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ORIGINAL ARTICLE
Year : 2007  |  Volume : 2  |  Issue : 2  |  Page : 45-52
 

Evaluation of mental retardation - Part 1: Etiologic classification of 4659 patients with mental retardation or multiple congenital abnormality and mental retardation


1 Department of Medical Genetics, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey
2 Istanbul Medical Faculty, Istanbul, Turkey

Correspondence Address:
Adnan Yuksel
Yesilyurt cad. Bora sitesi, Ünal apt. No 12, D5, Florya, Istanbul
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1817-1745.36762

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   Abstract 

Patients with multiple congenital abnormalities and mental retardation are the most frequent patient group who are referred to a genetic clinic. Specific diagnosis for these patients will provide a better understanding of the possible reasons of pathogenesis, thereby providing more true information to families on recurrence risk, prognosis, possible treatment options and prenatal diagnosis. With the aim of finding out the etiology of the genetic diseases, 4659 patients who were classified into mental retardation or multiple congenital anomaly and mental retardation (MR or MCA/MR) group who were referred to Istanbul University, Departments of Medical Genetics of Cerrahpasa Medical Faculty and Istanbul Medical Faculty in between 1985 and 2005 were analyzed retrospectively and a two step study was generated: first step involved the etiologic classification of MR or MCA/MR group and the second evaluation of the factors that help in finding out the etiologies such as age at first observation, number and periods of observations and completion of laboratory tests. In the first part of the study, etiologic classification of the patients with MR or MCA/MR who were referred to genetic clinics of the two medical faculty of Istanbul University were mentioned. 2847 patients have had an etiological diagnosis (61.10%): from these patients, 1541 out of them had a chromosomal abnormality (33.07%), 555 were known single gene mutations (11.91%), 20 were recognized syndromes (00.42%), 567 were sequences (12.16%), 6 were associations (00.12%), 29 had spectrums (00.62%), 98 had structural abnormality of CNS (2.10%), and finally, 31 suffered from prematurity and its complications, toxic drugs, infections and hypoxic ischemic encephalopathy. This study will be the one of the biggest studies in Turkey and also around the world, evaluating the most frequent patient group referred to genetic clinics: MCA or MR.


Keywords: Etiologic classification, mental retardation, multiple congenital abnormalities


How to cite this article:
Yuksel A, Kayserili H, Yesil G, Apak MY. Evaluation of mental retardation - Part 1: Etiologic classification of 4659 patients with mental retardation or multiple congenital abnormality and mental retardation. J Pediatr Neurosci 2007;2:45-52

How to cite this URL:
Yuksel A, Kayserili H, Yesil G, Apak MY. Evaluation of mental retardation - Part 1: Etiologic classification of 4659 patients with mental retardation or multiple congenital abnormality and mental retardation. J Pediatr Neurosci [serial online] 2007 [cited 2017 Jul 21];2:45-52. Available from: http://www.pediatricneurosciences.com/text.asp?2007/2/2/45/36762



   Introduction Top


Patients with mental retardation, both the isolated ones and those accompanying with multiple congenital abnormalities are the most frequently encountered entities in genetic clinics. To date, there have been numerous studies regarding the etiology of mental retardation. [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] The results revealed much variability. It was mostly due to the different classification patterns that were utilized. However, with a rapid progression in molecular genetics and cytogenetics and availability of descriptive cranial and metabolic analyses, the etiological and specific diagnosis reached its best.

The aim of this study is to find out the etiology by retrospective evaluation of patients with mental retardation (MR) or multiple congenital anomaly (MCA) and mental retardation (MCA/MR) who were being followed in Departments of Medical Genetics of Cerrahpasa Medical Faculty and Istanbul Medical Faculty.


   Materials and Methods Top


We examined and evaluated 4659 patients as MR or MCA/MR who were referred to our clinic from 01.06.1985 to 31.12.2005. The patient's data (personal, family history, physical examination, imaging, biochemical and genetic analyses) were noted.

Patients were classified into two groups: one group had an etiological diagnosis and the other group consisted of those who were to be diagnosed. The first group was further divided into two subgroups: one consisted of the patients diagnosed clinically and the other diagnosed the patients through genetic analysis, including GTG banding, FISH or mutation analysis.

