About galactosylceramidase deficiency
What is galactosylceramidase deficiency?
Krabbe's Leukodystrophy is a rare inherited lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as mental retardation, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe's Leukodystrophy is inherited as an autosomal recessive trait.
What are the symptoms for galactosylceramidase deficiency?
Common signs and symptoms early in the course of the disease include the following:
- Feeding difficulties
- Unexplained crying
- Extreme irritability
- Fever with no sign of infection
- Declines in alertness
- Delays in typical developmental milestones
- Muscle spasms
- Loss of head control
- Frequent vomiting
As the disease progresses, signs and symptoms become more severe. They may include:
- Loss of developmental abilities
- Progressive loss of hearing and sight
- Rigid, constricted muscles
- Stiff, fixed posture
- Progressive loss of ability to swallow and breathe
Older children and adults
When Krabbe disease develops later in childhood or during adulthood, signs and symptoms can vary widely. They may include:
- Progressive loss of vision
- Difficulty walking (ataxia)
- Decline in thinking skills
- Loss of manual dexterity
- Muscle weakness
As a general rule, the younger the age that Krabbe disease occurs, the faster the disease progresses and the more likely it is to result in death.
Some people diagnosed during adolescence or adulthood may have less severe symptoms, with Muscle Weakness as a primary condition. They may have no impairment of their thinking skills.
What are the causes for galactosylceramidase deficiency?
Krabbe disease is caused when a person inherits two copies of an altered (mutated) gene — one copy from each parent.
A gene provides a kind of blueprint for producing proteins. If there is an error in this blueprint, then the protein product may not work properly. In the case of Krabbe disease, two mutated copies of a particular gene result in little or no production of an enzyme called galactocerebrosidase (GALC).
Enzymes, such as GALC, are responsible for breaking down certain substances in a cell's recycling center (lysosome). In Krabbe disease, the short supply of GALC enzymes results in the accumulation of certain types of fats called galactolipids.
Damage to nerve cells
Galactolipids normally exist in cells that produce and maintain the protective coating of nerve cells (myelin). However, an abundance of galactolipids has a toxic effect. Some galactolipids trigger myelin-forming cells to self-destruct.
Other galactolipids are taken up by specialized debris-eating cells in the nervous system called microglia. The process of cleaning up excessive galactolipids transforms these normally helpful cells into abnormal, toxic cells called globoid cells, which promote myelin-damaging inflammation.
The subsequent loss of myelin (demyelination) prevents nerve cells from sending and receiving messages.
What are the treatments for galactosylceramidase deficiency?
For infants who have already developed symptoms of Krabbe disease, there is currently no treatment that can change the course of the disease. Treatment, therefore, focuses on managing symptoms and providing supportive care. Interventions may include the following:
- Anticonvulsant medications to manage seizures
- Drugs to ease muscle spasticity and irritability
- Physical therapy to minimize deterioration of muscle tone
- Nutritional support, such as the use of a tube to deliver fluids and nutrients directly into the stomach (gastric tube)
Interventions for older children or adults with less severe forms of the disease may include:
- Physical therapy to minimize deterioration of muscle tone
- Occupational therapy to achieve as much independence as possible with daily activities
Stem cell transplantation
Hematopoietic stem cells are specialized cells that can develop into all of the different types of blood cells in the body. These stem cells are also the source of microglia, specialized debris-eating cells that take up residence in the nervous system. In Krabbe disease, microglia are transformed 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. The donor stem cells help the body produce healthy microglia that can populate the nervous system and deliver functioning GALC enzymes. This treatment may help restore some degree of normal myelin production and maintenance.
This therapy may improve outcomes in infants if treatment begins before the onset of symptoms — that is, when a diagnosis results from a newborn screening test. Current evidence suggests that stem cell transplantation is most effective when started before an infant reaches 2 weeks of age.
