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Rothmund−Thomson Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Vikram K. Mahajan, Dhaarna Wadhwa
The prevalence of this rare genomic instability syndrome remains undefined due to its variable clinical spectrum and relative scarcity (with fewer than 400 cases being reported to date). Given its high phenotypic variation, cases showing atypical or borderline clinical presentations may be overlooked or undiagnosed. While no population is spared from RTS, which equally affects both genders of all ethnicities and many nationalities, specific mutations may exist within certain ethnic groups. As an autosomal recessive disorder, most affected patients appear as isolated cases, except those from consanguineous families.
Genetic counselling in Mendelian disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Conversely, the necessary contribution of both parents to an autosomal recessive disorder in a child can be a positive feature in genetic counselling. It is frequently found that one parent (commonly the mother) is assuming the burden of guilt for the occurrence of the disorder, and this may be reinforced by the views (spoken or tacit) of other relatives. The realisation that neither side of the family is solely ‘to blame’, and that everyone carries at least one harmful genetic factor, is frequently a great relief to couples to whom a child with an autosomal recessive disorder has been born.
The nervous system
Published in Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella, Essentials of Human Physiology and Pathophysiology for Pharmacy and Allied Health, 2019
Laurie K. McCorry, Martin M. Zdanowicz, Cynthia Y. Gonnella
Huntington’s disease is an inherited disorder that is characterized by a progressive destruction of brain neurons. The disease is inherited as an autosomal recessive disorder. Most patients begin to exhibit symptoms in their 30s to 40s. The condition affects a broad range of CNS neurons and, as a result, the disease can affect voluntary movements, cognitive function, and emotional stability. The genetic defect associated with Huntington’s disease is located on chromosome 4 in a gene that encodes for a protein called the huntingtin protein. Although the physiologic function of the normal huntingtin protein is uncertain, the abnormal huntingtin protein is larger in size than the normal protein and may not be properly processed or degraded within the CNS neurons. Accumulation of abnormal huntingtin protein fragments may alter neuronal function and lead to cell death.
Identification of novel variants in ten patients with Hermansky-Pudlak syndrome by high-throughput sequencing
Published in Annals of Medicine, 2019
Jose María Bastida, Sara Morais, Veronica Palma-Barqueros, Rocio Benito, Nuria Bermejo, Mutlu Karkucak, Maria Trapero-Marugan, Natalia Bohdan, Mónica Pereira, Ana Marin-Quilez, Jorge Oliveira, Yusuf Yucel, Rosario Santos, Jose Padilla, Kamila Janusz, Catarina Lau, Marta Martin-Izquierdo, Eduarda Couto, Juan Francisco Ruiz-Pividal, Vicente Vicente, Jesus Maria Hernández-Rivas, Jose Ramon González-Porras, Maria Luisa Lozano, Margarida Lima, Jose Rivera
Hermansky-Pudlak syndrome is a rare genetic disorder presenting with hypopigmentation, bleeding diathesis, and organ dysfunction secondary to the accumulation of ceroid-like material and resultant tissue damage. Variants in one of the ten currently known genes can result in this autosomal recessive disorder. Molecular analysis is useful in confirming the diagnosis and may offer some prognostic information that will aid in optimizing monitoring and surveillance for early detection of end-organ damage. Given the poor genotype-phenotype correlation, a sequential assessment of the most likely genes can be lengthy and expensive. A target gene panel analyzed by HTS can be considered and could be used in the first-line diagnosis of patients with biological and clinical manifestations suggestive of HPS. Our findings also expand the mutational spectrum of HPS, which may help in investigating phenotype-genotype relationships and assist genetic counselling for affected individuals.
The preclinical discovery and development of the combination of ivacaftor + tezacaftor used to treat cystic fibrosis
Published in Expert Opinion on Drug Discovery, 2020
Lorenzo Guerra, Maria Favia, Sante Di Gioia, Onofrio Laselva, Arianna Bisogno, Valeria Casavola, Carla Colombo, Massimo Conese
The clinical benefit of ivacaftor in CF patients with G551D mutation is considered to be the benchmark for treatment with highly effective CFTR modulators. Given the complexity of multiple defects associated with the F508del mutation, the achievement of a clinically relevant outcome in patients homozygous for F508del has been more difficult to achieve and needed the association of drugs with different mechanisms of action. Although the combination therapy of the potentiator ivacaftor and a corrector molecule has advanced the treatment of CF patients homozygous for the F508del mutation and also for those heterozygous for F508del and a MF mutation, the combination tezacaftor–ivacaftor shows some advantages over lumacaftor–ivacaftor. No discontinuation of tezacaftor–ivacaftor was observed due to severe respiratory adverse effects. Moreover, this dual therapy has a more favorable medications interaction profile. A prospective observational single-center trial is recruiting F508del homozygous patients to observe the effect of changing from lumacaftor–ivacaftor to tezacaftor–ivacaftor in order to ameliorate the safety profile (TRANSITION study; ClinicalTrials.gov identifier: NCT03445793). Finally, the introduction of triple therapy with elexacaftor–tezacaftor–ivacaftor is expected to lead to meaningful improvements in the lives of individuals with CF homozygous or heterozygous for the F508del mutation, encompassing almost the totality of this population. It is anticipated that in the future CF will no longer be the most common lethal autosomal recessive disorder in Caucasian individuals, but a chronic disease with a normal life expectancy.
C syndrome - what do we know and what could the future hold?
Published in Expert Opinion on Orphan Drugs, 2019
Roser Urreizti, Daniel Grinberg, Susanna Balcells
Unlike the relatively genetically homogeneous BOS syndrome, OCS appears to be an extremely heterogeneous entity, and somehow, a ‘private syndrome’ for each patient, as first postulated by Opitz et al [1]. It is evident now that there is no common genetic cause for OCS and in fact, some authors have declared it ‘extinct’ [54]. It is clear that it cannot be considered an ‘autosomal recessive disorder’ any more, as other inheritance patterns have been observed, mainly the de novo dominant pattern. This has to be taken into account during genetic counseling as the risk of recurrence is unknown until a molecular diagnosis is achieved. In our opinion, OCS still represents a useful clinical description that summarizes a constellation of symptoms helping clinicians and geneticists to narrow the clinical spectrum of the patient, helping in the difficult task of the diagnosis of severe neurodevelopmental disorders (NDD). Nowadays, whole exome sequencing (WES) is a powerful tool that will allow to identify the molecular basis of most (if not all) of the cases initially diagnosed with the OCS phenotype, as has been achieved in the 3 last cases previously mentioned, and thus, to re-diagnose each patient according with the particular molecular cause of the disease. The OCS phenotype also helps to highlight their particularities, as the thick palatal and alveolar ridges or the multiple dislocations in the MAGEL2 patient and the trigonocephaly in the FOXP1 patient diagnosed by us. Finally, the OCS clinical ‘label’ helps also the patients and their families to navigate during the diagnosis odyssey that usually represents their early lives, giving the families the solace of a name to an unknown condition, in contrast with the ‘unknown’ label that is usually extremely stressful for these families.