Aetiology
Children with cognitive impairment have an IQ that is below average, at <70. A specific learning difficulty, on the other hand, includes difficulties with learning but a normal IQ. Although the terms 'learning difficulty' and 'cognitive impairment' each have a specific definition, they are sometimes used interchangeably in children. There is a wide range of aetiologies, although inevitably, in some children, the disorder has no identifiable cause (idiopathic).
Learning difficulties or cognitive impairment may be developmental (congenital) or acquired.
Developmental causes include a range of genetic conditions (such as Down's syndrome or autism spectrum disorders); exposures during pregnancy including intra-uterine infections, fetal alcohol syndrome, and teratogenic drugs; premature birth; and congenital hypothyroidism.
Acquired causes include central nervous system (CNS) infections (bacterial meningitis, encephalitis), CNS tumours, hypoxia, traumatic brain injury, and psychosocial deprivation.
Specific learning difficulties without generalised cognitive impairment
In many cases, several specific learning difficulties may be comorbid with each other (e.g., dyslexia and specific language impairment) or with ADHD. These are nevertheless considered separate specific learning difficulties when other domains of cognition are preserved.
Dyslexia
Characterised by impaired cognitive skills related to reading; also known as specific reading disability.
Usually associated with difficulty in written language (dysgraphia), especially spelling.
In contrast to weaknesses in reading and spelling, dyslexics may show strengths in non-language visual processing.[9]
In most cases, it is probably attributable to a genetic susceptibility that leads to a deficit in the language areas of the brain.[10][11] About 15 different candidate genes have been identified.[12][13]
Dyscalculia
A condition characterised by impaired arithmetic skills.
The aetiology is unknown, but is believed to involve a genetic susceptibility leading to a deficit in the neural network involved in arithmetic skills.[14]
Attention-deficit hyperactivity disorder (ADHD)
A condition characterised by poor attention, hyperactivity, and/or impulsiveness.
Although not generally classed as a learning disability, it can be comorbid with many learning disabilities.
A combination of genetic susceptibility and environmental factors (e.g., low birth weight and maternal smoking) are likely to play a role in the aetiology.[15][16]
Specific language impairment
Characterised by disordered use of language across modalities (spoken, written, sign, etc.), which may be associated with delayed speech.
Highly comorbid with dyslexia, which may be diagnosed later in childhood.[17]
May be due to a genetic susceptibility;[18] some cases, in which motor speech processes are particularly affected, have been associated with mutations in the forkhead box protein P2 (FOXP2) gene.[19]
Central auditory processing disorder
Characterised by an impaired ability to localise, differentiate, and/or recognise elements of sound, which may lead to specific difficulties with learning. The definition and the degree to which this is a distinct entity remain controversial.
Developmental co-ordination disorder/dyspraxia
Characterised by disordered co-ordination skills, which may result in difficulty with fine motor skills (writing), or difficulty co-ordinating a timely response in the classroom (because of disorganised thinking).[20][21] Some authors have argued that the term developmental dyspraxia should be reserved specifically for children with impaired performance of skilled gestures.[22]
Genetic disorders
Down's syndrome
Caused by an extra chromosome 21 and associated with characteristic physical features, short stature, and hypotonia.
Children with Down's syndrome usually have cognitive impairment[23] and may have other neurodevelopmental disorders, such as autism.[24]
Fragile X (FRAX) syndrome
Caused by an unstable trinucleotide repeat expansion (or, much more rarely, a point mutation or deletion) in the FMR1 gene on the X chromosome at Xp27.3, causing loss of function of this protein.
Males usually have delayed language development and mild to moderate cognitive impairment, with declining cognitive performance after early childhood. In the absence of cognitive impairment, children often have weak attention and executive function and specific learning difficulties, particularly with maths, visual-motor coordination, and visuospatial cognition. Verbal skills tend to be a relative strength.[25] About 50% of females with full mutations have mild cognitive impairment and many have symptoms of ADHD or other learning difficulties.[26][27][28][29]
Males with fragile X syndrome often meet criteria for an autism spectrum disorder, as do approximately 20% of females with full mutations. Those who do have autism have greater impairment in cognitive skills and language, and are more likely to have seizures.[29]
Prader-Willi syndrome
Caused by a 15q11-13 deletion of paternal origin.
