What are the other Names for this Condition? (Also known as/Synonyms)

• Galactocerebrosidase Deficiency Disorder
• Galactosylceramide Beta-Galactosidase Deficiency Disorder
• Globoid Cell Leukodystrophy (GCL)

What is Krabbe Disease? (Definition/Background Information)

• Krabbe Disease is an inherited condition that affects the nervous system. The signs and symptoms of the condition and the disease severity differ by type
• Babies affected by early-onset (infantile) Krabbe Disease, the most common and severe form of the condition, typically develop features in the first six months of life
• Symptoms of infantile Krabbe Disease may include irritability; failure to thrive; slowed development; unexplained fevers; and progressive muscle weakness, hearing loss and vision loss
• People affected by the late-onset forms of Krabbe Disease may not develop symptoms until later in childhood, early adolescence or even into adulthood. Signs and symptoms of these forms are extremely variable but may include muscle weakness and rigidity; walking difficulties; vision loss; intellectual regression; and/or seizures
• Krabbe Disease is caused by changes (mutations) in the GALC gene and is inherited in an autosomal recessive manner
• Treatment for Krabbe Disease is generally based on the signs and symptoms present in each person; however, preliminary studies suggest that it may be beneficial to use hematopoietic stem cell transplantation (i.e. umbilical cord blood stem cells) as a treatment for patients in the early stages of infantile Krabbe Disease and older people with mild symptoms

(Source: Krabbe Disease; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Krabbe Disease? (Age and Sex Distribution)

• Krabbe Disease is a rare inherited disorder, with a prevalence of 1 in 100,000 to 250,000 worldwide
• The onset of symptoms may occur at any age. However, the infantile form is the most common (in the Northern European population, it accounts for up to 90% of all cases)
• Both genders may be affected by this disorder
• Worldwide, individuals of all races and ethnicities may be affected

What are the Risk Factors for Krabbe Disease? (Predisposing Factors)

• A positive family history may be an important risk factor, since Krabbe Disease is an inherited condition
• Children of consanguineous parents may bear an increased risk of being born with the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Krabbe Disease? (Etiology)

Krabbe Disease is a genetic disorder that is the result of mutation(s) involving the GALC gene.

• This gene codes for the galactosylceramidase, an enzyme that catalyzes the breakdown of a type of fat found in the brain and kidneys
• A mutation of GALC gene causes deficiency of the enzyme, and results in progressive loss of myelin sheath around nerve cells
• The loss of myelin leads to dysfunction of nerves, and the signs and symptoms of this disease
• Krabbe Disease is inherited in an autosomal recessive manner

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Krabbe Disease?

The signs and symptoms of Krabbe Disease can develop at different ages. Babies affected by early-onset (infantile) Krabbe Disease typically develop features in the first six months of life, while people affected by the late-onset forms may not develop symptoms until later in childhood, early adolescence, or even into adulthood.

Approximately 85-90% of people affected by Krabbe Disease have the infantile form, which is characterized by the following features:

• Irritability
• Hypertonia
• Sensitivity to loud sounds
• Developmental delay and/or regression
• Unexplained fevers
• Vomiting and other feeding difficulties
• Vision loss
• Failure to thrive
• Peripheral neuropathy
• Seizures
• Hearing loss

Signs and symptoms of the later-onset forms are extremely variable but may include muscle weakness and rigidity; walking difficulties; vision loss; intellectual regression; and/or seizures.

The signs and symptoms of Krabbe Disease may include:

• Abnormal flash visual evoked potentials 
• Autoimmune thrombocytopenia 
• Autosomal recessive inheritance 
• Blindness 
• CNS demyelination 
• Decerebrate rigidity 
• Decreased nerve conduction velocity 
• Developmental regression
• Diffuse cerebral atrophy 
• EEG abnormality 
• Episodic fever
• Failure to thrive
• Hearing impairment
• Hydrocephalus 
• Hyperactive deep tendon reflexes 
• Hypertonia 
• Increased CSF protein  
• Motor deterioration
• Muscular hypotonia 
• Neurodegeneration 
• Nystagmus 
• Optic atrophy 
• Peripheral demyelination 
• Progressive spasticity 
• Seizures
• Sensorimotor neuropathy 
• Vomiting

Based on the frequency of symptoms observed, the following information may be noted:

Very frequently present symptoms in 80-99% of the cases:

• Abnormality of the thumb
• Aplasia/Hypoplasia of the abdominal wall musculature
• Ataxia 
• Cloverleaf skull 
• EMG abnormality 
• Feeding difficulties
• Global developmental delay 
• Sensorineural hearing impairment 
• Sensory neuropathy 
• Spasticity 
• Visual impairment

Frequently present symptoms in 30-79% of the cases:

• Fever 
• Gait disturbance
• Generalized myoclonic seizures 
• Hemiplegia/hemiparesis 
• Irritability
• Recurrent respiratory infections

Occasionally present symptoms in 5-29% of the cases may include weight loss.

(Source: Krabbe Disease; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Krabbe Disease Diagnosed?

Krabbe Disease is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests, including blood tests to evaluate the levels of galactosylceramidase, the enzyme affected in Krabbe Disease
• Imaging studies
• Skin biopsy studies, to check for levels of galactosylceramidase, coded by the GALC gene
• Molecular genetic testing to check for or confirm causative GALC gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Krabbe Disease?

The complications of Krabbe Disease may include:

• Progressive worsening of symptoms
• Respiratory infections in infantile form
• Inability to walk
• Blindness
• Deafness
• Poor quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Krabbe Disease Treated?

There is no cure for Krabbe Disease, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops, with the aim of delaying progression of disease.

How can Krabbe Disease be Prevented?

Currently, Krabbe Disease may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Krabbe Disease? (Outcomes/Resolutions)

• The prognosis of Krabbe Disease is determined by the severity of symptoms, complications and rate of progression of disease
• In majority of cases of the infantile form, neurodegeneration occurs and most fatalities are noted before a child turns 3 years old
• If the onset of symptoms occur in the late infantile stages or during childhood, the affected children reportedly succumb to Krabbe Disease 2-7 years from onset of symptoms
• In individuals with adult-onset of disease, survival for many years following symptom manifestation is reported
• Typically, the prognosis is made on a case-by-case basis

Additional and Relevant Useful Information for Krabbe Disease:

Krabbe Disease may be known by the following additional synonyms:

• GALC Deficiency Disorder
• GLD
• Globoid Cell Leukoencephalopathy
• Krabbe Leukodystrophy

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/