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262


Familial dysautonomia

González-Duarte, Alejandra; Cotrina-Vidal, Maria; Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy
Familial dysautonomia (FD) is an autosomal recessive hereditary sensory and autonomic neuropathy (HSAN, type 3) expressed at birth with profound sensory loss and early death. The FD founder mutation in the ELP1 gene arose within the Ashkenazi Jews in the sixteenth century and is present in 1:30 Jews of European ancestry. The mutation yield a tissue-specific skipping of exon 20 and a loss of function of the elongator-1 protein (ELP1), which is essential for the development and survival of neurons. Patients with FD produce variable amounts of ELP1 in different tissues, with the brain producing mostly mutant transcripts. Patients have excessive blood pressure variability due to the failure of the IXth and Xth cranial nerves to carry baroreceptor signals. Neurogenic dysphagia causes frequent aspiration leading to chronic pulmonary disease. Characteristic hyperadrenergic "autonomic crises" consisting of brisk episodes of severe hypertension, tachycardia, skin blotching, retching, and vomiting occur in all patients. Progressive features of the disease include retinal nerve fiber loss and blindness, and proprioceptive ataxia with severe gait impairment. Chemoreflex failure may explain the high frequency of sudden death in sleep. Although 99.5% of patients are homozygous for the founder mutation, phenotypic severity varies, suggesting that modifier genes impact expression. Medical management is currently symptomatic and preventive. Disease-modifying therapies are close to clinical testing. Endpoints to measure efficacy have been developed, and the ELP1 levels are a good surrogate endpoint for target engagement. Early intervention may be critical for treatment to be successful.
PMID: 37204536
ISSN: 1619-1560
CID: 5503652

Cutaneous α-Synuclein Signatures in Patients With Multiple System Atrophy and Parkinson Disease

Gibbons, Christopher; Wang, Ningshan; Rajan, Sharika; Kern, Drew; Palma, Jose-Alberto; Kaufmann, Horacio; Freeman, Roy
BACKGROUND AND OBJECTIVES:Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls. METHODS:We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results. RESULTS:< 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders. DISCUSSION:α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.
PMID: 36657992
ISSN: 1526-632x
CID: 5466502

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

Ramprasad, Chethan; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Levy, Joseph; Chen, Lea Ann; Kaufmann, Horacio
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/CONCLUSIONS: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.
PMID: 36735101
ISSN: 1619-1560
CID: 5426782

A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations

Costello, Stephanann M.; Cheney, Alexandra M.; Waldum, Annie; Tripet, Brian; Cotrina-Vidal, Maria; Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Lefcort, Frances; Copié, Valérie
Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer"™s (AD) and Parkinson"™s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut"“brain axis of FD. Here, 1H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut"“brain"“metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.
SCOPUS:85151916624
ISSN: 2218-1989
CID: 5460752

Gut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia

Cheney, Alexandra M; Costello, Stephanann M; Pinkham, Nicholas V; Waldum, Annie; Broadaway, Susan C; Cotrina-Vidal, Maria; Mergy, Marc; Tripet, Brian; Kominsky, Douglas J; Grifka-Walk, Heather M; Kaufmann, Horacio; Norcliffe-Kaufmann, Lucy; Peach, Jesse T; Bothner, Brian; Lefcort, Frances; Copié, Valérie; Walk, Seth T
Familial dysautonomia (FD) is a rare genetic neurologic disorder caused by impaired neuronal development and progressive degeneration of both the peripheral and central nervous systems. FD is monogenic, with >99.4% of patients sharing an identical point mutation in the elongator acetyltransferase complex subunit 1 (ELP1) gene, providing a relatively simple genetic background in which to identify modifiable factors that influence pathology. Gastrointestinal symptoms and metabolic deficits are common among FD patients, which supports the hypothesis that the gut microbiome and metabolome are altered and dysfunctional compared to healthy individuals. Here we show significant differences in gut microbiome composition (16 S rRNA gene sequencing of stool samples) and NMR-based stool and serum metabolomes between a cohort of FD patients (~14% of patients worldwide) and their cohabitating, healthy relatives. We show that key observations in human subjects are recapitulated in a neuron-specific Elp1-deficient mouse model, and that cohousing mutant and littermate control mice ameliorates gut microbiome dysbiosis, improves deficits in gut transit, and reduces disease severity. Our results provide evidence that neurologic deficits in FD alter the structure and function of the gut microbiome, which shifts overall host metabolism to perpetuate further neurodegeneration.
PMCID:9839693
PMID: 36639365
ISSN: 2041-1723
CID: 5410572

