A Medical Genetic Approach To Mental Retardation
Ratna D. Puri*, IC Verma**
Consultant Geneticist, Sir Ganga Ram Hospital Email: ratnadpuri@yahoo.com*, Consultant Geneticist, Sir Ganga Ram Hospital Email: ratnadpuri@yahoo.com**
Mental retardation (MR) is a common problem in Pediatrics with a reported frequency of about 2-3%. Mild MR (IQ 50-70) occurs with a frequency of 20-30/1000 and is seven to ten times more common than severe MR (IQ < 50). The male to female ratio ranges between 1.3-1.9:1. There remains in clinical practice a dilemma over the extent and protocol for the evaluation of a child with mental retardation. Making an etiological diagnosis in a child is important. To the family, it provides an answer to the problem their child is facing. Prediction of the extent of the problem can be addressed along with treatment options, the risk of recurrence and prenatal diagnosis as applicable.
Definition of Mental Retardation
The definition of mental retardation given by the American Association of Mental retardation (1992) is 'Mental retardation refers to substantial limitations in present functioning. It is characterized by significantly subaverage intellectual functioning, existing concurrently with related limitations in two or more of the adaptive skill areas: community use, self direction, health and safety, functional academics, leisure and work'.

The IQ based coding of learning disability defines a learning disability where the IQ is less than 70.

Mild deficit is an IQ ranging from 51-70, moderate 36-50, severe is IQ between 21 and 35 and profound mental retardation is an IQ less than 20.

Conventionally the term MR is applied to children over 5 years of age and developmental delay in younger children.

Conventionally the term MR is applied to children over 5 years of age and developmental delay in younger children.
Etiology of Mental retardation
Review of many studies reveals that there are six major categories of causes of mental retardation:
  1. Mental congenital anomaly syndromes: Chromosomal anomalies and recognizable syndromes like.
    a) Down syndrome
    b) Coffin Lowry syndrome - severe MR, coarse facies, broad hands with tapering fingers. X-rays of hand, chest and spine help confirm the diagnosis. Caused by mutations in the Rsk-2 gene.
    c) Simpson Golabi Behmel syndrome-Overgrowth syndrome with coarse facies and thick lips. Due to mutations in the GPC3 gene.
    d) X-linked alpha thalassemia mental retardation syndrome
    e) Opitz FG syndrome - familial MR, macrocephaly, frontal upsweep of hair, agenesis of corpus callosum.
  2. Single Gene disorders - Fragile X Mental retardation, FRAXE, Rett syndrome
    CNS malformations
  3. Metabolic disorders - Hypothyroidism, Phenylketonuria, MPS, Sphingolipidosis.
  4. Acquired disorders - pre, peri and postnatal causes like fetal alcohol syndrome, teratogenic causes, infections, HIE.
  5. Non specific MR/Unclassified. The etiology in cases of mild mental retardation remains unknown in 60-70% cases whereas in severe mental retardation the cause can be established in about 50% cases.

Down syndrome remains the commonest inherited cause of mental retardation.
Clinical approach
Focused clinical evaluation is the mainstay to the evaluation of a child with mental retardation.

A detailed clinical history allows the geneticist to streamline the diagnostic evaluation, e.g., an X-linked pattern of inheritance would suggest Fragile X syndrome.
Clinical history should include the following:
  • Age of onset and progression of symptoms
  • Detailed development history
  • Associated symptoms like seizures. Exclude regression of milestones
  • Detailed antenatal and birth history with details of drug intake, intrauterine infection, alcohol. History of intrauterine growth retardation, birth asphyxia and complications in the neonatal period like infection.
  • Detailed family history - 3 generation family pedigree-Look for the presence of X-linked mental retardation. Take history of material line and children of maternal aunts. Presence of consanguinity alerts to a recessively inherited disorder. Family history of mental retardation, unexplained sib deaths, psychiatric disorders, history of repeated pregnancy losses might suggest the presence of a chromosomal rearrangement.

