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Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
HSAN is rarer than CMT and is characterized by prominent sensory loss that may result in mutilation, and autonomic features; motor involvement may also be present. HSAN1 presents in the second decade with lower limb sensory loss and lancinating pain. It is autosomal dominant and largely caused by mutations in the SPTLC4 gene. The phenotype shows considerable overlap with CMT2B caused by RAB7 mutations. HSAN II is caused by mutations in the HSN2 gene and is an early onset autosomal recessive sensory neuropathy. HSAN III is caused by mutations in the IKBKAP gene and presents in infancy and childhood with an autonomic and sensory neuropathy. It is an autosomal recessive condition seen in Ashkenazi Jewish people (Riley–Day syndrome). HSAN IV and V are autosomal recessive conditions that are characterized by congenital insensitivity to pain. HSAN IV is caused by mutations in the NTRK 1 (neurotrophic tyrosine kinase receptor type 1) gene and is associated with anhidrosis and mental retardation, as well as congenital insensitivity to pain. HSAN V is caused by mutations in either NTRK1 or NGFB genes and does not exhibit any additional features other than congenital insensitivity to pain. Mutations in the voltage gated sodium channel SCN9A have been shown to cause a phenotype similar to HSAN V.
Tocotrienol Vitamin E and Neurodegenerative Disorders
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Recent studies reported that tocotrienols upregulate transcription of the IKBKAP gene (Figure 14.5). This study investigated whether a similar effect was observed in vivo. The effects of tocotrienol supplement on FD patients’ symptoms and IKBKAP expression in white blood cells were reported in the same study (Table 14.2). The initial daily dose of 50 or 100 mg tocotrienol, doubled after 3 months, was given to 32 FD patients. Twenty-eight FD patients completed the 6-month study. Significant increase in IKBKAP expression level in FD patients’ blood were observed in the first 3 months of tocotrienol supplement. After doubling the dose after the initial 3 months of supplementation, IKBKAP expression level returned to baseline by the end of the 6-month supplementation of tocotrienol. Clinical information on the study was reported by clinical questionnaire (with regard to dizziness, bloching, sweating, number of pneumonia, cough episodes, and walking stability); however, no adverse effect of tocotrienol supplementation was observed in any clinical measurements (weight, height, oxygen saturation, blood pressure, tear production, histamine test, vibration threshold test, nerve conduction, and heart rate variability). Therefore, tocotrienol supplementation appears significantly beneficial on the basis of clinical evaluation. This study suggested the complexity of effect of tocotrienol treatment on FD patients’ clinical outcomes and on IKBKAP expression level compared to in-vitro study [60]. A broad and systematic study is mandatory to better understand the effect of tocotrienol on FD diseases.
Strategies for targeting RNA with small molecule drugs
Published in Expert Opinion on Drug Discovery, 2023
Christopher L. Haga, Donald G. Phinney
FD is a rare, heritable, autosomal recessive genetic disorder that affects the autonomic nervous system found almost exclusively in the Ashkenazi Jewish population [64]. As the disease progresses, patients show a marked reduction in nonmyelinated neurons accompanied by a reduction in myelinated axons culminating in widespread sensory and autonomic system dysfunction. The root cause of FD is a point mutation in intron 20 of IKBKAP, a gene consisting of 37 exons spanning ~68 kb that encodes IKAP [65]. The single point mutation induces a mis-splicing skip of exon 20 resulting in a frameshift and premature termination codon in exon 21. Consequently, tissue-specific expression of full-length IKAP is greatly reduced. As of this publication, antisense oligonucleotides (ASOs) have been shown to be effective in correcting IKBKAP splicing defects in transgenic mice [66]. However, no small molecule has been shown to interact with the IKBKAP mRNA to correct the splicing defect.
Congenital alacrima
Published in Orbit, 2022
Zhenyang Zhao, Richard C. Allen
Hereditary sensory and autonomic neuropathy type III (HSAN3) also known as Riley-Day syndrome, is an autosomal recessive disorder prevalent in Ashkenazi Jewish decedents. It is featured by progressive central and peripheral autonomic disturbance, as well as small-fiber sensory dysfunction.60 A single noncoding mutation in the gene IKBKAP, which is responsible for transcriptional elongation and histone acetylation, accounts for 99.5% cases of HSAN317. One of the earliest signs in these patients is difficult feeding, presenting as poor sucking, frequent aspiration, gastroesophageal reflux, and the propensity to vomit.60 Clinical diagnosis can be established following the ‘cardinal’ criteria: absence of fungiform papillae on the tongue, absence of axon flare after intradermal histamine injection, decreased or absent deep tendon reflexes, alacrima, and Ashkenazi Jewish descent.
Susceptibility to diarrhea is related to hemodynamic markers of sympathetic activation in the general population
Published in Scandinavian Journal of Gastroenterology, 2019
Viktor Hamrefors, Artur Fedorowski, Bodil Ohlsson
Independent of primary or secondary associations, neither the present nor previous studies support that a great part of the IBS population has developed the disease because of a primary autonomic dysfunction [8,25]. Familial dysautonomia often presents itself with dysphagia, esophageal dysmotility and vomiting [16]. Thus, the symptoms are not similar to classical functional GI symptoms [1]. Impaired baroreflex pathways have been found in familial dysautonomia [31], which is not supported in our cohort with a very low prevalence of orthostatic hypotension. The found association between gene mutations of IKBKAP and self-reported IBS may reflect that many patients with GI symptoms are not properly examined [15], and could have other diagnoses of autonomic dysautonomia with secondary GI symptoms [9–11].