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.

Quantitative magnetic resonance evaluation of the trigeminal nerve in familial dysautonomia.

PURPOSE: Familial dysautonomia (FD) is a rare autosomal recessive disease that affects the development of sensory and autonomic neurons, including those in the cranial nerves. We aimed to determine whether conventional brain magnetic resonance imaging (MRI) could detect morphologic changes in the trigeminal nerves of these patients. METHODS: Cross-sectional analysis of brain MRI of patients with genetically confirmed FD and age- and sex-matched controls. High-resolution 3D gradient-echo T1-weighted sequences were used to obtain measurements of the cisternal segment of the trigeminal nerves. Measurements were obtained using a two-reader consensus. RESULTS: Twenty pairs of trigeminal nerves were assessed in ten patients with FD and ten matched controls. The median (interquartile range) cross-sectional area of the trigeminal nerves in patients with FD was 3.5 (2.1) mm2, compared to 5.9 (2.0) mm2 in controls (P < 0.001). No association between trigeminal nerve area and age was found in patients or controls. CONCLUSIONS: Using conventional MRI, the caliber of the trigeminal nerves was significantly reduced bilaterally in patients with FD compared to controls, a finding that appears to be highly characteristic of this disorder. The lack of correlation between age and trigeminal nerve size supports arrested neuronal development rather than progressive atrophy.

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.

Spondylodiscitis in familial dysautonomia: a case report.

Familial dysautomonia (FD, or Riley-Day syndrome) is a rare but fatal autosomal recessive peripheral neuropathy caused by a point mutation in I-κ-B kinase complex associated protein (IKBCAP) gene. The disease, that affects primarily people of Ashkenazi Jewish origin, prejudices the development of primary sensory neurons determining depletion of autonomic and sensory neurons. Musculoskeletal problems include: spinal deformities, foot deformities, fractures and arthopathies. In this article we review a case of a 34 years old male of non-Jewish origin affected by FD presenting L2-L3 kyphosis and inability to walk due to chronic L2-L3 spondylodiscitis not surgically treated 14 years before as acute disease. De novo spondylodiscitis affecting patients presenting FD and its subsequent management was not previously described in the literature.

Chest computed tomography findings in familial dysautonomia patients: a model for aspiration.

BACKGROUND: Lung disease in patients with familia dysautonomia is caused mainly by recurrent aspiration of gastric contents, food and liquids swallowed incorrectly. OBJECTIVE: To describe chest computed tomography findings in patients with familial dysautonomia. METHODS: A retrospective analysis of chest CT findings was performed for 34 FD patients (15 females, 19 males) with a mean age of 18 +/- 12.8 years. RESULTS: The CT revealed bronchial wall thickening (in 94% of the patients), atelectasis (in 73%), ground glass opacities (in 53%), focal hyperinflation (in 44%), fibrosis (in 29%) and bronchiectasis (in 26%). The extrapulmonary abnormalities were scoliosis (79%) and esophageal dilatation (35%). Silent fractures were noted in two vertebral bodies and one rib. CONCLUSIONS: Pulmonary changes were consistent with chronic inflammation in the bronchi and interstitial tissues. Ground glass opacities and fibrosis support the theory that these changes could be due to gastric aspiration. Bronchiectasis is less frequent. Esophageal dilatation with fluid overflow adds to aspiration. Fractures can be asymptomatic and are often missed.

Echocardiographic abnormalities in familial dysautonomia.

