The Krabbe disease Or globoid leukodystrophy, is a rare genetic disorder that affects the central nervous system, producing a deficiency in the cerebral white matter or myelin.
It is a genetic disorder, hereditary and degenerative, relatively unknown despite the fact that it is a very serious and often fatal medical condition.
This type of leukodystrophy is manifested by the lack of Myelination of the nervous system , Leading to the appearance of deficits and other neurological disorders.
Krabbe's disease affects both boys and girls alike. It is estimated that worldwide, the prevalence of this disorder is about 1 in 100,000 births. However, there are countries where the incidence is much higher, as in Scandinavia (1 out of 50,000) or Israel (6 out of 1000).
Characteristics of Krabbe disease
Leukodystrophy:"Leukos", white +"Dys", bad or deficient +"Tréphein", nourishing. Nutritional disorder of the white matter. Globoide: Relative to the globoid cells.
Also known as Krabbe's disease. It receives its name from the Danish neurologist Knud Haraldsen Krabbe (1885-1965), for being the first to report the case of a patient with this pathology in 1916.
Krabbe's disease is a genetic disorder in the group of Leukodystrophies . Leukodystrophies are a type of medical condition that affects the production or integrity of the white matter of the brain, also known as myelin.
The Myelin Is the white substance of the brain that covers the axons of the nerve cells (place of the cell where the electric impulses are conducted), to form a sheath or layer around them, and thus to improve and increase the transmission rate of The nerve impulses.
The cellular envelope produced by the myelin ensures the correct transmission of the electrical impulses, so its integrity is essential for the functions of the Central Nervous System Y peripheral .
Under normal conditions, myelin covers the axon forming a layer of high resistance, which functions as an insulation and allows the correct propagation of electrical impulses. To understand it better, the myelin would be like the plastic cord that lines an electric wire.
When the integrity of the myelin is affected, it is said that the cell is demyelinated and the dispersion of the nervous impulse occurs, either reducing the speed of the same or preventing it from occurring.
In cases where myelin is compromised or generally impaired, we are talking about demyelination, or lack of White matter . The consequences of this condition are clearly visible and dramatic, since myelin ensures the correct transmission of impulses in the nervous system.
Thus, demyelination can lead to perceptual, sensory, cognitive or motor deficits; Leading in many cases to produce total paralysis and premature death. Every year, thousands of people are affected by disorders that compromise the integrity of myelin, such as leukodystrophies.
When leukodystrophy occurs, myelin is unable to properly coat the nerves of the central nervous system and therefore, the electrical impulses can not be conducted satisfactorily.
At present, the scientific community has identified as leukodystrophies more than a dozen diseases, classifying them into five different groups: peroxisomal leukodystrophies, lysosomal leukodystrophies, cavitary leukodystrophies, hypomyelinating leukodystrophy or indeterminate leukodystrophies.
The current classification of leukodystrophies according to their type is shown below:
Leukodystrophies, Peroxisomal
- Adrenoleukodystrophy / adrenomyeloneuropathy.
- Refsum's disease (Infantile or adult).
- Zellweger's syndrome.
- Neonatal adrenoleukodystrophy.
Lysosomal Leukodystrophies
- Metachromatic leukodystrophy (or LMD)
- Globoid leukodystrophy or Krabbe's disease.
Cavitary leukodystrophies
- Alexander's disease.
- Canavan's disease.
- CACH syndrome.
- Megaloencephalic leukodystrophy with subcortical cysts (MLC).
Hypomelinating leukodystrophy
- Pelizaeus-Merzbacher disease.
- Pelizaeus-Merzbacher-like disease.
- Spastic paraplegia 2.
- Hypomelination and congenital cataract (or HCC).
Leukodystrophies not classified
- The Aicardi-Goutières syndrome.
- Undetermined leukodystrophies. Those in which the responsible gene has not yet been identified or is in the process of identification.
Today we will focus on explaining and knowing one of the leukodystrophies of the lysosomal type, known as balloon-type leukodystrophy, or Krabbe's disease.
Causes
Krabbe disease is due to mutations in the GALC gene, located on the small arm of chromosome 14 (14q31). People who have the mutation in this gene do not produce enough of a substance called galactocerebrosidase, a lysosomal enzyme that participates in the large amount of myelin lipid catabolism.
The deficiency of galactocerebrosidase causes the accumulation of a cytotoxic substance, psychosin, leading to the Apoptosis (Programmed cell death). The accumulation of non-metabolised lipids affects the growth of the nerve myelin protective sheath.
Without this substance (galactocerebrosidase), myelin can not form the coating of axons and the formation of globular cell groups occurs in the White matter (Both in the central nervous system and peripheral), causing the nerve connections not to function properly.
The hereditary component of this disease is recessive (requires two copies of the gene) and is transmitted from parents to children. If both parents carry the defective mutation of the GALC gene, their children have a 25% chance of not inheriting any mutated copy, 50% inherit a mutated copy and a normal one, and a 25% probability of inheriting two mutated copies and So much, to suffer this condition.
When both parents are known carriers of the gene mutation and the risk of disease is suspected, prenatal screening, amniocentesis, should be performed. This technique involves the extraction of a small amount of the fluid from the sac that surrounds the baby for enzymatic and mutational analysis.
Diagnosis
The diagnosis of this pathology can be established through different tests. Blood, tissue, or CSF tests ( cerebrospinal fluid ), Evaluate the activity level of the GALC enzyme.
Very low or zero levels would indicate the presence of the disorder. Although this type of analysis can confirm the diagnosis, it does not provide information on what will be the course (slow or fast) of the disease.
It is also possible to obtain diagnostic evidence through other tests such as the EEG ( electroencephalogram ), Or PET ( Positron emission tomography ). Both tests would show a pattern of anomalous brain electrical activity in these patients.
Examinations through neuroimaging techniques may also provide evidence of the disorder. For example, through NMR / RMF ( nuclear magnetic resonance Functional magnetic resonance imaging ), We could observe deficits in the presence of cerebral white matter.
Of all the tests without doubt, the mutational examination of the gene is the most reliable and reliable technique to confirm the diagnosis of this disease. In addition, information about the particular type of mutation that the gene has undergone may help predict what the course of the disorder will be.
In some countries, in addition to the tests we have discussed, newborn screening tests are performed to rule out the presence of this condition. However, researchers are still working to find out which tests would be most convenient in this population.
Krabbe disease can develop at different times. If the affection occurs at birth or the first months of life (from 1 month to 1 year), we speak of Krabbe's disease of early or infantile appearance.
Most of these children will die before the age of two. When the affection occurs during childhood (from 1 to 8 years), we speak of Krabbe's disease of juvenile appearance. Finally, if the affection occurs from the age of 8, it is considered to be juvenile or adult late onset and its prognosis is somewhat less fatal.
symptom
As discussed earlier, this disease (and the rest of leukodystrophies) affects the integrity of the white matter or myelin. Knowing the importance of myelin for a correct electrical transmission in the nervous system, it is possible to imagine that a disease like this will produce fatal consequences for the organism.
The symptoms of this pathology will vary depending on, especially the time of onset of the disease. Thus, it is generally stated that the later the occurrence of Krabbe's disease, the slower its progression and the less fatal it will be for the person.
Babies with Krabbe disease do not have signs or symptoms of the disease at birth. In fact, in the early stages of the disease it is common for doctors to confuse the condition with cerebral palsy.
It is not until 3 or 6 months of age when the first symptoms in these babies begin to be appreciated, presenting a different picture of the pathology at different times or stages of the disease.
When the disorder is early or infantile, in the first phase the symptoms may include extreme irritability, stiffness of the limbs, poor control of the head, intermittent thumb flexion, muscle spasms and episodes of elevated temperature.
In the second phase hypertonic episodes occur and Convulsions , As well as auditory, visual and motor deficits (such as difficulty feeding or breathing properly).
In the third phase, a Hypotonia Generalized (decreased tension or muscle tone, or the tonicity of an organ). This hypotonia extends through the different organs of the baby preventing the normal development of the same. From this moment, the patients progress to a general vegetative state, dying mostly between 2 and 3 years of age.
When Krabbe disease develops during late childhood or adulthood, the symptoms are similar to those occurring in earlier stages of development but progression is less rapid and the course more varied.
The early symptoms of late forms include weakness and deficits can be related to higher acquired processes, such as loss of fine manual dexterity, ataxia (Difficulty or inability to walk) or Hemiplegia (Paralysis of the middle of the body).
However, some of these patients may have much less severe symptoms, with muscle weakness as the main symptom of the disease.
Treatment
Although there are specific treatments to limit the symptoms of this disorder, unfortunately there is currently no cure for Krabbe's disease. The health interventions performed in these patients are Improve your quality of life .
Different pharmacological treatments can be used to control symptoms such as irritability, muscle spasms, fever or seizures. Physical or physiotherapeutic rehabilitation is essential in these patients for the control and recovery of muscle tone.
These interventions are usually accompanied by psychotherapy that facilitates the restoration or improvement of Cognitive functions Affected.
There are other very promising treatments for this disorder, although the risk is greater and its usefulness seems to vary greatly from one particular case to another.
Transplantation of bone marrow or umbilical cord cells in the early stages of the disease can improve the evolution of these patients, especially when the disease is still asymptomatic. The efficiency of transplantation has been shown to be much more effective when performed in the first weeks of life.
Finally, gene therapy seems to give more hope in the control of this disease. Scientists have managed to get the GALC gene to the body's cells through the introduction of a virus.
The gene, which travels through the virus, is able to be installed in cells. Although this technique has only been applied to animals, different research groups around the world are already working so that this technique can be used soon in humans.