Triplet Repeat Expansion Disorders in Pediatric Age
Introduction to Triplet Repeat Expansion Disorders in Pediatric Age
Triplet repeat expansion disorders are a group of genetic conditions caused by an abnormal increase in the number of specific three-nucleotide repeats within a gene. These disorders are characterized by genetic anticipation, where symptoms appear earlier and more severely in subsequent generations. In pediatric populations, these disorders can have significant impacts on development and quality of life.
Key features of triplet repeat expansion disorders include:
- Genetic anticipation
- Variable expressivity
- Parent-of-origin effects in some disorders
- Progressive nature of symptoms
- Multisystem involvement
Fragile X Syndrome
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorders.
Genetics:
- Caused by CGG repeat expansion in the FMR1 gene
- Normal: 5-44 repeats
- Premutation: 55-200 repeats
- Full mutation: >200 repeats
Clinical Features:
- Intellectual disability (more severe in males)
- Autism spectrum disorders
- Hyperactivity and attention problems
- Anxiety and mood disorders
- Characteristic facial features (elongated face, prominent ears)
- Macroorchidism in postpubertal males
Huntington's Disease
Huntington's Disease (HD) is a neurodegenerative disorder that typically presents in adulthood but can occur in childhood (Juvenile Huntington's Disease).
Genetics:
- Caused by CAG repeat expansion in the HTT gene
- Normal: 10-35 repeats
- Reduced penetrance: 36-39 repeats
- Full penetrance: ≥40 repeats
Clinical Features of Juvenile HD:
- Onset before age 20
- Rigidity and dystonia (more common than chorea)
- Cognitive decline and learning difficulties
- Seizures
- Behavioral changes
Myotonic Dystrophy
Myotonic Dystrophy Type 1 (DM1) is a multisystem disorder that can present from birth to adulthood.
Genetics:
- Caused by CTG repeat expansion in the DMPK gene
- Normal: 5-34 repeats
- Premutation: 35-49 repeats
- Full mutation: ≥50 repeats
Clinical Features of Congenital DM1:
- Severe hypotonia at birth
- Respiratory distress
- Feeding difficulties
- Intellectual disability
- Characteristic facial features (tent-shaped mouth, high-arched palate)
Friedreich's Ataxia
Friedreich's Ataxia (FA) is the most common inherited ataxia, typically presenting in childhood or adolescence.
Genetics:
- Caused by GAA repeat expansion in the FXN gene
- Normal: 5-33 repeats
- Premutation: 34-65 repeats
- Full mutation: >66 repeats
Clinical Features:
- Progressive ataxia
- Loss of proprioception and vibratory sense
- Dysarthria
- Cardiomyopathy
- Scoliosis
- Diabetes mellitus
Spinocerebellar Ataxias
Spinocerebellar Ataxias (SCAs) are a group of inherited ataxias, some of which are caused by triplet repeat expansions.
Genetics:
- SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 are caused by CAG repeat expansions
- Different genes involved in each type
Clinical Features (variable depending on type):
- Progressive ataxia
- Dysarthria
- Nystagmus
- Cognitive impairment
- Peripheral neuropathy
- Retinal degeneration (SCA7)
Diagnosis and Management
Diagnosis:
- Detailed family history
- Clinical examination
- Genetic testing (PCR and Southern blot analysis)
- Prenatal testing available for some disorders
Management:
- Multidisciplinary approach
- Symptomatic treatment (e.g., anti-epileptic drugs for seizures)
- Physical therapy and occupational therapy
- Speech and language therapy
- Psychological support
- Genetic counseling for families
Emerging Therapies:
- Antisense oligonucleotides
- Gene therapy approaches
- Small molecule therapies
Triplet Repeat Expansion Disorders in Pediatric Age
- What are triplet repeat expansion disorders?
Genetic disorders caused by an increase in the number of trinucleotide repeats in specific genes - What is the normal range of trinucleotide repeats in most genes?
Usually less than 30 repeats - What phenomenon is associated with triplet repeat expansions?
Genetic anticipation (earlier onset and increased severity in subsequent generations) - Which triplet repeat expansion disorder is the most common form of inherited ataxia?
Friedreich's ataxia - What is the causative mutation in Fragile X syndrome?
Expansion of CGG repeats in the FMR1 gene - Which triplet repeat is expanded in Huntington's disease?
CAG repeat in the HTT gene - What is the typical age of onset for juvenile Huntington's disease?
Before 20 years of age - Which triplet repeat disorder is characterized by muscle wasting and cataracts?
Myotonic dystrophy type 1 (DM1) - What is the expanded repeat in myotonic dystrophy type 1?
CTG repeat in the DMPK gene - Which pediatric triplet repeat disorder affects DNA repair mechanisms?
Ataxia-telangiectasia - What is the typical trinucleotide repeat in Friedreich's ataxia?
GAA repeat in the FXN gene - Which triplet repeat disorder is associated with intellectual disability and autism-like features?
Fragile X syndrome - What is the mechanism of pathogenesis in most triplet repeat disorders?
Gain-of-function or loss-of-function of the affected protein - Which diagnostic technique is commonly used to detect triplet repeat expansions?
PCR and Southern blot analysis - What is the phenomenon of repeat instability?
The tendency of expanded repeats to further expand or contract during transmission to offspring - Which triplet repeat disorder is associated with spinal and bulbar muscular atrophy?
Kennedy's disease (CAG repeat in the AR gene) - What is the typical inheritance pattern of most triplet repeat expansion disorders?
Autosomal dominant (with some exceptions like Friedreich's ataxia) - Which triplet repeat disorder is characterized by progressive cerebellar ataxia and oculomotor apraxia?
Spinocerebellar ataxia type 1 (SCA1) - What is the role of somatic mosaicism in triplet repeat disorders?
It can lead to variable expression of the disorder in different tissues - Which triplet repeat disorder is associated with intellectual disability and characteristic facial features?
Fragile X syndrome - What is the concept of the "premutation" in Fragile X syndrome?
An intermediate number of repeats that may expand in future generations but doesn't cause full syndrome - Which triplet repeat disorder is associated with diabetes mellitus in addition to neurological symptoms?
Myotonic dystrophy type 1 - What is the typical repeat size that causes full mutation in Fragile X syndrome?
More than 200 CGG repeats - Which pediatric triplet repeat disorder is associated with progressive myoclonus epilepsy?
Unverricht-Lundborg disease (expansion of CSTB gene) - What is the role of DNA methylation in some triplet repeat disorders?
It can lead to silencing of the affected gene, as seen in Fragile X syndrome - Which triplet repeat disorder is associated with choreiform movements and cognitive decline in children?
Juvenile Huntington's disease - What is the concept of "toxic RNA" in some triplet repeat disorders?
Expanded repeats in RNA can sequester important proteins, disrupting cellular functions - Which triplet repeat disorder is associated with infantile spasms and hypsarrhythmia?
Infantile spasms syndrome (ARX gene mutations, which can include triplet repeat expansions) - What is the role of genetic counseling in triplet repeat disorders?
It helps families understand inheritance patterns, anticipation, and reproductive risks - Which triplet repeat disorder is associated with progressive external ophthalmoplegia?
Some forms of spinocerebellar ataxia (e.g., SCA2)
