Intellectual disability, formerly called mental retardation, involves impairments of general mental abilities that impact intellectual functioning (also known as IQ) and adaptive skills, including: communication, social and self-care skills. It can happen any time before the age of 18 years, even before birth. Intellectual disability is the most common developmental disability; approximately 1-3 percent of the worldwide population is affected by it. Symptoms may include lack of or slow development of motor skills, language skills, and self-help skills, failure to grow intellectually or continued infant-like behavior, lack of curiosity, inability to connect actions with consequences, difficulty with problem-solving and following social rules. Patients affected with MRT54 have been shown to have normal gross brain structure, but impaired cognition as well as hyperactivity.
Diagnosis of ID is based on abnormal Denver developmental screening test, development way below that of peers, adaptive behavior score below average, and intelligence quotient (IQ) score (between 70 and 55 or lower) on a standardized IQ test. About 25-50% of ID cases are due to germline defects in single genes. However, close to 60 different loci have been identified in such single gene disorders affecting ID.
Mental Retardation, Autosomal Recessive 54 is a specific form of autosomal recessive mental retardation that is caused due to defects in the TNIK gene, located on chromosome 3q26.2-q26.3. The TNIK gene is expressed within the spiny neurons and enriched in the postsynaptic density, where it plays a role in both dendrite growth and synaptic transmission. Knockout TNIK mice models have been shown to demonstrate dramatic behavioural changes, including increased locomotion and cognitive deficits, supporting the role of TNIK gene defects in causing ID in humans.
Anazi et al., (2016) reported on two multiplex consanguineous Saudi families with autosomal recessive intellectual disability. The proband of the first family was a 10.5 years-old boy born to healthy first-cousin once removed parents. The child had speech delay, ADHD, and severe mood swings. His younger brother aged 2.5 years-old also had significant speech delay and was diagnosed with ID. Two other siblings were normal. The second family had three children with ID, and four normal children. The IQ for the 27 and 23 years-old patients were 53 and 59 respectively, but the 35 years old patient had severe ID and didn’t cooperate for the IQ assessment. Performing autozygome, linkage analysis, and exome sequencing for both families identified the same novel variant (c.538C>T) in the TNIK gene that resulted in a premature stop codon. The mutation was considered to be a founder mutation that resulted in a null phenotype.
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