Krabbe disease – what is Krabbe disease?

By April Cashin-Garbutt, BA Hons (Cantab)

Krabbe disease is also known by many other names, these include Globoid cell leukodystrophy, Galactosylcerebrosidase deficiency and Galactosylceramidase deficiency. (1, 4) It is a very rare condition that is caused by a genetic defect that affects the nervous system. (2)

Types of Krabbe disease

There are two main types of Krabbe disease:

  • early-onset (infantile) Krabbe disease
  • late-onset (juvenile- or adult-onset) Krabbe disease (2, 3)

Usually Krabbe disease is early-onset. Around 90% of those with Krabbe disease have the infantile form.

Many children experience symptoms before the age of 1. Moreover, many children die before the age of 2. This is largely as a result of respiratory infection or cerebral hyperpyrexia.

The onset of Krabbe disease, however, depends on the exact genetic mutations. It is possible, although less common, for Krabbe disease to begin in childhood, adolescence or even adulthood. (1, 2, 4, 5, 14)

Cause of Krabbe disease

Krabbe disease is caused by the inheritance of two copies of an abnormal GALC gene. (6, 7) This gene is located on the long arm of chromosome 14 at position 31; consequently its location is referred to as 14q31 (where q refers to the long arm). (8, 9) The gene consists of 17 exons, which are the coding parts of the DNA. (15, 16)

The GALC gene is responsible for providing the instructions to synthesize an enzyme called galactosylceramidase (also known as galactocerebroside beta-galactosidase). (1, 8)

This enzyme plays a vital role in myelin metabolism. (3) Consequently, patients with Krabbe disease have insufficient myelin production. (12)

Myelin is made from proteins and fats and it is used to insulate nerves, such as those in the brain and spinal cord. This insulation is needed for nerve impulses to travel quickly along nerve cells. (10) In fact, without the type of cells that form the myelin sheath around the axons of the central nervous system, known as oligodendrocytes, a nerve impulse would travel 30 times slower. (11)

In addition to the deficiency in myelin, another feature of Krabbe disease is the incidence of globoid cells. These are a type of cell that tend to have more than one nucleus and are globe-shaped. (4)

Symptoms of early-onset Krabbe disease

Symptoms of early-onset Krabbe disease include:

  • irritability
  • sensitivity to loud sounds
  • hearing loss that may lead to deafness
  • muscle weakness
  • feeding difficulties
  • unexplained fever, i.e. fever with no other sign of infection
  • stiff posture
  • slow mental and physical development
  • trouble moving
  • trouble chewing and swallowing
  • trouble breathing
  • vision loss that may lead to blindness
  • seizures
  • vomiting (2, 4)

Symptoms of late-onset Krabbe disease

Symptoms of late-onset Krabbe disease include:

  • vision problems and loss of vision
  • walking difficulties
  • decreasing intelligence
  • decreasing motor skills (13)

Who does Krabbe disease affect?

Krabbe disease affects both males and females equally. In the United States, Krabbe disease is thought to affect around 1 in 100,000 births. This rate is similar in Europe. (14, 17)

In certain isolated communities in Israel there have been higher incidences of Krabbe disease reported – as high as 6 cases per 1,000 people. (4)

Krabbe disease is also said to be more common among people of Scandinavian descent. (1)

Krabbe disease affects those who have two defective copies of the GALC gene. People can inherit Krabbe disease when both parents are carriers of the defective GALC gene.

Carriers have one defective copy of the GALC gene and one normal copy. Consequently, they do not exhibit Krabbe disease themselves, as this requires a person to be homozygous for GALC, i.e. for them to have two copies of defective GALC gene, but they may pass it on, if their partner is also a carrier. (5)

This form of inheritance is known as an autosomal recessive pattern. (1) It is important to note that not all children with two carrier parents will inherit Krabbe disease. In fact, there is only a 1 in 4 chance that a child will inherit 2 defective genes and thereby inherit the disease. There is a 1 in 2 chance that the child will be a carrier. Finally, there is a 1 in 4 chance that the child will inherit two non-defective genes and thereby will be normal. (7)

How is Krabbe disease diagnosed?

Krabbe disease can be diagnosed from its characteristic symptoms. These include:

  • Globoid cells with multiple nuclei
  • Demyelination of nerves
  • Brain cell destruction (15)

Diagnosis of Krabbe disease can be confirmed with enzyme analysis and mutation analysis. Genetic testing, such as three-primer PCR analysis, may also be carried out. (18)

Enzyme analysis can be carried out by taking a sample of blood or skin cells and testing the activity of the GALC enzyme. GALC activity is expected to be low in those with Krabbe disease. (20)

Prenatal testing for Krabbe disease is also possible. This is carried out using amniotic fluid or chorionic villus (CV) sampling. The latter involves taking cells from the mother’s placenta. (15, 19)

Potential treatments for Krabbe disease

Currently, there are no cures for Krabbe disease; however, treatments have been attempted. Transplants, such as bone marrow and cord blood transplants, have been tried to treat Krabbe disease. It has been found that cord blood transplant stabilizes disease progression faster than bone marrow transplant. However, the latter too has been shown to be beneficial in patients with very early stage Krabbe disease or a very slowly progressing type. (3, 13)

Gene therapy, where scientists use a virus to deliver the GALC gene to the patient’s cells, is also another potential treatment for Krabbe disease. However, this method is yet to be been tried in humans. (21)

Sources

  1.  http://www.umm.edu/ency/article/001198.htm
  2.  http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002178/
  3.  http://www.ninds.nih.gov/disorders/krabbe/krabbe.htm
  4.  http://ghr.nlm.nih.gov/condition/krabbe-disease
  5.  http://www.tnprc.tulane.edu/public_krabbe.html
  6.  http://www.jefferson.edu/jmc/departments/neurology/faculty/wenger--david-a.html
  7.  http://www.nlm.nih.gov/medlineplus/ency/article/002052.htm
  8.  http://ghr.nlm.nih.gov/gene/GALC
  9.  http://learn.genetics.utah.edu/content/begin/traits/scientists/
  10.  http://www.umm.edu/ency/article/002261.htm
  11.  http://learn.genetics.utah.edu/content/addiction/reward/cells.html
  12.  http://spinwarp.ucsd.edu/neuroweb/Text/br-500.htm
  13.  http://bmt.umn.edu/world-class-bmt-program/globoid-cell-leukodystrophy-%28gld%29.php
  14.  http://www.usd.edu/medical-school/center-for-disabilities/upload/developmentaldisabilitieshandbook.pdf
  15.  http://www.labs.gosh.nhs.uk/media/384075/Krabbe%20v4.5.pdf
  16.  http://www.genome.gov/Glossary/index.cfm?id=61
  17.  http://www.ojrd.com/content/pdf/1750-1172-7-38.pdf
  18.  http://www.labs.gosh.nhs.uk/laboratory-services/genetics/tests/krabbe-disease
  19.  http://www.nhs.uk/conditions/Chorionic-Villus-sampling/Pages/Introduction.aspx
  20.  http://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Krabbe_Disease.aspx
  21.  http://ulf.org/krabbe-disease
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