Krabbe Disease
Overview
Plain-Language Overview
Krabbe Disease is a rare inherited disorder that affects the nervous system. It occurs when the body lacks an important enzyme called galactocerebrosidase, which helps break down certain fats in the brain. Without this enzyme, harmful substances build up and damage the protective covering of nerve cells, called the myelin sheath. This damage leads to problems with muscle control, movement, and development. Symptoms often begin in infancy and can include irritability, feeding difficulties, and delayed growth.
Clinical Definition
Krabbe Disease, also known as globoid cell leukodystrophy, is an autosomal recessive lysosomal storage disorder caused by mutations in the GALC gene leading to deficiency of the enzyme galactocerebrosidase. This enzyme deficiency results in accumulation of psychosine, a cytotoxic metabolite, causing widespread demyelination in the central and peripheral nervous systems. The disease typically presents in infancy with progressive neurodegeneration characterized by irritability, spasticity, developmental delay, and peripheral neuropathy. Histopathologically, it is marked by the presence of multinucleated globoid cells and loss of myelin. Diagnosis is confirmed by reduced GALC enzyme activity and genetic testing. Late-onset forms exist but are less common. The disease leads to severe neurological impairment and is usually fatal within the first two years of life without treatment. Current therapeutic options are limited, with hematopoietic stem cell transplantation showing some benefit if performed early.
Inciting Event
- There is no specific inciting event; the disease results from inherited enzyme deficiency.
Latency Period
- none
Diagnostic Delay
- Early symptoms can be nonspecific, leading to misdiagnosis as other neurological disorders.
- Lack of awareness and rarity of the disease contribute to delayed enzyme testing and diagnosis.
Clinical Presentation
Signs & Symptoms
- Progressive psychomotor regression beginning in infancy.
- Irritability and feeding difficulties.
- Seizures in advanced stages.
- Spasticity and hyperreflexia.
- Peripheral neuropathy causing muscle weakness and hypotonia.
History of Present Illness
- Infants typically present with irritability, feeding difficulties, and progressive stiffness or spasticity.
- Developmental regression and loss of motor milestones are common.
- Seizures and vision loss may develop as the disease progresses.
Past Medical History
- No specific past medical history is typically present before symptom onset in infants.
Family History
- A positive family history of Krabbe disease or unexplained infant deaths suggests autosomal recessive inheritance.
- Consanguinity may increase risk due to higher chance of inheriting two defective alleles.
Physical Exam Findings
- Presence of hypertonia and increased deep tendon reflexes due to central nervous system involvement.
- Marked developmental delay and regression in motor milestones.
- Optic atrophy leading to visual impairment.
- Peripheral neuropathy signs such as muscle weakness and decreased reflexes in later stages.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of Krabbe Disease is based on clinical presentation of progressive neurological symptoms in infancy, reduced galactocerebrosidase enzyme activity in leukocytes or fibroblasts, and identification of pathogenic mutations in the GALC gene. Neuroimaging typically shows diffuse white matter abnormalities consistent with demyelination. Histological examination may reveal characteristic globoid cells. Newborn screening programs may detect enzyme deficiency before symptom onset.
Pathophysiology
Key Mechanisms
- Krabbe disease is caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC), leading to accumulation of toxic metabolites like psychosine.
- The buildup of psychosine results in widespread demyelination of the central and peripheral nervous systems.
- Loss of oligodendrocytes and Schwann cells due to toxic metabolite accumulation causes progressive neurological decline.
| Involvement | Details |
|---|---|
| Organs | Brain is the main organ affected, showing progressive demyelination and neurological decline. |
| Peripheral nervous system involvement leads to motor and sensory deficits. | |
| Tissues | White matter of the central nervous system is primarily affected due to demyelination. |
| Peripheral nerves also undergo demyelination leading to peripheral neuropathy. | |
| Cells | Oligodendrocytes are the primary cells affected in Krabbe disease due to accumulation of toxic metabolites causing demyelination. |
| Macrophages accumulate as globoid cells in the nervous system and contribute to neuroinflammation. | |
| Chemical Mediators | Psychosine accumulates due to deficient galactocerebrosidase and is toxic to myelin-producing cells. |
| Proinflammatory cytokines released by activated macrophages contribute to neurodegeneration. |
Treatment
Pharmacological Treatments
Hematopoietic stem cell transplantation (HSCT)
- Mechanism: Provides donor-derived cells that can produce functional galactocerebrosidase enzyme to reduce substrate accumulation
- Side effects: Graft-versus-host disease, infection, transplant-related mortality
Non-pharmacological Treatments
- Supportive care including physical therapy to maintain mobility and prevent contractures.
- Nutritional support to manage feeding difficulties and maintain adequate growth.
- Respiratory support to manage recurrent infections and respiratory insufficiency.
Prevention
Pharmacological Prevention
- None currently available; no approved drug-based prevention.
Non-pharmacological Prevention
- Newborn screening for early detection in at-risk populations.
- Hematopoietic stem cell transplantation (HSCT) in presymptomatic patients may slow disease progression.
Outcome & Complications
Complications
- Respiratory failure due to bulbar dysfunction and aspiration pneumonia.
- Seizure disorders secondary to progressive CNS demyelination.
- Nutritional deficiencies from feeding difficulties.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
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Differential Diagnoses
Krabbe Disease versus Adrenoleukodystrophy
| Krabbe Disease | Adrenoleukodystrophy |
|---|---|
| Autosomal recessive inheritance without adrenal insufficiency | X-linked inheritance with adrenal insufficiency and progressive neurologic decline |
| Normal VLCFA levels in plasma | Very long chain fatty acids (VLCFA) accumulation in plasma |
| MRI shows diffuse cerebral white matter involvement including corticospinal tracts | MRI shows occipital white matter demyelination |
Krabbe Disease versus Canavan Disease
| Krabbe Disease | Canavan Disease |
|---|---|
| Galactocerebrosidase deficiency with no NAA accumulation | Aspartoacylase deficiency causing accumulation of N-acetylaspartic acid (NAA) |
| Normal head circumference or microcephaly in early infancy | Macrocephaly and severe developmental delay in infancy |
| MRI shows globoid cells and demyelination without spongiform changes | MRI shows diffuse symmetric white matter spongiform changes |
Krabbe Disease versus Metachromatic Leukodystrophy
| Krabbe Disease | Metachromatic Leukodystrophy |
|---|---|
| Galactocerebrosidase deficiency causing accumulation of psychosine | Arylsulfatase A deficiency leading to accumulation of sulfatides |
| Rapid infantile onset with irritability, spasticity, and peripheral neuropathy | Demyelination predominantly affecting the central and peripheral nervous system with ataxia and dementia |
| Elevated psychosine levels in blood and decreased galactocerebrosidase activity | Tandem mass spectrometry shows elevated sulfatides in urine |