Panniculitis as main clinical manifestation of alpha‐1 antitrypsin deficiency revealing a SerpinA1 gene mutation

2020 ◽  
Vol 61 (4) ◽  
Author(s):  
Beatrice Martinez Zugaib Abdalla ◽  
Paulo Ricardo Criado
Keyword(s):  
Gene Mutation ◽  
Clinical Manifestation ◽  
Serpina1 Gene ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin ◽  
Main Clinical Manifestation

Cluster Headache and Alpha 1-antitrypsin Deficiency

Cephalalgia ◽  
2009 ◽  
Vol 30 (1) ◽  
pp. 113-117 ◽  
Author(s):  
O Summ ◽  
N Gregor ◽  
M Marziniak ◽  
I Gralow ◽  
IW Husstedt ◽  
...  
Keyword(s):  
Cluster Headache ◽  
Sleep Apnoea ◽  
Primary Headaches ◽  
Wild Type ◽  
Attack Frequency ◽  
Serpina1 Gene ◽  
Significant Difference ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

Little is known about the pathophysiology of cluster headache (CH), one of the most debilitating primary headaches. Interestingly, associations of lung affecting diseases or lifestyle habits such as smoking and sleep apnoea syndrome and CH have been described. Certain genotypes for alpha 1-antitrypsin (α1-AT) are considered risk factors for emphysema. Our aim was to investigate possible associations between common genotypes of the SERPINA1 gene and CH. Our study included 55 CH patients and 55 controls. α1-AT levels in serum and the genotype were analysed. Patients CH characteristics were documented. We could not detect any association between CH and a genotype that does not match the homozygous wild type for α1-AT. Interestingly, there is a significant difference of CH attack frequency in patients who are heterozygous or homozygous M allele carriers. We conclude that the presence of an S or Z allele is associated with higher attack frequency in CH.

scholarly journals Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

2021 ◽  
Author(s):  
Deniz Kent ◽  
Soon Seng Ng ◽  
Payam Khoshkenar ◽  
Adam M. Syanda ◽  
Li Chao Zheng ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Kinase Inhibitors ◽  
Fibrotic Liver ◽  
Serpina1 Gene ◽  
Antitrypsin Deficiency ◽  
Threatening Condition ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Lrrk2 Kinase ◽  
Alpha 1 Antitrypsin ◽  
Fibrotic Liver Disease

Alpha-1 antitrypsin deficiency is a life-threatening condition caused by inheritance of the SERPINA1 gene Z variant. This single base pair mutation leads to protein misfolding, ER entrapment and gain of toxic function. Despite the significant unmet medical need presented by this disorder, there remain no approved medicines and the only curative option is liver transplantation. We hypothesized that an unbiased screen of human hepatocytes harbouring the Z mutation (ATZ) using small molecules targeted against protein degradation pathways would uncover novel biological insights of therapeutic relevance. Here we report the results of that screen performed in a patient-derived iPSC model of ATZ. Starting from 1,041 compounds we identified 14 targets capable of reducing polymer burden, including Leucine-rich repeat kinase-2 (LRRK2), a well-studied target in Parkinsons. Genetic deletion of LRRK2 in ATZ mice reduced polymers and associated fibrotic liver disease leading us to test a library of commercially available LRRK2 kinase inhibitors in both patient iPSC and CHO cell models. One of the molecules tested, CZC-25146, reduced polymer load, increased normal AAT secretion and reduced inflammatory cytokines with pharmacokinetic properties supporting its potential use for treating liver diseases. We therefore tested CZC-25146 in the ATZ mouse model and confirmed its efficacy for polymer reduction without signs of toxicity. Mechanistically, in both human and mouse models, our data show CZC-25146 inhibits LRRK2 kinase activity and induces autophagy. Cumulatively, these findings support the use of CZC-25146 and LRRK2 inhibitors in general in hepatic proteopathy disease research and as potential new treatment approaches for patients.

scholarly journals Systemic modified messenger RNA for replacement therapy in alpha 1-antitrypsin deficiency

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ahmad Karadagi ◽  
Alex G. Cavedon ◽  
Helen Zemack ◽  
Greg Nowak ◽  
Marianne E. Eybye ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Hepatic Uptake ◽  
Human Hepatocytes ◽  
Systemic Delivery ◽  
Primary Human Hepatocytes ◽  
Inhibitory Function ◽  
Serpina1 Gene ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

AbstractAlpha 1-antitrypsin (AAT) deficiency arises from an inherited mutation in the SERPINA1 gene. The disease causes damage in the liver where the majority of the AAT protein is produced. Lack of functioning circulating AAT protein also causes uninhibited elastolytic activity in the lungs leading to AAT deficiency-related emphysema. The only therapy apart from liver transplantation is augmentation with human AAT protein pooled from sera, which is only reserved for patients with advanced lung disease caused by severe AAT deficiency. We tested modified mRNA encoding human AAT in primary human hepatocytes in culture, including hepatocytes from AAT deficient patients. Both expression and functional activity were investigated. Secreted AAT protein increased from 1,14 to 3,43 µg/ml in media from primary human hepatocytes following mRNA treatment as investigated by ELISA and western blot. The translated protein showed activity and protease inhibitory function as measured by elastase activity assay. Also, mRNA formulation in lipid nanoparticles was assessed for systemic delivery in both wild type mice and the NSG-PiZ transgenic mouse model of AAT deficiency. Systemic intravenous delivery of modified mRNA led to hepatic uptake and translation into a functioning protein in mice. These data support the use of systemic mRNA therapy as a potential treatment for AAT deficiency.

scholarly journals Alternative transcripts of the SERPINA1 gene in alpha-1 antitrypsin deficiency

2015 ◽  
Vol 13 (1) ◽  
Author(s):  
Nerea Matamala ◽  
Maria Teresa Martínez ◽  
Beatriz Lara ◽  
Laura Pérez ◽  
Irene Vázquez ◽  
...  
Keyword(s):  
Alternative Transcripts ◽  
Serpina1 Gene ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

scholarly journals Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil

2016 ◽  
Vol 42 (5) ◽  
pp. 311-316 ◽  
Author(s):  
Rodrigo Russo ◽  
Laura Russo Zillmer ◽  
Oliver Augusto Nascimento ◽  
Beatriz Manzano ◽  
Ivan Teruaki Ivanaga ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Cross Sectional Study ◽  
Genotype Distribution ◽  
Cross Sectional ◽  
Serpina1 Gene ◽  
Copd Patients ◽  
Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin Deficiency ◽  
Alpha 1 Antitrypsin

ABSTRACT Objective: To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. Methods: This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of < 113 mg/dL underwent genotyping. In case of conflicting results, SERPINA1 gene sequencing was performed. Results: Of the 926 COPD patients studied, 85 had DBS AAT levels ≤ 2.64 mg/dL, and 24 (2.6% of the study sample) had serum AAT levels of < 113 mg/dL. Genotype distribution in this subset of 24 patients was as follows: PI*MS, in 3 (12.5%); PI*MZ, in 13 (54.2%); PI*SZ, in 1 (4.2%); PI*SS, in 1 (4.2%); and PI*ZZ, in 6 (25.0%). In the sample as a whole, the overall prevalence of AATD was 2.8% and the prevalence of the PI*ZZ genotype (severe AATD) was 0.8% Conclusions: The prevalence of AATD in COPD patients in Brazil is similar to that found in most countries and reinforces the recommendation that AAT levels be measured in all COPD patients.

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