Regression or loss of acquired maturational milestones

Specialty: Pediatrics.

• Developmental regression
• loss of neurodevelopmental guidelines
• cognitive or motor regression

Why it occurs

• Hereditary neurodegenerative disorders (leukodystrophies, Tay-Sachs disease, adrenoleukodystrophy or neuronal ceroid lipofuscinosis with progressive demyelination)
• Severe childhood epilepsies with cognitive impairment (West syndrome, Lennox-Gastaut syndrome or acquired epileptic aphasia/Landau-Kleffner syndrome)
• Autism spectrum disorders with regression (typically between 15 and 24 months of age, characterized by loss of previously stable social and communication skills)
• Progressive mitochondrial or metabolic encephalopathies (Alpers disease, Leigh syndrome or oxidative phosphorylation defects)
• Chronic infections of the central nervous system or subacute sclerosing panencephalitis (late sequelae of infection by mutated measles virus, currently very rare)
• Specific genetic developmental disorders (Rett syndrome in girls due to a mutation in the MECP2 gene, characterized by language regression and loss of functional use of the hands with manual stereotypies)

Initial workup

Conventional electroencephalogram (EEG) or 24-hour video-EEG (priority to rule out continuous epileptic activity during sleep or Landau-Kleffner syndrome). High-resolution brain magnetic resonance imaging (MRI) with spectroscopy (to assess myelination, integrity of the basal ganglia and rule out leukodystrophy patterns). Complete metabolic analysis: ammonium, lactate, pyruvate, amino acids in blood, organic acids in urine, study of very long chain fatty acids (VLCFA) and lysosomal enzymes in leukocytes. Whole exome sequencing (WES) or bulk sequencing panels (NGS) for neurodegenerative and neurodevelopmental disorders.

Standard management

• Treatment is strictly etiological and specialized. Broad spectrum antiepileptic drugs — as Valproic acid, Clobazam, Vigabatrin or Topiramate according to the epileptic syndrome detected in the EEG
• Systemic corticosteroid therapy or ACTH — adrenocorticotropic hormone, indicated of choice in infantile spasms/West Syndrome to stop maturational deterioration; highly individualized ACTH dosage under strict monitoring of blood pressure and electrolytes
• Enzyme replacement therapies or special metabolic diets in reference centers for specific metabolic errors.