Introduction
Mental retardation is defined as sub-optimal intellectual function followed by deficient adaptive functions like communication, self-care, home living, social or interpersonal skills, use of community resources, self‐direction, functional academic skills, work, leisure, health, and safety.
X-linked disorders are caused due to gene mutations or polysomy of the X-chromosome. The mutated chromosome can be inherited from either parent. Conditions developing due to a single copy of the mutant X-chromosome usually show a dominant pattern of inheritance and the ones developing from mutations in both X-chromosomes show a recessive pattern of inheritance. This implies that only one of the parents needs to carry and contribute mutated chromosomes for the offspring to develop the condition in dominant inheritance while both parents contribute in recessive inheritance. X-Linked mental retardation (XLMR) refers to inherited genetic abnormalities that result in mental retardation.
What Is the Prevalence of X-Linked Mental Retardation?
XLMR shows a male predilection with a ratio of 3:1 indicating three times male prevalence than females. XLMR accounts for about 16 % of all male mental retardation cases. The average IQ (intelligence quotient) of the general population is 100. An individual is said to be mildly intellectually challenged if the IQ falls below 70, moderate below 50, severely challenged below 35, and profound retardation below 20 IQ.
Approximately 2 to 3 % of the general population shows mild to moderate retardation, while severe disability is seen in 0.5 to 1 % of the population.
About 200 genes have been estimated as a causality of mental retardation and around 100 specific genes have been identified. Many of these genes are found in the P-arm (short arm) of the X-chromosome and also due to duplication of position 11.2 of the same arm.
How to Diagnose Mental Retardation?
An individual is regarded as part of the spectrum, on fulfilling three criteria:
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Sub-optimal intellect.
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Limited adaptive capacity in communication, self-care, home living, social/interpersonal skills, use of community resources, self‐direction, functional academic skills, work, leisure, health, and safety.
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Age of Onset: Below 18 years.
Investigations required to confirm a possible XLMR condition:
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Three-generation pedigree.
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Developmental charts of all possibly affected individuals.
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Maternal pre-pregnancy clinical history.
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Pregnancy history.
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Birth Records: History, height, weight, and head circumference.
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Developmental milestones and growth rates.
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Neonatal PKU and hypothyroidism.
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Educational history and IQ.
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Examination for dysmorphic features.
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Neurological signs.
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Karyotype analysis (550 banded resolution).
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Mutation analysis for possible Fragile-X syndrome.
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Telomere screen.
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Brain MRI (in case of abnormal neurological findings or abnormal head circumference.)
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EEG (to identify epilepsy phenotype).
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Metabolic screen.
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Urine and plasma screen (creatine/creatinine ratio)
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Free T3 thyroid function.
What Are the Syndromes Associated With X-Linked Mental Retardation?
Autism
Autism has a multi-factorial etiology involving genetics, prenatal and perinatal factors, neuroanatomical abnormalities, and environmental factors. Possible mutations in NLGN3 and NLGN4 are two of the genetic factors of autism. Autism is associated with severe mental retardation.
Coffin-Lowry Syndrome
Genetic mutations in RPS6KA3 are associated with Coffin-Lowry syndrome. The individual presents with mental retardation adjunct to short stature, distinctive facies with a prominent forehead and coarse facies, hypertelorism, prominent lips, large soft hands with thickened tapering fingers, hypotonia, hyperextensibility, and skeletal changes.
Gareis-Mason Syndrome
Also known as CRASH syndrome or MASA syndrome. The condition is caused due to mutations in the L1CAM gene which codes essential axonal glycoprotein required in the development of ANS and PNS. MASA is an acronym in which M stands for mental retardation, subsequent abbreviated symptoms are aphasia, shuffling gait, and adducted thumbs.
MECP2 Duplication Syndrome
It is an X-linked disorder caused due to overexpression of MeCP2 protein which regulates brain function. Overexpression caused abnormal neural and immune function along with mental retardation. It is also related to mental retardation in Angelman syndrome and Rett syndrome.
