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2023

NOELMA DE SOUSA FÉLIX 
 

 

 

TERAPIA DE REPOSIÇÃO ENZIMÁTICA PARA DOENÇA DE 

ANDERSON-FABRY: revisão sistemática de ensaios clínicos 

randomizados 

 



   

   
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

São José dos Campos 

2023 

NOELMA DE SOUSA FÉLIX 
 

 

TERAPIA DE REPOSIÇÃO ENZIMÁTICA PARA DOENÇA DE ANDERSON- 

FABRY: revisão sistemática de ensaios clínicos randomizados 

 

Dissertação apresentada ao Instituto de Ciência e Tecnologia, Universidade Estadual 

Paulista (Unesp), Campus de São José dos Campos, como parte dos requisitos para 

obtenção do título de MESTRA, pelo Programa de Pós-Graduação em CIÊNCIAS 

APLICADAS À SAÚDE BUCAL.  

Área: Biomateriais. Linha de pesquisa: Biomateriais para prevenção e tratamento 

de infecções.  

 

Orientadora: Profa. Dra. Alessandra Buhler Borges  
 



Instituto de Ciência e Tecnologia [internet]. Normalização de tese e dissertação
[acesso em 2024]. Disponível em http://www.ict.unesp.br/biblioteca/normalizacao

Apresentação gráfica e normalização de acordo com as normas estabelecidas pelo Serviço de
Normalização de Documentos da Seção Técnica de Referência e Atendimento ao Usuário e
Documentação (STRAUD).

Ficha catalográfica elaborada pela Biblioteca Prof. Achille Bassi e Seção Técnica de Informática, ICMC/USP 
 com adaptações - STATI, STRAUD e DTI do ICT/UNESP. 

 Renata Aparecida Couto Martins CRB-8/8376

Félix, Noelma de Sousa
   Terapia de reposição enzimática para doença de
Anderson-Fabry: revisão sistemática de ensaios clínicos
randomizados / Noelma de Sousa Félix. - São José dos Campos : [s.n.], 2023.
   112 f. : il.

   Dissertação (Mestrado) - Pós-Graduação em Ciências Aplicadas à Saúde Bucal -
Universidade Estadual Paulista (Unesp), Instituto de Ciência e Tecnologia,
São José dos Campos, 2023.
   Orientadora: Alessandra Buhler  Borges.
   

   1. Doença de Anderson-Fabry. 2. Terapia de reposição enzimática. 3.
Revisãosistemática. 4. Ensaios clínicos randomizados. I.  Borges, Alessandra
Buhler, orient. II. Universidade Estadual Paulista (Unesp), Instituto de
Ciência e Tecnologia, São José dos Campos. III. Universidade Estadual
Paulista 'Júlio de Mesquita Filho' - Unesp. IV. Universidade Estadual
Paulista (Unesp). V. Título.



   

   
 

IMPACTO POTENCIAL DESTA PESQUISA 

 

Uma revisão sistemática é necessária para estabelecer a base de evidências para a 

eficácia e segurança da TRE no tratamento da AFD. Esta revisão é de particular 

relevância, uma vez que a TRE já está disponível há quase 15 anos e uma revisão dos 

dados mais recentes pode fornecer mais orientações sobre seu uso. 

 

 

POTENTIAL IMPACT OF THIS RESEARCH 

 

A systematic review is needed to establish the evidence base for the efficacy and safety 

of TRE in the treatment of AFD. This review is particularly popular as TRE has been 

available for almost 15 years and a review of the most recent data may provide further 

guidance on its use. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



   

   
 

BANCA EXAMINADORA 

 
 

 
 
 

Alessandra Buhler Borges (Orientador)  

 Universidade Estadual Paulista (Unesp) 

 Instituto de Ciência e Tecnologia  

Campus de São José dos Campos 

 
Jose Benedito Oliveira Amorim 

 Universidade Estadual Paulista (Unesp) 

 Instituto de Ciência e Tecnologia 

 Campus de São José dos Campos 

 
Túlia de Souza Botelho 

 Universidade de São Paulo 

 Faculdade de Ciências Farmacêuticas 

Campus de São Paulo  

 
 
 

São José dos Campos, 22 de maio de 2023.  
 



