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Human Disease Pedigree Analysis
Gregor Mendel has started inheritance studies and founded genetics in the 19th century, which gave a comprehensive impulse to the modern understanding of medicine. Certain disorders occur in some families more frequently than in others. It is evident that genetics determines the risk of various diseases. Nowadays, even a student can perform the genetic analysis using the family history, or the pedigree. This paper describes the Huntington disease and assesses it through the prism of inheritance analysis.}}
Huntingtons disease is an incurable neurological disorder of the adults. In this condition, the basal ganglia, cortex and other regions in the brain lose neurons due to their gross atrophy. The molecular basis for Huntingtons disease is malproduction of a protein called huntingtin. It is normally located in the cytoplasm and has no apparent purpose. This protein probably assists in vesicle transport, microtubule and synaptic activities. It is assumed that huntingtin is critical in cell signaling process (Revilla, 2015). In Huntingtons disease, the protein gene has the expansion of a cysteine-adenine-guanine repeat encoding. The mutant polypeptide accumulates in the neurons Such inclusions can be toxic and cause neuron death.
The estimated prevalence of Huntingtons disease is 4.1-8.4 cases per 100,000 people in the U.S. (Revilla, 2015). The mean age of onset is 33 45 years old. However, there were cases of the disease in 2-year-old and 80-year-old patients.
Huntingtons disease is a progressive disorder that leads to disability and death. The cause of death is intercurrent infections, pneumonia or cardiovascular disorders. The average duration of illness is 19 years. Clinical presentation includes internal and social issues. Internal problems are movement and cognitive disorders while social problems are behavioral. Patients may suffer from chorea at early stages and akinetic-rigid syndrome at advanced stages. In addition, dysarthria and dysphagia develop frequently; dementia and epilepsy may occur in the young patients. Behavioral changes include distress, loss of interests, irritability, poor intellectual function, and memory disorders. The disease causes attention problems, depression and diminish verbal abilities. Patients are prone to suicide, psychosis, changes in personality, and sleep disorders. Nowadays, antipsychotics and antidepressants are used to palliate the condition (Revilla, 2015).
Huntingtons disease is an autosomal dominant inherited disease. Juvenile forms usually come from the father while onset at an older age is inherited from the mother. The greater instability of the Huntington disease gene during spermatogenesis explains this phenomenon (Revilla, 2015).
George Huntington described the inherited form of chorea for the first time in 1872 (Chial, 2008). His father was a physician; on his medical rounds, George witnessed the horror of the impact the disease had on a patients personality. When George became a doctor, he observed several generations of one family who experienced similar symptoms (Mandal, 2014). Huntington managed to outline the dominant inheritance of the symptoms even before Mendel described the principles of dominant and recessive traits.
In this paper, the pedigree covering seven generations in one family is discussed. This family history was described in 1983 by a team of researchers from the U.S. and Venezuela and allowed them to identify the gene located on the 4th chromosome responsible for the Huntigton disease (Gusella et al., 1983). A Venezuelan family pedigree is shown in Figure 1.
Figure 1. Pedigree of the Venezuelan Huntingtons disease family (Gusella et al., 1983)
Symbols in pedigree:
According to the authors, the entire family was studied even in more detail, but the results could not be presented in their article for ethical reasons (Gusella et al., 1983). In this kindred, a mating pair presents the first generation (generation I). The male in this pair was affected by Huntingtons disease and succumbed to it. The couple had two daughters (generation II). Both women were affected and died. The older female (to the left) married a healthy male and gave birth to two daughters (generation III). Both women in generation III were affected and succumbed to Huntingtons disease. The younger female of generation II (to the right) gave birth to a male who suffered from the disease (generation III).
One of the women from generation III married a healthy man and had one female offspring (generation IV) affected with the disorder. This female mated with a healthy male and gave birth to three female children (generation V). One of them was affected and married an unaffected male. This couple had six children (generation VI). Three females and one male in this generation inherited the disease. However, at the time of investigation all of them were alive. Male offspring in generation VI married a healthy female, and both their sons had Huntingtons disease (generation VII).
The other female in generation III mated with a healthy male and had one son with this condition (generation IV). He married a healthy woman, and they got two children healthy male and unhealthy female (generation V). The female offspring mated with a healthy male and gave birth to four children (generation VI). In generation VI, two individuals were ill, both male. One of them had an affected offspring (generation VII).
The man from generation III died from Huntingtons disease. He had four children, two females and one male were affected (generation IV). The first female from generation IV mated with a male and one of their four children inherited the disease (generation V). The second female mated with a healthy male and had eight children (generation VI). In this family, one female and three males suffered from Huntingtons disease. One man married a healthy woman, and both their sons were ill (generation VI). Finally, the affected male from generation IV mated with a healthy female and had three children (generation V). Two of them inherited the Huntingtons disease. One man had a son who was affected (generation VI).
From the pedigree analysis, it is evident that the Huntingtons disease is inherited in a dominant, unrelated to gender mode.
Dominant vs. Recessive Inheritance. The male from generation I was affected and died from the disease. The trait was inherited by his two female offspring. From this observation, it is possible to conclude that the disease-causing allele dominates in the healthy condition, and both parents can be carriers. The child will develop the disease if he or she receives this allele. In autosomal dominant inheritance, a child from a parent with Huntingtons chorea has a 50% chance of having the mutant huntingtin gene. For example, in generation V, there are five families, and the risks to die from Huntingtons disease are the following:
1 in 3 (33.3%) for family #1
1 in 2 (50%) for family #2
1 in 4 (25%) for family #3
4 in 8 (50%) for family #4
2 in 3 (66%) for family #5
In total, the percentage is more or less close to the theoretical 50%.
Sex-related Inheritance.From the presented pedigree, it is evident that neither male nor female have a predisposition to the Huntingtons chorea. For example, in generation III, there were two females and one male who died from the disease while in generation IV, three females and two males died and one male was healthy. If the analysis of other generations was performed, the same pattern would appear no vivid gender dependency. Huntingtons disease is of autosomal inheritance.
The accurate pedigree analysis allows the researcher to trace the inheritance pattern of a certain trait even not knowing its exact molecular mechanism. The pedigree analysis of seven real generations of a single family shows that Huntingtons disease has an autosomal inheritance pattern and does not depend on the gender of the carriers and their offspring. Thus, the analysis of the family history of the disease in the era of sophisticated molecular biology techniques remains a valuable tool for genetic counseling.