Patients were classified according to the etiology. The developmental parameters, cognitive and adaptive behavior questioning, intelligence tests, were applied. The degree of mental retardation was evaluated by Denver under 3 years; Stanford-Binet, 3-6 years; and by Wisc-R, over 6 years. Patients who had more than one major abnormality or one major and minor abnormality were considered as MCA. It should be noted that the entire study group were mentally retarded with or without congenital anomalies, despite the fact that mental retardation is not usually an expected finding in some single gene disorders (Stickler, Waardenburg) and in some sequences (Poland, Amniotic band).

Etiologically diagnosed patients were categorized into 8 groups:

  1. Chromosomal abnormalities: Known chromosomal syndromes and the other chromosomal abnormalities.
  2. Known single gene disorders: Disorders that have a known inheritance pattern or known gene localization or cloned genes.
  3. Recognizable syndromes: Disorders of unknown inheritance pattern or unlocalized gene patterns or which only clinical diagnosis is available.
  4. Sequences: Secondary defects and anomalies caused by a single abnormality originating from a unique primary defect.
  5. Associations: Disorders that are encountered unincidentally.
  6. Spectrums: Several structural anomalies localized to the same part of the body during the embryological process.
  7. Central nervous system abnormalities: Patients who had structural anomalies in CNS were included in this group.
  8. Others: Prematurity, exposure to toxic materials, infection and hypoxic ischemic encephalopathy were included in this group. Primary skeletal and connective tissue disorders that cause secondary malformations were excluded.



   Results Top


Four thousand six hundred and fifty nine patients who came to genetic clinics between June 1985 and December 2005 were evaluated in MR and MCA/MR groups. The age of 4659 patients ranged between 1 day and 29 years with an average age of 3.7; 2180 cases were females (46.80%), 2479 cases was males (53.20%) and 2847 cases had a diagnosis (61.10%) [Table - 1].

Chromosomal disorders

Out of 4659 patients with MR or MCA/MR, 1541 of them had a chromosomal disease (33.07%). Clinically diagnosed 234 patients with Down syndrome and six patients with Turner syndrome were added to chromosomal disease group. Out of 1301 cytogenetically analyzed patients, 1177 had numerical chromosomal disorders and 124 had structural chromosomal disorders [Table - 2].

Down syndrome was the most frequent disorder in the chromosomal diseases group (1179/1541, 76.50%). Out of 1541 clinically diagnosed patients with Down syndromes, 945 patients were confirmed by cytogenetic analysis (945/1541, 61.32%). Two hundred and thirty-four patients with Down syndrome and six patients with Turner syndrome who were clinically diagnosed were added to the chromosomal disease group. The second most frequent disease was Turner syndrome (192/1569, 12.45%). Cytogenetic analysis confirmed the diagnosis of Turner syndromes in 186 patients.

Out of 1301 patients who had a cytogenetic analysis, 124 of them had various chromosomal abnormalities (124/1301; 9.53%). Deletion abnormalities were the most frequently seen group and Cri-du-chat syndrome (del. 5p) was the most common one in the deletion group ( n : 8). Duplication abnormalities were detected in 22 cases. Duplication abnormalities were mostly detected in chromosome 22 ( n : 4).

Unbalanced translocation abnormalities were found in 20 cases. Fifteen of them were familial translocations. The remaining 3 out of 5 cases were de novo (deletions or duplications) and 2 cases had different structural abnormalities. In 8 patients with an unbalanced translocation, neither etiological nor structural abnormalities were detected. Balanced translocations were seen in 15 patients. The number of reciprocal, Robertsonian and double reciprocal translocations were 10, 4 and 1, respectively. Four patients had inversion-type chromosomal disorder: two patients were pericentric and the other two patients were paracentric.

Known single gene disorder

Five hundred and fifty-five patients with known single gene disorders who were diagnosed by clinical examination or laboratory tests (biochemical tests, imaging studies and genetic analyses) were involved (555/4659; 11.91%). The disorders and diagnostic methods are summarized in [Table - 3]a, b, c.

Known syndromes

This group of MR or MCA/MR patients includes known syndromes (20/4659-% 0.42). The diagnoses of all the cases were made by clinical examination [Table - 4].

Sequences, associations and spectrums

Neural tube defects, including anencephaly, were the most common disorders in the sequence group (567/4659, 12.17%) [Table - 5]. Associations with etiological diagnoses (6/4659-% 0.001) and spectrums (29/4659-% 0.006) are given in [Table - 6],[Table - 7] respectively. All the patients in this group were diagnosed by clinical examination.

