Clinical manifestations of the Mmalton alpha-1 antitrypsin deficiency variant

Gonçálves, Juan Marco Figueira; Bugallo, Francisco Martínez; Díaz-Pérez, David; Martinez, Maria Dolores Martin; García‐Talavera, Ignacio; Perez, R.

doi:10.1016/j.rppnen.2017.11.004

Cited by 9 publications

(6 citation statements)

References 6 publications

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“…73 So far, only a few studies performed a clinical evaluation of M Malton carriers, homozygous and heterozygous, confirming the association of p.Phe52del with both pulmonary and hepatic diseases. [76][77][78] Interestingly, one of those studies reports a case of end-stage liver disease in the presence of a non-deficiency allele, in an M3M Malton genotype, suggesting a high pathogenicity and heteropolymerization potential of p.Phe52del variant. 53,79 According to a recent work, M Malton granules found in the liver of AATD patients contain calcium and are mineralized.…”

Section: The S Allele and The Pglu264val Mutationmentioning

confidence: 99%

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Seixas

Marques

2021

TACG

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Alpha-1-Antitrypsin deficiency (AATD), caused by SERPINA1 mutations, is one of the most prevalent Mendelian disorders among individuals of European descend. However, this condition, which is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults, remains frequently underdiagnosed. AATD clinical manifestations are often correlated with two pathogenic variants, the Z allele (p. Glu342Lys) and the S allele (p.Glu264Val), which can be combined in severe ZZ or moderate SZ risk genotypes. Yet, screenings of AATD cases and large sequencing efforts carried out in both control and disease populations are disclosing outstanding numbers of rare SERPINA1 variants (>500), including many pathogenic and other likely deleterious mutations. Generally speaking, pathogenic variants can be subdivided into either loss-or gain-of-function according to their pathophysiological effects. In AATD, the loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT. This phenomenon can result from the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even from a modified inhibitory activity (dysfunctional alleles). On the other hand, the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses (deficiency alleles). Less frequently, the gain-of-function is related to a modified protease affinity (dysfunctional alleles). Here, we revisit SERPINA1 mutation spectrum, its origins and population history with a greater emphasis on variants fitting the aforementioned processes of AATD pathogenesis. Those were selected based on their clinical significance and wider geographic distribution. Moreover, we also provide some directions for future studies of AATD clinically heterogeneity and comprehensive diagnosis.

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Section: The S Allele and The Pglu264val Mutationmentioning

confidence: 99%

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Seixas

Marques

2021

TACG

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“…Moreover, in 229 AATD patients and relatives registered at the Central Hospital of Funchal (Madeira) there were a high number with the genotype PI*MMalton ( n = 60, 26%), as well as three members of a family with a new null genotype, called Q0Santana [8]. Finally, at the University Hospital of Tenerife a retrospective analysis carried out on samples from 325 subjects referred for clinical suspicion of AATD, various uncommon genotypes, including several Mmalton, Mpalermo, QOcardiff, QOamersfoort, and other poorly labelled genotypes, were found.…”

Section: Resultsmentioning

confidence: 99%

“…A bibliographic search was carried out in MEDLINE, Embase (through Ovid), and Google Scholar, until December 2023, looking for studies on prevalence of AATD in the general population and in screening of people clinically suspected of being affected by AATD in Macaronesia, selecting studies published in journals reviewed by peers in order to create a database with reliable results. With the keywords “Alpha-1 antitrypsin deficiency” and the name of each archipelago, in English, and some articles cited in the bibliography of those selected, 16 articles were compiled: 2 on Madeira [7, 8], 13 on the Canary Islands [9‒21], and 1 on Cape Verde [22]. None was found about the Azores.…”

Section: Methodsmentioning

confidence: 99%

Genetic Epidemiology of Alpha-1 Antitrypsin Deficiency in Macaronesia

Blanco,

Miravitlles

2024

Respiration

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Introduction: The prevalence of alpha-1 antitrypsin deficiency (AATD) in Macaronesia (i.e., Azores, Madeira, Canary Islands and Cape Verde archipelagos) is poorly known. Our goal is to update it by selecting the most reliable available articles. Method: Literature search using Medline, EMBASE (via Ovid) and Google Scholar, until December 2023, for studies on prevalence of AATD in the general population and in screenings, published in peer-reviewed journals. Results: Three studies carried out in the general population of Madeira, La Palma and Cape Verde, and three screenings carried out in La Palma (2) and Gran Canaria (1) were selected. The frequencies of PI*S in the general population showed an ascending gradient, from South to North, with values (per thousand) of 35 in Cape Verde, 82 in La Palma and 180 in Madeira. The PI*Z frequencies showed this same gradient, with values of 2 x1,000 in Cape Verde, 21 in La Palma and 25 in Madeira. Screenings detected high percentages of defective alleles, including several rare and null alleles, some unique to these islands. Conclusion: The frequencies of PI*S and PI*Z in Madeira are comparable to the highest in the world. Those of the Canary Islands are similar to those of the peninsular population of Spain, and contrast with the low rates of Cape Verde. Screenings detected high numbers of deficient alleles. These results support the systematic investigation of AATD in clinically suspected patients and in relatives of index cases, to reduce underdiagnosis and apply early preventive and therapeutic measures in those affected.

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“…These mutations are characterized by conformational abnormalities that result in polymerized/aggregated insoluble forms of AAT that accumulate in the endoplasmic reticulum of hepatocytes. Therefore, all three variants meet the requirements for endoplasmic reticulum storage diseases and conformational diseases [ 34 , 35 ]. Interestingly, the c.514G > A additional mutation of the PI*M nichinan does not contribute to AATD [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

et al. 2023

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Background Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. Methods This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. Results There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. Conclusions The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.

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Clinical manifestations of the Mmalton alpha-1 antitrypsin deficiency variant

Cited by 9 publications

References 6 publications

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Genetic Epidemiology of Alpha-1 Antitrypsin Deficiency in Macaronesia

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network

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