The Role of Uncertainty in Coping Efficacy: The Experience of Parents of Children with Undiagnosed Medical Conditions

Background: Uncertainty pervades all aspects of illness and health care and is especially relevant for those individuals with rare and undiagnosed medical conditions. Research has demonstrated that uncertainty can be a significant source of psychological distress and may affect adaptation. This study explores the perceived uncertainty, accounting for personality traits, among parents of a child with an undiagnosed medical condition. Methods: A cross-sectional, mixed methods design was used to examine the relationships among perceptions of uncertainty, coping efficacy, and coping, accounting for personality traits (tolerance of uncertainty, resilience, and optimism). The study design was informed by Lazarus and Folkman’s Transactional Model of Stress and Coping. Measures included a newly developed Parental Uncertainty of Children’s Health Scale which examined parents’ perceptions of uncertainty and the importance of resolving the uncertainty. Parents of children with undiagnosed medical conditions were recruited through online support and advocacy groups. All participants completed the survey electronically. Results: Among the 94 respondents, the majority were biological mothers (94%), Caucasian (94.7%), and married (76.6%). A slight majority of the children were female (57.6%) and were, on average, 8.0 years old. On average, parents perceived greater uncertainty than certainty about areas of their child’s undiagnosed condition that are important to them. Multivariate analysis revealed that optimism predicted perceptions of uncertainty (p <0.01), and that perceptions of uncertainty, optimism and resilience predicted coping efficacy (p <0.05). Additionally, multivariate analysis showed that coping efficacy and resilience predicted problem-focused coping (p < 0.01) while resilience and tolerance of uncertainty predicted emotion-focused coping (p < 0.05). Analysis revealed that perceptions of uncertainty greatly influence appraisals of coping efficacy such that higher perceptions of uncertainty result in lower coping efficacy. Conclusion: This study suggests that parents of children with undiagnosed medical conditions perceive uncertainty related to social support and medical management, which they view as important to resolve. The findings also suggest that personality traits contribute to the type of coping strategies parents choose to employ. Finally, this study contributes to the broader understanding of perceptions of uncertainty and the impact of these perceptions for parents of children with undiagnosed medical conditions

De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus

Subcellular membrane systems are highly enriched in dolichol, whose role in organelle homeostasis and endosomal-lysosomal pathway remains largely unclear besides being involved in protein glycosylation. DHDDS encodes for the catalytic subunit (DHDDS) of the enzyme cis-prenyltransferase (cis-PTase), involved in dolichol biosynthesis and dolichol-dependent protein glycosylation in the endoplasmic reticulum. An autosomal recessive form of retinitis pigmentosa (retinitis pigmentosa 59) has been associated with a recurrent DHDDS variant. Moreover, two recurring de novo substitutions were detected in a few cases presenting with neurodevelopmental disorder, epilepsy, and movement disorder. We evaluated a large cohort of patients (n=25) with de novo pathogenic variants in DHDDS and provided the first systematic description of the clinical features and long-term outcome of this new neurodevelopmental and neurodegenerative disorder. The functional impact of the identified variants was explored by yeast complementation system and enzymatic assay. Patients presented during infancy or childhood with a variable association of neurodevelopmental disorder, generalized epilepsy, action myoclonus/cortical tremor, and ataxia. Later in the disease course they experienced a slow neurological decline with the emergence of hyperkinetic and/or hypokinetic movement disorder, cognitive deterioration, and psychiatric disturbances. Storage of lipidic material and altered lysosomes were detected in myelinated fibers and fibroblasts, suggesting a dysfunction of the lysosomal enzymatic scavenger machinery. Serum glycoprotein hypoglycosylation was not detected and, in contrast to retinitis pigmentosa and other congenital disorders of glycosylation involving dolichol metabolism, the urinary dolichol D18/D19 ratio was normal. Mapping the disease-causing variants into the protein structure revealed that most of them clustered around the active site of the DHDDS subunit. Functional studies using yeast complementation assay and in vitro activity measurements confirmed that these changes affected the catalytic activity of the cis-PTase and showed growth defect in yeast complementation system as compared with the wild-type enzyme and retinitis pigmentosa-associated protein. In conclusion, we characterized a distinctive neurodegenerative disorder due to de novo DHDDS variants, which clinically belongs to the spectrum of genetic progressive encephalopathies with myoclonus. Clinical and biochemical data from this cohort depicted a condition at the intersection of congenital disorders of glycosylation and inherited storage diseases with several features akin to of progressive myoclonus epilepsy such as neuronal ceroid lipofuscinosis and other lysosomal disorders

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Everyday Life of the Etruscans

Автор рассказывает о многих аспектах жизни этрусков, географическом положении государства, его истории, освещает их военную, экономическую, политическую и социальную организацию, дает представление об их духовной жизни, обычаях и поверьях.Краткий глоссарий: с. 188-189. Важные даты: с. 189-191

Continuing a search for a diagnosis: the impact of adolescence and family dynamics

Abstract The “diagnostic odyssey” describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family’s decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475–491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child’s age was 11 years (range 3–18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses

Clinical, genetic, and structural characterization of a novel TUBB4B tubulinopathy

Microtubules are cytoskeletal polymers of ⍺/β-tubulin heterodimers essential for a wide range of cellular processes. Pathogenic variations in microtubule-encoding genes (e.g., TUBB4B, which encodes the β-4B tubulin isotype) are responsible for a wide spectrum of cerebral malformations, collectively referred to as “tubulinopathies.” The phenotypic manifestation of TUBB4B-associated tubulinopathy is Leber congenital amaurosis with early-onset deafness (LCAEOD), an autosomal dominant syndrome characterized by photoreceptor and cochlear cell loss; all known patients have pathogenic variations in amino acid R391. We present the clinical and molecular genetics findings of a 16-year-old female with a de novo missense variant in exon 1 of TUBB4B, c.32 A > G (p.Gln11Arg; Q11R). In addition to hearing loss and hyperopia without retinal abnormalities, our proband presented with two phenotypes of unknown genetic etiology, i.e., renal tubular Fanconi Syndrome (FS) and hypophosphatemic rickets (HR). The Q11R variant expands the genetic basis of early sensory hearing loss; its consequences with respect to microtubule structure are described. A mechanistic explanation for the FS and rickets, involving microtubule-mediated translocation of transporter proteins to and from the apical membrane of renal proximal tubular cells, is proposed

DYRK1A pathogenic variants in two patients with syndromic intellectual disability and a review of the literature.

Two patients diagnosed with DYRK1A Syndrome in the Undiagnosed Diseases Program with ophthalmologic abnormalities not previously described