Williams syndrome (WS-OMIM 194050, orphaned number: Orpha 904) is a rare condition mostly associated with intellectual disability. People with Williams syndrome are 8 times more likely to have ...anxiety disorders than the general population. Therapeutic solutions to treat the anxiety remain limited, particularly nonpharmacological therapy. However, cognitive behavioral therapy (CBT) has been found efficacious in managing anxiety disorders and can be used for people with intellectual disability.
This paper describes a protocol to assess the efficiency of a CBT program based on digital support for people with Williams syndrome and anxiety based on a research methodology designed for rare diseases.
We will recruit 5 individuals with Williams syndrome and anxiety. They will participate in 9 CBT sessions. Participants will perform daily self-assessments of anxiety using a digital app, which will allow for ecological and repeated evaluation of their anxiety. This digital app will provide support for each therapy session. Anxiety and quality of life will be externally assessed before and after the program and at a 3-month follow-up. This is a single-case intervention research design with multiple baselines implying repeated measures of judgment criteria. The present protocol ensures high internal validity and will help identify encouraging contributions for later clinical trials.
Participant recruitment and data collection began in September 2019, and we project that the study findings will be available for dissemination by spring 2023.
This study will allow the assessment of the efficiency of a CBT program based on digital support to treat anxiety in people with Williams syndrome. Finally, the program could be used as an example of nonpharmacological therapy for rare diseases.
ClinicalTrials.gov ID: NCT03827525; https://clinicaltrials.gov/ct2/show/NCT03827525.
DERR1-10.2196/44393.
Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and ...genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio OR 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.
The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well ...as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.
ABSTRACT
Mutations in the COL2A1 gene cause a spectrum of rare autosomal‐dominant conditions characterized by skeletal dysplasia, short stature, and sensorial defects. An early diagnosis is critical ...to providing relevant patient care and follow‐up, and genetic counseling to affected families. There are no recent exhaustive descriptions of the causal mutations in the literature. Here, we provide a review of COL2A1 mutations extracted from the Leiden Open Variation Database (LOVD) that we updated with data from PubMed and our own patients. Over 700 patients were recorded, harboring 415 different mutations. One‐third of the mutations are dominant‐negative mutations that affect the glycine residue in the G‐X‐Y repeats of the alpha 1 chain. These mutations disrupt the collagen triple helix and are common in achondrogenesis type II and hypochondrogenesis. The mutations resulting in a premature stop codon are found in less severe phenotypes such as Stickler syndrome. The p.(Arg275Cys) substitution is found in all patients with COL2A1‐associated Czech dysplasia. LOVD‐COL2A1 provides support and potential collaborative material for scientific and clinical projects aimed at elucidating phenotype–genotype correlation and differential diagnosis in patients with type II collagenopathies.
Type II collagenopathies cause a spectrum of rare autosomal dominant conditions characterized by skeletal dysplasia, short stature, and sensorial defects. A differential diagnosis of with other genetic causes of bone dysplasia is sometimes challenging. There are no recent exhaustive descriptions of mutations in the COL2A1 gene. We provide a review of COL2A1 mutations extracted from the Leiden Open Variation Database that we updated with data from PubMed and our own patients. Over 700 patients were recorded, harboring 415 different mutations.
Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the
ALPL
gene. Patients have ...consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an
ALPL
mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous
ALPL
mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an
ALPL
mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for
ALPL
mutations may have unspecific symptoms not attributable to their heterozygosity.
Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro‐osteolysis, facial features and an increased risk of fractures. The clinical ...heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow‐up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = −3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non‐invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow‐up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow‐up.
Recommendations for pycnodysotosis diagnosis and follow up based on a french cohort of patients.
Objective
Osteoarthritis (OA) is the most common joint disease worldwide. The etiology of OA is varied, ranging from multifactorial to environmental to monogenic. In a condition called early‐onset ...OA, OA occurs at an earlier age than is typical in the general population. To our knowledge, there have been no large‐scale genetic studies of individuals with early‐onset OA. The present study was undertaken to investigate causes of monogenic OA in individuals with nonsyndromic early‐onset OA.
