Neuro-ophthalmological findings in Krabbe disease

Key Points at a Glance

Key Points at a Glance

• Krabbe disease is a lysosomal storage disorder caused by GALC gene mutations and follows an autosomal recessive inheritance pattern.
• Approximately 90% are early infantile type (onset within 6 months of birth), and most die between 2 and 4 years of age.
• Optic atrophy is the most characteristic ocular finding and is known as a representative ocular symptom of Krabbe disease among sphingolipidoses.
• In the juvenile type, visual dysfunction is the most common clinical symptom.
• Hematopoietic stem cell transplantation (HSCT) is the only disease-modifying therapy, but for the infantile type, ultra-early administration before symptom onset is essential.
• GALC enzyme activity measurement, psychosine measurement, and brain MRI form the mainstay of diagnosis.
• Several treatments including AAV gene therapy have shown promising results in animal models, and clinical trials are ongoing.

1. Neuro-ophthalmological findings in Krabbe disease

Krabbe disease, also called globoid cell leukodystrophy (GLD), is an autosomal recessive lysosomal storage disorder. Deficiency of the enzyme galactocerebrosidase (GALC) leads to accumulation of galactocerebroside and psychosine, causing progressive demyelination. It is classified as a sphingolipidosis.

In 1916, Danish neurologist Knud Krabbe first reported five cases of white matter lesions as “diffuse brain sclerosis” ⁵⁾. The multinucleated giant cells (globoid cells) that appear in the affected white matter give the disease its name.

Epidemiology: Incidence is about 1:100,000 in Europe, 1:394,000 in New York State, and as high as 1:100 to 1:150 in consanguineous communities (e.g., Druze) ³⁾. Approximately 90% are early infantile type (onset within 6 months of birth), and most die by 2–4 years of age ²⁾.

Clinical classification: Classified into 5 types based on age of onset⁷⁾.

Type	Age of onset	Frequency
Early infantile type	0–6 months	85–95%
Late infantile type	7–12 months	Few
Late juvenile type	13 months–10 years	Few
Adolescent type	11–20 years	Few
Adult type	21 years and older	Few

Q What are the types of Krabbe disease?

A

Based on age of onset, it is classified into five types: early infantile, late infantile, late childhood, adolescent, and adult types⁷⁾. Approximately 90% are early infantile type, and late-onset types (late childhood and later) account for 5–15% of all cases.

2. Main symptoms and clinical findings

Subjective symptoms

Infantile type main symptoms are as follows.

• Irritability: Begins with nonspecific symptoms such as poor feeding and crying.
• Motor developmental delay: Presents with psychomotor regression where acquired motor functions are lost.
• Spasticity and hypertonia: Progresses to opisthotonos and decerebrate rigidity.

Symptoms of the late-onset type (late infantile/juvenile type) are as follows:

• Distal limb muscle weakness and lower limb spasticity. Presents with frequent falls and high-arched feet ²⁾.
• Visual dysfunction: The most common symptom in the juvenile type ⁷⁾.
• Gait disturbance: Progresses from spastic gait ²⁾.

The main symptoms of the adult-onset type are as follows.

• Chronic progressive spastic paralysis and gait disturbance are the main symptoms⁷⁾.
• Cognitive impairment, psychiatric symptoms, and peripheral neuropathy may be present⁷⁾.

Clinical Findings

Neuro-ophthalmological Findings

Optic atrophy is known as the representative ocular symptom of Krabbe disease among sphingolipidoses and is the most characteristic ocular finding.

Ocular findings in infantile type

Optic atrophy: Most characteristic. Confirmed on imaging as optic neuropathy or chiasmal lesion.

Visual loss to total blindness: Occurs bilaterally with progression.

Nystagmus (supine postural nystagmus): Supine postural nystagmus has been reported.

Poor optokinetic response: Decreased optokinetic responses are observed.

Cranial nerve palsy: Symmetric III and VI cranial nerve palsies (oculomotor and abducens nerves) appear.

Cherry-red spot: May be faintly observed.

Late-onset and adult-onset ocular findings

Visual dysfunction: Most common clinical symptom in the juvenile form⁷⁾.

Optic atrophy: Less common in the adult form compared to the juvenile form⁷⁾.

Visual loss or blindness: Visual impairment or blindness occurs in 12.5% of late infantile cases⁷⁾.

Optic nerve enlargement: Reported as a rare finding inconsistent with diffuse white matter atrophy.