Children have generalised developmental delay in infancy and mild cognitive impairment.[30]
Angelman's syndrome
Caused by a 15q11-12 deletion of maternal origin.
Children have developmental delay and severe cognitive impairment; they are usually non-verbal.[31]
15q11 duplication syndromes
Duplications in the locus associated with Prader-Willi and Angelman's syndromes are associated with complex phenotypes including epilepsy, autistic-like behaviour, language impairment, and behavioural problems.[32][33]
William's syndrome
Caused by a chromosome 7q11.23 deletion.
The majority of individuals have developmental delay and mild to moderate cognitive impairment, but with relative sparing of spoken language.[34]
Rett's syndrome
The majority of affected individuals are girls. In 80% of girls, the disorder is due to a sporadic mutation in the methyl CpG binding protein 2 (MECP2) gene. A rarer form, presenting with infantile spasms, occurs with a germline mutation in the gene coding for cyclin-dependent kinase-like 5 (CDLK5).
Following a period of normal development for 6 to 18 months after birth, girls develop severe or profound cognitive impairment that results in regression of language and motor skills.[35][36]
Turner's syndrome
A disorder affecting women in which part or all of one of the X chromosomes is missing.
Cognitive impairment is rare, but specific learning difficulties are common.[37]
Tuberous sclerosis
An autosomal dominant disorder with variable penetrance. Tuberous sclerosis results from a genetic mutation in one of two genes: tuberous sclerosis complex 1 (chromosome 9q34), or tuberous sclerosis complex 2 (chromosome 16p13.3). These genes code for proteins that act as tumour suppressors.
About 50% of individuals have mild to moderate cognitive impairment, and 20% to 30% have profound impairment. Children with no cognitive impairment often have specific learning disabilities.[38]
DiGeorge syndrome
Caused by a deletion of chromosome 22.
Developmental delay is often noted in early childhood. Children usually have an average IQ or mild cognitive impairment. Specific learning disabilities are common in children without cognitive impairment.[39]
16p11.2 deletion syndrome
Autism and related disorders
Autism spectrum disorder
A disorder characterised by a qualitative impairment in communication and social interaction, with a restricted, repetitive, and stereotypical pattern of behaviour and interests. There is often a history of language delay (single word or phrase speech delay), and 25% of children lose previously acquired skills (regression).
There is strong evidence for an underlying genetic susceptibility. Some well-characterised genetic syndromes are associated with autism (e.g., Down's syndrome, fragile X syndrome, tuberous sclerosis, 15q11 and 16p11.2 deletion syndromes). The heritability of non-syndromic autism is estimated to be as high as 80%.[43] However, in most cases specific genetic risk factors are unknown.[44]
Children with autism often have cognitive impairment. In those who have normal IQ, specific learning disabilities are common.[45]
Previous diagnostic categories of Asperger's syndrome (impairment of social interaction and communication, with a rigid and repetitive pattern of behaviour but without language delay) and pervasive developmental disorder are subsumed under autism spectrum disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR).[46]
Early diagnosis of autism spectrum disorder is crucial for early intervention, support, and recognition and treatment of co-occurring conditions.[47]
Social (pragmatic) communication disorder
Characterised by persistent difficulties in verbal or non-verbal communication, limiting social participation, relationships, and/or academic achievement.[48]
Differs from autism in that it is not accompanied by restricted, repetitive patterns of behaviour.
Intra-uterine infections and drugs
Cytomegalovirus (CMV)
Infection during pregnancy produces neurocognitive and neurodevelopmental defects. The effects are more severe if CMV is contracted during the first and second trimesters.[49]
Toxoplasmosis
Infection may occur or reactivate during pregnancy. Primary infection is more likely to lead to neurological impairment, chorioretinitis, and visual impairment.[50]
Rubella
Can result in congenital rubella syndrome following first-trimester infection. It may cause neurological impairment, deafness, blindness, and cardiac defects.[51]
Rubella is now rare due to immunisation in the developed world.
Fetal alcohol syndrome (FAS)
One of the most common causes of cognitive impairment.[3] FAS may result from regular or intermittent heavy alcohol use (4-6 drinks per occasion) during pregnancy.[52]
Cognitive impairment and specific learning difficulties are common in children with the full syndrome.
