-
Journal of Cardiovascular Development... Jan 2022Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely... (Review)
Review
Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.
PubMed: 35200700
DOI: 10.3390/jcdd9020047 -
Orphanet Journal of Rare Diseases Feb 2022Improving care coordination for people with rare conditions may help to reduce burden on patients and carers and improve the care that patients receive. We recently...
INTRODUCTION
Improving care coordination for people with rare conditions may help to reduce burden on patients and carers and improve the care that patients receive. We recently developed a taxonomy of different ways of coordinating care for rare conditions. It is not yet known which models of care coordination are appropriate in different situations. This study aimed to: (1) explore what types of care coordination may be appropriate in different situations, and (2) use these findings to develop hypothetical models of care coordination for rare conditions.
METHODS
To explore appropriateness of different types of care coordination, we conducted interviews (n = 30), four focus groups (n = 22) and two workshops (n = 27) with patients, carers, healthcare professionals, commissioners, and charity representatives. Participants were asked about preferences, benefits and challenges, and the factors influencing coordination. Thematic analysis was used to develop hypothetical models of care coordination. Models were refined following feedback from workshop participants.
RESULTS
Stakeholders prefer models of care that: are nationally centralised or a hybrid of national and local care, involve professionals collaborating to deliver care, have clear roles and responsibilities outlined (including administrative, coordinator, clinical and charity roles), provide access to records and offer flexible appointments (in terms of timing and mode). Many factors influenced coordination, including those relating to the patient (e.g., condition complexity, patient's location and ability to coordinate their own care), the healthcare professional (e.g., knowledge and time), the healthcare environment (e.g., resources) and societal factors (e.g., availability of funding). We developed and refined ten illustrative hypothetical models of care coordination for rare conditions.
CONCLUSION
Findings underline that different models of care coordination may be appropriate in different situations. It is possible to develop models of care coordination which are tailored to the individual in context. Findings may be used to facilitate planning around which models of care coordination may be appropriate in different services or circumstances. Findings may also be used by key stakeholders (e.g. patient organisations, clinicians and service planners) as a decision-making tool.
Topics: Caregivers; Delivery of Health Care; Humans; Qualitative Research
PubMed: 35164822
DOI: 10.1186/s13023-022-02190-3 -
Medicine Nov 2021Alström syndrome is a rare genetic disorder characterized by obesity, diabetes mellitus, cardiomyopathy, and liver dysfunction. Further, scoliosis, a common symptom of...
RATIONALE
Alström syndrome is a rare genetic disorder characterized by obesity, diabetes mellitus, cardiomyopathy, and liver dysfunction. Further, scoliosis, a common symptom of Alström syndrome, often requires surgical intervention for functional impairments. Motor evoked potential (MEP) monitoring and other electrophysiological tests are essential when performing surgery for functional scoliosis. However, there are few reports on how to maintain general anesthesia in Alström syndrome. Here, we describe a patient with Alström syndrome who underwent surgery for scoliosis under general anesthesia with remimazolam and MEP monitoring.
PATIENT CONCERNS
A 17-year-old woman (height, 140 cm, weight, 64.5 kg) diagnosed with Alström syndrome was scheduled for a posterior spinal fusion for functional scoliosis. Other associated comorbidities of Alström syndrome present were dilated cardiomyopathy, type 2 diabetes mellitus, obesity (body mass index, 32.1 kg/m2), amblyopia (light perception), and hearing impairment (speech awareness threshold 50 dBHL in each ear).
DIAGNOSES, INTERVENTIONS, AND OUTCOMES
Posterior spinal fusion was planned for functional scoliosis. While investigating the dilated cardiomyopathy, transthoracic echocardiography showed global wall hypokinesis, with 45% left ventricular ejection fraction. The left ventricle was dilated, with left ventricular end-diastolic and end-systolic diameters of 55 and 42 mm, respectively. This finding along with the hypertriglyceridemia associated with Alström syndrome led us to conclude that propofol should be avoided. Thus, we induced general anesthesia using remimazolam. MEP monitoring was performed, and the patient experienced no motor impairments during the surgery.
LESSONS
Myocardial and hepatic dysfunction determine the prognosis of patients with Alström syndrome. Thus, anesthesia that preserves liver function should be selected in such cases. In patients with hypertriglyceridemia, propofol should be avoided, and using remimazolam, an ultrashort-acting benzodiazepine, may be appropriate. In this case, reviewing the Patient State Index with SedLine allowed us to perform MEP monitoring uneventfully, and the posterior spinal fusion was completed without any motor impairment.
Topics: Adolescent; Alstrom Syndrome; Anesthesia, General; Benzodiazepines; Evoked Potentials, Motor; Female; Humans; Scoliosis; Spinal Fusion
PubMed: 34964794
DOI: 10.1097/MD.0000000000027990 -
Journal of Pediatric Genetics Jun 2024Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision,...
Alstrom's syndrome (AS) is an autosomal recessively inherited multisystemic disorder that falls under the umbrella of ciliopathy. It is characterized by poor vision, hearing impairment, cardiomyopathy, childhood obesity, diabetes mellitus type 2, dyslipidemia, pulmonary, hepatic, and renal failure besides systemic fibrosis. Biallelic pathogenic variants in gene cause AS. Retrospective study (1990-2017) included 12 Saudi patients with AS based on their phenotype, biochemical markers, and genotype. The study was approved by Fisal Specialist Hospital and Research Centre, Riyadh (RAC number 2131129) on October 2, 2012. This study showed clinical and genetic heterogeneity; six patients showed a founder mutation (IVS18-2A > T in exon 19), whereas six others showed private mutations. AS in Saudi Arabia is underdiagnosed probably because of its variable clinical manifestations. We report 12 Saudi patients with AS to enhance the awareness about this syndrome.
