What is the pathophysiology, diagnosis, and management of leukodystrophy in children?

Leukodystrophy in Children: Pathophysiology, Neuroimaging, and Etiologies

Leukodystrophies are genetically determined disorders primarily affecting central nervous system white matter development or maintenance, with an incidence of at least 1 in 4,700 live births and significant morbidity and mortality risk. 1

Pathophysiology

The pathophysiologic mechanisms vary by specific leukodystrophy type and involve different white matter cellular components 2:

Primary Cellular Targets

• Oligodendrocyte/myelin defects: Include hypomyelinating disorders (failure of myelin formation), demyelinating disorders (myelin breakdown), and disorders with myelin vacuolization 2
• Astrocytopathies: Primary astrocyte dysfunction affecting white matter support 2
• Leuko-axonopathies: Axonal pathology driving white matter changes 2
• Microgliopathies: Primary microglial dysfunction 2
• Leuko-vasculopathies: Vascular pathology affecting white matter 2

Example: Krabbe Disease (Globoid Cell Leukodystrophy)

Krabbe disease results from galactocerebrosidase (GALC) enzyme deficiency causing accumulation of galactosylceramide and psychosine, leading to progressive white matter damage in both peripheral and central nervous systems. 3

• The characteristic "globoid cells" are multinucleated macrophages storing myelin fragments and galactosylceramide around blood vessels in affected white matter 3
• Inherited as autosomal recessive with over 70 identified GALC gene mutations (missense, nonsense, small deletions) 3
• Incidence approximately 0.91:100,000 overall, with 0.26:100,000 for early infantile form 3

Neuroimaging Findings

General MRI Patterns

Pattern recognition on brain MRI plays a crucial role in diagnosing specific leukodystrophies, though white matter abnormalities may appear similar across different disorders. 4

• Cranial MRI typically shows demyelination of white matter 3
• Additional studies like MR spectroscopy and diffusion tensor imaging (DTI) help refine diagnosis 5

Krabbe Disease-Specific Imaging

• Diffusion tensor imaging can identify early motor tract involvement in asymptomatic neonates with Krabbe disease 3
• MRI may show demyelination without peripheral nerve involvement signs 3
• Imaging findings must be correlated with neurophysiologic studies for complete assessment 3

Etiologies in Children

Classification by Mechanism

Leukodystrophies can be categorized as 5:

• Dysmyelinating disorders: Abnormal myelin formation
• Hypomyelinating disorders: Insufficient myelin production
• Vacuolating disorders: Myelin with vacuolar changes

Specific Genetic Causes

Most leukodystrophies are NOT due to myelin- or oligodendrocyte-specific gene mutations, but rather defects in other white matter components including astrocytes, microglia, axons, and blood vessels. 2

Lysosomal Storage Disorders

• Krabbe disease: GALC gene mutations 3
• Metachromatic leukodystrophy (MLD): Arylsulfatase A deficiency 6

Peroxisomal Disorders

• X-linked adrenoleukodystrophy: Should be suspected in males with primary adrenal insufficiency and negative autoantibody screening; requires very long-chain fatty acid testing 7

Other Metabolic Causes

• Mitochondrial disorders (MELAS, MERRF, Kearns-Sayre syndrome) 6
• Organic acidurias (L-2-hydroxyglutaric aciduria) 6

Age-Specific Presentations

Clinical onset ranges from prenatal life to senescence, with variable disease progression (progressive, static, or improving). 2

Early Infantile Krabbe Disease (EIKD)

• Presents within first months of life with progressive irritability, noise-induced spasms, unexplained fever, blindness, and deafness 3
• Rapidly progressive course with seizures, hyperpyrexia, hypersalivation, loss of social contact, and bulbar dysfunction 3
• Death typically occurs within first 2 years from respiratory complications 3
• Peripheral neuropathy always present 3

Late-Onset Krabbe Disease (LOKD)

• Variable age of onset with visual impairment, ataxia, and irritability as initial symptoms 3
• Peripheral neuropathy may be absent 3

Diagnostic Approach

Krabbe Disease Diagnosis

Diagnosis requires demonstration of low GALC enzyme activity in leukocytes or dried blood spots. 3

• Molecular confirmation via GALC gene sequencing 3
• Genotype-phenotype correlation limited; homozygosity for 30-kb deletion may predict early infantile form 3
• Variability exists even with identical genotypes 3

Neurophysiologic Studies in Krabbe Disease

• All EIKD patients show abnormal nerve conduction studies 3
• 90% have abnormal brainstem auditory evoked responses 3
• 65% have abnormal electroencephalogram 3
• 53% have abnormal flash visual evoked potentials 3
• Only small percentage of LOKD patients show abnormal neurophysiologic studies 3

Modern Diagnostic Tools

Next generation sequencing (whole exome and whole genome sequencing) has dramatically increased the number of identified leukodystrophies to over 100 disorders. 4, 6

• Combination of MRI pattern recognition and genetic testing provides optimal diagnostic yield 4
• Newborn screening programs now include some leukodystrophies (e.g., Krabbe disease screening in New York State since 2006) 3

Management Considerations

Krabbe Disease Treatment

The only current therapy for Krabbe disease is early allogeneic hematopoietic stem cell or cord blood transplantation, which must be performed before symptom onset to impact mortality. 3

• Transplantation in symptomatic patients has poor outcomes 3
• One of two asymptomatic transplanted infants died from transplant complications in New York screening program 3

General Management Principles

While few leukodystrophies have curative treatments, significant opportunities exist for symptomatic care and quality of life improvements. 1

• Most disorders require supportive care 6
• Emerging therapies include gene therapy, enzyme replacement, and stem cell approaches 6
• Rapid diagnosis is critical as some treatments are time-sensitive and must be initiated presymptomatically 1

Common Pitfalls

• Assuming all white matter abnormalities on MRI indicate the same diagnosis—pattern recognition combined with genetic testing is essential 4
• Delaying genetic testing when MRI shows white matter changes—early diagnosis impacts treatment options 1
• Missing adrenoleukodystrophy in males with adrenal insufficiency—always test very long-chain fatty acids 7
• Failing to recognize that genotype-phenotype correlation is limited in many leukodystrophies, including Krabbe disease 3