Recent advances in understanding the pathogenesis and management of reticular dysgenesis

Hoenig, Manfred; Pannicke, Ulrich; Gaspar, H. Bobby; Schwarz, Klaus

doi:10.1111/bjh.15045

Cited by 23 publications

(36 citation statements)

References 51 publications

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“…A variety of mutations have been isolated in RD patients, ranging from missense and nonsense mutations affecting single amino acid positions or the AK2 pre-mRNA splicing, to a range of deletions (1,2,4,5,28,(59)(60)(61). Although the relative impact from the different genomic mutations has not been systematically evaluated, in most of the cases the mutations appear to induce a strong reduction of the AK2 protein level, without significantly affecting the mRNA levels(1, 2, 5, 62).…”

Section: Discussionmentioning

confidence: 99%

“…Reticular dysgenesis is a rare hematological disorder caused by mutations in the adenylate kinase 2 (AK2) gene (1,2). Although at least one RD patient with skeletal defects has been reported so far (28), the only non-hematological clinical feature required for the diagnosis of RD is the sensorineural deafness/hearing disability (4,5).…”

Section: The Zebrafish Adenylate Kinase 2 Gene Is Expressed In Sensormentioning

confidence: 99%

“…The immunodeficiencies associated with strong neutropenia leads these patients to recurrent severe infections and premature death within the first weeks or months of life. For these patients, a hematopoietic stem cell transplantation (HSCT) represents the only available treatment, but, because of the severity of the disease, pre-conditioning is necessary in order to increase the chances of engraftment of the donor stem cells (5). However, the HSCT does not improve the non-hematological defects such as the hearing loss, which has a huge impact on the cognitive functioning and quality of life of these children (6,7).…”

Section: Introductionmentioning

confidence: 99%

“…Although most of the work linked the AK2 role to its bio-energetic activity, other evidence highlighted the presence of alternative functions, partially unrelated to its enzymatic activity and/or the mitochondrial localization (5). AK2 protein has been found to associate with dual-specificity phosphatase 26 (DUSP26), resulting in the suppression of cell proliferation by FADD dephosphorylation (12).…”

Section: Introductionmentioning

confidence: 99%

“…hearing and vestibular functions) are fully conserved (22). Moreover, zebrafish possess another 5 mechanosensory system on their body surface called the lateral line, which provides feedback information about water flow along the body of the fish (23)(24)(25). The lateral line is composed of a network of several small sense organs, the neuromasts, distributed over the zebrafish body in a specific pattern (23).…”

Section: Introductionmentioning

confidence: 99%

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A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress

Rissone

Jimenez

Bishop

et al. 2019

Preprint

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Mutations in the gene AK2 are responsible for Reticular Dysgenesis (RD), a rare and severe form of primary immunodeficiency in children. RD patients have a severely shortened life expectancy and without treatment die a few weeks after birth. The only available therapeutic option for RD is bone marrow transplantation. To gain insight into the pathophysiology of RD, we previously created zebrafish models for an AK2 deficiency. One of the clinical features of RD is hearing loss, but its pathology and causes have not been determined. In adult mammals, sensory hair cells of the inner ear do not regenerate; however, their regeneration has been observed in several nonmammalian vertebrates, including zebrafish. Therefore, we use our RD zebrafish models to determine if AK2 deficiency affects sensory organ development and/or hair cell regeneration. Our studies indicated that AK2 is required for the correct development, survival and regeneration of sensory hair cells. Interestingly, AK2 deficiency induces the expression of several oxidative stress markers and it triggers an increased level of cell death in the hair cells. Finally, we show that glutathione treatment can partially rescue hair cell development in the sensory organs in our RD models, pointing to the potential use of antioxidants as a supportive therapeutic modality for RD patients, not only to increase their chances of survival, but to prevent or ameliorate their sensorineural hearing deficits.

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Section: Discussionmentioning

confidence: 99%

Section: The Zebrafish Adenylate Kinase 2 Gene Is Expressed In Sensormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress

Rissone

Jimenez

Bishop

et al. 2019

Preprint

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Neutropenia in the age of genetic testing: Advances and challenges

2019

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Identification of genetic causes of neutropenia informs precision medicine approaches to medical management and treatment. Accurate diagnosis of genetic neutropenia disorders informs treatment options, enables risk stratification, cancer surveillance, and attention to associated medical complications. The rapidly expanding genetic testing options for the evaluation of neutropenia have led to exciting advances but also new challenges. This review provides a practical guide to germline genetic testing for neutropenia.

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Organ‐based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians

Mohammadi

Yadegar

Mardani

et al. 2023

Immunity Inflam & Disease

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Inborn errors of immunity (IEI) comprise a group of about 490 genetic disorders that lead to aberrant functioning or the development of distinct immune system components. So far, a broad spectrum of IEI‐related manifestations has been noted in the literature. Due to overlapping signs and symptoms of IEI, physicians face challenges in appropriately diagnosing and managing affected individuals. The last decade has witnesses improving in the molecular diagnosis of IEI patients. As a result, it can be the mainstay of diagnostic algorithms, prognosis, and possibly therapeutic interventions in patients with IEI. Furthermore, reviewing IEI clinical complications demonstrates that the manifestations and severity of the symptoms depend on the involved gene that causes the disease and its penetrance. Although several diagnostic criteria have been used for IEI, not every patient can be explored in the same way. As a result of the failure to consider IEI diagnosis and the variety of diagnostic capabilities and laboratory facilities in different regions, undiagnosed patients are increasing. On the other hand, early diagnosis is an almost essential element in improving the quality of life in IEI patients. Since there is no appropriate guideline for IEI diagnosis in different organs, focusing on the clues in the patient's chief complaint and physical exams can help physicians narrow their differential diagnosis. This article aims to provide a practical guide for IEI diagnosis based on the involved organ. We hope to assist clinicians in keeping IEI diagnosis in mind and minimizing possible related complications due to delayed diagnosis.

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Recent advances in understanding the pathogenesis and management of reticular dysgenesis

Cited by 23 publications

References 51 publications

A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress

A model for reticular dysgenesis shows impaired sensory organ development and hair cell regeneration linked to cellular stress

Neutropenia in the age of genetic testing: Advances and challenges

Organ‐based clues for diagnosis of inborn errors of immunity: A practical guide for clinicians

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