Neurological findings and genetic alterations in patients with Kostmann syndrome and <i>HAX1</i> mutations

Roques, G.; Munzer, Martine; Barthez, Marie‐Anne; Beaufils, Sandrine; Beaupain, Blandine; Flood, Terry; Keren, Boris; Bellanné‐Chantelot, Christine; Donadieu, Jean

doi:10.1002/pbc.24964

Cited by 25 publications

(23 citation statements)

References 26 publications

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“…Almost all organs can present a dysfunction. Extra‐haematopoietic involvement may have a very strong impact on CN patients’ lives, such as the neurodevelopmental disorders observed in Kostmann syndrome (Roques et al , ), Shwachman‐Diamond syndrome (Kerr et al , ), and Cohen disease (Kivitie‐Kallio et al , ). Cardiac dysfunction may be very severe in Shwachman‐Diamond syndrome (Hauet et al , ) and WHIM syndrome (Badolato et al , ), and is almost always observed in Barth syndrome, leading to early death (Rigaud et al , ).…”

Section: The Phenotypes Of Congenital Neutropenia and Natural Historymentioning

confidence: 99%

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Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history

et al. 2017

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This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next-generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events.

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Section: The Phenotypes Of Congenital Neutropenia and Natural Historymentioning

confidence: 99%

“…Almost all organs can present a dysfunction. Extra-haematopoietic involvement may have a very strong impact on CN patients' lives, such as the neurodevelopmental disorders observed in Kostmann syndrome(Roques et al, 2014), Shwachman-Diamond syndrome(Kerr et al, 2010), and Cohen disease (Kivitie-KallioReview ª 2017 John Wiley & Sons Ltd…”

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Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history

et al. 2017

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“…15 Although a homozygous, 256C.T nonsense mutation in HAX1 (HAX1 R86X ) has been modeled previously using iPSCs, 16 this variant has been described in only 2 patients and lies outside of exon 2a, the region where the majority of the reported mutations reside. 4 Moreover, this variant has been linked to neurological deficits. 4,17 In addition, viralbased overexpression of wild-type (WT) HAX1 complementary DNA (cDNA) was applied to revert the granulocytic differentiation arrest compared with iPSCs derived from a healthy individual.…”

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confidence: 99%

“…4 Moreover, this variant has been linked to neurological deficits. 4,17 In addition, viralbased overexpression of wild-type (WT) HAX1 complementary DNA (cDNA) was applied to revert the granulocytic differentiation arrest compared with iPSCs derived from a healthy individual. 16 Here, we investigated iPSC-derived granulopoiesis from Kostmann patients (HAX1 W44X -iPSCs) and gene-corrected isogenic lines generated by CRISPR-Cas9 gene editing.…”

Section: /2mentioning

confidence: 99%

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

et al. 2017

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Key Points• HAX1W44X -iPSCs recapitulate Kostmann disease phenotype in vitro.• Genetic in situ correction of iPSCs reveals a dysregulated HAX1 and HCLS1-centered interaction network in Kostmann disease. nonsense mutation. Targeted correction of the HAX1 mutation using the CRISPR-Cas9 system and homologous recombination rescued neutrophil differentiation and reestablished an HAX1 and HCLS1-centered transcription network in immature myeloid progenitors, which is involved in the regulation of apoptosis, apoptotic mitochondrial changes, and myeloid differentiation. These findings made in isogenic iPSC-derived myeloid cells highlight the complex transcriptional changes underlying Kostmann disease. Thus, weshow that patient-derived HAX1 W44X

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“…If the cause of neutropenia is HAX gene mutation, neurological problems are present in 30% of the cases (epileptic seizures, learning difficulty, developmental disorder) (15,16 Tests to be ordered in neutropenic patients: one should not hurry to order tests for neutropenic patients. The clinical picture should always be directive for investigations.…”

Section: Neutrophil Reserve In the Vascular Wallmentioning

confidence: 99%

Approach to the patient with neutropenia in childhood

Çelkan

Koç

2015

Turk Pediatri Ars

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Neutrophils have an important role in host defense and acute inflammation. It is well known that susceptibility to infection increases when the neutrophil count is low. Neutropenia were classified as mild, moderate and severe according to the neutrophil counts, or acute and chronic depending on the duration of neutropenia, or congenital and acquired according to the mechanism. The patients with neutropenia are clinically different due to underlying mechanism, they have life-threatening infections or no infection may be observed. The most common cause of acquired neutropenia is viral infection, followed by drugs and autoimmune neutropenia. Congenital neutropenia are usually diagnosed by acute and life-threatening invasive bacterial and fungal infections. Immune system disorders and other systemic abnormalities may be accompanied or not. Recent years, novel single gen defects causing congenital neutropenia were defined through advanced genetic techniques. Molecular diagnosis is useful for risk stratification, choice of therapy and prognosis on follow-up. This review was prepared for pediatricians as a guide focused on approach neutropenia, which tests should be performed and when should be referred to a specialist. (Turk Pediatri Ars 2015; 50: 136-44)

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Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations

Abstract: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.

Cited by 25 publications

References 26 publications

Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history

Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

Approach to the patient with neutropenia in childhood

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