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An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome.

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An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome.

Pediatr Rheumatol Online J. 2019 May 22;17(1):25

Authors: Arduini A, Marasco E, Marucci G, Pardeo M, Insalaco A, Caiello I, Moneta GM, Prencipe G, De Benedetti F, Bracaglia C

Abstract
BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition that presents with fever, rash and arthritis. At onset systemic features are predominant and the diagnosis may be a challenge. Secondary hemophagocytic lymphohistiocytosis (sHLH) forms may be associated with different disorders, including rheumatic diseases, and this form is called macrophage activation syndrome (MAS). CXCL9 levels, a chemokine induced by IFNγ, are significantly elevated in patients with sHLH or MAS and are correlated with laboratory features of disease activity. High levels of IL-18 have been reported in patients with MAS during sJIA, as well as in some patients with sHLH and IL-18 is indeed known to induce IFNγ production.
FINDINGS: We report a patient with a clinical presentation highly suggestive for systemic juvenile idiopathic arthritis (sJIA) onset complicated by MAS, and was later diagnosed with purine nucleoside phosphorylase (PNP)-deficiency with HLH. Some unusual features appeared when HLH was controlled and further investigations provided the correct diagnosis. Serum CXCL9 and IL-18 levels were found markedly elevated at disease onset, during the active phase of MAS and decreased progressively during the course.
CONCLUSION: The reported case underlines the potential difficulties in discriminating sJIA from other causes of systemic inflammation. Furthermore, this supports the notion that especially in young children with a sJIA-like disease other mimicking conditions should be actively sought for. CXCL9 and IL-18 levels suggested that patients with PNP-deficiency may have a subclinical activation of the IFNγ pathway and indeed they are predisposed to develop sHLH.

PMID: 31118063 [PubMed – indexed for MEDLINE]

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Past and Present of Eye Movement Abnormalities in Ataxia-Telangiectasia.

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Past and Present of Eye Movement Abnormalities in Ataxia-Telangiectasia.

Cerebellum. 2019 Jun;18(3):556-564

Authors: Tang SY, Shaikh AG

Abstract
Ataxia-telangiectasia is the second most common autosomal recessive hereditary ataxia, with an estimated incidence of 1 in 100,000 births. Besides ataxia and ocular telangiectasias, eye movement abnormalities have long been associated with this disorder and is frequently present in almost all patients. A handful of studies have described the phenomenology of ocular motor deficits in ataxia-telangiectasia. Contemporary literature linked their physiology to cerebellar dysfunction and secondary abnormalities at the level of brainstem. These studies, while providing a proof of concept of ocular motor physiology in disease, i.e., ataxia-telangiectasia, also advanced our understanding of how the cerebellum works. Here, we will summarize the clinical abnormalities seen with ataxia-telangiectasia in each subtype of eye movements and subsequently describe the underlying pathophysiology. Finally, we will review how these deficits are linked to abnormal cerebellar function and how it allows better understanding of the cerebellar physiology.

PMID: 30523550 [PubMed – indexed for MEDLINE]

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An Update on Syndromes with a Hyper-IgE Phenotype.

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An Update on Syndromes with a Hyper-IgE Phenotype.

Immunol Allergy Clin North Am. 2019 02;39(1):49-61

Authors: Bergerson JRE, Freeman AF

Abstract
Improvement in genetic testing has allowed specific delineation of several distinct clinical causes characterized by the hyperimmunoglobulin E (IgE) phenotype of eczema, recurrent infections, and elevated serum IgE. Mutations in STAT3, DOCK8, PGM3, ERBIN, IL6ST, and CARD11 cause clinical phenotypes that can present in this manner. This article focuses on loss of function STAT3 mutations causing autosomal-dominant hyper-IgE syndrome and dedicator of cytokinesis 8 deficiency, with discussion of other more recently described diseases.

PMID: 30466772 [PubMed – indexed for MEDLINE]

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Newborn Screening for Severe Combined Immunodeficiency in the United States: Lessons Learned.

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Newborn Screening for Severe Combined Immunodeficiency in the United States: Lessons Learned.

Immunol Allergy Clin North Am. 2019 02;39(1):1-11

Authors: Dorsey MJ, Puck JM

Abstract
In the United States, significant improvement in diagnosis and outcomes for children affected with severe combined immunodeficiency has followed institution of newborn screening using an assay to measure T-cell receptor excision circles in newborn dried blood spot specimens. Key to this outcome is the avoidance of infectious complications in infants with severe combined immunodeficiency.

PMID: 30466767 [PubMed – indexed for MEDLINE]

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Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency.

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Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency.

J Clin Invest. 2019 02 01;129(2):583-597

Authors: Boisson B, Honda Y, Ajiro M, Bustamante J, Bendavid M, Gennery AR, Kawasaki Y, Ichishima J, Osawa M, Nihira H, Shiba T, Tanaka T, Chrabieh M, Bigio B, Hur H, Itan Y, Liang Y, Okada S, Izawa K, Nishikomori R, Ohara O, Heike T, Abel L, Puel A, Saito MK, Casanova JL, Hagiwara M, Yasumi T

Abstract
X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of-function and hypomorphic IKBKG (also known as NEMO) mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose 3 boys with EDA-ID died from ID. We identify the same private variant in an intron of IKBKG, IVS4+866 C>T, which was inherited from and occurred de novo in the European mother and Japanese mother, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudoexon (PE) generating a frameshift. Its leakiness accounts for NF-κB activation being impaired but not abolished in the boys’ cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell-derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the PE, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK.

PMID: 30422821 [PubMed – indexed for MEDLINE]

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Biodegradable Nanocarriers Resembling Extracellular Vesicles Deliver Genetic Material with the Highest Efficiency to Various Cell Types.

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Biodegradable Nanocarriers Resembling Extracellular Vesicles Deliver Genetic Material with the Highest Efficiency to Various Cell Types.

Small. 2019 Dec 16;:e1904880

Authors: Tarakanchikova Y, Alzubi J, Pennucci V, Follo M, Kochergin B, Muslimov A, Skovorodkin I, Vainio S, Antipina MN, Atkin V, Popov A, Meglinski I, Cathomen T, Cornu TI, Gorin DA, Sukhorukov GB, Nazarenko I

Abstract
Efficient delivery of genetic material to primary cells remains challenging. Here, efficient transfer of genetic material is presented using synthetic biodegradable nanocarriers, resembling extracellular vesicles in their biomechanical properties. This is based on two main technological achievements: generation of soft biodegradable polyelectrolyte capsules in nanosize and efficient application of the nanocapsules for co-transfer of different RNAs to tumor cell lines and primary cells, including hematopoietic progenitor cells and primary T cells. Near to 100% efficiency is reached using only 2.5 × 10-4 pmol of siRNA, and 1 × 10-3 nmol of mRNA per cell, which is several magnitude orders below the amounts reported for any of methods published so far. The data show that biodegradable nanocapsules represent a universal and highly efficient biomimetic platform for the transfer of genetic material with the utmost potential to revolutionize gene transfer technology in vitro and in vivo.

PMID: 31840408 [PubMed – as supplied by publisher]

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