   

   
 

DEDICATÓRIA  

 

Dedico à minha amiga e orientadora, Regina El Dib; cada palavra desse trabalho 

tem você, tem o seu jeito de enxergar a vida, tem a sua alegria mesmo nos momentos 

mais difíceis. Nós fizemos uma sequência de planos, eles significavam a esperança, 

e eles serão realizados. Você sempre disse que a morte não era o fim, e ela nunca 

será. Você continua aqui e eu continuo por você, horando o seu nome.  

 

Dedico ao meu pai, Raimundo Nonato Félix; obrigada por me ensinar sobre 

perseverança e esperança. A sua luta me motivou, me inspirou ao longo do caminho. 

Não poucas vezes, eu lembro das suas orações, da sua forma singela de acreditar 

que haveriam dias melhores, eu também acredito nesses dias. Você estaria orgulhoso 

da sua filha, assim como eu sempre fui e sempre serei do meu pai.  

 

Dedico à minha amiga, Maria da Conceição Albuquerque; esse momento não seria 

possível sem a sua presença, suas orações, sua fé na inabalável na minha vitória. 

Obrigada por todas as ligações, por me ouvir nos dias difíceis e também nos dias 

felizes. Você é o meu refencial de família, amizade e fé.  

 

 

 

 

 

 

 

 



   

   
 

AGRADECIMENTOS  

 

À Universidade Estadual Paulista “Júlio de Mesquita Filho” UNESP, na pessoa da 

diretora do Instituto de Ciência e Tecnologia de São José dos Campos, professora 

Adjunta Rebeca Di Nicoló.  

 

Ao Programa de Pós-graduação em Ciências Aplicadas à Saúde Bucal, na pessoa 

do coordenador professor Alexandre Luiz Souto Borges, sua ajuda foi essencial. Muito 

obrigada!  

 

À minha orientadora, Profa. Dra. Alessandra Buhler Borges, por toda dedicação no 

desenvolvimento desse trabalho. Seu conhecimento, humildade, paciência e foram 

muito valiosos e serão sempre exemplo para minha carreira como mestre. Obrigada 

por acreditar que seria possível.  

 

Minha gratidão aos professores Jose Benedito Oliveira Amorim, Luana Marotta Reis 

de Vasconcellos e Lucas de Paula Ramos. Muito obrigada por compartilhar o 

conhecimento  

 

Aos colegas do Programa que, durante esta jornada, foram importantes para meu 

crescimento e também apoio nas dificuldades. Desejo muito sucesso a vocês!  

 

 

 

 

 

 

 

 

 

 

 

 



   

   
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

"Porque a nossa leve e momentânea tribulação produz para nós um peso eterno de 
glória. Não atentando nós nas coisas que se vêem, mas nas que se não vêem; 

porque as que se vêem são temporais, e as que se não vêem são eterna” 
 
 

2 Coríntios 4:17,18. 



   

   
 

RESUMO 
 

 
Félix NS.Terapia de reposição enzimática para doença de Anderson-Fabry: revisão 
sistemática de ensaios clínicos randomizados [dissertação]. São José dos Campos 
(SP): Universidade Estadual Paulista (Unesp), Instituto de Ciência e Tecnologia; 2023.  
 
 

A doença de Anderson-Fabry, uma doença rara, é causada por uma deficiência da 
enzima alfa-galactosidase A. Isso leva ao acúmulo de um material gorduroso 
denominado globotriaosilceramida em várias células do corpo. Globotriaosilceramida 

