What are the causes of neuroregression in children?

Causes of Neuroregression in Children

Neuroregression in children results from a diverse array of etiologies, with neurometabolic disorders representing the most common genetic cause, while acquired conditions including infections, hypoxic-ischemic injury, and structural brain lesions constitute major non-genetic causes.

Neurometabolic and Genetic Causes

Primary Metabolic Disorders

• Over 200 neurometabolic diseases cause neurodegenerative disorders in childhood, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders, and lysosomal storage disorders 1
• Mitochondrial encephalomyopathies (MELAS) present with developmental regression, intractable seizures, failure to thrive, recurrent strokes, and lactic acidosis, with the A3243G mutation found in 80% of cases 2
• Inborn errors of metabolism disrupt enzymes that metabolize carbohydrates, amino acids, nucleic acids, or cause mitochondrial defects 3
• Glycogen storage diseases (mucopolysaccharidosis, Pompe disease) may present with facial dysmorphism, organomegaly, and early joint contractures; early enzyme therapy may improve outcomes 2

Specific Genetic Syndromes

• Rett syndrome is a leading cause of mental retardation and developmental regression in girls, caused by mutations in the MECP2 gene encoding methyl-CpG-binding protein 2 4
• Regression in Rett syndrome most commonly occurs between 12-18 months of age, with loss of hand skills and verbal/non-verbal communication skills being the most common features 5
• Fragile X syndrome is the most common inherited cause of intellectual disability and may present with motor delay and regression 2, 3
• Neurocutaneous syndromes (tuberous sclerosis, neurofibromatosis) result from specific gene disruptions and can cause progressive neurological deterioration 3, 6

Acquired Causes

Infectious and Inflammatory

• Viral encephalitis can cause acute encephalopathy with subsequent regression; sequelae may include anxiety, depression, behavioral problems, intrusive obsessive behavior, and hyperactivity/concentration difficulties 2
• Postinfectious cerebellar ataxia is the most common cause of acute ataxia in children presenting to emergency departments, accounting for approximately 50% of cases 2
• Congenital infections directly affect the developing fetus, with timing of exposure determining severity and type of impact 3
• Cerebral malaria in returning travelers can cause encephalopathy and regression 2

Vascular and Hypoxic-Ischemic

• Stroke in children can result from various etiologies including mitochondrial disorders, transient cerebral arteriopathy, Fabry disease, and hereditary endotheliopathy 2
• Hypoxemia and other CNS insults may result in acquired intellectual disability with regression of previously acquired skills 3
• Extremely premature birth (<26 weeks' gestational age) is an identified risk factor for neurodevelopmental regression 2

Structural and Neoplastic

• Brain tumors account for 11.2% of acute ataxia cases in children and can cause progressive neurological deterioration 2
• Hydrocephalus and other surgical conditions require neurosurgical consultation when identified on brain MRI 2
• Associated cortical malformations occur in 40-50% of drug-resistant epilepsies in children and serve as epileptogenic substrates 7

Toxic and Environmental

• Fetal alcohol spectrum disorders are the leading cause of preventable developmental disabilities worldwide 3
• In utero exposures to alcohol, drugs, toxins, or teratogens directly damage developing neural tissue 3
• Drug or toxin ingestion should be considered in acute presentations with pupillary abnormalities 2

Iatrogenic Causes

• Surgical interventions, radiation therapy, and chemotherapy can cause cognitive impairment leading to intellectual disability and regression 3
• Intractable epilepsy increases risk through direct neural disruption and secondary effects 3

Critical Clinical Clues for Diagnosis

Red Flag Features Requiring Urgent Evaluation

• Loss of motor milestones is suggestive of a neurodegenerative process 2
• Motor delays present during minor acute illness suggest mitochondrial myopathies that manifest during metabolic stress 2
• Respiratory insufficiency with generalized weakness indicates neuromuscular disorders with high risk of respiratory failure 2
• Fasciculations (most often in the tongue) suggest lower motor neuron disorders like spinal muscular atrophy with risk of rapid deterioration 2

Systemic Features Suggesting Neurometabolic Disease

• Encephalopathic features: microcephaly, macrocephaly, developmental regression, developmental arrest, change in sensorium, seizures, hypotonia, hypertonia, abnormal eye signs 8
• Extrapyramidal or cerebellar signs 8
• Systemic features: abnormal respiration, hepatosplenomegaly, abnormal hair, liver dysfunction, renal tubular dysfunction, cardiomyopathy, feeding difficulties, or growth problems 8

Diagnostic Approach

Initial Screening

• Tests for acidosis, ketosis, hyperlacticemia, and hyperammonemia should be performed initially 8
• Thyroid function studies (T4 and TSH) are reasonable even without classic signs of thyroid disease in children with low tone or neuromuscular weakness 2
• Formal hearing evaluation with audiologic testing must be performed, as even mild hearing loss can significantly impact development and mimic regression 9

Advanced Testing

• Amino acid chromatography and organic acid assays 8
• Specific enzyme assays of white cell or fibroblast culture 8
• Microarray testing as first-line chromosome study per American College of Medical Genetics and Genomics recommendations 2
• Brain MRI plays a critical role in diagnosis, particularly in young children where detailed neurological examination is challenging 2

Timing Considerations

• Patients with suspected acute encephalitis should have access to pediatric neurological specialist opinion within 24 hours of referral 2
• Patients with falling level of consciousness require urgent assessment by pediatric Intensive Care Unit staff 2

Common Pitfalls

• Distinguishing between acquired brain injury versus intellectual disability can be challenging when cognitive changes occur from tumor, hypoxemia, or CNS insult in a child without prior intellectual disability 3
• Pre-regression developmental delays or abnormalities are noted in over two-thirds of Rett syndrome cases, increasing to 85% in youngest cases; absence of a completely normal developmental period does not exclude regression 5
• Hypotonic cerebral palsy should not be diagnosed in children with uneventful perinatal history and normal brain imaging without considering other causes of hypotonia 2
• The timing of environmental insults during fetal development is crucial in determining type and severity of impact on brain structure and function 3