Clinical Examination:
  • Measure the head circumference (OFC), height, and weight with the associated centiles. Presence of microcephaly or macrocephaly would prompt investigation along those lines. Microcephaly excludes Fragile X syndrome. Head circumference at birth can be important to time the insult. Primary microcephaly is the presence of microcephaly at birth and is usually genetic. Secondary microcephaly is usually due to acquired causes, some exceptions being Rett syndrome, inborn errors of metabolism. Secondary microcephaly is usually due to acquired causes, some exceptions being Rett syndrome, inborn errors of metabolism.
  • Examination for neurocutaneous markers: In addition to Tuberous sclerosis and Neurofibromatosis examine for angiokeratomas (Fucosidosis), ichthyosis in multiple sulfatase deficiency/Sjogren Larsen syndrome, Hair abnormalities in Menkes disease and Argininosuccinic aciduria.
  • Detailed dysmorphologic examination: Association of mental retardation with congenital malformations has long been recognized and a through look for major and minor malformations is an essential part of the examination. Mental retardation is as a result of abnormal development of the central nervous system and this manifest as minor anomalies on examination, e.g., Down syndrome. In a study of 281 children with MR/DD van Karnebeek et al (5) made an etiological diagnosis in 545. One third of the diagnosis was on the basis of history and examination provided essential clues for further evaluation and in the rest the diagnosis was made on laboratory studies only, e.g., Prader Willi syndrome suspected on examination and confirmed by molecular tests. This study concluded that dysmorphologic diagnosis was contributory in 79% cases and essential in 62% cases. Some key dysmorphologic features for syndromic mental retardation:
    • Coarse facies - Simpson Golabi Behmel syndrome, Coffin Lowry syndrome
    • Adducted thumbs - MASA syndrome, X linked MR
    • Genital anomalies - hypospadias (Opitz G syndrome), macro-orchidism (Fragile X)
  • Neurologic Examination: Assessment of higher mental functions, tone and abnormalities of balance and movement and sensory system involvement, e.g., gait ataxia with seizures and inappropriate laughter would suggest Angelman syndrome.
  • Detailed ophthalmologic examination provides a vital clue to an etiologic diagnosis. Micro-ophthalmia in trisomy 13 / 18, Walker Warburg lissencephaly, Aicardi syndrome. Cataract, telangiectasia, retinal abnormalities and ectopia lentis to be looked for.
  • Behavior abnormalities: Characteristic behavioral changes are present in some cases providing in some cases providing a clue to the etiology of the mental retardation. Autism may be present in some disorders like Fragile X MR, dup15q. Self mutilation in Lesch Nyhan syndrome, Smith Magenis syndrome, Prader Willi syndrome. The latter also has compulsive hyperphagia and a food drive. Angelman syndrome has history of inappropriate laughter, Rett syndrome has hand wringing and breathing abnormalities.

After history and clinical evaluation of the child, it should be possible to ascertain if the proband has significant delay, global or selective, progressive or static. It is important to correct for prematurity. Exclude causes like neuromuscular disease, cerebral palsy, severe malnutrition and hearing and visual deficits which can cause a pure motor or speech delay. HYPOTHYROIDISM must be excluded in all cases of developmental delay/mental retardation.

