Neuro-Ophthalmic Findings in Krabbe Disease

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Disease Entity

Krabbe disease, or globoid cell leukodystrophy, is a lysosomal storage disease characterized by progressive neurodegeneration due to a genetic β-galactocerebrosidase deficiency.[1] It typically presents with bilateral loss of visual acuity, supine postural nystagmus, and extraocular movement defects.[1]


There are infantile, juvenile, and adult-onset forms of Krabbe disease, with the infantile-onset form being most common.[2]

The infantile form typically develops around 6 months of age, presenting with irritability and delayed motor development. Most patients succumb to the illness between 2 and 4 years of age.[3][4]

The later onset variant features slower progression than the adult form, which typically progresses over more than 10 years. [3][4]


Krabbe disease is a rare autosomal recessive disorder.[1] Mutations in the β-galactocerebrosidase gene (galc) on chromosome 14 result in decreased or absent functioning levels of the enzyme β-galactocerebrosidase (GALC).[5] Reduction of GALC activity causes an accumulation of galactocerebroside and psychosine, which are highly cytotoxic lipids.[6] Accumulation of galactocerebroside can be found in many visceral organs of affected individuals. It is especially toxic to oligodendrocytes and myelin, causing rapid and fatal neurodegeneration.[7]

The galc gene is a 60kb gene in length, containing 17 exons and 16 introns.[8] Over 130 distinct mutations, resulting from missense, nonsense, deletions, and insertions, have been cataloged in the Human Gene Mutation Database (HGMD).[9]

Of note, individuals with homozygous mutations of the galc gene tend to demonstrate earlier disease progression, and overall mortality rates for infancy-onset Krabbe disease is >90%.[10][11] Genetic research also indicates that the infantile form of Krabbe disease often has mutations in the central domain, while the adult-onset form results from mutations in the N-terminus or C-terminus.[12]

Additionally, large kilobase (30kb) deletions to the galc gene are the most common mutation and correlate with severe manifestations.[8] In Northern Europe, 30kb deletions are responsible for 40%-45% of the mutations in the infantile form. A similar trend was observed in Mexico with 30kb deletions being present in 35% of infantile form patients.[13]

Vision loss is a common manifestation of Krabbe disease. Accumulation of galactocerebroside and psychosine causes retrograde degeneration of the optic nerve, ultimately leading to loss of retinal axons and ganglion cells.[14]


Krabbe disease is caused by a deficiency of galactocerebrosidase. This enzyme functions as an acid hydrolase that degrades galactocerebrosides and sphingolipids, both of which are components of myelin. Their disruption eventually leads to the toxic accumulation of derivative byproducts in oligodendrocytes and Schwann cells.[2]

Despite the identification of over 75 pathogenic GALC mutations, a mutation that predicts age of onset remains unknown.[3]

Risk Factors

Due to the autosomal recessive nature of inheritance, key risk factors for Krabbe disease include:

  • Family history of the condition[1]
  • Presence of a mutated copy of the galc gene in either parent[1]



As Krabbe disease must be diagnosed early for currently available therapies to slow progression, a thorough history should be taken when suspecting Krabbe or other lysosomal storage diseases, including:

  • Age of onset[15]
  • Delayed or missed developmental milestones[15]
  • Family history of neurodevelopmental disorders[15]
  • Change in behavior/mood[15]

Physical examination

A thorough ophthalmic and neurologic exam should be performed. Positive neuro-ophthalmic findings can include:

  • Bilateral loss of visual acuity to total blindness[4]
  • Supine postural nystagmus[4]
  • Poor optokinetic responses[4]
  • Symmetric CN III and CN VI palsies[4]

Positive neurologic findings can include:

Ocular Findings

Slit lamp and dilated fundoscopic examination can be used to rule out anterior segment pathology along with other commonly identifiable etiologies. Both are typically unremarkable in Krabbe disease.[17]

Laboratory Testing & Imaging

The guidelines regarding laboratory testing vary based on the age of onset. Newborn screening for Krabbe disease is performed in a growing minority of states in the US. It is performed using tandem mass spectrometry assays followed by a second confirmatory tier of testing typically including full Sanger sequencing of the GALC gene in highly suspected cases.[15][16]

Brain MRI can be used to identify the location of demyelinating lesions, with white matter hyperintensities commonly affecting heterogenous locations along the corticospinal tract, the corpus callosum, and the optic radiations.[4][18] Enhancement of cranial nerves III and VI has also been reported. Interestingly, optic nerve enlargement is an uncommon finding that contradicts the diffuse white matter atrophy seen in Krabbe disease.[17]

A diagnostic algorithm summarizing the steps clinicians should take when evaluating patients for Krabbe disease is shown below.

Figure 1: Diagnostic Algorithm for Krabbe Disease

Differential diagnosis

The differential diagnosis for Krabbe Disease includes:

  • Metachromatic leukodystrophy[19][20]
  • GM1/GM2-gangliosidosis (and other Hexosaminidase A deficiency disorders)[20][21]
  • X-linked adrenoleukodystrophy[20]
  • Pelizaeus-Merzbacher disease[20]
  • Canavan disease[20][22]
  • Alexander disease[20][23]

Management & Outcomes

Currently, there are no curative treatments for Krabbe disease. Most management options focus on symptomatic treatment and supportive care.[3] Of note, hematopoietic stem cell transplantation (HSCT) is a disease-modifying treatment that can slow the progression of infantile-onset Krabbe disease.[24] However, HSCT is only effective in delaying progression of infantile-onset Krabbe disease if initiated before symptomatic onset.[2] There are no therapies available for adult-onset Krabbe disease.

Routine newborn screening for Krabbe disease is not currently recommended due to its severely limited treatment options and low prevalence.[25]

Exploration of combination therapies that include HSCT, enzyme replacement therapy (ERT) of β-galactocerebrosidase, and substrate reduction therapy (SRT) of galactocerebroside and psychosine and have yielded varying results in twitcher mice models.[26] Translation of these studies to human models have been severely limited by the interaction of these targeted enzymes and substrates with numerous other physiologic processes that share similar metabolic pathways.[2]

Very recently, small trials on adeno-associated virus (AAV) gene therapies in twitcher mice, rhesus monkey, and canine studies have yielded encouraging results, demonstrating significant improvements in mortality, symptoms, and disease progression for these animal models.[27][28][29]

Krabbe disease is a rapidly-progressing disorder, with most patients succumbing before the age of 2.[3] Despite the poor prognosis of Krabbe disease, advancing understanding of its pathophysiology and the advent of new treatments for complex genetic diseases, provide promise for improvements both management and prognosis.


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