Krabbe's disease: what is it, causes, symptoms, treatment, prognosis

What is Krabbe's disease?

Krabbe's disease (or sphingolipidosis, Krabbe type, galactosylceramide lipidosis) is a rare inherited disorder of lipid metabolism caused by enzyme deficiency galactocerebrosidase (GALC), which is required for the cleavage (metabolism) of sphingolipids galactosylceremide and psychosine.

Failure to break down these sphingolipids leads to degeneration of the myelin sheath surrounding the nerves in the brain (i.e., demyelination). In the affected areas of the brain, characteristic globoid cells appear. This metabolic disorder is characterized by progressive neurological dysfunction such as mental retardation, paralysis, blindness, deafness, and paralysis of certain facial muscles (pseudobulbar paralysis). Galactosylceramide lipidosis is inherited as an autosomal recessive disorder.

Signs and symptoms

The onset of Krabbe's disease in the predominant infantile form (90% of cases) occurs between the ages of one to seven months. The late form of the disorder occurs by age 18 months or older, including adolescence and adulthood.

The specific symptoms and degree of Krabbe's disease vary from case to case. Infants affected by the disease may be restless and overly irritable (hyperexcitability). Vomiting, unexplained fevers, and partial loss of consciousness are additional possible symptoms. The lower limbs may have spastic contractions. Seizures may also occur, characterized by alternating contraction and relaxation (clonic) or constant tension (tonic). Affected children are hypersensitive to various stimuli such as sounds.

Mental and physical development can be slow. In some cases, regression of previously acquired skills may occur. Due to degeneration of certain parts of the brain, the legs are sometimes stretched rigidly at the hip and knee; arms can rotate at the shoulder and stretch at the elbow; ankles, toes, and toes may be bent. Blindness caused by degeneration of the cerebral cortex can also occur. People with galactosylceramide lipidosis may also have trouble swallowing (dysphagia) and peripheral neuropathy, a condition characterized by muscle weakness; pain; numbness; redness; and / or a burning or tingling sensation in the affected areas, especially in the arms and legs (extremities). The disorder often leads to life-threatening complications.

In juvenile and adult forms of Krabbe's disease, the initial symptom may be impaired control of voluntary movements and progressive stiffness of the leg muscles (spastic paraparesis). Affected people with these forms of the disorder may also experience progressive vision loss and disease that affects multiple nerves (polyneuropathy).

Causes

Galactosylceramide lipidosis is an inherited disorder that is passed on to offspring through recessive genes. It is caused by a deficiency of the enzyme galactoside beta-galactosidase (galactosylkeramidase). This enzyme is essential for the metabolism of galactocerebroside (galactosylceramide), a component of the fatty sheath around nerves (myelin). Demyelination of nerve cells in the cerebral hemispheres (and in the brainstem) causes the neurological symptoms of Krabbe's disease.

Human traits, including classic genetic diseases, are the product of the interaction of two genes for a given condition, one from the father and the other from the mother. In recessive disorders, the condition does not appear unless the person inherits the same defective gene for one trait from each parent. If a person receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually asymptomatic. The risk of transmitting the disease to the children of a couple who are carriers of a recessive disorder is 25 percent. 50 percent of their children are at risk of being carriers of the disease, but usually do not show symptoms of the disorder. 25 percent of their children can receive both normal genes, one from each parent, and be genetically normal (for this particular trait). The risk is the same for every pregnancy.

Researchers have found that Krabbe's disease can be caused by a disorder or change (mutations) of the human galactocerebrosidase gene (GALC) located on the long arm (q) of the chromosome 14 (14q31). Chromosomes are found in the nucleus of all cells in the body. They carry the genetic characteristics of every person. Pairs of human chromosomes are numbered 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm, denoted by the letter "p" and a long arm, denoted by the letter "q". Chromosomes are further subdivided into stripes, which are numbered. For example, "chromosome 14q31" refers to lane 31 on the long arm of chromosome 14.

Affected populations

About 1 in 100,000 newborns have Krabbe disease. Men suffer as often as women.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of Krabbe's disease. Comparisons can be useful for differential diagnosis:

• Adrenoleukodystrophy (ALD, or Schilder's disease) is one of many different leukodystrophies. The disorder can manifest in two different genetic forms: sexual and neonatal ALD. Both are characterized by the destruction of the lipid sheaths surrounding the nerves (demyelination) in the brain. However, they differ in the type of inheritance, severity, and type of symptoms. All types of ALD are characterized by the accumulation of very long chain fatty acids (VLCFA), which is a type of fat molecule that accumulates in body tissues, especially in adrenal glands and white matter of the brain. Accumulation of lymphatic and plasma cells around blood vessels in the central nervous system can also occur.
• Canavan's disease​ (spongy degeneration of the brain) is a form of leukodystrophy that causes the white matter of the brain to be replaced by microscopic fluid-filled spaces. This disorder is hereditary and is characterized by structural abnormalities and impairment of motor, sensory and intellectual functions. It appears to most commonly affect individuals of Eastern European Jewish descent. The disorder is progressive and degenerative. Symptoms may include a progressive decline in mental function with loss of muscle tone, poor head control, an abnormally enlarged head (megalocephaly), and / or blindness.
• Metachromatic leukodystrophy (MLD or sulfatide lipidosis), the most common form of leukodystrophy, is a rare inherited neurometabolic disorder that affects the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (sphingolipid) in the brain and other parts of the body (for example, in liver, gallbladder, kidneys and / or spleen). The protective fatty coating on nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to sulfatide build-up. Symptoms of metachromatic leukodystrophy may include seizures, epilepsy, personality changes, spasticity, progressive dementia, movement disorders progressing to paralysis, and / or visual impairment leading to blindness. Metachromatic leukodystrophy is inherited as an autosomal recessive trait.
• Alexander's disease is an extremely rare, progressive neurological disorder that usually manifests itself in infancy or early childhood. However, fewer cases were described when the onset of symptoms occurred in later childhood or in adolescence (juvenile onset) or, less often, during the third to fifth decades of life (adult Start). In infants and young children with Alexander's disease, comorbid symptoms and signs include an inability to grow and gain weight at the expected rate (inability develop); delays in the development of certain physical, mental and behavioral skills that are usually acquired at certain stages (psychomotor retardation); and progressive enlargement of the head (macrocephaly). Additional symptoms usually include sudden episodes of uncontrolled electrical activity in the brain (epilepsy), spasticity, and progressive neurological deterioration. In some cases, there is hydrocephalus. In most cases, Alexander's disease occurs by chance for unknown reasons (sporadically), with no family history of the disease. In a very small number of cases, the disorder is believed to affect more than one family member.

Diagnostics

Krabbe disease can be diagnosed by testing the activity of the enzyme galactocerebrosidase (galactosylceramidase) in fibroblast cells obtained from an infant or fetus by amniocentesis.

Standard treatments

There is no specific treatment for Krabbe's disease. Treatment is symptomatic and supportive. Genetic counseling can be beneficial for families of children affected by the disease.

For infants who have already developed symptoms of Krabbe's disease, there is currently no treatment that can change the course of the disease. Therefore, treatment focuses on treating symptoms and providing supportive care. Interventions may include the following:

• Anticonvulsants for the treatment of epilepsy.
• Medicines to relieve muscle spasticity and irritability.
• Physical therapy to minimize the deterioration in muscle tone.
• Nutritional support, such as using a tube to deliver fluid and nutrients directly to the stomach (gastrostomy feeding).

Interventions for older children or adults with less severe disease may include:

• Physical therapy to minimize the deterioration in muscle tone.
• Occupational therapy to achieve as much independence as possible in daily activities.

Stem cell transplant

Hematopoietic stem cells are specialized cells that can develop into all types of blood cells in the body. These stem cells are also the source of microglia, specialized cells that eat the debris that lives in the nervous system. In Krabbe's disease, microglia turn into toxic globoid cells.

In stem cell transplantation, donor stem cells are delivered into the recipient's bloodstream through a tube called a central venous catheter. Donor stem cells help the body produce healthy microglia, which can fill the nervous system and deliver functioning GALC enzymes. This treatment can help restore some degree of normal myelin production and maintenance.

This therapy can improve outcomes in children if treatment is started before symptoms appear, that is, when the diagnosis is the result of newborn screening. Current evidence suggests that stem cell transplantation is most effective when started before the baby is 2 weeks old.

Research has shown that children with symptoms after stem cell transplantation may experience slower progression disease and improved quality and longevity of life compared to children who do not receive stem cell transplants before they appear symptoms. However, children who had stem cell transplants prior to symptom onset still have significant difficulties with speaking, walking, and other motor skills during childhood.

Older children and adults with mild symptoms of Krabbe's disease can also benefit from this treatment. As with infants, the severity of symptoms during stem cell transplantation affects treatment outcomes.

Prognosis and complications

Neurodegeneration and early death (<2–3 years) occur in most childhood cases. In late infants / juvenile patients, the disease is usually fatal 2-7 years after the onset of symptoms. Adult patients can survive many years after symptoms appear.

Children with advanced Krabbe's disease can develop a number of complications, including infections and respiratory problems. In the later stages of the disease, children become disabled, bedridden, and eventually become vegetative.

Most children who develop Krabbe disease in infancy die before age 2, most often from respiratory failure or complications associated with immobility and markedly reduced muscle tone. Children who develop the disease later in childhood may have a longer life expectancy, usually 2 to 7 years after diagnosis.