é uma substância gordurosa, formada por três açúcares, comumente denominada 
ceramida e é encontrada na maioria das células do corpo. Indivíduos não tratados 
podem apresentar dor, complicações na pele, olhos, e problemas gastrointestinais. A 
doença de Fabry pode causar complicações potencialmente fatais, como danos aos 
rins, ataque cardíaco e acidente vascular cerebral. Um dos tipos disponíveis de 
tratamento é a terapia de reposição enzimática com agalsidase alfa ou beta, que 
substitui a deficiência enzimática. Avaliamos a eficácia e segurança da terapia de 
reposição enzimática com agalsidase alfa ou beta para doença de Anderson-Fabry. 
Para realizar essa revisão analisamos revisões sistemática de ensaios clínicos 
randomizados (ECRs). Não houve restrições de idiomas. Pesquisamos o registro de 
ensaios clínicos de erros inatos do metabolismo do grupo Cochrane de fibrose cística 
e desordens genéticas, e as seguintes bases de dados: MEDLINE, EMBASE, LILACS, 
e clinicaltrials.gov. Os revisores examinaram de forma independente os artigos 
elegíveis, extraíram dados e avaliaram o risco de viés. Essa revisão está registrada na 
Cochrane e foi realizada juntamente com o grupo de Fibrose Cística e Doenças 
Genéticas. Foram selecionados onze estudos randomizados controlados, os 
resultados apontam para uma diminuição nos depósitos de Gb3 plasmático para os 
pacientes que receberam agalsidase beta, nos domínios do rim (MD -1,70 (95% CI - 
2,09 a -1,31) e coração (MD -0,90 95% CI (-1,18 a -0,62) e uma influência positiva na 
qualidade de vida relacionada à dor, porém, os estudos apresentam baixa qualidade 
metodológica e não fornecem evidências robustas que indiquem se a TRE é mais 
efetiva e segura quando comparada a outras terapias ativas, placebo, ou nenhuma 
intervenção.  
 
 

Palavras-chave: Doença De Anderson-Fabry; terapia de reposição enzimática; 
revisão sistemática; ensaios clínicos randomizados. 

 
 
 
 
 
 
 
 
 
 
 



   

   
 

ABSTRACT 
 
 

Félix NS. Enzyme synthesis therapy for Anderson-Fabry disease: systematic 
review of randomized clinical trials [dissertation]. São José dos Campos (SP): São 
Paulo State University (Unesp), Institute of Science and Technology; 2023. 
 
Anderson-Fabry disease, a rare disease, is caused by a deficiency of the enzyme 
alpha-galactosidase A. This leads to the accumulation of a fatty material called 
globotriaosylceramide in various cells of the body. Globotriaosylceramide is a fatty 
substance, made up of three sugars, commonly called ceramide and is found in 
most cells in the body. Untreated individuals may experience pain, skin, eye, and 
gastrointestinal problems. Fabry disease can cause life-threatening complications, 
such as kidney damage, heart attack, and stroke. One of the available types of 
treatment is enzyme replacement therapy with agalsidase alpha or beta, which 
replaces the enzyme deficiency. We evaluated the efficacy and safety of enzyme 
replacement therapy with agalsidase alfa or beta for Anderson-Fabry disease. To 
perform this review, we analyzed systematic reviews of randomized controlled 
trials (RCTs). There were no language restrictions. We searched the clinical trial 
registry of inborn errors of metabolism from the Cochrane group of cystic fibrosis 
and genetic disorders, and the following databases: MEDLINE, EMBASE, LILACS, 
and clinicaltrials.gov. Reviewers independently screened eligible articles, 
extracted data, and assessed risk of bias. This review is registered in Cochrane 
and was carried out jointly with the Cystic Fibrosis and Genetic Diseases group. 
Eleven randomized controlled trials were selected, the results point to a decrease 
in plasma Gb3 deposits for patients receiving agalsidase beta, in the kidney 
domains (MD -1.70 (95% CI -2.09 to -1.31) and heart (MD -0.90 95% CI (-1.18 to -
0.62) and a positive influence on pain- related quality of life, however, studies have 
low methodological quality and do not provide robust evidence to indicate whether 
ERT is more effective and safer when compared to other active therapies, placebo, 
or no intervention. 
 
 
Keywords: Anderson-Fabry disease; enzyme replacement therapy; systematic 
review; randomized clinical trials. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



   

   
 

 LISTA DE FIGURAS 
 
 

 

Figura 1- Herança Genética...................................................................................... 23  

Figura 2 - Órgãos acometidos pela DAF.................................................................... 24 

Figura 3 - Manifestações clinicas da DAF. ..............................................................  27 

Figura 4 - Programa Covidence gerenciador de referências...................................... 37  

Figura 5 - Programa Review Manager (RevMan) gerenciador de revisões sistemáticas 
da Colaboração Cochrane......................................................................................... 39 

Figura 6 - Programa GRADEpro para construção de tabelas................................... 40 

