rare disorders
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Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 93
Author(s):  
Noèlia Fernàndez-Castillo ◽  
Judit Cabana-Domínguez ◽  
Djenifer B. Kappel ◽  
Bàrbara Torrico ◽  
Heike Weber ◽  
...  

Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.


2021 ◽  
Vol 15 (12) ◽  
pp. 3351-3352
Author(s):  
Sumera Akram

Lipodystrophy syndromes are rare disorders characterized by either generalized or partial lack of adipose tissue. They are congenital or acquired. These syndromes are associated with various metabolic and harmonal disorders leading to severe comorbidities including hypertriglyceridemia, diabetes mellitus, acanthosis nigricans, xanthomas, polycystic ovarian syndrome (POS) and non-alcoholic fatty liver disease. Keywords: Lawrence syndrome, lipodystrophy, diabetes mellitus


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rima Izem ◽  
Robert McCarter

AbstractIn the United States, approximately 7000 rare diseases affect 30 million patients, and only 10% of these diseases have existing therapies. Sound study design and causal inference methods are essential to demonstrate the therapeutic efficacy, safety, and effectiveness of new therapies. In the rare diseases setting, several factors challenge the use of typical parallel control designs: the small patient population size, genotypic and phenotypic diversity, and the complexity and incomplete understanding of the disorder’s progression. Repeated measures, when spaced appropriately relative to disease progression and exploited in design and analysis, can increase study power and reduce variability in treatment effect estimation. This paper reviews these longitudinal designs and draws the parallel between some new and existing randomized studies in rare diseases and their less well-known controlled observational study designs. We show that self-controlled randomized crossover and N-of-1 designs have similar considerations as the observational case series and case-crossover designs. Also, randomized sequential designs have similar considerations to longitudinal cohort studies using sequential matching or weighting to control confounding. We discuss design and analysis considerations for valid causal inference and illustrate them with examples of analyses in multiple rare disorders, including urea cycle disorder and cystic fibrosis.


2021 ◽  
Vol 12 ◽  
Author(s):  
Foziah Alshamrani ◽  
Rawan Alyami ◽  
Ibrahim Alghanimi ◽  
Reef Alajaji ◽  
Modhi Alkhaldi ◽  
...  

Combined central and peripheral demyelination (CCPD) is not encountered frequently in the clinical practice, and it requires a high level of suspicion for diagnosis. We describe a case of a young man who was diagnosed with radiologically isolated syndrome (RIS) after presenting initially with symptoms suggestive of central nervous system (CNS) insult in the form of double vision, slurred speech, left-sided numbness, and unsteadiness. However, on the next day of admission, his neurological examination was remarkable for ataxia, areflexia, and ophthalmoplegia, the typical triad of Miller Fisher syndrome (MFS). After confirming both diagnoses, the final diagnosis of CCPD was made. The challenges one may face to diagnose and treat CCPD urge sharing of similar cases to open the door for further extensive and thorough investigations and to encourage further studies and analysis of available data to come up with consolidated management guidelines for rare disorders.


2021 ◽  
Vol 10 (21) ◽  
pp. 4834
Author(s):  
Louise Benarroch ◽  
Enzo Cohen ◽  
Antonio Atalaia ◽  
Rabah Ben Yaou ◽  
Gisèle Bonne ◽  
...  

Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes.


2021 ◽  
Vol 2021 (10) ◽  
Author(s):  
Nigel Rawson

In 2021, the Rare Disease Treatment Access Working Group (RDTAWG) of the International Rare Diseases Research Consortium, a European Union funded organization, published a list of medicinal products that they considered to be essential for the treatment of rare conditions. This study assesses the availability and accessibility of the RDTAWG medicines in Canada by comparing whether the rare disorder medicines approved for marketing in the United States also had regulatory approval for the same indication in Canada, and whether those medicines are ultimately covered under the 10 provincial government drug plans and the federal Non-Insured Health Benefits plan for indigenous persons. Data available at the end of August 2021 were accessed from the relevant online drug formularies. Most (85%) of the medicines with regulatory approval in the United States were also approved for the same indication in Canada. However, only just over half were covered by either open or conditional access in government drug plans, with the proportion ranging from under 36% in Manitoba to two-thirds in New Brunswick. Approximately 20% of the medicines had open access in all the plans, whereas the proportion with conditional access ranged from 13% in Manitoba to 45% in Ontario and New Brunswick. The average rate of coverage for medicines for disorders with a prevalence of ≤1 per 100,000 was only 28%, compared with 56% for disorders with a prevalence ranging from >1 case per 100,000 persons up to 1 case per 10,000 persons, and 60% for disorders with a prevalence of >1 case per 10,000 persons. Access to many medicines regarded by experts in the RDTAWG as essential for the welfare of individuals with rare disorders is inadequate to poor in Canada, especially for ultra-rare conditions. The federal Liberals and NDP are keen to introduce some type of national pharmacare. Any program developed by Canada’s governments must ensure that Canadians will have publicly funded access to all rare disorder medicines.


Author(s):  
Juliane Léger ◽  
Clemence Delcour ◽  
Jean-Claude Carel

Abstract Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay.Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Grave’s disease (GD) results from the passage of thyrotropin receptor antibodies (TRAb) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking TSH receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism,but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child’s prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism.


2021 ◽  
Vol 58 (S1) ◽  
pp. 85-85
Author(s):  
N. Bourgon ◽  
J. Sichitiu ◽  
E. Spaggiari ◽  
F. Audibert ◽  
A. Geipel ◽  
...  
Keyword(s):  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthieu Bouaziz ◽  
Jimmy Mullaert ◽  
Benedetta Bigio ◽  
Yoann Seeleuthner ◽  
Jean-Laurent Casanova ◽  
...  

AbstractPopulation stratification is a confounder of genetic association studies. In analyses of rare variants, corrections based on principal components (PCs) and linear mixed models (LMMs) yield conflicting conclusions. Studies evaluating these approaches generally focused on limited types of structure and large sample sizes. We investigated the properties of several correction methods through a large simulation study using real exome data, and several within- and between-continent stratification scenarios. We considered different sample sizes, with situations including as few as 50 cases, to account for the analysis of rare disorders. Large samples showed that accounting for stratification was more difficult with a continental than with a worldwide structure. When considering a sample of 50 cases, an inflation of type-I-errors was observed with PCs for small numbers of controls (≤ 100), and with LMMs for large numbers of controls (≥ 1000). We also tested a novel local permutation method (LocPerm), which maintained a correct type-I-error in all situations. Powers were equivalent for all approaches pointing out that the key issue is to properly control type-I-errors. Finally, we found that power of analyses including small numbers of cases can be increased, by adding a large panel of external controls, provided an appropriate stratification correction was used.


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