Neurological Findings (Non-ophthalmological)

• Spastic paraparesis, opisthotonus, decerebrate rigidity
• Dysarthria, cerebellar ataxia, tongue atrophy, cognitive decline
• Three-stage course in infantile form: nonspecific symptom stage → progressive stage (optic atrophy, worsening convulsions, psychomotor regression) → burnt-out stage ⁷⁾

Imaging Findings

Brain MRI shows white matter hyperintensities along the optic radiation. In the infantile form, the cerebellar white matter and dentate nucleus are mainly affected, while in the adult form, lesions are localized to the parietal white matter, corona radiata, optic radiation, and periventricular white matter around the posterior horns ⁷⁾. Contrast enhancement of the oculomotor and trigeminal nerves has been reported in the infantile form ⁷⁾.

Q What are the typical ocular findings seen in Krabbe disease?

A

Optic atrophy is the most characteristic ocular finding and is known as a representative ocular symptom of sphingolipidosis. Other reported findings include cherry red spot, nystagmus (supine positional nystagmus), decreased visual acuity to total blindness, and oculomotor and abducens nerve palsy. In the juvenile form, visual dysfunction is the most common clinical symptom ⁷⁾.

3. Causes and Risk Factors

Causative Gene

The GALC gene is the causative gene. It is located on chromosome 14 at 14q31.3 and consists of 17 exons and 16 introns. The total length is approximately 58-60 kb, and over 296 mutations (missense, nonsense, deletions, insertions) are registered in HGMD ²⁾³⁾.

The GALC protein consists of 669 amino acids and has six N-glycosylation sites. It adopts a three-domain structure: TIM barrel, β-sandwich, and lectin domain ³⁾.

Major Mutations

30kb deletion is the most common mutation, accounting for 30–50% of infantile cases. In Northern Europe, 40–45% of infantile mutations are due to this deletion, which is strongly correlated with severe disease ³⁾.

There are regional differences in mutations.

Region	Major Mutation
China	H253Y, S259L, P318L, F350V, T428A, L530P, G586D
Japan	I66M+I289V, G270D, T652P
Europe	P318R, G323R, I384T, Y490N

Common mutations in late-onset type: p.G57S, p.T112A, p.D187V, p.G286D, p.P318R, p.L634S⁶⁾. In particular, p.L634S (c.1901T>C) is frequently found in late-onset type in China and Japan and is associated with mild type²⁾.

As for genotype-phenotype correlation, infantile type tends to be associated with central domain mutations, while adult type tends to be associated with N-terminal and C-terminal mutations⁷⁾.

Other Risk Factors

• Family history, parents are carriers of GALC mutation
• SapA (Saposin A) deficiency: A rare condition where GALC activity is preserved but psychosine is elevated, presenting a Krabbe disease-like phenotype³⁾
• Inheritance pattern: Autosomal recessive (AR)

Genetic Counseling

Krabbe disease is inherited in an autosomal recessive pattern. If both parents are carriers of a GALC mutation, the risk of the child developing the disease is 25%. If there is a family history, genetic counseling is recommended.

Q Are there regional differences in the genetic mutations of Krabbe disease?

A

Regional differences in mutations are known. In Japan, I66M+I289V, G270D, and T652P are frequently reported³⁾. Additionally, p.L634S is a mutation commonly found in late-onset forms in China and Japan²⁾.

4. Diagnosis and Testing Methods

Enzyme and Biomarker Testing

• GALC enzyme activity measurement: Measured in leukocytes or cultured fibroblasts. Reduced activity is the basic diagnostic method³⁾⁷⁾. Normal values are 29.46–34.40 nmol/17h/mg, and the reference value is ≥12.70 nmol/17h/mg²⁾. In late-onset forms, activity may be only slightly below the reference value (e.g., 11.63, 11.65 nmol/17h/mg)²⁾.
• Psychosine level: Measured in dried blood spots. It is an excellent biomarker for early infantile forms³⁾. In late-onset forms, levels may be normal to low, requiring careful interpretation⁶⁾.
• Newborn screening (NBS): Measurement of GALC activity by tandem mass spectrometry. Performed in 8 states in the US³⁾.

Genetic Testing

Whole exome sequencing (WES) or Sanger sequencing identifies GALC mutations. In familial cases, targeted testing for known mutations is useful.