Height, weight, and body mass index in patients with familial dysautonomia

Cotrina, Maria L; Morgenstein, Barr; Perez, Miguel; Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio
BACKGROUND:Children with familial dysautonomia (FD) are smaller and grow more slowly than the general population. It is unknown whether this abnormal growth is due to comorbidities that patients with FD live with, or if it is a direct effect of the disease-causing homozygous ELP-1 mutations. Here, we created growth curves for weight, height, and body mass index (BMI) in male and female children with FD to monitor the nutritional status of patients with FD. METHODS:We used the New York University (NYU) FD Registry which includes data from 680 individuals with FD who were followed longitudinally since birth. We generated sex-specific FD growth charts for three age ranges (birth to 36 months, 2 to 20 years, and 2 to 40 years) and compared them to the general population. We generated Kaplan-Meier curves to test the hypothesis that FD patients with low BMI had shorter survival than the rest of the cohort. RESULTS:Growth charts generated from 591 individuals with FD show that these patients grow more slowly, reach less height, and gain less weight than the general population. The impact of FD on height was more pronounced in girls than in boys. However, both groups showed markedly low weights, which resulted in low BMI. Low weight, but not height, is already evident at birth. In a subpopulation of FD patients, we found that treatment with growth hormone or spinal fusion surgery helped patients achieve the expected growth characteristic of FD patients, but these treatments did not lead FD patients to achieve the growth pattern of the general population. Contrary to our hypothesis, low BMI had no impact on patient survival. CONCLUSIONS:Pediatric patients with FD have lower height, weight, and BMI compared to the general pediatric population, but this does not appear to affect survival. Growth curves specific to the FD population are an important tool to monitor growth and nutritional status in pediatric patients with FD when the general population growth curves are of limited use.
PMCID:10635437
PMID: 37943786
ISSN: 1932-6203
CID: 5609872

The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations

Krismer, Florian; Palma, Jose-Alberto; Calandra-Buonaura, Giovanna; Stankovic, Iva; Vignatelli, Luca; Berger, Anna-Karin; Falup-Pecurariu, Cristian; Foubert-Samier, Alexandra; Höglinger, Günter; Kaufmann, Horacio; Kellerman, Larry; Kim, Han-Joon; Klockgether, Thomas; Levin, Johannes; Martinez-Martin, Pablo; Mestre, Tiago A; Pellecchia, Maria Teresa; Perlman, Susan; Qureshi, Irfan; Rascol, Olivier; Schrag, Anette; Seppi, Klaus; Shang, Huifang; Stebbins, Glenn T; Wenning, Gregor K; Singer, Wolfgang; Meissner, Wassilios G
PMID: 36074648
ISSN: 1531-8257
CID: 5332552

Fear conditioning as a pathogenic mechanism in the postural tachycardia syndrome

Norcliffe-Kaufmann, Lucy; Palma, Jose Alberto; Martinez, Jose; Camargo, Celeste; Kaufmann, Horacio
Despite its increasing recognition and extensive research, there is no unifying hypothesis on the pathophysiology of the postural tachycardia syndrome. In this cross-sectional study, we examined the role of fear conditioning and its association with tachycardia and cerebral hypoperfusion upon standing in 28 patients with postural tachycardia syndrome (31 ± 12 years old, 25 women) and 21 matched controls. We found that patients had higher somatic vigilance (p = 0.0167) and more anxiety (p < 0.0001). They also had a more pronounced anticipatory tachycardia right before assuming the upright position in a tilt-table test (p = 0.015), a physiologic indicator of fear conditioning to orthostasis. While standing, patients had faster heart rate (p < 0.001), higher plasma catecholamine levels (p = 0.020), lower end-tidal CO2 (p = 0.005), and reduced middle cerebral artery blood flow velocity (p = 0.002). Multi-linear logistic regression modeling showed that both epinephrine secretion and excessive somatic vigilance predicted the magnitude of the tachycardia and the hyperventilation. These findings suggest that the postural tachycardia syndrome is a functional psychogenic disorder in which standing may acquire a frightful quality, so that even when experienced alone, it elicits a fearful conditioned response. Heightened somatic anxiety is associated with and may predispose to a fear-conditioned hyperadrenergic state when standing. Our results have therapeutic implications.
PMID: 35802513
ISSN: 1460-2156
CID: 5280662

Reply: Is postural tachycardia syndrome a psychogenic disorder?; Notes on establishing fear conditioning as causal in the postural orthostatic tachycardia syndrome; Patients with POTS fear that data on abnormal haemodynamic physiology have been ignored; and 'Psychogenic' POTS: the NYU team misinterprets association as causation

Norcliffe-Kaufmann, Lucy; Palma, Jose Alberto; Kaufmann, Horacio
PMID: 36151960
ISSN: 1460-2156
CID: 5335842

Patient-Reported Symptoms in the Global Multiple System Atrophy Registry

Palma, Jose-Alberto; Krismer, Florian; Meissner, Wassilios G; Kuijpers, Mechteld; Millar-Vernetti, Patricio; Perez, Miguel A; Fanciulli, Alessandra; Norcliffe-Kaufmann, Lucy; Bower, Pam; Wenning, Gregor K; Kaufmann, Horacio
Background/UNASSIGNED:The Global Multiple System Atrophy Registry (GLOMSAR) was established in 2013. It is an online patient-reported contact registry open and free that relies on self-reported diagnosis by the patient or caregiver. Objectives/UNASSIGNED:To report the demographics of patients enrolled in GLOMSAR and the results of an ancillary online symptom questionnaire. Methods/UNASSIGNED:Patients enrolled in GLOMSAR were invited to complete a custom-designed online questionnaire about disease onset and symptom prevalence. Results/UNASSIGNED:At the time of writing, there were 1083 participants in GLOMSAR, of which 33% (365) completed the questionnaire. The onset and frequency of most symptoms was similar to those reported in the literature in physician-reported studies. Some were understudied or not typically associated with multiple system atrophy (MSA), including reduced female sexual sensation (55%), forgetfulness (60%), pseudobulbar affect (37%), olfactory changes (36%), and visual hallucinations (21%). Conclusions/UNASSIGNED:Patient-reported studies and ancillary online questionnaires are valid, underused research tools useful to advance our knowledge on understudied MSA features and highlight the patients' voice.
PMCID:9547130
PMID: 36247899
ISSN: 2330-1619
CID: 5360142