Autoantibodies blocking M3 muscarinic receptors cause postganglionic cholinergic dysautonomia
A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M1 -M5 ) we identified in the patient's serum antibodies that selectively bound to M3 receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M3 receptor activation. Thus, autoantibodies against M3 acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.
Afferent Baroreflex Dysfunction: Decreased or Excessive Signaling Results in Distinct Phenotypes
Head and neck tumors can affect afferent baroreceptor neurons and either interrupt or intermittently increase their signaling, causing blood pressure to become erratic. When the afferent fibers of the baroreflex are injured by surgery or radiotherapy or fail to develop as in familial dysautonomia, their sensory information is no longer present to regulate arterial blood pressure, resulting in afferent baroreflex failure. When the baroreflex afferents are abnormally activated, such as by paragangliomas in the neck, presumably by direct compression, they trigger acute hypotension and bradycardia and frequently syncope, by a mechanism similar to the carotid sinus syndrome. We describe our observations in a large series of 23 patients with afferent baroreflex dysfunction and the cardiovascular autonomic features that arise when the sensory baroreceptor neurons are injured or compressed. The management of afferent baroreceptor dysfunction is limited, but pharmacological strategies can mitigate blood pressure swings, improve symptoms, and may reduce hypertensive organ damage. Although rare, the prevalence of afferent baroreflex dysfunction appears to be increasing in middle-aged men due to human papillomavirus related oropharyngeal cancer.
Presentation, Causes, and Hemodynamic Features of Acquired Afferent Baroreflex Failure [Meeting Abstract]
Nerve Conduction Studies in Familial Dysautonomia [Meeting Abstract]
Frequency of Seizures and Epilepsy in Familial Dysautonomia [Meeting Abstract]
Neurogenic bladder dysfunction in patients with familial dysautonomia: a cross-sectional study [Meeting Abstract]
Familial dysautonomia and congenital adrenal hyperplasia: One patient with two rare genetic disorders [Meeting Abstract]
Objective: To describe an unusual case of a young girl of Jewish Ashkenazi descent with two rare genetic disorders: familial dysautonomia and congenital adrenal hyperplasia.
Method(s): Case report.
Result(s): Female patient presenting with hypotonia, failure to thrive, recurrent vomiting and frequent lower respiratory tract infections during the first year of life. Her physical exam disclosed genital ambiguity and, because an older sister had a diagnosis of congenital adrenal hyperplasia, the diagnosis was suspected in this case, and confirmed by low levels of cortisol and aldosterone. Targeted genetic testing showed homozygosis for a pathogenic variant in the CYP21A2 gene (c.293-13C[G, aka I2G, well-described in Jewish Ashkenazi patients) and heterozygosis for 7 other variants in the same gene. She was started on fludrocortisone for mineralocorticoid replacement therapy. Additional signs and symptoms were identified including frequent aspiration pneumonias prompting a gastrostomy tube placement at 6 months of age, emotionally-induced episodes of face, hand and feet blotching, frequent falls, impaired sensitivity to pain, and lack of tears. Additional genetic testing at age 2 disclosed homozygous copies of the founder mutation variant of familial dysautonomia (variant IVS20?6 T[C) in the IKBKAP gene.
Conclusion(s): The presence of one rare genetic disorder does not preclude the presence of another rare genetic disorder. Signs and symptoms not consistent with one diagnosed genetic disorder should prompt suspicion of additional causes
Site-directed mutagenesis study of yeast peptide:N-glycanase. Insight into the reaction mechanism of deglycosylation
Yeast peptide:N-glycanase (Png1p; PNGase), a deglycosylation enzyme involved in the proteasome dependent degradation of proteins, has been reported to be a member of the transglutaminase superfamily based on sequence alignment. In this study we have investigated the structure-function relationship of Png1p by site-directed mutagenesis. Cys-191, His-218, and Asp-235 of Png1p are conserved in the sequence of factor XIIIa, where these amino acids constitute a catalytic triad. Point mutations of these residues in Png1p resulted in complete loss in activity, consistent with a role for each in catalyzing deglycosylation of glycoproteins. Other conserved amino acid residues, Trp-220, Trp-231, Arg-210, and Glu-222, were also vitally important for folding and structure stability of the enzyme as revealed by circular dichroism analysis. The potential effects of the mutations were predicted by mapping the conserved amino acids of Png1p within the known three-dimensional structure of factor XIIIa. Our data suggest that the lack in enzyme activity when any of the catalytic triad residues is mutated is either due to the absence of charge relay in the case of the triad or due to the disruption of the native fold of the enzyme. These findings strongly suggest a common evolutionary lineage for the PNGases and transglutaminases.