Figura 7 - Fluxograma da pesquisa bibliográfica e seleção de artigos...................... 43 

Figura 8 - Avaliação do risco de viés programa Review Manager Web (RevMan Web) 
gerenciador de revisões sistemáticas da Colaboração Cochrane ............................ 69 

Figura 9 - Avaliação do risco de viés de todos os estudos conforme os domínios 
sequência da geração, sigilo da alocação, mascaramento dos participantes, 
investigadores e avaliadores de desfechos, dados dos desfechos incompletos e outros 
vieses programa RevMan ......................................................................................... 60 

Figura 10 - Meta-análise comparando Agalsidase alfa 0,2 mg/kg duas vezes por 
semana versus placebo referente à concentração de Gb3 no plasma e nos tecidos 
................................................................................................................................... 67 

Figura 11 - Meta-análise comparando Agalsidase alfa versus agalsidase beta referente 
ao evento morte  ....................................................................................................... 76 

Figura 12 - Meta-análise comparando Agalsidase alfa versus agalsidase beta referente 
aos eventos cardíacos .............................................................................................. 79 

Figura 13 - Meta-análise comparando Agalsidase alfa versus agalsidase beta referente 
aos eventos cardíacos ……………………………………………………………………  82 
 
Figura 14 - Meta-análise comparando Agalsidase alfa versus agalsidase beta referente 
aos eventos adversos................................................................................................ 86 
 

 

 
 
 
 
 
 
 
 
 
 
 
 
 



   

   
 

LISTA DE QUADROS 
 
 

 
Quadro 1 - Estratégia de busca para a The Cochrane Library................................... 32 

Quadro 2 - Estratégia de busca para a EMBASE....................................................... 33 

Quadro 3 - Estratégia de busca para a PubMed......................................................... 35 

Quadro 4 - Estratégia de busca para a LILACS.......................................................... 35 

Quadro 5 - Características dos estudos incluídos referente aos grupos de intervenção 

e controle, rotas de administração dos medicamentos e os desfechos 

medidos..................................................................................................................... 45 

Quadro 6 - Características dos estudos incluídos referente aos participantes, critério 

de elegibilidade, duração da intervenção e projeto teste. 

....................................................................................................................................54 

Quadro 7 - Características dos estudos incluídos referente à sequência de 

randomização, alocação, mascaramento dos participantes, investigadores e 

avaliadores, dados de desfechos incompletos, financiamento e conflito de 

interesse.....................................................................................................................43 

Quadro 8 - Resumo dos achados: Terapia de reposição enzimática para doença de 

Anderson-Fabry - Agalsidase beta versus placebo.................................................... 88 

Quadro 9 - Resumo dos achados: Terapia de reposição enzimática para doença de 

Anderson-Fabry -  agalsidase alfa versus placebo..................................................... 90 

Quadro 10 - Resumo dos achados: Terapia de reposição enzimática para doença de 

Anderson-Fabry -  TRE versus migalastat.................................................................. 92 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



   

   
 

 
LISTA DE ABREVIATURAS E SIGLAS 

 

 

 

EAs Eventos adversos 

AVE Acidente vascular encefálico 

BPI Inventário Breve da Dor 

CFDI Iniciativa Canadense da Doença de Fabry 

DAF Doença de Anderson-Fabry 

ECG Eletrocardiograma 

ELISA Ensaio imunossorvente ligado a enzima 

Gb3 Globotriaosilceramida 

ITT Intenção de tratar 

IV Intravenosa 

RM Ressonância magnética 

TRE Terapia de reposição enzimática 

TFG Taxa de filtração glomerular 

  

  

  
 

  

 

 

 

 

 

 

 

 

 

 

 



   

   
 

SUMÁRIO 

 

