Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

Abstract Background Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1 -deficiency is an exceedingly rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features indicating hemophagocytosis lymphohistiocytosis. Clinical findings have included asplenia, nephritis, hepatitis, and evidence of vasculitis. Pulmonary features and evaluation of the immune response have been limited. Results Here, we present the fifth reported case in literature of a young boy who remarkably also presented with chronic respiratory failure due to nonspecific interstitial pneumonia in addition to infection-triggered recurrent hyperinflammatory flares notable for hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

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Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

10.21203/rs.3.rs-17045/v1 ◽

2020 ◽

Author(s):

Alice S Chau ◽

Bonnie L Cole ◽

Jason S Debley ◽

Kabita Nanda ◽

Aaron BI Rosen ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Heme Oxygenase ◽

Macrophage Activation ◽

Autosomal Recessive Disorder ◽

Clinical Findings ◽

Heme Oxygenase 1 ◽

Compound Heterozygous ◽

Biliverdin Reductase ◽

Frame Shift

Abstract Background: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited.Case presentation: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636+2 T>A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow that can mimic systemic-onset juvenile arthritis.

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Heme oxygenase-1 deficiency presenting with interstitial lung disease and hemophagocytic flares

Pediatric Rheumatology ◽

10.1186/s12969-020-00474-1 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Alice S. Chau ◽

Bonnie L. Cole ◽

Jason S. Debley ◽

Kabita Nanda ◽

Aaron B. I. Rosen ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Heme Oxygenase ◽

Macrophage Activation ◽

Autosomal Recessive Disorder ◽

Clinical Findings ◽

Heme Oxygenase 1 ◽

Compound Heterozygous ◽

Biliverdin Reductase ◽

Frame Shift

Abstract Background Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited. Case presentation We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. Conclusions Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.

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Heme oxygenase-1 in patients with interstitial lung disease: A review of the clinical evidence

The American Journal of the Medical Sciences ◽

10.1016/j.amjms.2021.02.009 ◽

2021 ◽

Author(s):

Yu Hara ◽

Kentaro Nakashima ◽

Ryo Nagasawa ◽

Kota Murohashi ◽

Yoichi Tagami ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Heme Oxygenase ◽

Clinical Evidence ◽

Heme Oxygenase 1

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Serum heme oxygenase-1 measurement is useful for evaluating disease activity and outcomes in patients with acute respiratory distress syndrome and acute exacerbation of interstitial lung disease

BMC Pulmonary Medicine ◽

10.1186/s12890-020-01341-1 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ryo Nagasawa ◽

Yu Hara ◽

Kota Murohashi ◽

Ayako Aoki ◽

Nobuaki Kobayashi ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Respiratory Distress Syndrome ◽

Interstitial Lung Disease ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Lung Disease ◽

Acute Exacerbation ◽

Heme Oxygenase ◽

Distress Syndrome ◽

Heme Oxygenase 1

Abstract Background Oxidative stress plays an important role in acute lung injury, which is associated with the development and progression of acute respiratory failure. Here, we investigated whether the degree of oxidative stress as indicated by serum heme oxygenase-1 (HO-1) is clinically useful for predicting prognosis among the patients with acute respiratory distress syndrome (ARDS) and acute exacerbation of interstitial lung disease (AE-ILD). Methods Serum HO-1 levels of newly diagnosed or untreated ARDS and AE-ILD patients were measured at diagnosis. Relationships between serum HO-1 and other clinical parameters and 1 and 3-month mortality were evaluated. Results Fifty-five patients including 22 of ARDS and 33 of AE-ILD were assessed. Serum HO-1 level at diagnosis was significantly higher in ARDS patients than AE-ILD patients (87.8 ± 60.0 ng/mL vs. 52.5 ± 36.3 ng/mL, P < 0.001). Serum HO-1 correlated with serum total bilirubin (R = 0.454, P < 0.001) and serum LDH (R = 0.500, P < 0.001). In both patients with ARDS and AE-ILDs, serum HO-1 level tended to decrease from diagnosis to 2 weeks after diagnosis, however, did not normalized. Composite parameters including serum HO-1, age, sex, and partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F) ratio for prediction of 3-month mortality showed a higher AUC (ARDS: 0.925, AE-ILDs: 0.892) than did AUCs of a single predictor or combination of two or three predictors. Conclusion Oxidative stress assessed by serum HO-1 is persistently high among enrolled patients for 2 weeks after diagnosis. Also, serum HO-1 levels at the diagnosis combined with age, sex, and P/F ratio could be clinically useful for predicting 3-month mortality in both ARDS and AE-ILD patients.

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Serum heme oxygenase-1 measurement is useful for evaluating disease activity and outcomes in patients with acute respiratory distress syndrome and acute exacerbation of interstitial lung disease

10.21203/rs.3.rs-39746/v2 ◽

2020 ◽

Author(s):

Ryo Nagasawa ◽

Yu Hara ◽

Kota Murohashi ◽

Ayako Aoki ◽

Nobuaki Kobayashi ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Respiratory Distress Syndrome ◽

Interstitial Lung Disease ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Lung Disease ◽

