|Year : 2019 | Volume
| Issue : 1 | Page : 28-32
Prenatal counseling and diagnosis of Gaucher disease in Egypt: an 18-year experience
Ahmed L Aboulnasr1, Ekram M Fateen2
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Biochemical Genetics, National Research Centre, Cairo, Egypt
|Date of Submission||13-Jan-2019|
|Date of Acceptance||24-Jun-2019|
|Date of Web Publication||25-Nov-2019|
Ekram M Fateen
Prof.of Biochemical Genetics, Department of Biochemical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo
Source of Support: None, Conflict of Interest: None
To provide prenatal counseling (PC) and prenatal diagnosis (PD) of Gaucher disease in pregnant women with previous affected sibling (s).
Patients and methods
PC was done in 154 pregnancies among 109 females from June 2000 to July 2018. Positive consanguinity was found in 98 (89.9%) couples. Chorionic villus sampling (CVS) was done between 11 and 12 weeks of gestational age in 115 pregnancies among 84 women. Two women had CVS in four pregnancies, five in three pregnancies, and 15 in two pregnancies. β-glucocerebrosidase activity was measured in chorionic villi.
Of 154 pregnancies, 115 (74.68%) proceeded to CVS and 39 (25.32%) did not. Of the 39, 18 did not show up, eight already came late for PD, nine had missed or spontaneous abortion, three refused, and one had induced abortion before PD. In 110 (95.65%) pregnancies, enough chorionic villi were retrieved, and β-glucocerebrosidase was measured; 79 (71.82%) had normal enzyme activity and 31 (28.18%) had low activity. In five cases, we could not retrieve enough villi.
In spite of the presence of enzyme replacement therapy for Gaucher disease, it is not effective for all types, in addition to high cost and variable response. So, our responsibility in PC is to offer early diagnosis by CVS, as one of the options, to the pregnant women/couples.
Keywords: chorionic villus sampling, Gaucher disease in Egypt, prenatal counseling and diagnosis, β-glucocerebrosidase
|How to cite this article:|
Aboulnasr AL, Fateen EM. Prenatal counseling and diagnosis of Gaucher disease in Egypt: an 18-year experience. Middle East J Med Genet 2019;8:28-32
|How to cite this URL:|
Aboulnasr AL, Fateen EM. Prenatal counseling and diagnosis of Gaucher disease in Egypt: an 18-year experience. Middle East J Med Genet [serial online] 2019 [cited 2020 Feb 24];8:28-32. Available from: http://www.mxe.eg.net/text.asp?2019/8/1/28/271565
| Introduction|| |
Gaucher disease (GD) is an autosomal recessive disorder caused by a genetic deficiency of the lysosomal enzyme β-glucocerebrosidase which leads to the storage of glucocerebroside and other glycolipids in various tissues that cause damage to several organ systems (Grabowski, 2008; Grabowski et al., 2013).
GD is classified based on clinical characteristics into three types: type 1 is nonneuropathic, type 2 is acute neuropathic, and type 3 is chronic neuropathic (Grabowsky et al., 2004).
Type 1, which affects most patients, is characterized by organomegaly. The main cause of the anemia, cytopenia, hepatosplenomegaly, and the bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells (Stirnemann et al., 2017).
The definitive diagnosis of GD is by the measurement of β-glucosidase enzyme activity in leukocytes or skin fibroblasts (Ho et al.,1972; Di Rocco et al.,2014). There is no role for histological examination of the bone marrow, liver, or spleen for the diagnosis of the disease (Nagral, 2014).
Prenatal diagnosis (PD) of GD is possible by direct measurement of glucosidase activity in chorionic villus sample (CVS) (Besley and Broadhead, 1989).
Our objective was prenatal counseling (PC) and diagnosis of GD in pregnant women with previous affected sibling(s).
| Patients and Methods|| |
Primary intervention: prenatal counseling
This is a retrospective study. PC was done in the period from June 2000 to July 2018 in 154 pregnancies among 109 females: one female was counseled in five pregnancies, three females were counseled in four pregnancies, 10 were counseled in three pregnancies, and 12 women were counseled in two pregnancies. The age of the women ranged from 18 to 38 years.
All the pregnant women were subjected to history taking, pedigree construction, clinical examination, and ultrasound scan.
All the 109 pregnant women have an affected sibling with GD, except two with family history in a close relative. Overall, five have three affected siblings, and 14 have two affected siblings.
At first visit counseling, 67 (51.15%) affected siblings were living and 64 (48.85%) were dead. Among the 67 affected living siblings, 35 (52.24%) were under enzyme replacement therapy (ERT), and 32 (47.76%) did not receive treatment.
Among the 64 affected dead siblings, nine were under ERT before death: six died after variable period of ERT (11, 5, 2.5, 2 years, and 6 months, correspondingly), two died after few injections of ERT, and another died 3 days after ERT from bloody diarrhea.
Among the 109 pregnant women, at their first visit, 57 (52.3%) had no normal child and 52 (47.7%) had normal children (25 have girls, 21 have boys, and six have girls and boys). Accordingly, 82 (75.23%) families have no normal boys.
Of the 109 pregnant women/couples, 98 (89.9%) have positive consanguinity and only 11 (10.1%) have negative consanguinity. Among the 154 pregnancies, 137 (88.96%) were positive and 17 (11.04%) were negative.
Proper counseling was done explaining the following items:
- The nature of GD
- The possibility of recurrence in each pregnancy
- The idea (rationale) of PD
- The procedure of CVS.
Finally, an informed consent was provided by the pregnant women, and they were scheduled for PD by CVS.
Secondary intervention: prenatal diagnosis
CVS was done between 11 and 12 weeks of gestational age in 115 pregnancies among 84 women: four times in two women, three times in five women, and two times in 15 women.
Chorionic villi were sampled by transabdominal route using the free-hand, fine-needle aspiration method with 20-G needle under simultaneous ultrasound guidance. If sufficient villi were not obtained in the first attempt, a second one was made with another needle with a maximum of three attempts.
Chorionic villi were retrieved successfully in 110 (95.65%) cases by one CVS puncture in 49 (44.55%) cases, two CVS punctures in 37 (33.64%), and three CVS punctures in 24 (21.81%) cases.
The retrieved chorionic villi were immediately dissected from the maternal decidua. The importance of the immediate separation of decidua from chorionic villi is highly stressed (Besley et al., 1988). The sample was placed in sterile medium or saline and frozen. After thawing, β-glucosidase activity was measured in the chorionic villi fluorometrically.
| Results|| |
Primary outcome: cases subjected to chorionic villus sampling
Of the 154 counseled pregnancies, 115 (74.68%) proceeded to CVS and 39 (25.32%) were not subjected to CVS. Among these 39 pregnancies, 18 (46.15%) did not show up at scheduled time, nine (23.08%) had missed or spontaneous abortion, eight (20.51%) already come late for PD, three (7.69%) refused, and one (2.56%) had induced abortion before PD.
Secondary outcome: enzyme activity measurement
β-glucosidase activity was measured in 110 CVS. Normal enzyme activity, denoting normal fetus, was found in 79 (71.82%) cases, and low enzyme activity, denoting affected fetus, was found in 31 (28.18%) cases. In five cases subjected to CVS, we could not retrieve enough chorionic villi for the biochemical diagnosis. Three patients were not cooperative (moving during puncture), one patient was very obese (needle could not reach the placenta) and one patient had a posterior and very low lying placenta (inaccessible placenta).
| Discussion|| |
In our study, many factors affected the decision-making process of the parents to do PD. The following are among these factors:
- Personal experience and suffering with the affected sibling
- Absence of a normal boy
- Proper PC
- Family and society pressures
- Negative influence of other doctors.
Overall, 154 pregnancies were counseled; however, 39 pregnancies were not subjected to CVS. [Table 1] illustrates the reasons and the proposed explanations of these cases.
|Table 1: Reasons and the proposed explanations of 39 cases not subjected to chorionic villus sampling|
Click here to view
Many of our patients came from rural areas where they were dealing with other physicians, general practitioners, or even obstetricians. These physicians may have negatively influenced the patient's decision to do PD.
The following are examples of other physicians' opinions that may affect negatively patient's decision:
- No PD for such disease
- Tests are neither accurate nor conclusive
- Tests are for research and not for clinical practice
- Placenta is not formed in third month for CVS
- CVS will harm the fetus
- CVS will definitely cause abortion.
As a prerequisite for PD and before PD can be offered, the diagnosis in the proband must be precisely established. A clinical diagnosis alone is not sufficient (Kleijer and Verheijen, 2009). In all cases, it is important to establish the enzyme deficiency in the proband (Besley and Wraith, 1997).
GD is the commonest type of lipidoses in Egypt. However, if GD and/or Niemann–Pick disease are suspected clinically in an affected child with hepatosplenomegaly, three enzymes, namely, β-glucosidase, sphingomyelinase, and chitotriosidase, should be estimated simultaneously for better evaluation of the case and to exclude the possibility of Niemann–Pick disease. Chitotriosidase is an important enzymatic biomarker in all cases of hepatosplenomegaly accompanied with or without neurologic manifestations (AboulNasr and Fateen, 2008).
Consanguineous marriage is common in Egypt. It varies from 29 to 40% in different areas (Temtamy and Aglan, 2012). This explains the high consanguineous rate among couples with children of autosomal recessive diseases such as GD in our study.
Concerning the motivation of the pregnant women/couples for PD. A previous study of PD for mucopolysaccharidoses among pregnant Egyptian women found out that parents were keen to do PD to have a normal child (AboulNasr and Fateen, 2004). In the present study, we found that pregnant women/couples were eager not only to have a normal child or to avoid having an affected one but more importantly sometimes to have a normal boy as they have already normal girls.
We will try in the following discussion to answer three important controversial questions concerning PD of GD by measuring β-glucosidase enzyme activity in chorionic villi:
- Why PD in spite of the presence of ERT?
- Why CVS and not amniocentesis?
- Why enzyme assay and not mutation analysis?
First question: why prenatal diagnosis?
Parents having an affected child with GD will have a 25% recurrence risk in subsequent pregnancies. Therefore, they may refrain from having further children unless PD is available with the option of termination of the affected pregnancy (Kleijer and Verheijen, 2009).
Prenatal testing for couples with family history of GD should be offered in conjunction with genetic counseling so that they can be aware of available options and can make informed decisions (Zuckerman et al., 2008).
The cost of ERT is very high and may reach hundreds of thousands of US dollars annually for a single patient in addition that it is to be continued for life (Singh et al., 2010). Moreover, ERT cannot reverse the neurological manifestations in type 2 or type 3 GD (Germain and Benistan, 2007).
GD may be associated with other serious conditions. Increased risk of multiple myeloma and hematological and nonhematological malignancies has been reported with type 1 GD (Cappellini, 2015). The pathophysiology of cancer development in GD is not well understood (Astudillo et al., 2015).
There is a recent discovery of association between GD and Parkinson's disease. This association has now refocused research toward delineating the role of glucocerebrosidase in the brain (Lal and Sidransky, 2017).
So, PD is the option that should be discussed and offered for every pregnant woman with a history of an affected sibling (AboulNasr and Fateen, 2008).
Second question: why chorionic villus sampling?
Chorionic villi has been proved to be suitable for direct enzyme assay in different metabolic disorders (Poenaru et al., 1979; Desnick et al., 1992). It is agreed that PD of GD can be done by measuring β-glucosidase activity in fresh chorionic villi (Stirnemann et al., 2017). Many have recommended uncultured chorionic villi for reliable prenatal enzymatic diagnosis of various lysosomal disorders including GD (Verma et al., 2015).