Structural abnormalities of the central nervous system

There were 98 patients in this group (98/4659-%2.10). Various structural abnormalities of the nervous system were detected by imaging techniques. The etiology could not be illuminated in these cases [Table - 8].

The last group comprised patients with prematurity and its complications ( n : 6), toxic drugs ( n : 3), infections ( n : 3) and hypoxic ischemic encephalopathy ( n : 19)


   Discussion Top


To date, there have been numerous studies regarding the etiology of mental retardation. The results revealed much variability. It was mostly because of the different classification patterns that were utilized. Mentally retarded children admitted to an institute were selected to be a part of the study; [2],[8],[9],[12],[21],[32],[33],[34] however, some study groups represent the whole community. [1],[14],[19],[25],[31],[35],[36],[37],[38],[39],[40],[41] The classifications were also diversified as the degree of the mental retardation was categorized into mild and serious in some studies, [2],[11],[34],[42],[43] whereas the opposite was true in some others. [3],[9],[44] In some cases, adult patients were included [2],[4],[8],[19] in contrast to some of the studies that categorized only children [12],[16],[18],[31],[32] as well as Down syndrome patients [3] or the patients who have referred with a specific diagnosis were excluded from some of the study groups. [9] CNS patients were included in the patient groups who had a specific diagnosis. [3],[8],[9] Moreover, in some studies, infections, drug toxicity, trauma in prenatal-postnatal and perinatal periods, CNS disorders or complications of prematurity were counted as one group and are excluded from the study. [2],[4],[19],[33] Obviously, the rate of the diagnosis greatly varies between the studies, ranging from 24.51% to 80.8%. Moreover, this rate has been increasing in recent years. [2],[3],[8],[9],[12],[16],[18],[20],[45]

In this study, chromosomal analyses were performed on 2365 out of 4659 patients (50.76%). In 1301 patients (29.8%), we detected numerical or structural chromosomal disorders. When clinically diagnosed, patients with Turner and Down syndrome were included without a cytogenetical analysis and the ratio reaches up to 36.04%. This ratio is significantly higher than other studies. [21],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60] The high ratio was due to the high number of Down syndrome patients.

Another study in the literature was performed by Laxova et al. in 1977 that involved 146 patients in childhood, whose findings showed the greatest similarity with our findings in the chromosomal abnormality segment, which reported a ratio of 32.9%, and most of them were Down syndrome patients with a ratio of 97.8%.

When chromosomal abnormalities were analyzed, the most frequent cause seemed to be numerical anomalies ( n : 1177/1301, 90.46%). Among the numerical abnormalities, the largest patient population was for Down syndrome patients (945/1541, 61.32%). The reason for the high frequency of these patients was the facility of diagnosis of Down syndrome patients and high frequency of referrals. [51],[55],[58],[60],[61],[62]

In present study, known single gene disorders that have a cytogenetic marker like Frajile X ( n : 64), Angelman syndrome ( n : 6), Prader Willi syndrome ( n : 11), Williams syndrome ( n : 32) and Di George sequence ( n : 13) were not included in the etiological classification of chromosomal abnormalities.

In our study, the second most frequent chromosome abnormality was Turner syndrome ( n : 186, 14.29%). The rates of sex chromosome abnormalities in MR or MCA/MR patients were found to be 0.35-2.1%. Further, the most frequent sex chromosome abnormality was Turner syndrome. Phelan et al. determined this ratio as 0.55%, while according to Hunter et al. it was 0.24%. [9],[63] Comparing studies showed that Turner frequency was strictly higher than that in the other studies.

The third frequent chromosome abnormality was from the group of structural abnormalities (124/1301, 3.23%). Interstitial-type abnormalities were found in five patients and terminal type was found in 32 out of 37 patients who had deletions. The ratio we detected was greatly higher than other studies in the literature. Schreppers-Tijdink found this ratio as 1.11% and according to Phelan et al. , it was 1.3%. [62],[63]

The analysis of the studies in literature on the basis of years shows that structural abnormalities became higher during the recent years. This situation is considered to be related with the wide usage of FISH technique in microdeletion syndromes and HRBT (high-resolution banding technique) for more detailed chromosome banding.