Hypothyroidism must be excluded in all cases of developmental delay/mental retardation.
The usefulness of baseline investigations like full blood count with indices, electrolytes, liver function tests, CPK and urine metabolic screen is debatable. Other specific investigations are:
  1. Cytogenetic analysis:
    Routine testing at a 500 band level is recommended in all children without an etiological diagnosis for mental retardation. Various studies have shown cytogenetics analysis to be a valuable cytogenetics tool. Authors have found a high correlation between the presence of minor anomalies and karyotype abnormalities both numerical and structural. However others also find a correlation (4 of 10 patients) with chromosomal abnormalities and MR without dysmorphism.
    • It is essential for a geneticist to review the cytogenetics analysis report. If the clinical suspicion of a chromosomal abnormality is very high a repeat high level banding maybe requested to look for smaller rearrangements.
    • Subtelomeric deletions: Some deletions of the telomeres are visible on routine cytogenetics analysis and their phenotype is well characterized to suspect them clinically e.g., 5p- or cri-du-chat syndrome. However some are submicroscopic deletions, not visible on routine karyotype analysis and their phenotype is not easily recognized. On routine karyotyping these would be easily missed. Fluorescence in situ hybridization (F.I.S.H.) or MLPA analysis has been used to identify these telomeric deletions and these are now regarded as the second most common cause of mental retardation after Down syndrome. 7.4% children with moderate and severe mental retardation have subtelomeric deletions whereas this is identified in 0.5% children with mild retardation. Rarely subtelomeric deletions may be benign familial variants and it is important to examine the family members in such situations. Devries et al have proposed a 5 item check list to increase the yield for evaluation for subtelomeric deletions.
    • Thus when the routine karyotype is normal, a FISH study for subtelomeric deletions is an important diagnostic tool in the evaluation of children with metal retardation.
    Thus when the routine karyotype is normal, a FISH study for subtelomeric deletions is an important diagnostic tool in the evaluation of children with metal retardation.
  2. Molecular genetic testing:
    There are some phenotypes of mental retardation which occur due to mutations in single genes, e.g., Rett syndrome, Fragile X mental retardation. Studies show that mental retardation is more in males and this excess would be due to genes present on the X chromosome. X-linked MR is very heterogeneous caused by as many as 60 genes on the X chromosome. Syndromic e.g., Fragile X, Rett syndrome, Coffin-Lowry syndrome and non syndromic forms of XLMR are present, the latter being characterized by only cognitive abnormalities in the absence of other physical signs and symptoms.

    Fragile X syndrome (FRAXA)
    This is the most common genetic cause of mental retardation with an incidence of about 2%. It is characterized by the presence of a fragile site near the tip of the long arm of the X chromosome. At the molecular level this is an expanded CGG triple repeat at the 5' untranslated region of the FMRI gene at Xq27.3. A repeat length expansion beyond 200 is consistent with a clinical phenotype. The full mutation allele is methylated resulting in low to absent production of the FMR protein.
    Males with FRAXA have an average IQ of 40. Milder forms are also known. There is history of behaviour abnormalities and speech delay. They have problems in concentration, are overactive and impulsive. Autistic features like lack of eye contact, stereotyped, repetitive behavior and difficulty in social interaction are some of the other features. Females carrying the full mutation are less severely affected with milder learning and behaviour problems.
    Molecular diagnosis of Fragile X MR is by analysis of the CGG repeat expansion by Polymerase chain reaction/Southern Blot analysis and methylation of studies of the FMRI gene. Molecular genetic testing for fragile X MR is recommended in all cases of undiagnosed MR, both males and females, especially where the history and examination are suggestive of the disorder.
    FMRI molecular testing is recommended routinely in all patients with mental retardation. Use of the clinical checklist for the signs of Fragile X in older children and adults can be used to streamline the investigations.
    Fragile X mental retardation can also be due to mutations in the FMR2 gene (FRAXE). These boys are not dysmorphic and have variable degree of speech and behavior problems. This mutation is tested in the presence of an X linked mode of inheritance.
    Other common molecular analysis for mental retardation include Prader Willi syndrome, Angelman syndrome, Rett syndrome due to mutations in the MECP2 gene is a neurodevelopmental disorder. It is the commonest cause of mental retardation with autistic features in females. However, the phenotype is very heterogeneous and recent studies show the mutation to be present in many clinical syndromes including neonatal encephalopathy in males.
  3. Imaging studies:
    Recommendations for the use of neuroimaging in patients with mental retardation is variable ranging from the use in all patients to that in only clinically indicated cases. In some situations neuroimaging can establish the etiology of MR but in others the cause of the associated brain anomaly may not be known e.g., holoprosencephaly. This can be a part of Miller Dieker syndrome but is also present in patients of mental retardation with unknown etiology. Various studies of the yield of CT/MRI in mental retardation report a diagnostic utility of about 30%. It is essentially to be done in patients with micro/macrocephaly and/or neurological signs. MRI is the preferred modality unless there is a suspicion of craniosynostosis or congenital infection.