PubMed: 38721579
DOI: 10.1055/s-0041-1740369 -
Intractable & Rare Diseases Research Nov 2021Alström syndrome is a rare monogenic ciliopathy caused by a mutation to the () gene. Alström syndrome has an autosomal recessive nature of inheritance. Approximately... (Review)
Review
Alström syndrome is a rare monogenic ciliopathy caused by a mutation to the () gene. Alström syndrome has an autosomal recessive nature of inheritance. Approximately 1,200 cases of Alström syndrome have been identified worldwide. Complications of the disease are likely caused by dysfunctional cilia with complications arising early in life. The known complications of Alström syndrome have been reported to impact multiple major organ systems, including the endocrine system, cardiac system, renal system, sensory system, and hepatic system. The symptoms of Alström syndrome have great variability in presentation and intensity but often lead to organ damage. This has resulted in a shortened lifespan for individuals affected by Alström syndrome. Individuals with the disease rare exceed the age of 50. Currently, there are no specific treatments for Alström syndrome that can cure the disease, prevent the complications, or reverse the complications. Current management involves management of symptoms with the goal of improving quality of life and lifespan. This review aims to summarize the current knowledge on the epidemiology, diagnosis, pathophysiology, complications, management, and prognosis of Alström syndrome. In addition to that, this review also aims to raise awareness and encourage research on Alström syndrome as the condition has a huge impact on affected individuals.
PubMed: 34877237
DOI: 10.5582/irdr.2021.01113 -
ENeuro 2021The hedgehog signaling pathway is best known for its role in developmental patterning of the neural tube and limb bud. More recently, hedgehog signaling has been...
The hedgehog signaling pathway is best known for its role in developmental patterning of the neural tube and limb bud. More recently, hedgehog signaling has been recognized for its roles in growth of adult tissues and maintenance of progenitor cell niches. However, the role of hedgehog signaling in fully differentiated cells like neurons in the adult brain is less clear. In mammals, coordination of hedgehog pathway activity relies on primary cilia and patients with ciliopathies such as Bardet-Biedl and Alström syndrome exhibit clinical features clearly attributable to errant hedgehog such as polydactyly. However, these ciliopathies also present with features not clearly associated with hedgehog signaling such as hyperphagia-associated obesity. How hedgehog signaling may contribute to feeding behavior is complex and unclear, but cilia are critical for proper energy homeostasis. Here, we provide a detailed analysis of the expression of core components of the hedgehog signaling pathway in the adult mouse hypothalamus with an emphasis on feeding centers. We show that hedgehog pathway genes continue to be expressed in differentiated neurons important for the regulation of feeding behavior. Furthermore, we demonstrate for the first time that pathway activity is regulated at the transcriptional level by fasting. These data suggest that hedgehog signaling is involved in the proper functioning of brain regions that regulate feeding behavior and that hedgehog pathway dysfunction may play a role in the obesity observed in certain ciliopathies.
Topics: Animals; Cilia; Fasting; Hedgehog Proteins; Humans; Hypothalamus; Mice; Signal Transduction
PubMed: 34535504
DOI: 10.1523/ENEURO.0276-21.2021 -
Nefrologia Aug 2021
PubMed: 34462146
DOI: 10.1016/j.nefro.2021.07.005 -
Journal of Molecular Medicine (Berlin,... Nov 2021Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized,...
Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband's dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy. KEY MESSAGE: Primary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology. Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology. In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology. Infants with pEFE should be examined for syndromic features of Alstrom syndrome. Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.
Topics: Alstrom Syndrome; Cardiomyopathies; Cell Cycle Proteins; Ciliopathies; Endocardial Fibroelastosis; Epithelial-Mesenchymal Transition; Female; Fibroblasts; Humans; Infant; Mutation; Myocardium; Phenotype; RNA-Seq; Transcriptome
PubMed: 34387706
DOI: 10.1007/s00109-021-02112-z -
EBioMedicine Aug 2021Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is...
BACKGROUND
Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alström syndrome (AS), they are known as the 'obesity ciliopathies' due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies.
METHODS
Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alström Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function.
FINDINGS
mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2 fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2 and ALMS1 fibroblasts, suggesting rescue of ciliary function.
INTERPRETATION
The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2 and ALMS1 fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies.
FUNDING
Wellcome Trust 205174/Z/16/Z, National Centre for the Replacement, Refinement & Reduction of Animals in Research. Deutsche Forschungsgemeinschaft SPP2127 (DFG Grant MA 6139/3-1).
Topics: Adolescent; Adult; Alstrom Syndrome; Aminopyridines; Bardet-Biedl Syndrome; Cell Cycle Proteins; Cells, Cultured; Codon, Nonsense; Fibroblasts; Humans; Male; Oxadiazoles; Proteins; Receptors, Somatostatin; Tumor Suppressor Proteins
PubMed: 34365092
DOI: 10.1016/j.ebiom.2021.103515