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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 852-855

Nonsyndromic X-linked mental retardation


1 Pediatric Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pediatrics, Ministry of Health, Berket Elsabaa General Hospital, Menoufia, Egypt

Date of Submission12-Nov-2018
Date of Decision04-Feb-2019
Date of Acceptance10-Feb-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
Shiamaa E El-Nashar
Berket Elsabaa, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_360_18

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  Abstract 


Objective
To evaluate the role of the Aristaless-related homeobox (ARX2) gene to detect cases of nonsyndromic X-linked mental retardation (MR) and genetic counseling of patients and their families to detect possible cases and high risk group.
Background
MR is a genetic disorder manifested in significantly below average overall intellectual functioning and deficits in adaptive behavior.
Patients and methods
This study included 50 boys who had an intelligence quotient of less than 70. They were recruited from the pediatrics genetic clinic at El Menoufia University Hospital in the period from October 2015 to April 2017. Their ages ranged between 3 and 16 years. After presenting a written informed consent from parents, all patients have been clinically evaluated and had routine assessment.
Results
The ages of the included patients ranged between 3 and 16 years, most of them were in the late childhood period (6–12 years), followed by the pubertal period (12–15 years). Regarding the genotypes of ARX2: 16% had full mutation, 12% had premutation and 72% had unexpanded alleles. Distribution of the degree of mentality between genotypes of the studied patients has shown that 63% of patients of full mutation had moderate MR; of the premutation patients 50% had moderate MR; and 69% of the unexpanded allele had moderate MR with highly significant P value = 0.001.
Conclusion
Diagnosis of ARX gene prevalence should depend on proper selection of cases and sensitive molecular techniques in detecting gene mutations in mentally retarded patients and their relatives to detect full mutation and premutation cases for early diagnosis, intervention, and give proper genetic counseling for patients and their families.

Keywords: child, genetic counseling, intellectual disability, male


How to cite this article:
Tawfik MA, Abo El-Fotoh WM, El-Nashar SE. Nonsyndromic X-linked mental retardation. Menoufia Med J 2020;33:852-5

How to cite this URL:
Tawfik MA, Abo El-Fotoh WM, El-Nashar SE. Nonsyndromic X-linked mental retardation. Menoufia Med J [serial online] 2020 [cited 2020 Oct 29];33:852-5. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/852/296670




  Introduction Top


Mental retardation (MR) is a genetic disorder characterized by significant limitations both in intellectual functioning and in adaptive behavior, which covers many every day social and practical skills. This disability originates before the age of 18 years [1].

Nonsyndromic X-linked intellectual retardation is defined as a nonprogressive circumstance that influences cognitive characteristic in the absence of other specific capabilities. It has been predicted that 2/3 of X-related MR is nonsyndromic [2]. The products of X-connected intellectual retardation genes are thought to be involved inside the improvement of better cognitive capabilities [3].

ARX gene is one of the maximum often mutated genes in X-linked intellectual retardation positioned in Xp22.13 in proximity to the 3' end of DNA polymerase-alpha (encoding DNA polymerase-alpha). It is far composed of five exons and transcribed into a 2.8 kb messenger RNA, which encodes a protein of 562 amino acids. This gene is expressed in the fetal and adult brains and in the skeletal muscle, where two shorter mRNA isoforms are discovered [4]. The current study aimed to evaluate Aristaless-related homeobox (ARX2) gene to detect cases of nonsyndromic X-linked MR and genetic counseling of patients and their families to detect the possible cases and high risk group.


  Patients and Methods Top


Ethical consideration approval became acquired by means of the health facility Ethics Committee and written knowledgeable affected person consent with an explanation regarding the reason, techniques, results, and complications have been taken from the parents of the enrolled patients. This study included 50 boys with an intelligence quotient (IQ) of less than 70. They were recruited from the Pediatrics Genetic Clinic at El Menoufia University Hospital in the period from October 2015 to April 2017. Their ages ranged between 3 and 16 years. Inclusion criteria were male patients with nondistinguishing features rather than MR. Exclusion criteria were patients with known cause of MR including well-defined syndromes; history of prenatal, natal, and postnatal insults; and severe and profound MR with an IQ of less than 20.

All included patients underwent detailed history taking; they were clinically evaluated, had habitual laboratory investigations, IQ assessment using Stanford-Binet intelligence test (4th edition), and molecular study of ARX gene by PCR (by kits from Sigma Scientific Services Company, 6th of October, Egypt), which was carried out in the genetic unit of the Pediatric Department of Menoufia University and included the following steps:

  1. DNA extraction from blood samples.
  2. PCR for ARX gene.
  3. Gel electrophoresis for amplified gene products.


We used a 100 bp DNA ladder, which is composed of chromatography-purified individual DNA fragments with two reference bands (1000 and 500 bp) for easy orientation [Figure 1].
Figure 1: ARX molecular study on agarose gel using ladder 100 with two reference bands (1000 and 500 bp).

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All data were collected, tabulated, and statistically analyzed using SPSS 19.0 for Windows (SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean ± SD. Student's t test was used to assess the difference between the studied parameters in the two groups. The frequencies were expressed in %. χ2 was used to assess the difference between the studied frequencies in the two groups. P was considered significant if less than 0.05 and highly significant if less than 0.001.


  Results Top


Analysis of demographic data of the included patients has shown that the ages of the included patients ranged between 3 and 16 years, most of them were in the late childhood period (6 years < 12 years), followed by the pubertal period (≥15 years), and then the prepubertal period (12 years <15 years). Regarding birth ordering 28% of the included patients were of the first ordering, 40% were of the second ordering, 20% were of the third ordering, 8% were of the fourth ordering, and 4% were more than the fourth ordering. Sixty-four percent of the included patients lived in rural areas, 88% delivered at full-term gestational age, 72% delivered by vaginal delivery, positive consanguinity was evident in 72%, and positive family history was evident in all the included patients [Table 1].
Table 1: Demographic and historical data of the studied patients

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Regarding genotypes of ARX2: 16% had full mutation, 12% had premutation, and 72% had unexpanded alleles [Figure 2].
Figure 2: Genotypes of ARX mental retardation gene.

