krabbe disease a case study

Krabbe disease is a rare genetic condition caused by a decrease in galactosylceramidase production (GALC). This enzyme deficiency impedes the formation and preservation of myelin, a protective coating on the surface of the sensory system that guarantees the rapid transmission of nerve impulses. Krabbe disease is categorized as one of a group of diseases known as leukodystrophies, which are caused by myelin destruction. This disorder is often distinguished by the unusual presence of globoid cells, which are broadly developed and, for the most part, contain more than one nucleus. Krabbe disease was named after a Danish neurologist called Knud Haraldsen Krabbe, who started his profession as a neurologist in the beginning of the 1900s. In the course of conducting his obligations as a neurologist, he came across 5 unrelated babies (aged 4-6 months) who had a disease that presented the same symptoms.The symptoms slowly worsened everyday and after some time, all the babies died. Krabbe later discovered that the disease was an inherited condition caused by the deficiency of GALC, and the disease was later named after him. This disorder mainly affects children under the age of two; it affects about 1 out of 100000 children. Children with this disorder have a rapid onset of signs and symptoms precisely before they are six months of age (Wenger, Rafi & Luzi, 2016). It is worth noting that this disorder has no cure and therefore its treatment is focused on managed and supportive care to the patients. The children with this disease hardly make it celebrate their 2nd birthday.


Mode of inheritance
This disease is inherited from the parents; both parents of a child with Krabbe disease usually are carriers; this means that both parents each carry one mutated copy of the gene that is responsible for causing the disease. In most cases, carriers depict no symptom or signs of the condition. Fertilization entails an X chromosome from the mother and the Y or X chromosome from the father. In a single fertilization when both parents are carriers of an abnormal gene, it can either be transferred to the children or the children can also become carriers, or still, the child will not have the abnormal genes (Wenger, Rafi &Luzi, 2016). For that reason, the inheritance of the disorder happens when 2 parents who are the two bearers of an autosomal recessive ailment have kids, each of the kids is at a 25% danger of having the illness. The odds of being a carrier just like the guardians are higher at 50 percent. The remaining percentage of 25% is a chance of neither having the condition nor not being a carrier of the disease (Marques et al., 2017).
Clinical description
The Krabble disease develops at different ages. The first stage is characterized by hyperactivity and on and off fevers. Most children develop symptoms in the early first six months of age. In other cases, children may develop the symptoms at a later stage in childhood and even adulthood. The disease can be characterized by the following signs and symptoms; children with this disorder have delayed developmental milestones. The motor skills for are delayed and the child is not able to sit correctly by the age of five (Isakova et al., 2017). They cannot even move their hand voluntarily. On the other side, the children with this disorder are highly irritable and sensitive to loud sounds. They excessively throw tantrums and are always crying. Everything around them seems to be disgusting and irritating. A child with this disorder has no balance especially the head control, therefore, he or she cannot stay upright or lift up his head for a minute; the head often falls to the side which means that they continuously need support to remain upright during feeding; it is for this reason that eating becomes very difficult. In general, a person with this condition has delayed developmental milestones such as delayed movement. On the other hand, such a person is always irritated by almost everything and will still be mood less most of the time. On the other side, they are often sensitive especially to sounds which make them easily irritated (Marques et al., 2017).
Treatment
As mentioned earlier, this disorder has no cure, and it is typically managed through supportive care to the patients. After the diagnosis of a person, the very first treatment is focused on the symptoms present. In a case where the patient is vomiting and doesn’t feed, various medications are given to relieve the pain. Secondly, different therapies are provided to improve the state of the patient. It includes physical, respiratory and even speech therapies (Wenger, Rafi &Luzi, 2016). Physical therapy has been used to increase the masculine activities through circulation and toning of the muscles; this is in a bid to rectify the developmental delays. Speech therapy also improves the speech development of the patient hence improving the condition. Recent studies have suggested that stem cell transplants; (the umbilical cord blood stem cells) can be utilized proficiently to manage the condition in children who have not depicted signs and in older individuals with mild manifestations. This type of treatment reduces the rate at which the disease progresses to adverse stages (Isakova et al., 2017).
Genomics
Mapping
The GALC gene is a protein product made up of 685 amino acids and has a molecular mass of 77063Da. It is found on chromosome 14 (14q31). The gene has 17 exons spanning approximately sixty kb of genomic DNA. Numerous mutations, and in particular insertions, missense, and deletions, traversing the entire length of the GALC gene have been found to be responsible for causing the Krabbe disease. The most perceptible mutation, with approximated 40% alleles from affected people with European ancestry and 35 percent of alleles from people with a Mexican family line, is a deletion of 30 kb of the length of the gene that starts in intron 10 and extending past the polyadenylation flag. The deletion of the thirty kb prompts the development of the classic infantile type of the disease in the homozygous state. Over 70 GALC mutations, including many small insertions and deletions, have been discovered in people with all clinical types of the Krabbe disease.

Fig 1: the genomic location of the GALC gene
There is information to suggest that there is a genotype-phenotype correlation of the GALC gene. In their study aimed at investigating GALC gene mutations in Japanese patients, Xu et al (2006) discovered that there is some genotype-phenotype correlation with regard to the mutations distribution within the GALC gene. They found twenty seven mutations. Out of these mutations, 6 were novel, encompassing 2 nonsense mutations, a tiny insertion, 2 missense mutations, and a tiny deletion. Krabbe disease’s clinical phenotype differs widely from infantile onset to adult onset. Expression investigations of alleles that have undergone changes have demonstrated that disparities of phenotype in people with Krabbe disease reflect contrasting degrees of abatement in the action of GALC associated with the changing mutant alleles. Disparity of phenotype between homozygotes within a similar sibship, with seemingly a similar primary GALC mutation, is more difficult to clarify but has however been reported. For example, Bajaj et al (2002) states that the disparities found within sibships may not be a function of the mutation of GALC alone but rather should be identified with changing psychosine turnover rates.
Population genetics
This disease affects 1 in 100000 children in every country. The carrier frequency in people who do not have the history of the disease in their family is estimated to be 1 in 150 individuals. It majorly affects children less than a year. This condition mainly affects people of the Scandinavian descent. On the other hand, the disease can affect just anyone as long as the parents were carriers of the defective gene. In certain segregated communities in Israel, there have been higher prevalence of the disorder reported to be as high as six cases in every 1000 people. For instance, the prevalence of the infantile form of the disorder has been found to be high in 2 quite distinct inbred communities found in Israel (i.e. the Moslem Arab and Druze populations). Approximately 1 in 150 live births have been reported to have Krabbe disease, and this high prevalence can be attributed to 2 dissimilar mutations, c.1630G>A and c. 1796>G (OMIM Entry, 2017). In the Jewish community, there has been no case recorded (Isakova et al., 2017). Patients in the adult stage are more in southern Europe whereas infantile examples are high in Nordic countries. The Krabbe disease affects both females and males equally. This means that the risk of both sexes developing the disease is the same.
Detection
It is detected through conducting a skin tissue biopsy or a blood test. In the laboratory,the sample is tested for GALC enzyme activity; if the action is low, then there is a likelihood of the presence of the Krabbe disease. An MRI scan on the brain can also be done to detect the abnormalities present. An eye examination can also be conducted to check the state of the optic nerve (Bongarzone et al., 2016).
The disease is also detected through prenatal testing whereby the parents of a child decide to have their unborn baby tested prior to birth. If a family has a history of Krabbe disease, then molecular genetic testing (able to detect mutations) can be utilized for prenatal diagnosis. A tissue sample can be extracted from the placenta to test for mutations in the GALC gene, and this test is referred to as chorionic villus sampling. Another test entails extracting a sample of amniotic fluid surrounding the growing fetus, and this process is known as amniocentesis. Cells referred to as amniocytes are extracted from the fluid and studies for mutations in the GALC gene.
Conclusion
There are three animal models that have been used in the research of the Krabbe disease; a mouse model, the model of a dog and a model of a monkey. The mouse model conveys comparative hereditary deformities that are found in human patients with the illness. The affected mice often develop signs equivalent to Krabble disease and if untreated die by 35 or more days. Transplantation of bone marrow increases the days of the mice. Notably, different treatments have been attempted on these models of animals, with differing degrees of success. The most promising treatment so far is genetic therapy, where the GALC gene is delivered in a virus that is harmless. Stem cell therapy is yet another promising treatment method, which can offer healthy cells with GALC activity to give room for remyelination. Nonetheless, none of these techniques have yet been tried on human beings.















References
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