Methods
The study probands were 45 patients with nonsyndromic early‐onset OA who were referred to our skeletal disease center by skeletal dysplasia experts between 2013 and 2019. Criteria for early‐onset OA included radiographic evidence, body mass index ≤30 kg/m2, age at onset ≤50 years, and involvement of ≥1 joint site. Molecular analysis was performed with a next‐generation sequencing panel.
Results
We identified a genetic variant in 13 probands (29%); the affected gene was COL2A1 in 11, ACAN in 1, and SLC26A2 in 1. After familial segregation analysis, 20 additional individuals were identified. The mean ± SD age at onset of joint pain was 19.5 ± 3.9 years (95% confidence interval 3–47). Eighteen of 33 subjects (55%) with nonsyndromic early‐onset OA and a genetic variant had had at least 1 joint replacement (mean ± SD age at first joint replacement 41 ± 4.2 years; mean number of joint replacements 2.6 per individual), and 21 (45%) of the joint replacement surgeries were performed when the patient was <45 years old. Of the 20 patients age >40 years, 17 (85%) had had at least 1 joint replacement.
Conclusion
We confirmed that COL2A1 is the main monogenic cause of nonsyndromic early‐onset OA. However, on the basis of genetic heterogeneity of early‐onset OA, we recommend next‐generation sequencing for all individuals who undergo joint replacement prior to the age of 45 years. Lifestyle recommendations for prevention should be implemented.
Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal ...and postnatal growth retardation, early feeding difficulties) and molecular overlap.
To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS.
We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis.
Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation.
Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.
Inflammasomes are multiprotein complexes that sense pathogens and trigger biological mechanisms to control infection. Nucleotide-binding oligomerisation domain-like receptor (NLR) containing a PYRIN ...domain 1 (NLRP1), NLRP3 and NLRC4 plays a key role in this innate immune system by directly assembling in inflammasomes and regulating inflammation. Mutations in
and
are linked to hereditary autoinflammatory diseases, whereas polymorphisms in
are associated with autoimmune disorders such as vitiligo and rheumatoid arthritis. Whether human
mutation is associated with autoinflammation remains to be determined.
To search for novel genes involved in systemic juvenile idiopathic arthritis, we performed homozygosity mapping and exome sequencing to identify causative genes. Immunoassays were performed with blood samples from patients.
We identified a novel disease in three patients from two unrelated families presenting diffuse skin dyskeratosis, autoinflammation, autoimmunity, arthritis and high transitional B-cell level. Molecular screening revealed a non-synonymous homozygous mutation in
(c.2176C>T; p.Arg726Trp) in two cousins born of related parents originating from Algeria and a de novo heterozygous mutation (c.3641C>G, p.Pro1214Arg) in a girl of Dutch origin. The three patients showed elevated systemic levels of caspase-1 and interleukin 18, which suggested involvement of NLRP1 inflammasome.
We demonstrate the responsibility of human
in a novel autoinflammatory disorder that we propose to call NAIAD for
associated autoinflammation with arthritis and dyskeratosis. This disease could be a novel autoimmuno-inflammatory disease combining autoinflammatory and autoimmune features. Our data, combined with that in the literature, highlight the pleomorphic role of
in inflammation and immunity.
NCT02067962; Results.
Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder associated with high variability of symptoms and anticipation. DM1 is caused by an unstable CTG repeat expansion that usually ...increases in successive generations and tissues. DM1 family pedigrees have shown that ∼90% and 10% of transmissions result in expansions and contractions of the CTG repeat, respectively. To date, the mechanisms of CTG repeat contraction remain poorly documented in DM1. In this report, we identified two new DM1 families with apparent contractions and no worsening of DM1 symptoms in two and three successive maternal transmissions. A new and unique CAG interruption was found in 5′ of the CTG expansion in one family, whereas multiple 5′ CCG interruptions were detected in the second family. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood. By specific triplet‐prime PCR, we observed that CTG repeat changes (contractions/expansions) occur preferentially in 3′ of the interruptions for both families.
Myotonic dystrophy type 1 is a dominant multisystemic disorder caused by an unstable CTG repeat expansion that usually increases in successive generations and tissues. We described an unique CAG interruption or multiple CCG interruptions in the 5' end of the CTG repeat tract in two atypical DM1 families. We showed that these interruptions are associated with maternal intergenerational contractions and low somatic mosaicism in blood.
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