1 INTRODUÇÃO ……………….......…………………………………………..… 17 

2 REVISÃO DE LITERATURA ….......……………………………………..…… 19 

2.1 Genética ...…………………………....……………………………….…......  21 

2.2 Fisiopatogenia ....…………………………………………………….……… 22 

2.3 Epidemiologia ....…………………………………………………………….  23 

2.4 Tratamento ....………………………………………………………………..  24 

2.5 Triagem e Diagnóstico .....………………………………………………….. 25 

3 PROPOSIÇÃO …….......……………………………………………….…........ 26 

3.1 Objetivo geral .....…………………………………………………………….. 26 

3.2 Pergunta .....………………………………………………………………….. 26 

3.3 Hipótese nula - H0 ....……………………………………………………...... 26 

3.4 Hipótese alternativa - H1 ....……………………………………...………… 27 

4 MATERIAL E MÉTODO .......………………………………………………….. 28 

4.1 Tipo de estudo .....…………………………………………………………… 28 

4.1.1 Local .……...………………………………………………………………... 28 

4.1.2 Tamanho da amostra ………...………………………………………….. 29 

4.2 Critérios de inclusão ....………………………………………………......... 29 

4.2.1 Tipo de estudos incluídos …………………………...…………………. 29 

4.2.2 Tipos de participantes ………………………………………………...… 29 

4.2.3 Tipos de intervenções ………………………………...………………… 29 

4.3 Tipos de medidas de resultado ..………………………………………… 30 

4.3.1 Desfechos primários …………………………………………………….. 30 

4.3.2 Desfechos secundários …………………………………………………  30 

4.4 Métodos de busca para identificação dos estudos ………………… 31 

4.4.1 Pesquisa em bases de dados eletrônicas ……………………………. 31 

4.4.2 Pesquisa de outros recursos …………………………………………… 34 

4.5 Coleta de dados e análise …………………………………………......... 34 

4.5.1 Seleção dos estudos ….…………………………………………………. 34 

4.5.2 Extração dos dados …………………………………………...…………. 35 

5 RESULTADOS ......……………………………………………..………..…….. 40 

5.1 Seleção dos títulos ………………………………….……………………. 40 



   

   
 

5.1.1 Tipos de intervenção............................................................................44 

5.2 Descrição dos estudos incluídos ……………………………………… 49 

5.2.1 Agalsidase alfa versus placebo...........................................................49 

5.2.2 Agalsidase beta versus placebo.........................................................50 

5.2.3 Agalsidase alfa versus agalsidase beta..............................................51 

5.2.4 Vários esquemas de dosagem de alfa agalsidase.............................52 

5.2.5 Vários esquemas de dosagem de agalsidase beta............................53 

5.3 Avaliação do Risco de viés.....................................................................57 

5.3.1 Sequência de geração..........................................................................57 

5.3.2 Sigilo de alocação................................................................................57 

5.3.3 Cegamento (viés de desempenho e viés de detecção) ……….……. 61 

5.3.4 Dados de resultados incompletos (viés de atrito) …………..….…… 62 

5.3.5 Relatórios seletivos (viés de relatórios) …………………...…………. 62 

5.4 Efeitos das intervenções ..………………………………………………. 66 

5.4.1 Desfechos primários para Agalsidase alfa versus placebo..............66 

5.4.1.1 Alterações na concentração de Gb3 no plasma e tecido 
..……………………………………………………………………………… 66 

5.4.1.2 Morte ……………………….……..........………………………………… 68 

5.4.1.3 Acroparaestesia …............………………………………...…………… 68 

5.4.1.4 Crises de Fabry ….........….……………….……………………….……. 68 

5.4.1.5 Inventário Breve da Dor – gravidade …..........………………….…… 68 

5.4.1.6 O Inventário Breve da Dor - qualidade de vida relacionada à dor 
………………………………………………………………………….......... 69 

5.4.2 Desfechos secundários para agalsidase alfa versus placebo..........69 

5.4.2.1 Efeito da terapia na função renal .........……………………………... 69 

5.4.2.2 Sintomas e complicações da doença ............……………………… 70 

5.4.2.3 Análise histológica de depósitos endoteliais capilares 
microvasculares de Gb3 em espécimes de biópsia ………………… 70 

5.4.2.4  Efeitos adversos do tratamento ….........……………………………. 70 

5.4.2.5 Qualidade de vida..............................................................................70  

5.4.3. Desfechos primários para agalsidase beta versus placebo............71 

5.4.3.1 Alterações na concentração de Gb3 no plasma e tecido..............71 

5.4.3.2 Morte...................................................................................................71 

5.4.3.3 Acroparestesia..................................................................................71 



   

   
 