Brain MRI

• Infantile type: White matter hyperintensities along the cerebellar white matter, dentate nucleus, corticospinal tract, corpus callosum, and optic radiation⁷⁾
• Adult type: Lesions localized to the parietal white matter, corona radiata, optic radiation, and periventricular white matter around the posterior horns⁷⁾
• Contrast enhancement: Generally rare, but contrast enhancement of cranial nerves (oculomotor, trigeminal) has been reported
• Optic nerve hypertrophy: A rare finding inconsistent with diffuse white matter atrophy

Nerve conduction study

Useful for detecting demyelinating sensorimotor neuropathy. Prolonged F-wave latency and reduced motor nerve conduction velocity are common findings ⁷⁾.

Diagnostic algorithm

Wu et al. (2022) proposed diagnostic criteria for adult-onset GLD ⁷⁾. The core symptom is “chronic progressive symmetric spastic paralysis,” and the approach proceeds in the order of electrophysiological testing → imaging → enzyme/genetic testing.

Differential Diagnosis

• Metachromatic leukodystrophy, GM1/GM2 gangliosidosis, X-linked adrenoleukodystrophy
• Pelizaeus-Merzbacher disease, Canavan disease, Alexander disease
• In adult-onset cases, differentiation from Charcot-Marie-Tooth disease (CMT) and hereditary spastic paraplegia (HSP) is particularly important²⁾⁷⁾

5. Standard Treatment

No curative treatment currently exists. Management is centered on symptomatic and supportive therapy.

Hematopoietic Stem Cell Transplantation (HSCT)

Currently, this is the only disease-modifying therapy available³⁾⁷⁾.

• Indications for infantile type: Must be initiated before symptom onset (before 31 days of age) for effectiveness; otherwise, benefits are limited³⁾. Successful treatment at 24–40 days of age has been reported with survival at 30–58 months¹⁾.
• Indications for late-onset type: High recovery rates have been reported in 5 cases of late-onset type after HSCT¹⁾. However, long-term outcome data for late-onset and adult types are extremely scarce⁶⁾.
• After symptom onset in infantile type: Effectiveness is limited.

Indications for HSCT

Infantile type (pre-symptomatic): The only condition where significant disease-modifying effects can be expected. The goal is administration before 31 days of age.

Late-onset and adult types: A few successful cases have been reported. Long-term outcome data are limited, and indications are determined on a case-by-case basis.

Infantile type (post-symptomatic): Effects are limited. It is highly likely that disease progression cannot be halted.

Side effects and risks

Graft-versus-host disease (GVHD): A major complication risk of HSCT.

Infertility and growth abnormalities: Reported as long-term side effects ⁴⁾.

Limited effectiveness: In cases where the timing is missed, no disease-modifying effect is obtained.

Symptomatic and supportive therapy

• Management of spasticity: Muscle relaxants and physical therapy
• Epileptic seizures: Antiepileptic drugs
• Nutritional management: Tube feeding according to dysphagia
• IVIg (intravenous immunoglobulin): Improvement of limb muscle strength has been reported in adult-type KD patients¹⁾⁷⁾

Enzyme Replacement Therapy (ERT)

Due to the challenge of crossing the blood-brain barrier (BBB), its effectiveness is limited, and it is not an established treatment at present⁷⁾.

Precautions in Treatment

In infantile Krabbe disease, HSCT must be performed very early before symptom onset to achieve significant benefit. Asymptomatic cases detected by newborn screening are most likely to benefit from HSCT. Once symptoms appear, disease modification is difficult, and symptomatic treatment becomes the mainstay of therapy.

Q What is the current standard treatment for Krabbe disease?

A

There is no curative treatment; HSCT is the only disease-modifying therapy. In the infantile form, very early administration (before 31 days of age) before symptom onset is essential³⁾. If this timing is missed, symptomatic and supportive care become the mainstay. Long-term outcome data for late-onset and adult forms are extremely limited⁶⁾.

6. Pathophysiology and Detailed Pathogenesis

Psychosine Hypothesis

GALC deficiency leads to accumulation of galactocerebroside and psychosine (galactosylsphingosine)³⁾. Psychosine can only be degraded by GALC, so its accumulation becomes uncontrollable in GALC deficiency³⁾. Recently, acid ceramidase (ACD) was identified as the main pathway for psychosine production from galactocerebroside⁵⁾.

Toxic Mechanisms of Psychosine

Accumulated psychosine causes nerve damage through multiple mechanisms.