    MRI is the preferred modality unless there is a suspicion of craniosynostosis or congenital infection.
  4. HbH inclusion bodies in erythrocytes in males with mental retardation and abnormal genitalia. (Alpha thalassemia mental retardation syndrome).
  5. Metabolic studies:
    Inborn errors of metabolism are a rare cause of mental retardation.
    However the importance of diagnosis cannot be underestimated as specific treatment can alter the prognosis of the disease. Diagnostic yield of metabolic evaluation varies from 0.2-8.4% in various studies with a mean of about 1%. Consensus states that routine metabolic screening is not recommended. Targeted metabolic studies can be offered on the basis of history and medical examination. Clinical pointers to metabolic disorders are as in Table 1.
    With the use of Tandem Mass spectrometry of new born screening, many metabolic diseases can be identified with a single blood sample and at a cheap cost. However the optimal use of this technology for the evaluation in MR is still to be addressed.

    Tests available for metabolic evaluation are:
    1. Urine metabolic screening and qualitative aminoacidogram
    2. Quantitative amino acid estimation
    3. Tandem mass spectrometry
    4. Gas chromatography - Mass spectrometry analysis for organic acid estimation
    Other studies as indicated: EEG, NCV, EMG, audiologic examination, etc.
Treatment of Mental retardation:
This depends on the etiological diagnosis. Treatment in mental retardation is a multidisciplinary approach. It is usually supportive and symptomatic e.g., early stimulation programme in Down syndrome and dietary therapy in Inborn errors of metabolism. Management of associated complications like seizures is to be started as indicated.
Risk of recurrence
  1. For cases where the etiology has been identified - Recurrence risk as per the etiology and its pattern of inheritance. For an autosomal recessive inheritance the recurrence is 25% in each pregnancy, 50% for autosomal dominant disorders and in X linked recessive inheritance the recurrence is 50% for male sibs. In chromosomal disorders, the risk of recurrence is low, about 1%. Where the parents are carriers of a translocation the risk of recurrence increases and prenatal diagnosis can be offered.
  2. Non-specific mental retardation refers to a patient with normal head circumference, no recognizable dysmorphic syndrome, and no other neurologic signs after appropriate evaluation. The recurrence risk is empirical, derived from various studies. The sex of the index case influences the recurrence risk, it being higher for brothers of a male index case. (Table 1). This is due to X linked mental retardation as an etiological factor.
Evaluation of a child with mental retardation continues to be challenging. With the advent of newer diagnostic techniques, it is now possible to arrive at an etiological diagnosis in many cases. It is important to counsel the families and explain them the relevance of investigations. Etiological diagnosis may not alter the management in all cases. However it can help in better understanding of the disorder, the prognosis, risk of recurrence and the prenatal diagnosis if possible in subsequent pregnancies. At the end of this, there still remain some cases for which the cause of the delay cannot be ascertained. These patients and families would need re-evaluation by a clinical geneticist to appreciate any evolving phenotype or offer any new diagnostic test to try and determine the etiology of the mental retardation.
Table 1: Risk of recurrence for mental retardation in the sibs of index cases
Index case Affected brothers Affected sisters All affected sibs
Male 13% 5% 10%
Female 8% 6.5% 7.5%
Table 2: Estimated risk of recurrence of severe MR to the offspring of sibs of index cases (assuming normal intelligence and no learning difficulties in the consultand and the consultand's mother)
  Offspring risk (%)
Brother (CRT) Brother (Telomere screen negative) Sister (XLMR & CRT) Sister (telomere screen negative)  
1 affected male sib
1-2 ~ 1 2-5 1.5-3
1 affected female sib Mild MR
~ 1 ~ 1 1.5-3 1.5-3
Severe MR
1-2 ~ 1 1-2 ~ 1
2 affected male sibs
1-2 ~ 1 11-12 10
2 affected female sibs
Unknown Unknown Unknown Unknown

CRT (cryptic translocation risk)
Telomere screen must be done in proband
Recommendations for evaluation of Mental retardation
  • Focused Clinical Evaluation
    • Three generation pedigree
    • Pre, peri, Post natal history
    • Dysmorphologic examination
    • Neurologic examination
    • Assessment of behavioral phenotype
  • Laboratory testing
    • 500 band karyotype
    • FISH subtelomeric analysis
    • Fragile X molecular genetic analysis
    • Molecular Genetic testing
    • Metabolic testing
    • Neuroimaging
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