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.

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. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30 cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1-10 cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.

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. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26 of 30. RESULTS: Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7° ± 1.0°, and the range was very wide (2.8°-18.1°); conversely, absolute error was only 2.7° ± 0.3° (1.6°-5.5°) in the controls and 3.0° ± 0.2° (2.1°-3.4°) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients. CONCLUSIONS: These results suggest that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.

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. The possibility of genetic confirmation by molecular testing for specific diagnosis is increasing but treatments tend to remain only supportive and directed toward particular symptoms.

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. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during a manoeuvre that unloads the baroreceptors. Conversely, skin sympathetic nerve activity (SSNA), recorded in four patients, appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement.

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. For comparison, measurements were repeated at follow-up after the symptoms had resolved and the patients were feeling calm and well. RESULTS: During a typical attack, patients were hypertensive and tachycardic. In all patients, circulating levels of norepinephrine (P < 0.002) and dopamine (P < 0.007) increased significantly. CONCLUSIONS: Activation of dopamine receptors in the chemoreceptor trigger zone may explain the cyclic nausea/retching/vomiting of patients with Riley-day syndrome.

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). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years. RESULTS: Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (P < .005 and P < .001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (P = .01), and expressive speech improved (P = .045). From age 17 to 27 years, balance worsened markedly (P = .048). CONCLUSION: The Functional Severity Scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials.

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. Homozygosity mapping followed by exome sequencing is a successful approach to identify mutated genes in rare monogenic disorders.

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 0.05 to 1.0 decimal units and was reduced in 15 of 16 patients. Mild to moderate corneal opacities were found in most patients but were visually significant in only 2 eyes. Red-green color vision was impaired in almost all cases. Depression of the central visual fields was present on automated visual fields in all patients, even in those with normal visual acuity. Temporal optic nerve pallor was present in all cases and was associated with retinal nerve fiber layer loss in the papillomacular region. Various ocular motility abnormalities also were observed. CONCLUSION: Patients with FD have a specific type of optic neuropathy with predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function. Defects of eye movements, particularly saccades, also appear to be a feature of patients with FD.

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. To better understand the specificity of neuron loss in FD, we modeled the molecular mechanisms of IKBKAP mRNA splicing by studying human olfactory ecto-mesenchymal stem cells (hOE-MSCs) derived from FD patient nasal biopsies. We explored how the modulation of IKBKAP mRNA alternative splicing impacts the transcriptome at the genome-wide level. We found that the FD transcriptional signature was highly associated with biological functions related to the development of the nervous system. In addition, we identified target genes of kinetin, a plant cytokinin that corrects IKBKAP mRNA splicing and increases the expression of IKAP/hELP1. We identified this compound as a putative regulator of splicing factors and added new evidence for a sequence-specific correction of splicing. In conclusion, hOE-MSCs isolated from FD patients represent a promising avenue for modeling the altered genetic expression of FD, demonstrating a methodology that can be applied to a host of other genetic disorders to test the therapeutic potential of candidate molecules.

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. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10-30 µA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion.

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. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients.

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. Familial dysautonomia children scored significantly higher in visceral symptoms, while children with autism spectrum disorders scored significantly higher in psychosocial symptoms. In familial dysautonomia, the concordance for the presence of symptoms within sections and overall scores ranged from 71% to 100%. The concordance for absence of autonomic dysfunction symptoms in controls ranged from 75% to 87.5%. The Pediatric Autonomic Symptoms Scale is comprehensive and can profile autonomic dysfunction in the 2 neurodevelopmental disorders. Its usefulness in other pediatric disorders remains to be studied.

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. Here, we present the first 3 instances of gastric ulcers in patients with FD and discuss their common presenting features and the special management that was required.

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. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells. METHODOLOGY/PRINCIPAL FINDINGS: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation. CONCLUSIONS/SIGNIFICANCE: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases.

Renal transplantation in familial dysautonomia: report of two cases and review of the literature.

BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is an increasingly recognized complication of familial dysautonomia (FD), a neurodevelopmental disorder with protean systemic manifestations that are the result of sensory and autonomic dysfunction. Progressive renal dysfunction occurs due to chronic volume depletion and cardiovascular lability with supine hypertension and orthostatic hypotension. By age 25, nearly one-half of all patients with FD will have reached stage 3 CKD. Furthermore, dialysis for ESRD in FD patients is associated with multiple complications and poor outcomes. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: We report two patients with FD who developed ESRD at ages 27 and 16, respectively, and underwent renal transplantation. Transplant was performed after 3 months on intermittent hemodialysis (HD) in the first case and after 1 month on twice-weekly continuous veno-venous hemodialysis (CVVHD) in the second case. RESULTS: Both patients tolerated surgery well and have maintained good graft function at 20 and 24 months posttransplantation, respectively. Symptomatic and functional improvements have included lower supine BP and increased sensitivity to antihypertensive agents. CONCLUSIONS: As general supportive care improves the lifespan of FD patients, issues related to the management of ESRD will become more important. Renal transplantation provides a viable alternative to dialysis for FD patients with ESRD.

Neuroimaging supports central pathology in familial dysautonomia.

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

Neoplasia in familial dysautonomia: a 20-year review in a young patient population.

We reviewed the charts of all patients with familial dysautonomia (n = 631) and found that 2% had been diagnosed with tumors. We hypothesize that the IkappaB Kinase-associated protein gene mutation, which causes aberrant RNA splicing in patients with familial dysautonomia, may contribute to tumorigenesis in this genetically homogenous patient population.