Balkan Journal of Medical Genetics

PRENATAL DIAGNOSIS OF ORGANIC ACIDEMIAS AT A TERTIARY CENTER
Tanacan A1,*, Gurbuz BB2, Aydin E1, Erden M1, Coskun T2, Beksac MS1
*Corresponding Author: Dr. Atakan Tanacan, Department of Obstetrics and Gynecology, Division of Perinatology, Hacettepe University Hospital, Tıp Fakültesi Street, Sıhhiye, Ankara, Turkey. Tel: +90- 532-353-0892. Fax: +90-312-305-1910. E-mail: atakantanacan@yahoo.com
page: 29

DISCUSSION

Prenatal diagnostic procedures were performed for MSUD, MMA and IVA in this study. Maple syrup urine disease is an OA caused by a deficiency of branched-chain α-ketoacid dehydrogenase complex, the second enzyme of the metabolic pathway of the three branched-chain amino acids, leucine, isoleucine and valine [14]. Psychomotor delay, feeding problems, and a maple syrup odor of the urine are the main characteristics of this disease [14]. Methylmalonic acidemia results from impaired metabolism of methylmalonic acid that is generated during the metabolism of certain amino acids (isoleucine, methionine, threonine or valine) and odd-chain fatty acids. Lethargy, seizures, muscular hypotonia and hypoglycemia are observed in neonates with MMA mut(0) or MMA mut(–) during an episode of metabolic decompensation. Microcephaly, pig-mentary retinopathy, nystagmus, secondary reduced visual acuity, hydrocephalus or megaloblastic anemia can develop in infancy. Isovaleric acidemias are caused by a deficiency of isovaleryl-CoA dehydrogenase, the enzyme that converts isovaleryl-CoA to 3-methylcrotonyl CoA in the breakdown pathway of leucine. The accumulation of isovaleric acid in urine leads to a specific odor described as “sweaty feet.” Vomiting, ketoacidosis, lethargy and coma may be observed depending on the severity of the disease [15]. There is usually no sign of OAs during the followup of the pregnancy. Family history of consanguineous marriage and/or siblings who died during the neonatal period may evoke suspicion for clinicians [16]. Unfortunately, there is no curative treatment for OAs at this time [6,7]. Treatment of metabolic decompensation periods, dietary management and application of medications such as L-carnitine, multivitamins and carglumic acid are the main conservative management protocols for OAs [6,7]. Thus, neonatal screening by tandem mass spectrometry in high-risk populations may be beneficial in order to detect cases at earlier stages of life and to take precautions for preventing life-threatening complications [17,18]. On the other hand, there are still ongoing debates about the ethical and cost-effective issues related to the newborn screening programs for OAs [9,19]. Therefore, establishing the most appropriate screening programs based on the specific characteristics of the populations seems to be the logical approach. Prenatal diagnosis of inherited metabolic diseases is crucial, especially in countries with higher rates of consanguineous marriages due to the autosomal recessive pattern for the majority of the diseases [1]. According to the Turkish Demographic and Health Surveys, the rate of consanguineous marriage was found to be between 22.0- 24.0% in Turkey [20]. Thus, inherited metabolic diseases are still an important healthcare problem for our country [20]. Although, current studies have reported promising results with cell-free DNA, IPDTs are still regarded as the gold standard method for the PND of OAs [21,22]. Amniocentesis, CVS and cordocentesis can all be performed with different procedure-related adventages and disadventages. Chorion villus sampling provides PND at earlier weeks of gestation but it has a procedure related fetal loss rate of 0.7-1.3%, which was slightly higher than the rates reported for amniocentesis [23]. Additionally, CVS may sometimes lead to diagnostic uncertainty due to placental mosaicism [24]. Cordocentesis was reported to be associated with fetal-loss rates of 5.0-6.0% [25]. Therefore, it is not routinely performed for PND of OAs [21,22]. Chorion villus sampling was the most common (70.0%) IPDT procedure in this study and median gestational week for the IPDTs was 11.5 weeks. Two prenatally diagnosed cases with organic acidemia (one case with IVA and one case with MMA) were terminated after appropriate counseling. As PND of the case with IVA was performed by CVS, it gave us the opportunity for termination of pregnancy at an earlier gestational week compared to the case with MMA, which was diagnosed by amniocentesis. Earlier diagnosis of OAs facilitated the appropriate management of pregnancy in our institution. Targeted mutation analysis was performed for all cases in this study. Although, metabolite studies and enzymatic assays are the other alternative diagnostic approaches, targeted mutation analysis has become the preferred method due to higher rates of sensitivity and specifity [14,22]. Mutation analysis in fetal DNA is a method of choice also in guidelines for MMA/PA [26]. Moreover, targeted mutation analysis gives the physician the opportunity for carrier screening that results in more effective preconceptional counseling [14,22]. Preimplantation genetics diagnosis may be an appropriate clinical option for couples with known mutations for OAs [27]. In conclusion, PND of OAs is critical. Appropriate prenatal counseling should be provided to families with known risk factors.

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