The fourth frequent chromosome abnormality was isochromosomes (3.23%). This group includes 37 Turner syndrome patients with i(Xq). In the study by Phelan et al. , the isochromosome ratio was found to be 1.1%. [63]

The fifth frequent chromosome abnormality seemed to be the group of duplications (1.75%). The most frequent duplications were on chromosome 22. However, in the biggest study on this group by Phelan et al. , the duplication of the fifteenth chromosome was the most frequent type, and the ratio of entire duplication was 0.34%, while in the study of Jacops et al. , this ratio was 0.014-0.02. [55],[63]

The sixth frequent abnormality was translocations with a ratio of 1.8%. Unbalanced translocations with a less frequency were detected as 1.57%. Thirteen out of these patients presented with familial translocations; three of them presented with de nova derivative translocation and two of them presented with two different structural abnormalities.

The unbalanced translocation ratios were as follows: 0.31% by Phelan et al. , 0.63% by Jacops et al. and 0.6-1.05% by Schreppers-Tizdink et al . [55],[62],[63] It is important to note that balanced translocations is an etiological factor for the MR or MCA/MR group in such a way that it might lead to microdeletions, breakage of critical genes or impairment of regulator regions.

Other chromosomal abnormalities in decreasing frequency are as follows: Klinefelter's syndrome (1.69%). Trisomy 18 and 13 syndromes (1.84%), inversion (0.30%), ring chromosome (% 0.23), marker chromosome (%0.30) and double chromosome abnormality (0.14%).

In the present study, the known single gene mutation was found as 11.91%. The highest value was 19.59% and the lowest was 1.1% in the literature. [3],[32],[63],[64] In 1971, Moser et al. found this ratio to be 4.1%; in 1786, Fryns et al. obtained a value of 19.59%, and finally, Battaglia et al. obtained 8.3% as the ratio in a study conducted in 1999. [3],[8],[45] According to these values, we cannot exactly state that there is an increase in the rate of diagnosis by years since the study groups and places are different.

The known single gene mutation was the highest in the ratio in a study performed by Fryns et al. in 1986. The research included 173 cases in the age group of 1-25 years, and 34 cases out of them were defined to have a known single gene mutation (19.59%). When we observe the case distribution, OR diseases seemed to be the most frequent and we also had detected the same.

In our study, we have analyzed 555 patients and founded 74 different diseases and most of them (n: 41) were OR diseases. The most commonly seen diseases in the order of decreasing frequency were Mucopolysaccaridosis, Frajile X and Williams syndrome. [2],[3],[8],[31],[45],[54]

In the group of etiologically diagnosed MR or MCA/MR patients, known syndromes, sequences and spectrums declared a minimum ratio of 0.80% and a maximum ratio of 15.8% to date. [3],[8],[54],[63]

Nevertheless, in some studies there was no patient declared in the group. [32] The reason for the great difference in the ratio is due to variety in patient choices. In most of the studies, neural tube defects was placed into the group of structural abnormalities of the CNS. [2],[31] The highest ratio detected in the study of Battaglia et al ., which was performed by 120 patients in the age group of 2-19 years. [3] Of 129, 19 patients have diagnosed known syndromes. When we analyzed the literature, the frequency ordering was determined as follows: neural tube defects, oculoauriculovertebral spectrum, rupture of amnios and Di George sequence and in general, the ratio of this group was 14.81%.

In this group, etiologically diagnosed patients also included CNS abnormalities in the ratio range of 1.6-4.62%. In the present study, we have detected the ratio to be 2.10%. [2],[3],[8],[18],[31],[32] The minimal usage of magnetic resonance imaging, placing the neural tube defects into sequences group and selecting the study group from genetic polyclinics group and selecting the study group from Medical Genetics polyclinic lead to a lower ratio of the group of CNS structural abnormalities in our study. The highest ratio was detected in the study of Wellesley et al. and Fryns et al . In 1991, Wellesley et al. made the study with 815 patients that were in the age group of 6-16 years. From 815 cases, 34 patients had structural CNS abnormality. However, they did not specify the type of disease in their article. In 1986, Fryns et al . detected 8 patients out 173 patients (4.62%) to be in the age group of 1-25 years. It should be noted that neural tube defects were included in this group.

This study will be the one of the most comprehensive studies both in Turkey and around the world, evaluating the most frequent patient groups referred to genetic clinics - MR or MCA/ MR. Specific diagnosis of the patients with MR or MCA/MR will lead to the identification of the exact mechanisms in disease pathogenesis, thereby providing more relevant information to the families regarding the recurrence risk, prognosis, possible treatment options and prenatal diagnosis.

 
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    Tables

  [Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6], [Table - 7], [Table - 8]


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