Developmental Regression ✅ Flashcards
What should a history of developmental regression prompt?
Immediate referral for investigation into underlying aetiology and ensure no treatable cause
Is developmental regression common?
No, is rare
What are the more common causes of developmental regression?
- Landau-Kleffner syndrome
- Leukodystrophy
- MECP2 duplication syndrome
- Rett syndrome
- Metabolic or mitochondrial disorders
- Dravet syndrome
What is Landau-Kleffner syndrome?
A rare epileptiform disorder
What is Landau-Kleffner syndrome characterised by?
- Developmental issues
- Marked regression of language skills
- Abnormal EEG
When does Landau-Kleffner syndrome present?
5-7 years
How does the incidence of Landau-Kleffner syndrome compare in boys and girls?
It affects twice as many boys
What % of children with Landau-Kleffner syndrome have epileptic seizures?
70%
What EEG pattern develops in Landau-Kleffner syndrome?
Electrographic status epilepticus of slow-wave sleep
What % of children with Landau-Kleffner syndrome develop electrographic status epilepticus of slow-wave sleep?
85%
What causes Landau-Kleffner syndrome?
Unknown, many theories - genetic, infective, inflammatory
What is often helpful in the treatment of Landau-Kleffner syndrome?
Oral steroids
What is the prognosis of Landau-Kleffner syndrome?
Variable, and encompasses a spectrum of outcomes, but most children have ongoing moderate language deficits
What is leukodystrophy?
A group of conditions characterised by progressive degeneration of the white matter of the brain
What causes leukodystrophy?
Abnormal growth or development of the myelin sheath
How is leukodystrophy acquired?
Genetic
How many substances is myelin made up of?
At least 10
What causes degeneration of the white matter of the brain in leukodystrophy?
A genetic defect alters the way the substances making up myelin are metabolised (enzyme action) or produced
How does leukodystrophy present?
Initially developmental milestones are attained as expected, but then children show progressive regression
In what areas do children show regression in leukodystrophy?
- Gross motor skills
- Speech
- Ability to eat
- Vision
- Hearing
- Behaviour
Give 6 examples of leukodystrophies?
- Metachromatic leukodystrophy
- Adenoleukodystrophy
- Krabbe disease
- Pelizaeus-Merzbacher disease
- Canavan disease
- Alexander disease
What is metachromatic leukodystrophy caused by?
Deficiency of arylsulphatase enzyme
What is adenoleukodystrophy caused by?
Disorder of perioxisomal fatty acid beta oxidation and accumulation of very long chain fatty acids
What is Krabbe disease caused by?
Deficiency of galactocerebrosidase enzyme
What is Pelizaeus-Merzbacher disease caused by?
Defect in gene coding for myelin proteolipid protein 1
What is Canavan disease caused by?
Deficiency of aspartoacylase enzyme
What is Alexander disease caused by?
Defect in gene coding for glial fibrillary acidic protein
What is prognosis for children with leukodystrophies?
In general is poor, but varies between different types
How are children with leukodystrophies managed?
Directed towards symptomatic and supportive care
What are clinical trials looking into as treatments for leukodystrophies?
- Gene replacement
- Bone marrow transplantation
- Enzyme replacement
Which gender do MECP2 duplication syndromes affect?
Almost exclusively males
When does MECP2 duplication syndrome present?
Many from infancy, some later
How do infants with MECP2 duplication syndrome present?
Disordered or impaired development
How do older children with MECP2 duplication syndrome present?
Developmental regression and seizures
What causes MECP2 duplication syndrome?
Duplication of genetic material on the long arm of the X chormosome
Are genes other than MECP2 involved in MECP2 duplication syndrome?
They can be
How is MECP2 duplication syndrome managed?
Symptomatic, based on clinical manifestations of the syndrome
What is Rett syndrome a disorder off?
Grey matter of the brain
Which gender does Rett syndrome affect?
Mostly girls
How does Rett syndrome present?
Developmental regression after a period of static developmental process
When does Rett syndrome present?
6-18 months
What is Rett syndrome caused by?
Mutations on MECP2 gene located on chromosome X
What can resemble Rett syndrome?
Mutations on other genes - CDKL5 or FOXG1
What are the clinical features of Rett syndrome?
- Small hands and feet
- Deceleration in rate of head growth
- Repetitive stereotyped midline hand movements, such as hand wringing
- Incrased incidence of GI disorders
- Seizures
- Loss of language skills and become non-verbal
What can the deceleration in head growth in Rett syndrome lead to?
Microcephaly
What % of children with Rett syndrome have seizures?
80%
What % of girls with Rett syndrome do not walk?
50%
What are clinical trials looking into as a treatment for Rett syndrome?
Restoration of MECP2 gene function
What is the prognosis of males with MECP2 mutations?
Usually die within first 2 years of life
What do boys with MECP2 mutations usually die from?
Complications of severe encephalopathy
What is the prognosis of girls with Rett syndrome?
Can have relatively normal life expectancy, but tends to be dependent upon complications of the disorder
When do inborn errors of metabolism cause little in the way of disability?
If they are managed effectively and the damaging effects of accumulating poisonous metabolites is counteracted
Give an example of a inborn error of metabolism that can be managed effectively
Glutaric aciduria type 1
When should a diagnosis of glutaric aciduria type 1 be suspected?
In children with macrocephaly
Why should a diagnosis of glutaric aciduria type 1 be suspected in any child with macrocephaly?
A large head circumference can be one of the earliest signs
What causes Tay-Sachs disease?
Deficiency of the enzyme hexosaminidase A
What is the heritence pattern of Tay-Sachs?
Autosomal recessive
What does the enzyme deficiency in Tay-Sachs lead to?
Accumulation of gangliosides in the neurons and cell death
What is the problem when inborn errors of metaboilsm present as developmental regression?
Once the child has reached the stage of developmental regression, a degree of damage to the developing brain will have already occured
What is the focus of management of inborn errors of metabolism when presenting at the point of developmental regression?
Identify the cause to minimise further damage
Who should inborn errors of metabolism be suspected in?
- Those with family history
- History of neonatal encephalopathy
- Vomiting
- Unusual smell of urine
- When several symptoms involved with acute symptoms
Why can it be hard to diagnose inborn errors of metabolism?
Present in a wide variety of ways
What is the implication of it being difficult to diagnose inborn errors of metabolism?
Should have low threshold for screening for these disorders, particularly in children with unusual presentations of illness or developmental regression
What is Dravet syndrome also known as?
Severe myoclonic epilepsy of infancy (SMEI)
What is the most common mutation in Dravet syndrome?
SCN1A
What % of children with Dravet syndrome have a mutation in SCN1A?
80%
What does the SCN1A gene do?
Codes for proteins that regulate the function of sodium channels
When does Dravet syndrome present?
Usually in the first year of life
How does Dravet syndrome present?
Intractable, severe epileptic seizures
What may the seizures in Dravet syndrome initially manifest as?
Atypical febrile seizures
What course does development take in Dravet syndrome?
Typical course prior to onset of seizures, then period of regression
What does the degree of eventual developmental impairment on Dravet syndrome depend on?
Tends to correlate with frequency of seizures
How severe is Dravet syndrome in most individuals?
Most affected individuals have severe learning disabilities and difficult to treat epilepsy
