 2014.

Project description:WDR45-related neurodevelopmental disorder (NDD) is a clinically-heterogenous congenital disorder of macroautophagy/autophagy. The natural history of this ultra-orphan disease remains incompletely understood, leading to delays in diagnosis and lack of quantifiable outcome measures. In this cross-sectional study, we model quantitative natural history data for WDR45-related NDD using a standardized analysis of 160 published cases, representing the largest cohort to date. The primary outcome of this study was survival. Age at disease onset, diagnostic delay and geographic distribution were quantified as secondary endpoints. Our tertiary aim was to explore and quantify the spectrum of WDR45-related phenotypes. Survival estimations showed low mortality until 39 years of age. Median age at onset was 10 months, with a median diagnostic delay of 6.2 years. Geographic distribution appeared worldwide with clusters in North America, East Asia, Western Europe and the Middle East. The clinical spectrum was highly variable with a bi-phasic evolution characterized by early-onset developmental and epileptic encephalopathy during childhood followed by a progressive dystonia-parkinsonism syndrome along with cognitive decline during early adulthood. Female individuals showed milder disease severity. The majority of pathogenic WDR45 variants were predicted to result in a loss of WDR45 expression, without clear genotype-phenotype associations. Our results provide clinical and epidemiological data that may facilitate an earlier diagnosis, enable anticipatory guidance and counseling of affected families and provide the foundation for endpoints for future interventional trials.Abbreviations: BPAN: beta-propeller protein-associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NDD: neurodevelopmental disorder; NGS: next-generation sequencing; WDR45/WIPI4: WD repeat domain 45.

Project description:Surgeons usually witness only the limb-threatening stages of infected, closed pedal puncture wounds in diabetics. Given that this catastrophic outcome often represents failure of conservative management of pre-infected wounds, some suggest consideration of invasive intervention (coring or laying-open) for pre-infected wounds in hope of preventing contamination from evolving into infection, there being no evidence based guidelines. However, an invasive pre-emptive approach is only justifiable if the probability of progression to catastrophic infection is very high. Literature search revealed no prior studies on the natural history of closed pedal puncture wounds in diabetics.A survey was conducted via an interviewer-administered questionnaire on 198 adult diabetics resident in the parish of St. James, Jamaica. The sample was selected using a purposive technique designed to mirror the social gradient and residential distribution of the target population and is twice the number needed to detect a prevalence of puncture wounds of 14% with a range of 7-21% in a random sample of the estimated adult diabetic population.The prevalence of a history of at least one closed pedal puncture wound since diagnosis of diabetes was 25.8% (CI; 19.6-31.9%). The only modifiable variable associated at the 5% level of significance with risk of pedal puncture wound, after adjustment by multivariable logistic regression, was site of interview/paying status, a variable substantially reflective of income more so than quality-of-care.Of 77 reported episodes of closed pedal puncture wound among 51 participants, 45.4% healed without medical intervention, 27.3% healed after non-surgical treatment by a doctor and 27.3% required surgical intervention ranging from debridement to below-knee amputation. Anesthetic foot (failure to feel the puncture) and sole of the forefoot as site of puncture were the variables significantly associated with risk of requiring surgical intervention.That 72.7% of wounds healed either spontaneously or after non-surgical treatment means that routine, non-selective surgical intervention for pre-infected closed pedal puncture wounds in diabetics is not justifiable. However the subset of patients with an anesthetic foot and a wound on the sole of the forefoot should be marked for intensive surveillance and early surgical intervention if infection occurs.

Project description:PurposeTo describe in detail the central retinal structure of a large group of patients with choroideremia (CHM).DesignA prospective, cross-sectional, descriptive study.ParticipantsPatients (n = 97, age 6-71 years) with CHM and subjects with normal vision (n = 44; ages 10-50 years) were included.MethodsSubjects were examined with spectral-domain optical coherence tomography (SD OCT) and near-infrared reflectance imaging. Visual acuity (VA) was measured during their encounter or obtained from recent ophthalmic examinations. Visual thresholds were measured in a subset of patients (n = 24) with automated static perimetry within the central regions (±15°) examined with SD OCT.Main outcome measuresVisual acuity and visual thresholds; total nuclear layer, inner nuclear layer (INL), and outer nuclear layer (ONL) thicknesses; and horizontal extent of the ONL and the photoreceptor outer segment (POS) interdigitation zone (IZ).ResultsEarliest abnormalities in regions with normally appearing retinal pigment epithelium (RPE) were the loss of the POS and ellipsoid zone associated with rod dysfunction. Transition zones (TZs) from relatively preserved retina to severe ONL thinning and inner retinal thickening moved centripetally with age. Most patients (88%) retained VAs better than 20/40 until their fifth decade of life. The VA decline coincided with migration of the TZ near the foveal center. There were outer retinal tubulations in degenerated, nonatrophic retina in the majority (69%) of patients. In general, RPE abnormalities paralleled photoreceptor degeneration, although there were regions with detectable but abnormally thin ONL co-localizing with severe RPE depigmentation and choroidal thinning.ConclusionsAbnormalities of the POS and rod dysfunction are the earliest central abnormalities observed in CHM. Foveal function is relatively preserved until the fifth decade of life. Migration of the TZs to the foveal center with foveal thinning and structural disorganization heralded central VA loss. The relationships established may help outline the eligibility criteria and outcome measures for clinical trials for CHM.

Dataset Information

Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies.

Purpose

Methods

Results

Conclusion

Publications

Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets