Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance

Tanner, Laura M.; Kurko, Johanna; Tringham, Maaria; Aho, Heikki; Mykkänen, Juha; Näntö‐Salonen, Kirsti; Niinikoski, Harri; Lukkarinen, Heikki

doi:10.1007/8904_2016_15

Cited by 14 publications

(12 citation statements)

References 20 publications

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“…Tanner also reported two patients diagnosed LPI with PAP who were treated with inhaled rGM‐CSF and achieved positive results 10. Our patient from case one inhaled rGM‐CSF for 1.5 years.…”

Section: Discussionsupporting

confidence: 54%

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

Zhang

Cao

2017

Pediatric Pulmonology

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Lysinuric protein intolerance (LPI) is an inherited aminoaciduria with an autosomal recessive mode of inheritance.The first two cases of sisters being diagnosed with LPI in China is contained within this report. In our cases, there were two heterozygous mutations in the SLC7A7 gene of the two sisters: deletion of c.1387: del C and IVS4+1C>T. One patient was treated with inhaled rGM‐CSF for 1.5 years at 5 μg/kg two times a day. Her condition is improving with no side effects.

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Section: Discussionsupporting

confidence: 54%

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

Zhang

Cao

2017

Pediatric Pulmonology

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“…Lung histology revealing collapsed alveoli with surfactant accumulations is the gold standard for diagnosis in experimental models of PAP. Slc7a7 −/− developed PAP in ~30% of the animals (i.e., 7 out of the 21 mice studied), a similar percentage as in LPI patients, which ranges from 10–60% in the different LPI cohorts [39,40]. Thus, PAS-positive material was found inside alveoli and was further confirmed by immunohistochemistry against surfactant protein B (SP-B, Figure 4).…”

Section: Resultsmentioning

confidence: 65%

Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

Bodoy

Sotillo

Guarch

et al. 2019

IJMS

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Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7−/−). The Slc7a7−/− model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7−/− mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7−/− model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.

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“…Treatment of the immunological and bone marrow complications, including clinical hemophagocytic lymphohistiocytosis, is still experimental, but immunosuppressive drugs have had good responses in individual cases ( Bader-Meunier et al, 2000 ). Bronchoalveolar lavage and steroid therapy have been effective in some alveolar proteinosis cases ( Parto et al, 1994 ), and immunostimulating adjuvant therapy has been tried to mitigate the immunological abnormalities ( Tanner et al, 2017 ). The first in vivo model for LPI, a tamoxifen-inducible Slc7a7 KO mouse that recapitulates the human disease phenotype and responds to citrulline treatment, has emerged as a promising tool for designing future therapies, especially for the immunological complications of the disease ( Bodoy et al, 2019 ).…”

Section: The Fdhmentioning

confidence: 99%

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Uusimaa

Kettunen

Varilo

et al. 2022

Disease Models &Amp; Mechanisms

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Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

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Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance

Cited by 14 publications

References 20 publications

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

The Finnish genetic heritage in 2022 – from diagnosis to translational research

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