Krabbe’s Disease
Krabbe’s disease is a rare, inherited condition that progressively damages the protective covering of nerve cells in the brain and nervous system, leading to severe neurological problems that worsen over time and usually result in death, most commonly affecting babies in their first year of life.
Table of contents
- What is Krabbe’s Disease?
- Other Names for This Condition
- Types of Krabbe’s Disease
- What Causes Krabbe’s Disease
- How Common is Krabbe’s Disease
- Signs and Symptoms
- How Krabbe’s Disease is Diagnosed
- Treatment and Management
- Outlook and Life Expectancy
- Prevention and Genetic Counseling
What is Krabbe’s Disease?
Krabbe’s disease is a rare, inherited condition that affects the nervous system. The disease belongs to a group of disorders called leukodystrophies, which are conditions that damage the white matter of the brain and nervous system[1][3]. In Krabbe’s disease, the body lacks an important enzyme that helps break down certain fats in the nervous system. When this enzyme is missing or not working properly, harmful substances build up and destroy myelin, the protective coating around nerve cells that helps signals travel quickly between the brain and body[5][6].
Without healthy myelin, nerve cells cannot work properly, and the brain becomes damaged. This leads to progressive problems with movement, vision, hearing, and mental development[1]. The disease is named after Danish neurologist Knud Krabbe, who first described it[1][3].
Another characteristic feature of this disease is the presence of abnormal cells in the brain called globoid cells. These are large cells that usually have more than one nucleus, which is why the condition is also known as globoid cell leukodystrophy[1][4].
Globoid cell leukodystrophy, Galactosylceramide lipidosis, GALC deficiency, Galactocerebrosidase deficiency, Galactosylceramidase deficiency
Other Names for This Condition
Krabbe’s disease is known by several medical names. Healthcare professionals may refer to it as globoid cell leukodystrophy, galactocerebrosidase deficiency, galactosylceramidase deficiency, or GALC deficiency[5][7]. All of these names describe the same condition.
Types of Krabbe’s Disease
Krabbe’s disease is divided into different types based on when symptoms first appear. The earlier the symptoms start, the more severe the disease tends to be[4][7].
Infantile Krabbe’s disease is the most common form, accounting for about 85 to 90 percent of all cases. In this type, symptoms usually begin between 1 and 7 months of age, though they can appear as early as birth or as late as 12 months[1][3][6]. This form progresses very quickly and is the most severe. Without treatment, children with infantile Krabbe’s disease typically do not survive beyond 2 to 3 years of age[1][6].
Late infantile Krabbe’s disease begins between 13 and 36 months of age. Children with this form may have a slightly slower disease progression than those with the infantile form[4].
Juvenile Krabbe’s disease starts between approximately 3 and 16 years of age. This form progresses more slowly than the infantile types, and children may live longer[4][6].
Adult-onset Krabbe’s disease is the rarest form and begins after 16 years of age. People with this form typically have less severe symptoms and may survive many years after the disease begins[4][5].
What Causes Krabbe’s Disease
Krabbe’s disease is caused by changes, called mutations, in a gene called GALC. This gene provides instructions for making an enzyme called galactocerebrosidase, which breaks down certain fats in the nervous system[5][6]. About 200 different GALC gene mutations have been identified[4].
When the GALC gene is not working properly, the body cannot produce enough of the galactocerebrosidase enzyme. One important fat that this enzyme normally breaks down is called galactosylceramide, which is a key component of myelin. Another substance called psychosine is toxic if not broken down by this enzyme. When these substances cannot be broken down properly, they accumulate in the nervous system[5][8].
The buildup of psychosine is particularly harmful. It damages the cells that make myelin, which leads to the destruction of the protective covering around nerve cells. Without myelin, nerves cannot transmit signals properly, leading to the progressive symptoms of Krabbe’s disease[5][12].
Krabbe’s disease is inherited in an autosomal recessive pattern. This means that a child must receive one changed copy of the GALC gene from each parent to develop the disease[3][5][6]. Parents who each carry one changed copy of the gene are called carriers. Carriers do not have symptoms of Krabbe’s disease themselves. When both parents are carriers, there is a 25 percent chance with each pregnancy that their child will have Krabbe’s disease[6].
How Common is Krabbe’s Disease
Krabbe’s disease is generally rare, but its frequency varies widely around the world. In Europe, researchers estimate that it occurs in about 1 per 100,000 live births. In the United States, the estimated rate is about 1 per 250,000 live births[1][4][5].
Some communities have much higher rates due to marriages between relatives. For example, in certain isolated communities in Israel, particularly among the Druze population, the incidence can be as high as 6 cases per 1,000 live births[1][4][5].
Signs and Symptoms
The symptoms of Krabbe’s disease depend on when the disease begins. The infantile form causes the most severe symptoms that progress rapidly, while late-onset forms tend to have milder symptoms that progress more slowly[1][7].
Infantile Krabbe’s Disease Symptoms
Babies with infantile Krabbe’s disease usually appear healthy and develop normally in their first few months of life. They meet early developmental milestones such as smiling, cooing, and holding their heads up[6]. Symptoms typically begin to appear between 4 and 6 months of age, though they can start earlier or later[1].
The disease progresses through three general stages. In the first stage, symptoms include extreme irritability and fussiness, restlessness, difficulty feeding, vomiting, unexplained fevers without signs of infection, failure to gain weight and grow properly, and muscle weakness[1][6]. Babies may also become very sensitive to touch, noise, or bright light, and can develop muscle spasms when exposed to these triggers[1][3]. These symptoms are sometimes mistaken for colic or reflux[6].
As the disease progresses to the second stage, babies experience vision changes and problems with their optic nerve, abnormal body postures caused by stiff muscles in the neck, trunk, and legs that cause severe backward arching, episodes that look like seizures, slowed mental and physical development, and loss of developmental milestones they had previously achieved[1][6].
In the third and final stage, children become blind and deaf, develop abnormal body positions with arms and legs held straight out and head arched backward, and have greatly decreased ability to move[1][6].
Late-Onset Krabbe’s Disease Symptoms
When Krabbe’s disease begins after the first year of life, symptoms are generally less severe and progress more slowly. Late infantile Krabbe’s disease, which begins between 13 and 36 months of age, causes irritability, vision changes, abnormal walking, seizures, and periods of stopped breathing[1].
In juvenile and adult forms of the disease, common early symptoms include progressive vision loss and problems with walking[3][5]. People may also experience muscle weakness, loss of manual skills, cognitive delays or impairment, and signs of nerve damage[3][7]. Some adults may experience burning sensations in their arms and legs, muscle wasting, and loss of sensation[3].
How Krabbe’s Disease is Diagnosed
Krabbe’s disease can be diagnosed in several ways. Some babies are identified through newborn screening, which is a test done shortly after birth to check for serious health conditions. However, not all states or countries screen for Krabbe’s disease at birth[6][14].
Doctors may suspect Krabbe’s disease when a baby or child shows typical symptoms such as extreme irritability, loss of developmental milestones, muscle weakness or stiffness, feeding difficulties, and unexplained fevers[6]. Because symptoms can appear similar to other conditions like cerebral palsy, correct diagnosis is important[3].
To confirm a diagnosis, doctors use several tests. A blood test can measure the level of galactocerebrosidase enzyme activity. People with Krabbe’s disease have very low or absent enzyme activity[6]. Genetic testing can identify mutations in the GALC gene, which confirms the diagnosis[3][6].
Imaging tests of the brain, such as MRI scans, can show changes in the brain’s white matter that are characteristic of Krabbe’s disease[6]. Other tests may include examination of cerebrospinal fluid, which is the fluid that surrounds the brain and spinal cord, and nerve conduction studies to assess how well nerves are working[6].
In some cases, particularly before birth, prenatal testing can be done if parents are known carriers or have had a previous child with Krabbe’s disease[6].
Treatment and Management
There is currently no cure for Krabbe’s disease. Treatment focuses on managing symptoms and trying to slow disease progression[1][7].
The main treatment option that has shown some benefit is hematopoietic stem cell transplantation, also called HSCT or bone marrow transplant. This treatment works best when done very early, ideally in babies who are diagnosed before symptoms begin or when symptoms are very mild, and preferably within the first month of life[14][12]. Studies have shown that babies who receive HSCT before symptoms appear may have delayed disease progression and improved survival compared to those who do not receive this treatment[14].
However, HSCT is not a complete cure. Even with transplantation, children may still develop neurological problems over time, including small head size, muscle stiffness, growth problems, and delays in speech and motor development. Many children need assistive devices to walk[14]. The procedure also carries risks, with a mortality rate of about 15 percent[14].
For individuals with late-onset or slowly progressive Krabbe’s disease, HSCT may also be considered[14]. However, babies who already have symptoms when diagnosed often have irreversible brain damage that makes them poor candidates for transplantation[6].
Other treatments focus on managing symptoms and providing supportive care. This may include medications to control seizures, physical therapy to help with movement problems, feeding support when swallowing becomes difficult, and management of pain and discomfort[1][14]. Some families may choose palliative care, which focuses on comfort and quality of life[14].
Researchers continue to study other potential treatments, including enzyme replacement therapy, gene therapy, and neural stem cell transplantation, although these have not yet advanced to routine clinical use[14][12].
Outlook and Life Expectancy
The outlook for people with Krabbe’s disease depends largely on when the disease begins and whether treatment is received early. Krabbe’s disease is a degenerative condition, meaning it progressively gets worse over time[1].
For infantile Krabbe’s disease, the prognosis is generally poor. Without treatment, most children with this form of the disease do not survive beyond 2 years of age, and rarely live past 3 years[1][6][7]. One study reported one-year, two-year, and three-year survival rates of 60 percent, 26 percent, and 14 percent, respectively[3].
However, when babies receive HSCT before symptoms begin, outcomes can be better. These children may live longer and have improved quality of life compared to those who do not receive treatment, although they often still develop some neurological problems over time[14].
Late-onset forms of Krabbe’s disease generally have a better prognosis, with slower disease progression and longer survival. People with juvenile or adult-onset disease may live many years after symptoms begin[5][6]. Life expectancy varies considerably among individuals with late-onset disease.
Prevention and Genetic Counseling
Because Krabbe’s disease is an inherited genetic condition, prevention focuses on genetic counseling and testing for at-risk families[1].
If a family has had a child with Krabbe’s disease, both parents are carriers of the GALC gene mutation. These parents have a 25 percent chance with each pregnancy of having another child with the disease. Genetic counseling can help families understand their risks and options[5][6].
For couples who are known carriers, prenatal testing during pregnancy can determine whether a baby has inherited Krabbe’s disease. This allows families to prepare and make informed decisions about care[4][6].
Newborn screening programs in some states and countries test all babies for Krabbe’s disease shortly after birth. Early identification through newborn screening allows for the possibility of early treatment with HSCT before symptoms develop, which offers the best chance for improved outcomes[6][14].
Siblings of children with Krabbe’s disease should also be evaluated. For siblings who do not have the disease themselves, there is a 50 percent chance that they are carriers of the gene mutation[6].
