What are the clinical features, diagnostic work‑up, and treatment options for leukodystrophy?

Leukodystrophy: Clinical Features, Diagnostic Work-Up, and Treatment

Overview

Leukodystrophies are genetically determined disorders primarily affecting central nervous system white matter, presenting across a spectrum from infancy to adulthood with progressive neurodegeneration, requiring urgent diagnosis through enzyme testing and genetic analysis, with hematopoietic stem cell transplantation being the only disease-modifying therapy for select types when performed presymptomatically. 1

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Clinical Features by Disease Type

Krabbe Disease (Globoid Cell Leukodystrophy)

Early Infantile-Onset Krabbe Disease (EIKD):

• Presents within first months of life with progressive irritability, spasms triggered by noise stimulation, recurrent unexplained fever, blindness, and deafness 2
• Rapidly progressive course leading to frequent seizures, hyperpyrexia, hypersalivation, complete loss of social contact, and loss of bulbar functions 2
• Death typically occurs within first 2 years due to respiratory complications 2
• Peripheral neuropathy is always present in EIKD 2

Late-Onset Krabbe Disease (LOKD):

• Initial symptoms include visual impairment, ataxia, and irritability, with highly variable age of onset 2
• Peripheral neuropathy may not be observed in LOKD 2

Metachromatic Leukodystrophy (MLD)

Clinical subtypes based on age of onset:

• Late infantile MLD: Most common subtype with uniform presentation and disease dynamics 2
• Juvenile and adult forms: Considerably more variable presentation 2
• Neurologic symptoms: Clumsiness, gait disturbance, worsening coordination, and fine motor skills 2
• Psychiatric symptoms: Bizarre behaviors, emotional lability, personality changes, or psychotic episodes 2
• Disease progression: Most patients progress toward complete loss of cognitive skills and function, with some experiencing periods of stability punctuated by episodic deterioration 2

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Diagnostic Work-Up

Initial Diagnostic Approach

For Suspected Krabbe Disease:

1. Demonstrate low GALC enzyme activity in leukocytes or dried blood spots 2, 1
2. Confirm with GALC gene mutation analysis 2, 1
3. Genotype-phenotype correlation is limited—homozygosity for 30-kb deletion may predict EIKD, but variability exists even with identical genotypes 2

Neurophysiologic Studies

For EIKD patients:

• 100% show abnormal nerve conduction studies (NCS) 2
• 90% have abnormal brainstem auditory evoked responses (BAER) 2
• 65% have abnormal electroencephalogram 2
• 53% have abnormal flash visual evoked potentials (VER) 2

For LOKD patients:

• Only a small percentage show abnormal neurophysiologic studies 2

Neuroimaging

Cranial MRI findings:

• Demyelination of white matter without signs of peripheral nerve involvement 2
• Diffusion tensor imaging (DTI) can identify early motor tract involvement in asymptomatic neonates with Krabbe disease 2, 1

Newborn Screening

New York State screening program:

• Started in August 2006 using MS/MS technology 2
• Through June 2009, screened 769,853 infants with recall rate of 0.018% 2
• Identified 2 infants with EIKD who were transplanted (one died of transplant complications) 2
• Additional infants with low, moderately low, or borderline low enzyme activity are followed closely 2

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Treatment Options

Krabbe Disease

Early hematopoietic stem cell or cord blood transplantation is the only available therapy:

• Timing is critical: Transplantation must occur preferably before 30 days of age for predicted EIKD cases 2, 1
• Presymptomatic infants continue to show psychomotor development and gain milestones after transplantation 2
• Symptomatic infants show only minimal neurologic improvement after transplantation 2
• Mortality rate: 15% overall mortality in presymptomatic transplanted infants 2
• Important caveat: Despite successful engraftment, most transplanted infants still develop signs of neurological disease related to Krabbe disease 2

Transplantation candidates:

• Immediate consideration for cases predicted to have EIKD (e.g., homozygosity for 30-kb deletion, compound heterozygosity for 30-kb deletion with another severe mutation and very low GALC activity) 2
• Genotype cannot predict phenotype in most cases, requiring clinical judgment 2

Follow-Up for Non-Transplanted Cases

Regular monitoring at 6-12 month intervals should include: 2

1. Neurologic examination
2. Cranial MRI
3. Neurophysiologic studies (BAER, VER, electroencephalogram, NCS)
4. Lumbar puncture for cerebrospinal fluid protein if subtle neurological signs present
5. Diffusion tensor imaging to identify early motor tract involvement

Other Leukodystrophies

General treatment landscape:

• No curative treatment available for most leukodystrophies 3, 4
• Symptomatic treatments can significantly decrease disease burden 3
• Stem cell transplantation, gene replacement therapy, and gene editing are under investigation for various leukodystrophies 5
• Hematopoietic stem cell transplant (HSCT) shows promise in select conditions when performed early 3

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Critical Clinical Pitfalls

Timing is everything:

• Transplantation after symptom onset provides minimal benefit in Krabbe disease 2
• Rapid diagnosis is essential as treatments are time-sensitive and must be initiated presymptomatically 1

Diagnostic challenges:

• Genotype-phenotype correlation is limited in many leukodystrophies, including Krabbe disease 1
• Clinical presentation varies widely even with identical genotypes 2
• Fewer than half of leukodystrophy patients receive a specific diagnosis despite incidence of 1 in 7,500 live births 4

Transplant considerations:

• 15% mortality rate even in presymptomatic infants 2
• Most transplanted infants still develop neurological disease despite successful engraftment 2
• Risk-benefit analysis must be individualized based on predicted phenotype and enzyme activity levels 2