• Cell membrane damage: Detergent-like action disrupts the structure and function of lipid rafts⁷⁾
• Apoptosis induction: Induces apoptosis of oligodendrocytes and Schwann cells, leading to demyelination³⁾⁷⁾
• Signal abnormality: SAPK (stress-activated protein kinase) activation, PI3K pathway inhibition⁷⁾
• Mitochondrial dysfunction: ATP consumption due to sPLA2 activation and AMPK inactivation⁷⁾
• Neuroinflammation: Elevation of cytokines and chemokines such as TNF-α, IL-1β, IL-6, CCL2³⁾
• Axonal transport impairment: Neurofilament abnormalities due to GSK3β activation⁷⁾
• Microvascular damage: BBB disruption, inhibition of angiogenesis⁷⁾

Mechanism of visual impairment

Accumulation of galactocerebroside and psychosine causes retrograde degeneration of the optic nerve, leading to loss of retinal axons and ganglion cells. This pathway forms the pathological basis of optic atrophy and visual impairment.

Relationship with myelination stage

Since damage occurs during active myelination, the affected site differs depending on the disease type. In the adult form, cerebellar white matter myelination is complete by adulthood, so cerebellar lesions do not occur⁷⁾.

Globoid cells

Macrophage-derived multinucleated giant cells (globoid cells) appear in the white matter with positive periodic acid-Schiff staining. They form prior to demyelination³⁾.

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7. Latest Research and Future Prospects (Research-stage Reports)

For Patients: Please Read Carefully

The following content is currently in the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

AAV Gene Therapy

Results in animal models have been remarkable, and translation to clinical trials is progressing.

According to Nasir et al. (2021), twitcher mice receiving AAV9 via ICV, IT, and IV routes reached a survival of 263 days (untreated control group: 40 days)³⁾.

IV administration of AAVrh10 to twitcher mice extended lifespan to 72 days with a standard dose (4×10¹³ gc/kg) and to 280 days with a 10-fold dose (4×10¹⁴ gc/kg)⁴⁾.

In a canine model, AAV9 administered via cisterna magna resulted in survival over 3 years (normal survival 16 weeks)⁵⁾, and vector distribution to deep white matter such as the internal capsule has been noted as a future challenge.

Forge Biologics Clinical Trial (NCT04693598): A phase I/II trial combining AAV and HSCT is ongoing³⁾.

Substrate Reduction Therapy (SRT)

Several approaches are being investigated as strategies to suppress the production of accumulated substrates.

• L-cycloserine (serine palmitoyltransferase inhibitor) + BMT → twitcher mouse survival 120 days (untreated 40 days)⁵⁾
• Triple combination therapy (BMT + AAV5 + L-cycloserine) → twitcher mouse survival 300 days⁵⁾
• S202 amide (galactosyltransferase inhibitor): has been shown to reduce GalCer and psychosine and prolong survival¹⁾
• Acid ceramidase inhibitors (e.g., carmofur): Reduction of brain psychosine has been reported⁵⁾

Other Treatment Approaches

• rapamycin (mTOR inhibitor): autophagy activation, induction of cortical myelination, and normalization of neurite density have been reported¹⁾
• iPSC/NSC model: Used as an in vitro tool to elucidate the pathology of GLD ¹⁾
• BBB penetration strategy: Development of focused ultrasound, mannitol osmotic disruption, and engineered AAV constructs (ApoB-BD, IDS signal peptide) is ongoing ⁴⁾

Q Are clinical trials for gene therapy progressing?

A

Forge Biologics is conducting a clinical trial of AAV combined with HSCT (NCT04693598) ³⁾. In animal models, triple combination therapy (BMT + AAV5 + L-cycloserine) has been reported to significantly extend survival of twitcher mice to 300 days ⁵⁾, but all are currently at the research stage.

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8. References

1. Maghazachi AA. Globoid Cell Leukodystrophy (Krabbe Disease): An Update. ImmunoTargets Ther. 2023;12:105-111.

2. Sun Y, Zheng J, He L, et al. Late-Onset Krabbe Disease: Case Report of Two Patients in a Chinese Family and Literature Review. Mol Genet Genomic Med. 2025;13:e70065.

3. Nasir G, Chopra R, Elwood F, Ahmed SS. Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy. Front Med. 2021;8:760236.

4. Rafi MA. Krabbe disease: A personal perspective and hypothesis. BioImpacts. 2022;12(1):3-7.

5. Bradbury AM, Bongarzone ER, Sands MS. Krabbe disease: New hope for an old disease. Neurosci Lett. 2021;752:135841.

6. Nicita F, Stregapede F, Deodato F, et al. “Atypical” Krabbe disease in two siblings harboring biallelic GALC mutations including a deep intronic variant. Eur J Hum Genet. 2022;30:984-988.

7. Wu G, Li Z, Li J, et al. A neglected neurodegenerative disease: Adult-onset globoid cell leukodystrophy. Front Neurosci. 2022;16:998275.