The Relationship Between Scoliosis, Spinal Bone Density, and Truncal Muscle Strength in Familial Dysautonomia Patients.

This combined retrospective and prospective study aimed to investigate the relationship between scoliosis, spinal bone mineral density (BMD), and truncal muscle strength in patients with familial dysautonomia (FD). A total of 79 FD patients (40 male, 39 female) aged 5-44 years were included. The severity of scoliosis, lumbar spine BMD (Z-score), and truncal muscle strength were assessed. Correlations were analyzed using Pearson's correlation coefficient. Inverse correlations were observed between scoliosis severity and BMD (r = - 0.328, p = 0.001), as indicated by increasingly negative Z-score values with worsening osteoporosis. There were also inverse correlations between scoliosis and truncal muscle strength (r = - 0.595, p < 0.001). The correlation between scoliosis and age was notable up to 22 years (r = 0.421, p = 0.01), but not in the older age group (22-44 years). Our study identified inverse correlations between osteoporosis and scoliosis, as well as between scoliosis and truncal muscle strength, in FD patients. These findings suggest that there may be a relationship between bone density, muscle strength, and the severity of spinal curvature in this population. While our results highlight the potential importance of early diagnosis and management of osteoporosis, and possibly the benefits of physical therapy to strengthen truncal muscles, further research is needed to determine the direct impact of these interventions on preventing the progression of scoliosis and its associated complications in FD patients. A long-term longitudinal study could provide more insights into these relationships and inform treatment strategies for FD patients.

Gastrointestinal bleeding in children with familial dysautonomia: a case-control study.

OBJECTIVE: Familial dysautonomia (FD) is a rare inherited autosomal recessive disorder with abnormal somatosensory, enteric, and afferent autonomic neurons. We aimed to define the incidence of gastrointestinal bleeding and its associated risk factors in patients with FD. METHODS: In this retrospective case-control study, we identified all episodes of gastrointestinal bleeding in patients with FD, occurring over four decades (January 1980-December 2017), using the New York University FD registry. RESULTS: We identified 104 episodes of gastrointestinal bleeding occurring in 60 patients with FD. The estimated incidence rate of gastrointestinal bleeds in the FD population rate was 4.20 episodes per 1000 person-years. We compared the 60 cases with 94 age-matched controls. Bleeding in the upper gastrointestinal tract from gastric and duodenal ulcers occurred most frequently (64 bleeds, 75.6%). Patients were more likely to have a gastrostomy (G)-tube and a Nissen fundoplication [odds ratio (OR) 3.73, 95% confidence interval (CI) 1.303-13.565] than controls. The mean time from G-tube placement to first gastrointestinal bleed was 7.01 years. The mean time from Nissen fundoplication to bleed was 7.01 years. Cases and controls had similar frequency of intake of nonsteroidal antiinflammatory drugs (NSAID) and selective serotonin reuptake inhibitors (SSRI). CONCLUSION: The incidence of gastrointestinal bleeding in the pediatric FD population was estimated to be 4.20 per 1000 person-years, 21 times higher than in the general pediatric population (0.2 per 1000 person-years). Patients with FD with a G-tube and a Nissen fundoplication had a higher risk of a subsequent gastrointestinal bleeding.

Fludrocortisone for orthostatic hypotension.

BACKGROUND: Orthostatic hypotension is an excessive fall in blood pressure (BP) while standing and is the result of a decrease in cardiac output or defective or inadequate vasoconstrictor mechanisms. Fludrocortisone is a mineralocorticoid that increases blood volume and blood pressure. Fludrocortisone is considered the first- or second-line pharmacological therapy for orthostatic hypotension alongside mechanical and positional measures such as increasing fluid and salt intake and venous compression methods. However, there has been no Cochrane Review of the benefits and harms of this drug for this condition. OBJECTIVES: To identify and evaluate the benefits and harms of fludrocortisone for orthostatic hypotension. SEARCH METHODS: We searched the following databases on 11 November 2019: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL. We also searched trials registries. SELECTION CRITERIA: We included all studies evaluating the benefits and harms of fludrocortisone compared to placebo, another drug for orthostatic hypotension, or studies without comparators, including randomized controlled trials (RCTs), quasi-RCTs and observational studies. We included studies in people with orthostatic hypotension due to a chronic peripheral neuropathy, a central autonomic neuropathy, or autonomic failure from other causes, but not medication-induced orthostatic hypotension or orthostatic hypotension from acute volume depletion or blood loss. DATA COLLECTION AND ANALYSIS: We used Cochrane methodological procedures for most of the review. We developed and used a tool to prioritize observational studies that offered the best available evidence where there are gaps in the evidence from RCTs. We assessed the certainty of evidence for fludrocortisone versus placebo using GRADE. MAIN RESULTS: We included 13 studies of 513 participants, including three cross-over RCTs and 10 observational studies (three cohort studies, six case series and one case-control study). The included RCTs were small (total of 28 participants in RCTs), short term (two to three weeks), only examined fludrocortisone for orthostatic hypotension in people with two conditions (diabetes and Parkinson disease), and had variable risk of bias (two had unclear risk of bias and one had low risk of bias). Heterogeneity in participant populations, comparators and outcome assessment methods prevented meta-analyses of the RCTs. We found very low-certainty evidence about the effects of fludrocortisone versus placebo on drop in BP in people with diabetes (-26 mmHg versus -39 mmHg systolic; -7 mmHg versus -11 mmHg diastolic; 1 cross-over study, 6 participants). For people with Parkinson disease, we found very-low certainty evidence about the effects of fludrocortisone on drop in BP compared to pyridostigmine (-14 mmHg versus -22.1 mmHg diastolic; P = 0.036; 1 cross-over study, 9 participants) and domperidone (no change after treatment in either group; 1 cross-over study, 13 participants). For orthostatic symptoms, we found very low-certainty evidence for fludrocortisone versus placebo in people with diabetes (4 out of 5 analyzed participants had improvements in orthostatic symptoms, 1 cross-over study, 6 participants), for fludrocortisone versus pyridostigmine in people with Parkinson disease (orthostatic symptoms unchanged; 1 cross-over study, 9 participants) or fludrocortisone versus domperidone (improvement to 6 for both interventions on the Composite Autonomic Symptom Scale-Orthostatic Domain (COMPASS-OD); 1 cross-over study, 13 participants). Evidence on adverse events was also very low-certainty in both populations, but indicated side effects were minimal. Observational studies filled some gaps in evidence by examining the effects in larger groups of participants, with more diverse conditions, over longer periods of time. One cohort study (341 people studied retrospectively) found fludrocortisone may not be harmful in the long term for familial dysautonomia. However, it is unclear if this translates to long-term improvements in BP drop or a meaningful improvement in orthostatic symptoms. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of fludrocortisone on blood pressure, orthostatic symptoms or adverse events in people with orthostatic hypotension and diabetes or Parkinson disease. There is a lack of information on long-term treatment and treatment of orthostatic hypotension in other disease states. There is a need for standardized reporting of outcomes and for standardization of measurements of blood pressure in orthostatic hypotension.

Frequency and burden of gastrointestinal symptoms in familial dysautonomia.

PURPOSE: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (HSAN-3) that is clinically characterized by impaired pain and temperature perception and abnormal autonomic function. Patients with FD have gastrointestinal dysmotility and report a range of gastrointestinal symptoms that have yet to be systematically evaluated. The aim of this study was to establish the frequency and severity of gastrointestinal symptoms in patients with FD. METHODS: The validated National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey questionnaire, together with additional FD-specific questions, were distributed to 202 living patients with genetically confirmed FD who had been identified from the New York University FD Patient Registry or, when relevant, to their respective caretaker. As a comparison group, we used a general US adult population for whom PROMIS scores were available (N = 71,812). RESULTS: Of the 202 questionnaires distributed, 77 (38%) were returned, of which 53% were completed by the patient. Median age of the respondents was 25 years, and 44% were male. Gastrostomy tube was the sole nutrition route for 25% of the patients, while 53% were reliant on the gastrostomy tube only for liquid intake. The prevalence of gastrointestinal symptoms was significantly higher in each of the eight domains of PROMIS in patients with FD than in the controls. Gastrointestinal symptoms as measured by raw scores on the PROMIS scale were significantly less severe in the FD patient group than in the control population in all domains with the exception of the abdominal pain domain. The surveys completed by caregivers reported the same burden of symptoms as those completed only by patients. CONCLUSION: Gastrointestinal symptoms affect nearly all patients with FD. Gastrointestinal symptoms are more prevalent in adult patients with FD than in the average US adult population but are less severe in the former.

Longitudinal changes in the macula and optic nerve in familial dysautonomia.

OBJECTIVE: Familial Dysautonomia (FD) disease, lacks a useful biomarker for clinical monitoring. In this longitudinal study we characterized the structural changes in the macula, peripapillary and the optic nerve head (ONH) regions in subjects with FD. METHODS: Data was consecutively collected from subjects attending the FD clinic between 2012 and 2019. All subjects were imaged with spectral-domain Optical Coherence Tomography (OCT). Global and sectoral measurements of mean retinal nerve fiber layer (RNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness, and ONH parameters of rim area, average cup-to-disc (C:D) ratio, and cup volume were used for the analysis. The best fit models (linear, quadratic and broken stick linear model) were used to describe the longitudinal change in each of the parameters. RESULTS: 91 subjects (149 eyes) with FD of ages 5-56 years were included in the analysis. The rate of change for average RNFL and average GCIPL thicknesses were significant before reaching a plateau at the age of 26.2 for RNFL and 24.8 for GCIPL (- 0.861 µm/year (95% CI - 1.026, - 0.693) and - 0.553 µm/year (95% CI - 0.645, - 0.461), respectively). Significant linear rate of progression was noted for all ONH parameters, except for a subset of subjects (24%), with no cupping that did not show progression in any of the ONH parameters. CONCLUSIONS: The rapidly declining RNFL and GCIPL can explain the progressive visual impairment previously reported in these subjects. Among all structural parameters, ONH parameters might be most suitable for longitudinal follow-up, in eyes with a measurable cup.

Chemoreflex failure and sleep-disordered breathing in familial dysautonomia: Implications for sudden death during sleep.

Familial dysautonomia (Riley-Day syndrome, hereditary sensory and autonomic neuropathy type III) is a rare autosomal recessive disease characterized by impaired development of primary sensory and autonomic neurons resulting in a severe neurological phenotype, which includes arterial baroreflex and chemoreflex failure with high frequency of sleep-disordered breathing and sudden death during sleep. Although a rare disease, familial dysautonomia represents a unique template to study the interactions between sleep-disordered breathing and abnormal chemo- and baroreflex function. In patients with familial dysautonomia, ventilatory responses to hypercapnia are reduced, and to hypoxia are almost absent. In response to hypoxia, these patients develop paradoxical hypoventilation, hypotension, bradycardia, and potentially, death. Impaired ventilatory control due to chemoreflex failure acquires special relevance during sleep when conscious control of respiration withdraws. Overall, almost all adult (85%) and pediatric (95%) patients have some degree of sleep-disordered breathing. Obstructive apnea events are more frequent in adults, whereas central apnea events are more severe and frequent in children. The annual incidence rate of sudden death during sleep in patients with familial dysautonomia is 3.4 per 1000 person-year, compared to 0.5-1 per 1000 person-year of sudden unexpected death in epilepsy. This review summarizes recent developments in the understanding of sleep-disordered breathing in patients with familial dysautonomia, the risk factors for sudden death during sleep, and the specific interventions that could prevent it.

Case Series: Management of Neurotrophic Keratitis from Familial Dysautonomia.

SIGNIFICANCE: Familial dysautonomia is a rare genetic disorder that affects the sensory and autonomic nervous systems. Affected individuals have decreased corneal sensation and can develop serious complications from neurotrophic keratitis. Scleral devices are an excellent option for the long-term management of patients with familial dysautonomia and neurotrophic keratitis. PURPOSE: In this series, we describe three patients with familial dysautonomia and classic ocular complications fit with scleral devices. No identifiable health information is included in this case report. CASE REPORTS: Case 1: A 35-year-old white male presented with blurred vision without complaint of pain or dryness. He had moderate punctate corneal staining and central stromal corneal scarring in both eyes despite use of artificial tears, punctal plugs, and therapeutic soft lenses. He was fit with 18.2-mm commercial scleral devices, which improved vision and protected the ocular surface. Case 2: A 20-year-old cognitively impaired white female presented with history of frequent eye rubbing and self-mutilation. She had recurrent corneal abrasions with corneal scarring in both eyes and was fit with 16-mm gas-permeable prosthetic replacement of the ocular surface ecosystem devices. Case 3: An 18-year-old white male with history of frequent corneal abrasions and blurred vision was referred by his medical doctor. He and his mother were trained in the safe handling of 16- and 16.5-mm gas-permeable prosthetic replacement of the ocular surface ecosystem devices in the right and left eyes. Corneal epithelial defects healed and vision improved with daily use. CONCLUSIONS: Individuals with familial dysautonomia present unique clinical challenges owing to severe ocular surface disease and inability to perceive pain. Initial therapy for neurotrophic keratitis includes lubrication, punctal occlusion, and therapeutic lenses. Additional therapies include autologous serum tears, amniotic membrane treatment, scleral devices, and tarsorrhaphy. In this series, scleral devices are an excellent option to protect the ocular surface and prevent common ocular complications.

Respiratory care in familial dysautonomia: Systematic review and expert consensus recommendations.

BACKGROUND: Familial dysautonomia (Riley-Day syndrome, hereditary sensory autonomic neuropathy type-III) is a rare genetic disease caused by impaired development of sensory and afferent autonomic nerves. As a consequence, patients develop neurogenic dysphagia with frequent aspiration, chronic lung disease, and chemoreflex failure leading to severe sleep disordered breathing. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of respiratory disorders in familial dysautonomia. METHODS: We performed a systematic review to summarize the evidence related to our questions. When evidence was not sufficient, we used data from the New York University Familial Dysautonomia Patient Registry, a database containing ongoing prospective comprehensive clinical data from 670 cases. The evidence was summarized and discussed by a multidisciplinary panel of experts. Evidence-based and expert recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. RESULTS: Recommendations were formulated for or against specific diagnostic tests and clinical interventions. Diagnostic tests reviewed included radiological evaluation, dysphagia evaluation, gastroesophageal evaluation, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, laryngoscopy and polysomnography. Clinical interventions and therapies reviewed included prevention and management of aspiration, airway mucus clearance and chest physical therapy, viral respiratory infections, precautions during high altitude or air-flight travel, non-invasive ventilation during sleep, antibiotic therapy, steroid therapy, oxygen therapy, gastrostomy tube placement, Nissen fundoplication surgery, scoliosis surgery, tracheostomy and lung lobectomy. CONCLUSIONS: Expert recommendations for the diagnosis and management of respiratory disease in patients with familial dysautonomia are provided. Frequent reassessment and updating will be needed.

Prevalence and characteristics of sleep-disordered breathing in familial dysautonomia.

OBJECTIVE: Familial dysautonomia (FD) is an autosomal recessive disorder characterized by impaired development of sensory and afferent autonomic nerves. Untreated sleep-disordered breathing (SDB) has been reported to increase the risk of sudden unexpected death in FD. We aimed to describe the prevalence and characteristics of SDB in FD. PATIENTS/METHODS: Seventy-five patients with FD (20 adults and 55 children) underwent in-lab polysomnography, including peripheral capillary oxygen saturation (SpO2) and end-tidal capnography (EtCO2) measurements. A t-test and Spearman's correlation analysis were performed to evaluate the impact of age on sleep, occurrence of apneas, SpO2 and EtCO2 levels; and to determine the relationship between apneas and SpO2/EtCO2 measurements during different sleep stages. RESULTS: Overall, 85% of adults and 91% of pediatric patients had some degree of SDB. Obstructive sleep apneas were more severe in adults (8.5 events/h in adults vs. 3.5 events/h in children, p = 0.04), whereas central apneas were more severe (10.8 vs. 2.8 events/h, p = 0.04) and frequent (61.8% vs. 45%, p = 0.017) in children. Overall, a higher apnea-hypopnea index was associated with increased severity of hypoxia and hypoventilation, although in a significant fraction of patients (67% and 46%), hypoxemia and hypoventilation occurred independent of apneas. CONCLUSION: Most adult and pediatric patients with FD suffer from some degree of SDB. There was a differential effect of age in the pattern of SDB observed. In some FD patients, hypoventilation and hypoxia occurred independently of apneas. Therefore, we recommend including EtCO2 monitoring during polysomnography in all patients with FD to detect SDB.