DDX3X Syndrome
The condition is caused due to mutations in the DDX3X gene which has important roles in embryogenesis, spermatogenesis, and cellular growth and division. The condition predominantly affects females causing varying clinical phenotypic symptoms.
Cerebral Ataxia
A study of familial history with OPHN1 gene mutations has shown limited evidence of decreased cerebellum size and mental retardation. The mutation is of translocation and a singleton variant.
ATRX
Alpha thalassemia-mental retardation syndrome presents with severe mental retardation, commonly with absent speech, microcephaly, hypotonia, spasticity or seizures, and growth retardation with midface hypoplasia and skeletal abnormalities.
MICPCH or MRXSNA
‘Mental retardation and microcephaly with pontine and cerebellar hypoplasia’ or ‘Mental retardation, X-linked, syndromic, Najm type’ presents with mental retardation and pontocerebellar hypoplasia. The conditions generally affect females as most males die prenatally. The condition is linked to a mutation in the CASK gene in the X-chromosome that affects mitochondrial function.
Epilepsy
It is common to observe intellectual disability in epileptic patients. Mutations in the SLC6A8 gene present with epilepsy, severe mental retardation, and autistic spectrum behavior. Mutations in the ARX gene may cause West syndrome or Partington syndrome, both of which present varying symptoms along with mental retardation. A truncating mutation in SYN1 or mutation in the AGTR2 gene results in various symptoms along with epilepsy-associated mental retardation.
Short Stature and Microcephaly
Mutations in the PQBP1 gene result in microcephaly, short stature, and mental retardation along with a variety of mid-line defects. Phenotypic similarities are found in Renpenning syndrome, Hamel syndrome, and Sutherland-Hann syndrome which are also caused due to mutations in the same gene. Mutations in the SMCX are also associated with short stature and microcephaly.
High T3 Concentrations
Mutations in the SLC16A2 gene are associated with high T3 concentration and mental retardation. Patients with Allan‐Herndon‐Dudley syndrome have a similar phenotype.
What Are the Genes Associated With X-Linked Mental Retardation?
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IL1RAPL1: Deletion mutation causes mental retardation, adrenal hypoplasia, Duchenne muscular dystrophy, and glycerol kinase deficiency.
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TM4SF2: Associated with neuropsychiatric diseases such as Huntington's chorea.
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ZNF41: Zinc finger family transcription factor.
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FTSJ1: Involved in the processing and modification of tRNA.
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DLG3: A member of the membrane-associated guanylate kinase family of proteins.
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FACL4: Deletions mutation in patients with Alport's syndrome and mental retardation.
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PAK3: Necessary for dendritic development and for rapid cytoskeletal reorganization.
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ARHGEF6: Numerous cellular processes are initiated by extracellular stimuli mediated by G protein-coupled receptors.
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FMR2: Most prevalent form of non-specific X-linked mental retardation.
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GDI1: Regulates the GDP-GTP exchange reaction.
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IQSEC2: Involved in the formation of secretory vesicles.
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AP1S2: Mutations are associated with Pettigrew syndrome (mental retardation, choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain)
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ACSL4: Key role in lipid biosynthesis and fatty acid degradation.
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MECP2: Mutation results in Rett syndrome (progressive neurological developmental disorder).
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ARX: Mutations in this gene cause X-linked intellectual disability and epilepsy.
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KDM5C: Involved in the regulation of transcription and chromatin remodeling.
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PHF8: Activates epithelial to the mesenchymal transition-like process by upregulating factors SNAI1 and ZEB1.
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SLC6A8: Essential for maintaining ATP levels in cells with high energy demand.
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GSPT2: It is a positive regulator of the polypeptide chain release factor.
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MAGED1: Controlling the reward circuitry in the brain that is responsible for addictive behaviors.
Conclusion
Since XLMR is a symptom associated with various genetic syndromes and mutations, there is no treatment for the same but for social lifestyle management systematic screening of all other X-linked genes in families with mental retardation is not feasible but prenatal screening can reveal some of the genetic disorders. The patients require extra attention, care, and patience. Growing up, individuals learn to live with their condition with major adjustments and lifestyle balances.
