Krabbe Disease

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Top Contributors - Trista Chan and Vidya Acharya

Introduction

Krabbe disease, also known as crab-A or globoid cell leukodystrophy. Krabbe Disease is a rare progressive neurodegenerative condition caused by deficits in an autosomic recessive GALC gene, often pass from carrier parents to child. The broken GALC gene leads to deficiency of the enzyme galactosylceramidase, and results in the breakdown of the myelin sheath in the nervous system. Individuals affected presents with severe neurological symptoms, muscle rigidity, and motor function loss. The incidence of Krabbe disease varies by region, with estimates of 1 per 100,000 live births in Europe, 1 per 250,000 in the U.S., and as high as 6 per 1,000 in Israel's Druze community from consanguineous marriages.

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Mechanism of Injury / Pathological Process

Krabbe Disease primarily affects the nervous system. It is caused by a deficiency of the enzyme galactosylceramidase, which is responsible for breaking down specific glycolipids found mainly in the myelin sheath. The absence of galacosylceramidase leads to accumulation of toxic substrate, such as galactosylceramide and psychosine in oligodendrocytes and Schwann cells and causes demyelination. This can occur in the central and peripheral nervous system. Extensive astrocytic scarring (fibrillary gliosis) occurs to replace the lost oligodendrocytes and myelin, followed by infiltration of globoid cells, which are macrophages that cluster around blood vessels in areas of active demyelination. Peripheral nerves also becomes enlarged, fibrotic, and show signs of demyelination. The pathology in later-onset forms of Krabbe Disease is less severe, and these individuals usually have longer life expectancy.

Clinical Presentation

The symptoms of Krabbe disease can vary significantly depending on whether it has infantile, juvenile, or adult onset.

Early Onset Krabbe Disease

Classic infantile Krabbe disease primarily affecting the brain's white matter. Krabbe disease in early childhood often progressing quickly, and results in early death. Children usually born normal and starts to show regression in developmental milestones. This usually occur by 6 months, and children rarely live past 4-6 years old. Around 85-90% of cases are infantile-onset, the most severe form, with a mortality rate of 90% within the first two years.

Infantile Onset

Early onset Krabbe diseas occurs in infants 0-13 months. This usually progresses through 3 stages:

Stage I: increase irritability, sensitivity to stimuli, and frequent unexplained crying. Other symptoms include delayed development, vomiting, feeding difficulties, unexplained fever and convulsive seizures.

Stage II: The disease rapidly worsens, with severe motor and mental decline. The child develops extensor tone and hyperreflxia. Minor tonic or clonic seizures may also occur. Vision deteriorates due to optic nerve damage, and the pupils don't react well to light.

Stage III: This final stage occurs within a few months. The child loses brain function, vision and becomes unresponsive to the environment. Most children with this form of Krabbe disease do not survive beyond 2 to 3 years.

Late Infantile Onset

Children from 13-36 months with late infantile onset of Krabbe Disease often experience early symptoms include irritability, psychomotor decline, muscle stiffness, ataxia, and vision loss. Similar to infantile onset, the condition progressively worsens, typically leading to death within 2 to 3 years after symptoms begin.

Late Onset Krabbe Disease

The presentation of late onset Krabbe Disease is variable. While most patients develop first signs or symptoms by the age of 10, some can still develop neurological signs up to their 40s.

Juvenile Onset

Juvenile onset refers to indivisuals who developed signs or symptoms from 3-16 years old.Cerebrospinal fluid protein levels are usually normal or only slightly elevated in juvenile patients. These patients typically experience vision loss along with hemiparesis, ataxia, and psychomotor decline. Some may present as attention deficit hyperactivity disorder. The disease often worsen over time, and children often have lifespan of 10 years from their time of onset.

Adult Onset

Adult onset typically refers to Krabbe disease onset that occurs after 16 years old. In adult patients, cerebrospinal fluid protein levels are typically normal or only mildly elevated. Adult patients may occasionally develop a slowly progressive spastic paraparesis.Other reported symptoms in adult onset Krabbe disease include burning paresthesias in the extremities, mood and behavior changes, ataxia, spasticity, visual impairments or blindness, seizures, hearing loss or deafness, and psychomotor retardation. Most experience combination of motor and cognitive decline. Some adults may live a normal lifespan.

Diagnostic Procedures

Early diagnosis is essential to ensure better quality of life.

Previously pathologic examination of the brain or peripheral nerves was the only method of definitive diagnosis before knowing about the enzymatic defect.

Diagnosis methods:

• newborn screening
• MRI, neuropathological screening
• psychosine level
• exome gene sequencing & detection of GALC mutation
• opthalmologic & Otoloaryngologic assessment
• lumbar puncture
• EMG & nerve conduction studies
  

Outcome Measures

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Management / Interventions

Medical Management

• Enzyme replacement
• Substrate reduction
• Enzyme chaperones
• Gene therapy

Differential Diagnosis

• Alexander disease
• Canavan disease
• GM2 gangliosidoses
• Metachromatic leukodystrophy
• Sphingomyelinase deficiency

Resources

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