5.4.3.4 Crises de Fabry.................................................................................72 

5.4.4 Resultados secundários - Agalsidase beta versus placebo............72 

5.4.4.1 Efeito da terapia na função renal.....................................................72 

5.4.4.2 Eventos cardíacos.............................................................................72 

5.4.4.3 Eventos cerebrovasculares..............................................................73 

5.4.4.4 Análise histológica de depósitos endoteliais capilares 
microvasculares de Gb3 em espécimes de biópsia...........................73 

5.4.4.5  Qualquer evento adverso.................................................................74 

5.4.5 Resultados primários para agalsidase alfa versus agalsidase 
beta........................................................................................................74 

5.4.5.1 Alterações das concentrações de Gb3 no plasma e no tecido.......75 

5.4.5.2 Morte...................................................................................................75  

5.4.5.3 Acroparestesia..................................................................................77 

5.4.5.4 Crises de Fabry..................................................................................77 

5.4.6 Desfechos secundários para Agalsidase alfa versus agalsidase 
beta........................................................................................................77 

5.4.6.1 Efeito da terapia na função renal......................................................77 

5.4.6.2 Eventos cardíacos.............................................................................77 

5.4.6.3 Eventos cerebrovasculares..............................................................80 

5.4.6.4 Porcentagem de participantes que atingiram pontuação zero na 
pele........................................................................................................80 

5.4.6.5 Parâmetros ecoradiográficos...........................................................80 

5.4.6.6 Análise histológica de depósitos endoteliais capilares 
microvasculares de Gb3 em espécimes de biópsia...........................80 

5.4.6.7 Qualquer evento adverso..................................................................80 

5.4.6.8 Qualidade de vida..............................................................................83 

5.4.7 Desfechos primários para esquemas de doses múltiplas de 
Agalsidase alfa.....................................................................................83 

5.4.7.1 Alterações na concentração de Gb3 no plasma e tecido................83 

5.4.7.2 Morte...................................................................................................84 

5.4.7.3 Dor......................................................................................................84 

5.4.8 Desfechos secundários para esquemas de doses múltiplas de 
Agalsidase alfa.....................................................................................84 

5.4.8.1 Efeito da terapia na função renal......................................................84 

5.4.8.2 Sintomas e complicações da doença...............................................84 



   

   
 

5.4.8.3 Análise histológica de depósitos endoteliais capilares 
microvasculares de Gb3 em espécimes de biópsia...........................85 

5.4.8.4 Efeitos adversos do tratamento.......................................................85 

5.5 Certeza da evidência …………………..……………………………….…... 87 

6 Discussão...................................................................................................96 

6.1 Resumo dos principais resultados........................................................96 

6.2. Integridade geral e aplicabilidade das evidências ………..………..…. 97 

6.3 Qualidade da evidência ……………………………………………….…. 97 

6.4    Possíveis vieses no processo de revisão..........................................98 

6.5 Concordâncias e discordâncias com outros estudos ou revisões 
……………………………………………………………………………….. 98 

REFERÊNCIAS ..……………………………………………………………….. 101 

 

 
 
  



  
101  

 

   
 

 

REFERÊNCIAS 

 
 

 
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Sci U S A. 2008;105(8):2812-7. 
 
Alamartine E. Enzyme replacement therapy in nine patients with Fabry disease. Med 
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Arends M, Hollak CE, Biegstraaten M. Quality of life in patients with Fabry disease: a 
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Banikazemi M, Ullman T, Desnick RJ. Gastrointestinal manifestations of Fabry disease: 
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Beck M, Ricci R, Widmer U, Dehout F, Garcia AL, Kampmann C, et al. Fabry disease: 
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Beer M, Weidemann F, Breunig F, Knoll A, Koeppe S, Machann W, et al. Impact of 
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Benjamin ER, Hamler R, Brignol N, Boyd R, Yu J, Bragat A, et al. Migalastat reduces 
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448. 
 
Breunig F, Weidemann F, Strotmann J, Knoll A, Wanner C. Clinical benefit of enzyme 
replacement therapy in Fabry disease. Kidney Int. 2006;69(7):1216-21. 
 
Bichet DG, Aerts JM, Auray-Blais C, Maruyama H, Mehta AB, Skuban N, Krusinska E, 
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