Characteristics of ataxic gait in familial dysautonomia patients.

INTRODUCTION AND OBJECTIVES: Progressive ataxic gait is a common symptom in individuals with Familial Dysautonomia (FD). At least 50% of adults with FD require assistance with walking. Our aims were to describe the medical condition of individuals with FD (ii) compare their gait characteristics to healthy individuals, and (iii) assess correlations between gait measures, presence of unstable gait pattern and frequency of falls. METHODS: Twelve subjects with FD (7 males, age 25.3±10.6 years) and 16 healthy participants (6 males, age 35.9±11.9 years) were recruited. Gait kinematics, gait symmetry, dynamic muscle activity, and foot deep vibration sensation were recorded. RESULTS: Ataxic gait degrees were: severe (6 out of 12), moderate (4 out of 12) and low (2 out of 12). The number of falls correlated with base width asymmetry. Crouch gait was noted in 3 out of 12 of the subjects. CONCLUSIONS: In-depth quantitative gait analysis of individuals with FD revealed ataxic gait. The ataxic pattern might be a result of combined neurological deficiencies and osseous deformities. Increasing the base of support of patients with FD might increase the symmetry of the base width during gait and decrease the number of falls. Additionally, perturbation treatment and dynamic balance exercises may be recommended in order to improve compensatory strategies. Future investigation of this population should include quantification of osseous rotations of the lower limb in order to fully understand its effect on their gait pattern and falls.

A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia.

BACKGROUND: Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS: We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS: A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION: Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.

PURPOSE: To report the use of intranasal dexmedetomidine, an α2-adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. METHODS: Case series. RESULTS: Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. CONCLUSIONS: Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia.

Clinical data suggest that optic neuropathy and retinal ganglion cell loss are the main cause of visual decline in patients with familial dysautonomia, but this has not previously been confirmed by pathological analyses. We studied retinas and optic nerves in 6 eyes from 3 affected patients obtained at autopsy. Analyses included routine neurohistology and immunohistochemistry for neurofilaments, cytochrome c oxidase (COX), and melanopsin-containing ganglion cells. We observed profound axon loss in the temporal portions of optic nerves with relative preservation in the nasal portions; this correlated with clinical and optical coherence tomography findings in 1 patient. Retinal ganglion cell layers were markedly reduced in the central retina, whereas melanopsin-containing ganglion cells were relatively spared. COX staining was reduced in the temporal portions of the optic nerve indicating reduced mitochondrial density. Axonal swelling with degenerating lysosomes and mitochondria were observed by electron microscopy. These findings support the concept that there is a specific optic neuropathy and retinopathy in patients with familial dysautonomia similar to that seen in other optic neuropathies with mitochondrial dysfunction. This raises the possibility that defective expression of the IkB kinase complex-associated protein (IKAP) resulting from mutations in IKBKAP affects mitochondrial function in the metabolism-dependent retinal parvocellular ganglion cells in this condition.

Cerebral autoregulation and symptoms of orthostatic hypotension in familial dysautonomia.

Familial dysautonomia is an inherited autonomic disorder with afferent baroreflex failure. We questioned why despite low blood pressure standing, surprisingly few familial dysautonomia patients complain of symptomatic hypotension or have syncope. Using transcranial Doppler ultrasonography of the middle cerebral artery, we measured flow velocity (mean, peak systolic, and diastolic), area under the curve, pulsatility index, and height of the dictrotic notch in 25 patients with familial dysautonomia and 15 controls. In patients, changing from sitting to a standing position, decreased BP from 124 ± 4/64 ± 3 to 82 ± 3/37 ± 2 mmHg (p < 0.0001, for both). Despite low BP, all patients denied orthostatic symptoms. Middle cerebral artery velocity fell minimally, and the magnitude of the reductions were similar to those observed in healthy controls, in whom BP upright did not fall. While standing, patients had a greater fall in cerebrovascular resistance (p < 0.0001), an increase in pulsatility (p < 0.0001), and a deepening of the dicrotic notch (p = 0.0010), findings all consistent with low cerebrovascular resistance. No significant changes occurred in controls. Patients born with baroreflex deafferentation retain the ability to buffer wide fluctuations in BP and auto-regulate cerebral blood flow. This explains how they can tolerate extremely low BPs standing that would otherwise induce syncope.