Studies have found that pre-symptomatic children treated with stem cell transplantation may have slower disease progression and improved quality — and length — of life, compared with children who don't receive stem cell transplantation before symptoms develop. However, infants who have stem cell transplants before symptoms appear still develop significant difficulties with speech, walking and other motor skills during childhood.
Older children and adults with mild symptoms of Krabbe disease also may benefit from this treatment. As with infants, the severity of symptoms at the time of stem cell transplantation affects treatment outcomes.
What are the risk factors for galactosylceramidase deficiency?
Autosomal recessive inheritance pattern
To have an autosomal recessive disorder, you inherit two changed genes (mutations), one from each parent. These disorders are usually passed on by two carriers. Their health is rarely affected, but they have one changed gene (recessive gene) and one unaffected gene (dominant gene) for the condition. Two carriers have a 25% chance of having an unaffected child with two unaffected genes (left), a 50% chance of having an unaffected child who also is a carrier (middle), and a 25% chance of having an affected child with two recessive changed genes (right).
The gene mutation associated with Krabbe disease only causes the disease if two mutated copies of the gene are inherited. A disease resulting from two mutated copies is called an autosomal recessive disorder.
If each parent has one mutated copy of the gene, the risk for a child would be as follows:
- A 25 percent chance of inheriting two mutated copies, which would result in the disease
- A 50 percent chance of inheriting only one mutated copy, which would result in the child being a carrier of the mutation but would not result in the disease itself
- A 25 percent chance of inheriting two normal copies of the gene
Genetic testing to understand the risk of having a child with Krabbe disease may be considered in certain situations:
- If one or both parents are likely carriers of a GALC gene mutation because of a known family history of Krabbe disease, a couple may want to have tests to understand the risks in their own family.
- If one child is diagnosed with Krabbe disease, a family may consider genetic tests to identify other children who could develop the disease later in life.
- If the parents are known carriers, they may request a prenatal genetic test to determine if their child is likely to develop the disease.
- Known carriers, who are using in vitro fertilization, may request a genetic test with fertilized eggs before implantation.
Genetic testing should be carefully considered. Ask your doctor about genetic counseling services that can help you understand the benefits, limits and implications of genetic testing.
Is there a cure/medications for galactosylceramidase deficiency?
A rare autosomal recessive lysosomal storage condition called galactosylceramidase deficiency is brought on by a lack of galactocerebrosidase.
Galactocerebrosidase deficiency is a rare autosomal recessive condition brought on by a lack of the enzyme (GALC, also known as galactosylceramidase). The liposomal hydrolysis of galactolipids produced during white matter myelination is carried out by the enzyme galactocerebrosidase.
It is believed that the pathological changes in the peripheral and central nervous systems (globoid cell development and diminished myelin) are brought on by the accumulation of poisonous psychosine (galactosylsphingosine), which cannot be broken down due to a lack of galactocerebrosidase. The oligodendrocytes in the central nervous system and the Schwann cells in the peripheral nervous system are hypothesized to be poisoned by psychosine buildup. There are many unknowns regarding the pathophysiology of galactosylceramidase deficiency.
1. Globoid cell leukoencephalopathy has no known cure.
2. Children who received umbilical cord blood stem cells from unrelated donors before the beginning of symptoms developed with little neurological impairment, according to the findings of a very small clinical trial of globoid cell leukoencephalopathy patients.
3. In contrast to individuals who received adult bone marrow, results also demonstrated that those who received cord blood experienced faster illness stabilization.
4. Early in the course of the disease, modest instances have been proven to benefit from bone marrow transplantation.
5. The disorder is often treated with supportive and symptomatic care. Physical therapy may support or improve circulation and muscular tone.
Irritability,Unexplained fever,Limb stiffness,Seizures,Feeding difficulties,Vomiting,Slowing of mental and motor development,Muscle weakness,Spasticity,Deafness,Blindness
Blindness,Deafness,Severe loss of muscle tone,Severe mental deterioration,Respiratory failure