Teratogenic drugs
Various drugs, both recreational and prescription, can be teratogenic.[53] Historically, antiepileptic drugs (especially valproic acid) have been the main cause of teratogenicity.[54]
This cause is now less common due to an increased awareness of drug effects and altered prescribing practices among doctors.
Perinatal events
Extreme premature birth
The likelihood of cognitive and neurological impairment with premature birth is variable; it is more likely in the presence of other complicating factors, such as intra-uterine growth retardation or congenital infections.[49][55] The likelihood of morbidity increases with earlier gestational age and lower birth weight.[56]
Perinatal hypoxia
Central nervous system (CNS) disorders
Bacterial meningitis
Acute meningitis is unlikely to present as a learning difficulty, but a history of meningitis as a child may account for residual cognitive impairment and be the cause of specific learning difficulties.
Pneumococcus or Haemophilus meningitis are most likely to cause cognitive impairment.[59][60]
Encephalitis
Herpes simplex encephalitis frequently causes disability, particularly in young children.[59]
Tumour
Intracerebral malignancy may occur de novo or secondary to another neurodevelopmental disorder (e.g., giant cell astrocytoma in tuberous sclerosis).
Children frequently have cognitive impairment or specific learning disability, either as a result of the tumour itself or as a result of the treatment (surgery, radiotherapy, or chemotherapy).[61]
Traumatic brain injury
Traumatic brain injury may occur following falls, road traffic accidents, or child abuse. The likelihood of cognitive impairment rises with increased severity of the injury, as reflected by the degree of coma and extent of brain injury. In children without cognitive impairment, specific learning or behavioural difficulties are common.[62][63][64]
Hypoxia/asphyxia
Although rare during childhood, hypoxia or asphyxia may follow cardiac arrest, suffocation, or near-drowning. The likelihood of neurological or cognitive impairment is high in children with an out-of-hospital episode; children with brain lesions visible on magnetic resonance imaging (MRI) scans are likely to have significant cognitive impairment.[65][63]
Seizures
Absence epilepsy
Children with absence epilepsy may have specific difficulties with fine motor skills and executive function.[66]
ADHD is common in children with absence seizures.[67]
Acquired epileptic aphasia (Landau-Kleffner syndrome)
Landau-Kleffner syndrome presents as a gradual deterioration of language function, usually beginning around 3 to 6 years of age, associated with seizures.
Electroencephalogram (EEG) characteristically shows electrical status epilepticus during sleep (ESES).
Up to 20% of patients may have mutations in GRIN2A; several other genetic causes have also been identified. GRIN2A mutations may also cause speech difficulties in the absence of clinical seizures.[68]
Epileptic encephalopathies
Children with epileptic encephalopathies have seizures and developmental regression in multiple domains (including language, behaviour, memory, and motor skills); development is usually normal until 2 to 4 years of age.
As in Landau-Kleffner syndrome, EEG shows ESES.[69]
Metabolic /endocrine disorders
Congenital hypothyroidism
A heterogeneous disorder caused by partial or total failure of thyroid gland development, or by defects in thyroid hormone production.[70]
Babies appear normal at birth, but the absence of thyroid hormone leads to failure to thrive, developmental delay, and cognitive impairment if the condition is not identified and treated quickly.
In developed countries, screening of all newborns for congenital hypothyroidism is carried out ideally after 24 hours of life (preferably between 48 to 72 hours) and before hospital discharge or 1 week of life; consult local protocols.[70][71] Evidence suggests that as many as 20% of cases may be missed on newborn screen, and additional cases may be identified by screening a second time at 2 weeks of age.[72]
Inborn errors of metabolism
Phenylketonuria is an autosomal recessive genetic disorder characterised by a deficiency in the hepatic enzyme phenylalanine hydroxylase. Accumulation of phenylalanine in the blood leads to abnormal myelination, small brain size, seizures, and cognitive impairment.[73]
Phenylketonuria was one of the most common causes of cognitive impairment; however, with the implementation in the developed world of newborn screening and early treatment, cognitive impairment rarely occurs today.
Psychosocial causes
Deprivation
Neglect, severe poverty, or institutionalisation can leave children without sufficient stimulation and opportunities to develop normally. The likelihood of cognitive impairment or specific learning difficulties is related to the degree of deprivation.
In children with significant deprivation, there is evidence of improved long-term outcomes once deprivation is reversed, but not of complete recovery.[74][75]
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