Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

Introduction: Human papillomavirus (HPV) vaccination has been anecdotally connected to development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome.

Objectives: To critically evaluate a potential connection between HPV vaccination and above noted conditions.

Methods: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

Introduction: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome.

Objectives: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions.

Methods: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders.

Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia.

Study Objectives: In familial dysautonomia (FD) patients, sleep-disordered breathing (SDB) might contribute to their high risk of sleep-related sudden death. Prevalence of central versus obstructive sleep apneas is controversial but may be therapeutically relevant. We, therefore, assessed sleep structure and SDB in FD-patients with no history of SDB.

Norepinephrine deficiency with normal blood pressure control in congenital insensitivity to pain with anhidrosis.

Objective: Congenital insensitivity to pain with anhidrosis (CIPA) is caused by mutations in the NKTR1 gene. This affects the development of nerve growth factor (NGF)-dependent neurons including sympathetic cholinergic neurons in the skin, causing anhidrosis. Cardiovascular and blood pressure regulation appears normal, but the integrity of sympathetic adrenergic neurons has not been tested.

Disturbances in affective touch in hereditary sensory & autonomic neuropathy type III.

Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley-Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients.

Selective retinal ganglion cell loss in familial dysautonomia.

To define the retinal phenotype of subjects with familial dysautonomia (FD). A cross-sectional study was carried out in 90 subjects divided in three groups of 30 each (FD subjects, asymptomatic carriers and controls). The study was developed at the Dysautonomia Center, New York University Medical Center.

Relationship between proprioception at the knee joint and gait ataxia in HSAN III.

Background: Hereditary sensory and autonomic neuropathy type III features marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia.

Methods: Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied.

Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa.

Objective: The purpose of this study was to determine whether carbidopa (Lodosyn), an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD) and hyperdopaminergic nausea/retching/vomiting attacks.

Methods: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy.

Genetic autonomic disorders.

Genetic disorders affecting the autonomic nervous system can result in abnormal development of the nervous system or they can be caused by neurotransmitter imbalance, an ion-channel disturbance or by storage of deleterious material. The symptoms indicating autonomic dysfunction, however, will depend upon whether the genetic lesion has disrupted peripheral or central autonomic centers or both. Because the autonomic nervous system is pervasive and affects every organ system in the body, autonomic dysfunction will result in impaired homeostasis and symptoms will vary.

Cardiac-locked bursts of muscle sympathetic nerve activity are absent in familial dysautonomia.

Familial dysautonomia (Riley-Day syndrome) is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced pain and temperature sensibilities and absent baroreflexes, causing orthostatic hypotension as well as labile blood pressure that increases markedly during emotional excitement. Given the apparent absence of functional baroreceptor afferents, we tested the hypothesis that the normal cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in patients with familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 12 patients with familial dysautonomia.

Cyclic vomiting associated with excessive dopamine in Riley-day syndrome.

Goals: To analyze the neurochemical profile during the recurrent attacks of nausea and vomiting in patients with Riley-day syndrome.

Background: One of the most disabling features of patients with Riley-day syndrome are recurrent attacks of severe nausea/retching/vomiting accompanied by hypertension, tachycardia, and skin flushing, usually triggered by emotional or other stresses.

Study: We monitored blood pressure and heart rate and measured plasma catecholamines during typical dysautonomic crises triggered by emotionally charged situations.

A rating scale for the functional assessment of patients with familial dysautonomia (Riley Day syndrome).

Objective: To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time, and determine whether severity within a particular functional category at a young age affected survival.

Study Design: Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years ± 6 months. Each of the 10 Functional Severity Scale categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular, and nutritional status) were scored from 1 (worst or severely affected) to 5 (best or no impairment).

Hereditary sensory autonomic neuropathy caused by a mutation in dystonin.

In 4 infants with a new lethal autonomic sensory neuropathy with clinical features similar to familial dysautonomia as well as contractures, we identified a deleterious mutation in the DST gene, using homozygosity mapping followed by exome sequencing. DST encodes dystonin, a cytoskeleton linker protein, and the mutation results in an unstable transcript. Interestingly, dystonin is significantly more abundant in cells of familial dysautonomia patients with IKBKAP (I-κ-B kinase complex-associated protein) mutation compared to fibroblasts of controls, suggesting that upregulation of dystonin is responsible for the milder course in familial dysautonomia.

Genome-wide analysis of familial dysautonomia and kinetin target genes with patient olfactory ecto-mesenchymal stem cells.

Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder. The most common mutation is a c.2204+6T>C transition in the 5' splice site (5'ss) of IKBKAP intron 20, which causes a tissue-specific skipping of exon 20, resulting in lower synthesis of IKAP/hELP1 protein.

Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome?

The Riley-Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients.

Clinical neuro-ophthalmic findings in familial dysautonomia.

Background: To define the clinical neuro-ophthalmic abnormalities of patients with familial dysautonomia (FD).

Methods: Sixteen patients (32 eyes) with the clinical and molecular diagnoses of FD underwent thorough neuro-ophthalmic clinical evaluation.

Results: Visual acuity ranged from 0.

Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia.

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-κ-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation.

Cardiovascular and neuroendocrine features of Panayiotopoulos syndrome in three siblings.

Objective: Panayiotopoulos syndrome is a benign idiopathic childhood epilepsy characterized by altered autonomic activity at seizure onset.

Methods: Three siblings with Panayiotopoulos syndrome underwent 24-hour EEG recording and head-up tilt testing with continuous blood pressure and RR interval monitoring. Plasma catecholamines and vasopressin were measured while supine, upright, and during a typical seizure.

Increased Incidence of Tumors With the Gene Mutation? A Case Report and Review of the Literature.

An increased incidence of neoplasia was recently reported in patients with familial dysautonomia. This suggests that, in addition to its role in neuronal development, the gene may also influence DNA repair. Here we report the case of a 28-year-old male with familial dysautonomia who was found to have neoplastic lesions detected post mortem as incidental findings.

Assessing autonomic dysfunction symptoms in children: a pilot study.

As a screening tool to identify symptoms of autonomic dysfunction, the Pediatric Autonomic Symptoms Scale was administered to parents of children with familial dysautonomia, autism spectrum disorders, and age-matched controls. The total scores for the presence of symptoms were compared among the 3 groups for each section and overall. The Pediatric Autonomic Symptoms Scale distinguished controls from children with familial dysautonomia and autism spectrum disorders with scores from each section and overall scores.

Olfactory stem cells, a new cellular model for studying molecular mechanisms underlying familial dysautonomia.

Background: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system.

Afferent baroreflex failure in familial dysautonomia.

Background: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause.

Methods: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons.

Complicated peptic ulcer disease in three patients with familial dysautonomia.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by autonomic and sensory neuropathy. Owing to pervasive dysfunction, the disease has protean clinical manifestations, affecting the ocular, gastrointestinal, pulmonary, orthopedic, vasomotor, and neurologic systems. The gastrointestinal perturbations, including dysphagia, gastroesophageal dysmotility, gastroesophageal reflux, and vomiting crises, are among the earliest signs.