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Distribution of degree of mentality between the genotypes of studied patients revealed that 63% of patients of full mutation had moderate MR, 50% permutation patients had moderate MR, and 69% of unexpanded allele had moderate MR [Table 2].
Table 2: Distribution of degree of mentality between genotypes of the studied patients

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  Discussion Top


In the present research, most of the studied patients were in the late childhood period (6 years < 12 years), followed by the pubertal period (≥ 15 years), and then prepubertal period (12 years < 15 years). According to the patients' age, our result is in accordance with De Ligt et al.[5], who reported that the average age of diagnosis of nonsyndromic X-linked MR was currently less than 12 years reflecting the subtle features in young children.

According to our results, the most common mentally retarded child is the second child. Also, De Ligt et al. [5] reported that the first child is the most affected.

According to family history our result is in accordance with Gronskov et al.[6], who reported that 80% of nonsyndromic X-linked MR in children had a positive family history for MR either from paternal or maternal side, without parental consanguinity; Gronskov et al. [6] reported that 70% of patients had affected siblings.

As regards genotypes of ARX prevalence of nonsyndromic X-linked MR, most of the included children had unexpanded alleles. Our prevalence of ARX in this study is in accordance with De Ligt et al.[5], who reported a frequency of 16% of nonsyndromic X-linked MR that had full mutation in ARX.

In this study, the percentage of ARX is lower than the percentage reported by Stepp et al.[7], who reported that ARX full mutation was seen in 25% and ARX premutation in 20%; Abedini et al.[8], reported that 70% had full mutation.

In this study, the prevalence of ARX is higher than Nawara et al.[9], who reported that ARX full mutation is 6.6%. Poirier et al. [10] and Gecz et al. [11] reported that 9.5% of cases had full mutation.

According to the mentality of our patients, patients with moderate mentality was mostly evident in full mutation and mild mentality was evident in half of permutation cases.

These above results were in accordance with Nawara et al.[9], who stated that MR in ARX mutation in men varies from mild to severe with the most affected men being moderately retarded (63%).

Partington et al. [12] reported that MR degrees range from mild to severe with the most affected men being moderately retarded (47%), and Bienvenu et al. [13] reported that the most affected patients being moderately retarded, while De Ligt et al. [5] reported that 62% have severe MR.


  Conclusion Top


Diagnosis of ARX gene prevalence should depend on proper selection of cases and sensitive molecular techniques in detecting gene mutations in mentally retarded patients and their relatives to detect full mutation and premutation cases for early diagnosis, intervention, and to give proper genetic counseling for patients and their families.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Tomac V, Puseljic S, Skrlec I, Anđelic M, Kos M, Wagner J. Etiology and the genetic basis of intellectual disability in the pediatric population. SEEMEDJ 2017; 1:144–153.  Back to cited text no. 1
    
2.
Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2010; 2:182–209.  Back to cited text no. 2
    
3.
Chelly J, Khelfaoui M, Francis F, Chérif B, Bienvenu T. Genetics and pathophysiology of mental retardation. Eur J Hum Genet 2006; 14:701–713.  Back to cited text no. 3
    
4.
Fullston T, Finnis M, Hackett A, Hodgson B, Brueton L, Bayna G, et al. Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. Clin Genet 2011; 80:510–522.  Back to cited text no. 4
    
5.
De Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, et al. The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity. N Engl J Med 2012; 367:1921–1929.  Back to cited text no. 5
    
6.
Gronskov K, Hjalgrim H, Nielsen IM, Brondum-Nielsen K. Screening of the ARX gene in 682 retarded males. Eur J Hum Genet 2004; 12:701–705.  Back to cited text no. 6
    
7.
Stepp ML, Cason AL, Finnis M, Mangelsdorf M, Holinski-Feder E, Macgregor D, et al. XLMR in MRX families results from the dup24 mutation in the ARX (Aristaless related homeobox) gene. BMC Med Genet 2005; 6:16.  Back to cited text no. 7
    
8.
Abedini SS, Kahrizi K, Behjati F, Banihashemi S, Ghasemi Firoozabadi S, Najmabadi H. Mutational screening of ARX gene in Iranian families with X-linked intellectual disability. Arch Iran Med 2012; 15:361–365.  Back to cited text no. 8
    
9.
Nawara M, Szczaluba K, Poirier K, Chrzanowska K, Pilch J, Bal J, et al. The ARX mutations: a frequent cause of X-linked mental retardation. Am J Med Genet A 2006; 140:727–732.  Back to cited text no. 9
    
10.
Poirier K, Abriol J, Souville I, Laroche-Raynaud C, Beldjord C, Gilbert B, et al. Maternal mosaicism for mutations in the ARX gene in a family with X linked mental retardation. Hum Genet 2006; 118:45–48.  Back to cited text no. 10
    
11.
Gecz J, Cloosterm D, Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev 2006; 16:308–316.  Back to cited text no. 11
    
12.
Partington MW, Turner G, Boyle J, Gécz J. Three new families with X-linked mental retardation caused by the 428– 451dup (24bp) mutation in ARX. Clin Genet 2004; 66:39–45.  Back to cited text no. 12
    
13.
Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D, Fauchereau F, et al. ARX, a novel Prd-class-homeobox gene highly expressed inthe telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 2002; 11:981–991.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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