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. METHODS: 11 mildly affected FD-patients (28 ± 11 years) without clinically overt SDB and 13 controls (28 ± 10 years) underwent polysomnographic recording during one night. We assessed sleep stages, obstructive and central apneas (≥ 90% air flow reduction) and hypopneas (> 30% decrease in airflow with ≥ 4% oxygen-desaturation), and determined obstructive (oAI) and central (cAI) apnea indices and the hypopnea index (HI) as count of respective apneas/hypopneas divided by sleep time. We obtained the apnea-hypopnea index (AHI4%) from the total of apneas and hypopneas divided by sleep time. We determined differences between FD-patients and controls using the U-test and within-group differences between oAIs, cAIs, and HIs using the Friedman test and Wilcoxon test. RESULTS: Sleep structure was similar in FD-patients and controls. AHI4% and HI were significantly higher in patients than controls. In patients, HIs were higher than oAIs and oAIs were higher than cAIs. In controls, there was no difference between HIs, oAIs, and cAIs. Only patients had apneas and hypopneas during slow wave sleep. CONCLUSIONS: In our FD-patients, obstructive apneas were more common than central apneas. These findings may be related to FD-specific pathophysiology. The potential ramifications of SDB in FD-patients suggest the utility of polysomnography to unveil SDB and initiate treatment. COMMENTARY: A commentary on this article appears in this issue on page 1583.

[ORO-DENTO-FACIAL MANIFESTATIONS IN PATIENTS WITH FAMILIAL DYSAUTONOMIA].

INTRODUCTION: The oro-dento-facial features and dysfunctions of children with hereditary sensory and autonomic neuropathy type III (HSAN III), known as familial dysautonomia (FD) or Riley-Day syndrome, were first described in the scientific literature in 1949. They include: dental trauma, dental and soft tissue selfmutilation, normal dental age, normal sequence and timing of eruption and exfoliation of teeth, smaller tooth size, different and disproportional tooth components, normal alveolar bone height, small jaws, mild crowding and malocclusion. These individuals have different craniofacial morphology from accepted norms, but resemble norms of their ethnic origin. The subjects often display gray, pale, shiny faces with an asymmetric suffering expression; frontal bossing, with eventual hypertelorism and narrow lips; a low dental caries rate; drooling, and genuine hypersalivation. They may have changes in salivary composition and content, which influence plaque and calculus accumulation and increase the risk of gingival and periodontal diseases. They also have difficulty in controlling oral muscles, a progressive decrease in the number of tongue fungiform papillae, accompanied by a reduced number of taste buds and specific dysgeusia, but a normal sense of smell.

Increased frequency of rhabdomyolysis in familial dysautonomia.

INTRODUCTION: Familial dysautonomia (FD; OMIM # 223900) is an autosomal recessive disease with features of impaired pain and temperature perception and lack of functional muscle spindles. After 3 FD patients presented with rhabdomyolysis in a short time span, we aimed to determine the frequency of rhabdomyolysis is this population. METHODS: This study was a retrospective chart review of 665 FD patients. RESULTS: Eight patients had at least 1 episode of rhabdomyolysis. Two patients had 2 episodes. The average incidence of rhabdomyolysis in FD was 7.5 per 10,000 person-years. By comparison, the average incidence with statins has been reported to be 0.44 per 10,000 person-years. Mean maximum creatine kinase (CK) level was 32,714 ± 64,749 U/L. Three patients had hip magnetic resonance imaging showing gluteal hyperintensities. CONCLUSIONS: Patients with FD have an increased incidence of rhabdomyolysis. We hypothesize that this may result from a combination of absent functional muscle spindles and muscle mitochondrial abnormalities.