Direct enzyme assay in CVSs between 11 and 12 weeks of gestational age should provide early diagnosis. This is more favorable than later diagnosis by amniocentesis between 14 and 15 weeks of gestational age, from medical, ethical, and psychological aspects (AboulNasr and Fateen, 2002).
Third question: why enzyme assay?
Clinical phenotype of GD cannot be discerned from the genotype (Goker-Alpan et al., 2003). There seem to be factors other than genotype affecting the phenotypic expression as severity may vary among siblings, even identical twins (Lachmann et al., 2004).
It is challenging to understand genotype-phenotype correlation in GD as individuals sharing the same genotype, even siblings or twins, can differ in their disease manifestations, clinical course, and response to therapy (Biegstraaten et al., 2011).
β-glucosidase assay is accurate with rapid result. Detection of many mutations is more expensive and time consuming. In addition, mutation analysis does not add more information relevant to the decision making in PD.
Although, the benefits of PD procedures are well documented, the investigation of psychological consequences related to these procedures has remained a surprisingly neglected area of research (Leithner et al., 2004).
PC is not a one-way meeting. Enough time should be given for listening to couples, understanding their problems and fears, and explaining clearly and patiently all the available options including PD. PC should be comprehensive, nondirective, and nonjudgmental. PC should be considered as a psychoanalysis session ([Table 2]).
PC is not only a prediagnostic process but also a postdiagnostic one ([Table 3]).
|Table 3: Prediagnostic and postdiagnostic processes of prenatal counseling|
Click here to view
In any medical issue with an ethical aspect, there is what we call 'the ethical puzzle.' It comprises the three sides interinfluencing each other and finally affecting the decision making. These sides are the society, the patient, and the physician. We should consider and respect every side and avoid conflicts of interests between them.
Obstetricians working in the field of PD should be aware of the scientific, psychological, and ethical aspects of each disease-patient condition; considering collectively these aspects in the decision making is mandatory. Counseling is a dynamic and nondogmatic process helping couple's decision and not doctor's decision imposing.
CVS between 11 and 12 weeks of gestational age will provide early diagnosis and consequently give the patient the option and opportunity of an early termination which is medically safer. In addition, many Muslims believe that 'the Soul' comes to the fetus after the first four months (i.e., 120 days) of pregnancy. So, if termination is to be done, it should be in that gestational period, that is, before ensoulment of the fetus.
Obstetricians offering PD bear a heavy responsibility. Diagnostic errors may result in loss of normal pregnancies or the avoidable birth of affected children. Obstetricians must be aware of the test available so that they can counsel their patients accordingly. Our duty and responsibility as physicians/counselors is to offer all the available options to the patients/couples.
| Conclusion|| |
In spite of the presence of ERT for GD, it is not effective for all types in addition to high cost and variable response. It is the right of the couple with history of an affected child with GD to understand that PD is possible and available. So, PC should offer early PD of GD by CVS to measure β-glucosidase activity in chorionic villi as an option to allow couples at risk to make an informed reproductive decision.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
AboulNasr A, Fateen E (2002). Prenatal diagnosis of lipidoses using chorionic villus sampling (CVS): an Egyptian experience. Lab Med Suppl
Aboul Nasr AL, Fateen E (2004). Prenatal diagnosis of mucopolysaccharidoses (MPS): the first Egyptian experience. Bratisl Lek Listy105