Sudden death accounts for up to 43% of all deaths in patients with familial dysautonomia (FD). The classic features of FD, namely, autonomic dysfunction, high blood pressure, and blood pressure labiality, are all risk factors for cardiac remodeling and hypertrophy. Myocardial remodeling and hypertrophy are independent risk factors for arrhythmias, cardiovascular events, and sudden death. An extensive review of the medical literature found no documentation of structural heart defects or myocardial remodeling in patients with FD. Sixteen patients with FD underwent physical examination, in-clinic blood pressure measurements, and echocardiographic study. On the basis of the findings, the patients were categorized by left ventricular geometric pattern. Twenty-four-hour ambulatory blood pressure monitoring was recommended to all participants. The majority of FD patients were found to have very high blood pressure values both during in-clinic measurements and during ambulatory blood pressure monitoring. Echocardiographic abnormalities were found in 43.75% of the study group; 18.75% of the study group had concentric hypertrophy, among which severe hypertrophy was found in 2 patients. Unknown previously, cardiac remodeling or hypertrophy is common in FD. We recommend that routine cardiac echocardiography be performed in this population, and attempts to treat high blood pressure should begin earlier in life.

Cardiac sympathetic hypo-innervation in familial dysautonomia.

OBJECTIVE: Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[(18)F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD. METHODS: Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[(18)F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model. RESULTS: FD patients had decreased uptake and accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.

The effect of hereditary disorders on tooth components: a radiographic morphometric study of two syndromes.

OBJECTIVE: The purpose of this study was to compare tooth components (enamel and dentin) in Familial Dysautonomia (FD) and Down syndrome (DS) in order to assess the extent to which each was affected. DESIGN: The design was cross-sectional. The sample consisted of 20 FD patients and 45 DS patients. The control group comprised 250 healthy subjects. Mesio-distal crown width (CW), enamel and dentin thickness and pulp chamber dimensions were measured on standardized bitewing radiographs of mandibular second primary and first permanent molars. Statistical analyses were performed between groups using SAS programs. RESULTS: CW was reduced in both hereditary disorders. In the DS group enamel height (EH) and dentin thickness were reduced. In FD enamel thickness in the primary and permanent molars as well as dentin height (DH) in permanent molars was increased. CONCLUSIONS: In both syndromes the reduction in CW suggests reduced proliferation during tooth germ formation. However, the differences in enamel and dentin thickness suggest that ameloblasts and odontoblasts were affected differently in the later phases of cell function. In FD cell function is stimulated resulting in thicker enamel and dentin. In DS cell function is reduced resulting in thin enamel and dentin.

Long-term survival in Stuve-Wiedemann syndrome: a neuro-myo-skeletal disorder with manifestations of dysautonomia.

Stuve-Wiedemann syndrome (SWS) is a multiple congenital anomalies syndrome mostly considered to have an early lethality. Only few patients have been reported with long survival; therefore, the clinical phenotype with age has not yet been clearly characterized. We report on two patients with SWS aged 12 and 3 years who have both the osteodysplastic symptoms of the entity as well as autonomic nervous system symptoms resembling familial dysautonomia: lack of corneal reflex and neuropathic keratitis, absence of fungiform papillae, ulcerations of the tongue, paradoxical sweating at low temperature, patellar hyporeflexia, and progressive scoliosis. The clinical and radiological similarities between patients with SWS and patients with Schwartz-Jampel syndrome have led to the suggestion that these two syndromes are a single entity. SWS and Schwartz-Jampel syndrome type II are now indeed considered to be identical, but the radiographic phenotype of SWS long survivors such as the presently reported patients justifies the distinction between SWS and the classical type of Schwartz-Jampel syndrome. An increased number of lipid droplets in muscle fibers and decreased muscle mitochondrial enzyme activities have been found in one patient, confirming a previously reported association between SWS and respiratory chain abnormalities.

Radiographic assessment of the alveolar bone height in children and adolescents with familial dysautonomia.

PURPOSE: Familial dysautonomia (FD) is a progressive neuropathy, characterized by somatic and skeletal abnormalities, and by a variety of oral and diet disturbances. The purpose of the study was to assess the alveolar bone height at the molar areas of children and adolescents with FD. METHODS: The distance from the cemento-enamel junction (CEJ) to the alveolar bone crest (ABC) was measured on routine diagnostic bitewing radiographs of nine males and seven females with FD (mean age = 122 months) and in those of two matching groups (C1 = 119 months; C2 = 122 months). RESULTS: The mean values for the maxilla were significantly larger than those in the mandible. A positive significant correlation was found between the CEJ-ABC measurements of the primary and the permanent teeth, and between the CEJ-ABC measurements and age. The mean values per patient for the CEJ-ABC distances of the FD group were smaller than the control groups, but the difference was not statistically significant. The CEJ-ABC measurements in the primary and the permanent molars were smaller in the FD group, and in the premolars and permanent cuspids they were larger than those in the two control groups. These differences were not statistically significant. No differences were found between the FD and the control groups in the primary cuspids. CONCLUSIONS: The alveolar bone height of children and adolescent with familial dysautonomia does not differ from that of healthy controls.

