Children typically acquire developmental milestones in a variable but predictable sequence (Chapter 7). Rarely, children present with stagnation of development or frank loss of previouslyacquired skills. These neurodegenerative disorders encompassa large heterogenous group of diseases that result from specificgenetic and biochemical defects and varied unknown causes.Neurodegenerative disorders can present at any age. Clinical phenotypes also vary, but neurologic deterioration may bedemonstrated as loss of speech, vision, hearing, and intellectualor motor abilities—sometimes in concert with seizures, feedingdifficulties, and mental retardation. Progression may be slowover many years, or may lead to death in early childhood.
Degenerative diseases may affect gray matter (neuronal degenerative disorders), white matter (leukodystrophies),both gray and white matter, or specific, focal regions of the brain. Early seizures and intellectual impairment mark grey matter disorders, whereas upper motor neuron signs and progressive spasticity are the hallmarks of white matter disorders. Many neurodegenerative illnesses result from enzymatic disorders within subcellular organelles, including lysosomes, mitochondria, and peroxisomes (Table 185-1). Therefore, any
Cognitive regression, hepatosplenomegaly, jaundice, seizures Test: acid sphingomyelinase (ASM) enzyme activity
Hepatosplenomegaly, cytopenia, spasticity, hyperextension, extraocular palsies, trismus, difficulty swallowing
Test: glucosylceramidase enzyme activity
Infantile form—early feeding difficulties, global retardation, seizures, coarse facial features, hepatosplenomegaly, cherry red spot
Juvenile form—incoordination, weakness, language regression; later, seizures, spasticity, blindness
Test: GM1 ganglioside enzyme activity; GLB1 gene testing
Tay-Sachs—progressive weakness, marked startle reaction, blindness, convulsions, spasticity, and cherry red spots
Test: β-hexosaminidase A (HEX A) enzymatic activity Sandhoff disease—phenotype similar to Tay-Sachs
Test: hexosaminidase A and B enzyme activity (both deficient)
Irritability, hyperpyrexia, vomiting, seizures, hypertonia, blindness Test: galactocerebrosidase (GALC) enzyme activity
Late infantile form—stiffening and ataxia of gait, spasticity, optic atrophy, intellectual deterioration, absent reflexes Juvenile and adult forms
Test: 1. arylsulfatase A (ARSA) enzyme activity 2. If ARSA activity is <10% of controls, exclude ARSA pseudodeficiency with genetic testing of ARSA and/or abnormal urinary sulfatide excretion
Visual loss, progressive dementia, seizures, motor deterioration
Test: Diagnostic algorithm depends on age of symptom onset, and replies on stepwise testing for palmitoyl-protein thioesterase 1 (PPT1) and tripeptidyl-peptidase 1 (TPP-1) enzyme activity
Academic difficulties, behavioral disturbances, hypoadrenalism, seizures, spasticity, ataxia, and swallowing difficulties.
Spastic paraparesis, urinary incontinence, adrenal insufficiency Test: very long chain fatty acids
Short stature, kyphoscoliosis, coarse facies, hepatosplenomegaly, cardiovascular abnormalities, and corneal clouding
Test: 1. lysosomal enzymes 2. urinary glycosaminoglycan excretion
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes