Familial dysautonomia (FD), also known as Riley-Day syndrome and autonomic neuropathy type III (HSAN type III), is a genetic pathology, which is characterized by a violation of the myelin axons in the vegetative centers of the nervous system (Gutiérrez et al., 2018).
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This disease develops as a result of a mutation in chromosome Q319, and it is inherited by the autosomal recessive principle. Gutiérrez et al. (2018) assume that the etiology of the given disease is designated by IKBKAP, an inhibitor of kappa light polypeptide gene enhancer in B-cells kinase complex-associated protein, as the presence of point mutations in splice sites. As for pathogenesis, FD is produced by the protein belonging to the superfamily of interleukins and protein kinase complex of associated proteins (Dietrich & Dragatsis, 2016). This protein binds various structures of this complex through two different domains and regulates the functioning of three different kinases involved in the initial stages of inflammation.
The reasons for the development of FD have not been elucidated, which makes treatment difficult, yet some mechanisms of pathogenesis indicate a violation in the exchange of the neurotransmitter norepinephrine, which is responsible for the transmission of nerve impulses in the autonomic nervous system. Shohat and Weisz (2014) claim that more than 99.5 percent of patients have the same mutation, leading to the deletion of the 20th intron in the information matrix RNA (mRNA). This mutation cannot cause a complete inactivation of the gene, yet it affects negatively on various body systems (Hervé & Ibrahim, 2017). In other words, FD is regarded as a genetic disease caused by a gene mutation.
Riley-Day syndrome is prevalent mainly among Ashkenazi Jews. The identified disease occurs when a copy of the IKBKAP gene is transmitted from a mother or a father to the baby. FD is most common among people who are Jews of Eastern European origin (Norcliffe-Kaufmann, Slaugenhaupt, & Kaufmann, 2017). In their population, it occurs with a frequency of one case per 10-20 thousand population (Shohat & Weisz, 2014).
The disease is a combination of severe autonomic dysfunction and sensitive disorders, which is 40 percent of cases is accompanied by convulsive paroxysms as well as a delay in the psychomotor development of a child. According to Norcliffe-Kaufmann et al. (2017), the diagnosis of FD is facilitated by a histamine sample, DNA analysis, and exclusion of pathology by neuro sonography or magnetic resonance imaging (MRI).
Symptoms include a combination of dysphagia, vomiting, reduced sensitivity, autonomic dysfunction, ataxia, inadequate secretion of tears, etc. The most constant signs are alacrimia, the absence of fungiform papillae, vasomotor lability, a decrease or absence of deep tendon reflexes and pain sensitivity, and impaired coordination (Rubin & Anderson, 2017). Disturbance of lacrimation can lead to ulceration of the cornea.
Adolescents and adults often develop chronic lung diseases due to swallowing difficulty, repeated reflux of food from the stomach into the esophagus, and pulmonary aspiration. The development of scoliosis aggravates the problem of breathing due to the restrictive component. Rubin and Anderson (2017) emphasize that there is an increased sensitivity to cholinergic and adrenergic drugs. Also, there is a delay in physical development, retardation, and convulsions. In single observations, microcephaly, hydrocephalus, megacolon, and mega-esophagus are mentioned.
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Management of FD is symptomatic and aimed at stopping vomiting, compensating for fluid loss, normalizing blood pressure, as well as reducing muscle hypotension, and establishing neuropsychological correction (Norcliffe-Kaufmann et al., 2017). Squats and slopes are recommended for treatment and prevention of orthostatic hypotension. Regular use of eye drops reduces the risk of ulceration of the cornea. Permanent respiratory physiotherapy and exercises to prevent joint contractures are necessary for all patients. As suggested by Cuajungco et al. (2003), a tissue-specific increase in splicing efficiency of IKBKAP may be used in further research to discover a potential solution to FD.
Cuajungco, M. P., Leyne, M., Mull, J., Gill, S. P., Lu, W., Zagzag, D.,… Slaugenhaupt, S. A. (2003). Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. The American Journal of Human Genetics, 72(3), 749-758.
Dietrich, P., & Dragatsis, I. (2016). Familial dysautonomia: Mechanisms and models. Genetics and Molecular Biology, 39(4), 497-514.
Gutiérrez, J. V., Kaufmann, H., Palma, J. A., Mendoza-Santiesteban, C., Macefield, V. G., & Norcliffe-Kaufmann, L. (2018). Founder mutation in IKBKAP gene causes vestibular impairment in familial dysautonomia. Clinical Neurophysiology, 129(2), 390-396.
Hervé, M., & Ibrahim, E. (2017). Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia. Neurobiology of Disease, 103, 113-122.
Norcliffe-Kaufmann, L., Slaugenhaupt, S. A., & Kaufmann, H. (2017). Familial dysautonomia: History, genotype, phenotype and translational research. Progress in Neurobiology, 152, 131-148.
Rubin, B. Y., & Anderson, S. L. (2017). IKBKAP/ELP1 gene mutations: Mechanisms of familial dysautonomia and gene-targeting therapies. The Application of Clinical Genetics, 10, 95-103.
Shohat, M., & Weisz, H. M. (2014). Familial dysautonomia. In Adam, M. P., Ardinger, H. H., Pagon, R. A., Wallace, S. E., Bean, L. J. H., Mefford, H. C.,… Ledbetter, N. (Eds.), GeneReviews (pp. 1-22). Seattle, WA: University of Washington.