AboulNasr AL, Fateen EM (2008). Prenatal diagnosis of perplexing cases of lipidosis. Bratisl Lek Listy109
Astudillo L, Therville N, Colacios C, Sergui B, Andrieu-Abadie N, Levade T (2015). Glucosylceramidases and malignancies in mammals. Biochimie125
Besley GTN, Broadhead DM (1989). Prenatal diagnosis of inherited metabolic disease by chorionic villus analysis: the Edinburgh experience. J Inher Metab Dis12 (Suppl 2)
Besley G, Wraith JE (1997). Lysosomal disorders. Curr Pediatr128
Besley GTN, Ferguson-Smith ME, Frew C, Morris A, Gilmore DH (1988). First trimester diagnosis of Gaucher disease in fetus with trisomy 21. Prenat Diagn8
Biegstraaten M, van Schaik IN, Aerts JMFG, Langeveld M, Mannen MMAM, Bour LJ, Hollak CEM (2011). A monozygotic twin pair with highly discordant Gaucher phenotypes. Blood cells Mol Dis46
Cappellini MD (2015). A rare condition in haematological practice – Gaucher disease. Eur Oncol Haematol11
Desnick RJ, Schuette JL, Golbus MS, Jackson L, Lubs HA, Ledbetter DN, et al
. (1992). First trimester biochemical and molecular diagnosis using chorionic villi high accuracy in the US Collaborative study. Prenatal Dign12
Di Rocco M, Andria G, Deodato F, Giona F, Micalizzi C, Pession A (2014). Early diagnosis of Gaucher disease in pediatric patients: proposal for a diagnostic algorithm. Pediatr Blood cancer61
Germain DP, Benistan K (2007). Le diagnostic prénatal de la malaidie de Gaucher. Rev Med Intern28
Grabowski GA (2008). Phenotype, diagnosis and treatment of Gaucher's disease. Lancet372
Grabowsky GA, Andria G, Baldellou A (2004). Pediatric nonneuropathic Gaucher disease: presentation, diagnosis and assessment. Consensus statement. Eur J Pediatr163
Grabowski GA, Petsko GA, Kolodny E (2013). Gaucher disease. In The online metabolic and molecular bases of inherited disease (OMMBID) – part 16: lysosomal disorders – chapter 146. McGraw – Hill globel education holding, LLC Inc., NewYork, Available from: www.ommbid.com/OMMBID/the-online--metabolic-and-molecular-bases-of-inherited-disease/b/abstract/part 16/ch146.
Goker-Alpan O, Schiffmann R, Park JK, Stubblefield BK, Tayebi N, Sidransky E (2003). Phynotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3. J Pediatr143
Ho MW, Seck J, Schmidt D (1972) Adult Gaucher's disease: kindred studies and demonstration of a deficiency of acid beta-glucosidase in cultured fibroblasts. Am J Hum Genet24
Kleijer WJ, Verheijen FW (2009). Inborn errors of metabolism. In: Rodeck CH, Whittle MJ eds. Fetal medicine: basic science and clinical practice
ed. Netherland: Elsevier; p. 357-376.
Lachmann RH, Grant IR, Halsall D, Cox TM (2004). Twin pairs showing discordance of phenotype in adult Gaucher's disease. QJM97
Lal TR, Sidransky E (2017). The spectrum of neurological manifestation associated with Gaucher disease. Diseases5
Leithner K, Maar A, Fischer-Kern M, Hilger E, Loefler-Stastka H, Ponocny- Seliger E (2004). Affective state of women following a prenatal diagnosis: predictors of a negative psychological outcome. Ultrasound Ob Gyn23
Nagral A (2014). Gaucher disease. J Clin Exp Hepatol4
Poenaru L, Girard S, Thepot F, Madelenat P, Huraux-Rendu C, Vinet MC, Dreyfusi J-C (1979). Antenatal diagnosis in three pregnancies at risk of mannosidosis. Clin Genet16
Singh Y, Arora D, Kochar SPS (2010). Prenatal diagnosis of Gaucher disease. MJAFI66
Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al
. (2017). A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci18
Temtamy SA, Aglan MS (2012). Consanguinity and genetic disorders in Egypt. Middle East J Med Genet1
Verma J, Thomas DC, Sharma S, Jhingen G, Saxena R, Kohli S, et al
. (2015). Inherited metabolic disorders: prenatal diagnosis of lysosomal strorage disorders. Prenatal Diagn11
Zuckerman S, Lahad A, Zimran A, Levy- Lahad E, Sagi M (2008). Attitude of couples identified through screening as carriers of Gaucher disease type I. Clin Genet74
[Table 1], [Table 2], [Table 3]