Ictal SPECT during autonomic crisis in familial dysautonomia.

The authors report results of SPECT cerebral perfusion studies in two patients with familial dysautonomia (FD) during dysautonomic crises and when clinically stable. SPECT imaging studies used 99mTc ethylene cysteine dimer. During dysautonomic crises, regions in the temporoparietal and frontal lobes had increased uptake. Uptake in these areas was less during asymptomatic periods. Episodic asymmetric cerebral perfusion during crises especially affecting the frontal and temporal lobes is suggestive of ictal activity.

Scintigraphic evaluation of esophageal transit and gastric emptying in familial dysautonomia.

Gastroesophageal dysfunction is a major cause of morbidity and mortality in patients with familial dysautonomia (FD). Most studies evaluating esophageal and gastric function in FD patients are either insensitive or invasive. Thus we have used a "milk" scan to quantitate abnormalities in esophageal transit and gastric emptying, while searching for gastroesophageal reflux and aspiration in these patients. The quantitative scintigraphic evaluation was performed in 35 patients with FD, 10 of whom were studied after fundoplication, pyloroplasty and gastrostomy. A prolonged esophageal transit time, ranging from 8 s to more than 60 s duration, was demonstrated in 11 patients. Gastroesophageal reflux was detected in 26 patients. In 16 patients delayed gastric emptying ranging from 63-94% was detected at 30 min, and in 13 patients delayed emptying ranging from 37-86% was observed at 120 min. Pulmonary aspiration was detected in 8 non-operated patients, four of whom had abnormal gastric emptying. The scintigraphic analysis of both esophageal transit and gastric emptying in familial dysautonomia is presented, and its role in evaluation and management of these patients discussed.

The effects of postural change and exercise on renal haemodynamics in familial dysautonomia.

Cardiovascular instability is a prominent manifestation of familial dysautonomia [FD] while renal insufficiency occurs in a large number of adult FD patients. To determine if there was a causative relationship, renal artery blood flow velocity using Doppler technology, was recorded and the ratio of the peak systolic velocity (point A) to the end diastolic velocity (point B) was calculated. The A/B ratio was assessed in response to change of position and exercise, and was correlated with renal function, heart rate and systemic blood pressure. Studies were performed in 54 FD patients with a mean age of 24 years +/- 9.8 years, and 20 controls, with a mean age of 24.7 +/- 7.6 years. In the supine position, the mean A/B ratios were not significantly different, but FD subjects had a significantly higher mean blood pressure and heart rate than controls. When erect and post exercise, the mean A/B ratios in FD subjects were significantly higher than controls, p = 0.0004 and p = 0.0001, respectively. In contrast to controls, when FD subjects were standing erect and post exercise, mean blood pressure decreased significantly without a significant change in heart rate. When FD subjects were divided into two groups based on their creatinine clearance value, the group with the lower creatinine clearances had a significantly greater fall in diastolic pressure when they moved from the supine to the erect position. Our results indicate that noninvasive Doppler techniques are helpful in detecting changes in renal blood flow in subjects with familial dysautonomia.(ABSTRACT TRUNCATED AT 250 WORDS)

The "chest-abdomen sign" in familial dysautonomia.

Both lung pathology and bowel distension are seen simultaneously on radiographs in familial dysautonomia. These are constant findings even in the absence of acute disease. One may thus speak of a "chest-abdomen sign" in this entity. Cases with this sign are presented in illustration and the differential diagnosis is discussed.