Acute Exacerbation ◽

Heme Oxygenase ◽

Distress Syndrome ◽

Heme Oxygenase 1

Abstract Background: Oxidative stress plays an important role in acute lung injury, which is associated with the development and progression of acute respiratory failure. Here, we investigated whether the degree of oxidative stress as indicated by serum heme oxygenase-1 (HO-1) is clinically useful for predicting prognosis among the patients with acute respiratory distress syndrome (ARDS) and acute exacerbation of interstitial lung disease (AE-ILDs).Methods: Serum HO-1 levels of newly diagnosed or untreated ARDS and AE-ILD patients were measured at diagnosis. Relationships between serum HO-1 and other clinical parameters and 1 and 3-month mortality were evaluated. Results: Fifty-five patients including 22 of ARDS and 33 of AE-ILD were assessed. Serum HO-1 level at diagnosis was significantly higher in ARDS patients than AE-ILD patients (87.8 ± 60.0 ng/mL vs. 52.5 ± 36.3 ng/mL, P < 0.001). Serum HO-1 correlated with serum total bilirubin (R = 0.454, P < 0.001) and serum LDH (R = 0.500, P < 0.001). In both patients with ARDS and AE-ILDs, serum HO-1 level tended to decrease from diagnosis to 2 weeks after diagnosis, however, did not normalized. Composite parameters including serum HO-1, age, sex, and partial pressure of oxygen in arterial blood/fraction of inspired oxygen (P/F) ratio for prediction of 3-month mortality showed a higher AUC (ARDS: 0.925, AE-ILDs: 0.892) than did AUCs of a single predictor or combination of two or three predictors. Conclusion: Oxidative stress assessed by serum HO-1 is persistently high among enrolled patients for 2 weeks after diagnosis. Also, serum HO-1 levels at the diagnosis combined with age, sex, and P/F ratio could be clinically useful for predicting 3-month mortality in both ARDS and AE-ILD patients.

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Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

International Journal of Molecular Sciences ◽

10.3390/ijms22073625 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3625

Author(s):

Filomena Napolitano ◽

Giorgia Bruno ◽

Chiara Terracciano ◽

Giuseppina Franzese ◽

Nicole Piera Palomba ◽

...

Keyword(s):

Pompe Disease ◽

Rare Variants ◽

Clinical Symptoms ◽

Late Onset ◽

Respiratory Muscles ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Enzyme Replacement ◽

Whole Exome ◽

Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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Products of heme oxygenase and their potential therapeutic applications

AJP Renal Physiology ◽

10.1152/ajprenal.00220.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. F563-F571 ◽

Cited By ~ 148

Author(s):

Kristin A. Kirkby ◽

Christopher A. Adin

Keyword(s):

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Inexpensive Method ◽

Waste Products ◽

Biliverdin Reductase ◽

Therapeutic Applications ◽

Beneficial Effects ◽

Tissue Protection ◽

Organ Systems ◽

Dose Dependent

Heme oxygenase 1 (HO-1) is induced in response to cellular stress and is responsible for converting the prooxidant heme molecule into equimolar quantities of biliverdin (BV), carbon monoxide (CO), and iron. BV is then converted to bilirubin (BR) by the enzyme biliverdin reductase. Experimental evidence suggests that induction of the HO system is an important endogenous mechanism for cytoprotection and that the downstream products of heme degradation, CO, BR, and BV, may mediate these powerful beneficial effects. These molecules, which were once considered to be toxic metabolic waste products, have recently been shown to have dose-dependent vasodilatory, antioxidant, and anti-inflammatory properties that are particularly desirable for tissue protection during organ transplantation. In fact, recent work has demonstrated that administration of exogenous CO, BR, or BV may offer a simple, inexpensive method to substitute for the cytoprotective effects of HO-1 in a variety of clinically applicable models. This review will attempt to summarize the relevant biochemical and cytoprotective properties of CO, BR, and BV, and will discuss emerging studies involving the therapeutic applications of these molecules in the kidney and other organ systems.

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Novel Pathogenic Mutations of FERMT1 in two Chinese Kindler Syndrome Families

10.21203/rs.3.rs-354474/v1 ◽

2021 ◽

Author(s):

Min Li ◽

Weisheng Li ◽

Dan Zhu ◽

Likui Lu ◽

Jingliu Liu ◽

...

Keyword(s):

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Loss Of Function ◽

Nonsense Mutations ◽

Chinese Families ◽

Kindler Syndrome ◽

Pathogenic Mutations ◽

Whole Exome ◽

Palmoplantar Hyperkeratosis ◽

Cigarette Paper

Abstract Background: Kindler syndrome (KNDLRS) is a very rare autosomal recessive disorder characterized by bullous poikiloderma with photosensitivity. Loss-of-function mutations in FERMT1, which located on chromosome 20p12.3, were responsible for KNDLRS. Numerous mutations in FERMT1 have been reported to be associated with KNDLRS. Results: The present study reported two Chinese KNDLRS families, and affected individuals from both families presented with poikiloderma, palmoplantar hyperkeratosis, and diffuse cigarette paper like atrophy on hands. Skin biopsy of the proband from family 2 showed atrophy of epidermis, hyperkeratosis, dilated blood vessels in upper dermis, and microbubbles at the dermis and epidermis junction. Medical Whole Exome Sequencing V4 combined with Sanger sequencing revealed mutations in FERMT1 with affected individuals. Compound heterozygous nonsense mutations (c.193C>T, c.277C>T) were found with family 1, and a homozygous frameshift mutation (c.220delC) was observed in family 2. According to the clinical features and genetic analysis, KNDLRS was diagnosed in two Chinese families. Conclusions: This study revealed two novel pathogenic mutations in FERMT1 that caused KNDLRS and briefly summarized all pathogenic mutations in FERMT1 that have been documented via the PubMed.

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