Gabrielle Gold-von Simson

Hereditary sensory and autonomic neuropathies: types II, III, and IV

The hereditary sensory and autonomic neuropathies (HSAN) encompass a number of inherited disorders that are associated with sensory dysfunction (depressed reflexes, altered pain and temperature perception) and varying degrees of autonomic dysfunction (gastroesophageal reflux, postural hypotention, excessive sweating). Subsequent to the numerical classification of four distinct forms of HSAN that was proposed by Dyck and Ohta, additional entities continue to be described, so that identification and classification are ongoing. As a group, the HSAN are rare diseases that affect both sexes. HSAN III is almost exclusive to individuals of Eastern European Jewish extraction, with incidence of 1 per 3600 live births. Several hundred cases with HSAN IV have been reported. The worldwide prevalence of HSAN type II is very low. This review focuses on the description of three of the disorders, HSAN II through IV, that are characterized by autosomal recessive inheritance and onset at birth. These three forms of HSAN have been the most intensively studied, especially familial dysautonomia (Riley-Day syndrome or HSAN III), which is often used as a prototype for comparison to the other HSAN. Each HSAN disorder is likely caused by different genetic errors that affect specific aspects of small fiber neurodevelopment, which result in variable phenotypic expression. As genetic tests are routinely used for diagnostic confirmation of HSAN III only, other means of differentiating between the disorders is necessary. Diagnosis is based on the clinical features, the degree of both sensory and autonomic dysfunction, and biochemical evaluations, with pathologic examinations serving to further confirm differences. Treatments for all these disorders are supportive.

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.

Kinetin in Familial Dysautonomia Carriers: Implications for a New Therapeutic Strategy Targeting mRNA Splicing

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IκB kinase–associated protein gene (IKBKAP) that leads to partial skipping of exon 20 and tissue-specific reduction of IκB kinase–associated protein/elongator protein 1 (IKAP/ELP-1 protein). Kinetin increases IKBKAP mRNA and protein expression in FD cell lines. To determine whether oral kinetin alters IKBKAP splicing in vivo, we administered kinetin to 29 healthy carriers of the major FD mutation for 8 d. Adverse effects, kinetin, and IKBKAP mRNA levels were monitored. In the highest dosing cohorts (23.5 mg/kg/d), the target plasma kinetin level was achieved in 91% of subjects at 2 h. After 8 d, IKBKAP mRNA expression in leukocytes increased as kinetin levels increased. There is a linear association between log plasma kinetin level and corresponding log change from baseline in IKBKAP mRNA expression that allows estimation of IKBKAP mRNA levels because of kinetin ingestion. Adverse effects were transient and mild. This is the first report of in vivo IKBKAP splicing modification and strongly suggests kinetins therapeutic potential in FD and perhaps in other splicing disorders. Furthermore, our findings support our hypothesis that treatments, which target a particular splicing mutation, can be successfully developed.

Pacemakers in patients with familial dysautonomia--a review of experience with 20 patients.

Familial dysautonomia (FD) is a genetic disease associated with a high incidence of sudden death. If fatal bradyarrhythmia is an etiological factor then the incidence of sudden death should decrease after pacemaker placement. Retrospective review of 596 registered FD patients revealed that 22 FD patients (3.7%) had pacemakers placed between December 1984 and June 2003. Clinical and electrocardiographic indications for placement and demographic data were assessed for 20 of the 22 patients (10 males, 10 females, ages 4 to 48 years). Two patients were excluded because of insufficient data. Prior to pacemaker placement, presenting symptoms were syncope and cardiac arrest, 16/20 (80%) and 6/20 (30 %), respectively. Asystole was the most frequent electrocardiographic finding and was documented in 17/20 patients (85 %). Other electrocardiographic abnormalities included bradycardia, AV block, prolonged QTc and prolonged JTc. The average duration of pacemaker utilization was 5.7 years (range 5 months to 14.5 years). Complications included infection (1 patient) and wire migration (2 patients). In the one patient with infection, the pacemaker was permanently removed. This patient then experienced multiple syncopal episodes and death. There were 7 other deaths. Three deaths occurred suddenly without preceding events, and 4 patients had non-cardiac causes of death. None of these 7 deceased patients had recurrence of syncope after pacemaker placement. In the 12 surviving patients, 6 had recurrence of syncope but none had cardiac arrest. Pacemaker placement may protect FD patients from fatal bradyarrhythmia and may decrease the incidence of syncope. However, data are limited and prospective analysis is needed.

Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression.

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone’s efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisonetreated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

IKBKAP mRNA in Peripheral Blood Leukocytes: A Molecular Marker of Gene Expression and Splicing in Familial Dysautonomia

The common familial dysautonomia (FD) mutation results in tissue specific mis-splicing with reduced amount of wild-type (WT) IκB kinase associated protein gene (IKBKAP) mRNA and ELP1. ELP1 is a subunit of Elongator, formerly called the IκB kinase associated protein (IKAP) protein. We measured IKBKAP mRNA in peripheral blood leukocytes to determine whether FD subjects and carriers have characteristic levels. Estimated mean IKBKAP mRNA levels, measured by quantitative PCR and expressed as amount relative to the noncarrier average, were significantly different for the two groups when not adjusted for age and sex (p < 0.001): FD subjects 0.23, 95% confidence interval (CI) (0.19, 0.28); carriers 0.58, 95% CI (0.50, 0.68); or adjusted for age and sex (p < 0.001): FD subjects 0.21, 95% CI (0.16, 0.26); carriers 0.66, 95% CI (0.55, 0.79). Comparison of IKBKAP mRNA levels of the 22 FD subjects and their related carriers showed a strong correlation, providing evidence for genetic control of splicing efficiency. IKBKAP mRNA levels were not higher in those subjects using tocotrienols or epigallocatechin gallate. Levels of IKBKAP mRNA in peripheral blood leukocytes can be used to assess molecular response to therapies aimed at enhancing exon 20 inclusion and increasing cellular levels of ELP1/IKAP.

Should Infliximab be Used as an Adjuvant to IVIG in the Treatment of Children With Kawasaki Disease Who Are at High Risk for Resistance to Conventional Therapy

The recently published article, entitled “Extensive Coronary Aneurysms with Thrombosis in Resistant Kawasaki Disease” by Sivakumar and Pavithran [5], concisely delineates the limitations in the treatment of Kawasaki disease (KD). There is no one accepted treatment algorithm for treatment-refractory patients, and the efficacy of infliximab as a first-line therapy adjunct has not yet been studied. Although a retrospective study showed improvement in various clinical outcomes, use of infliximab as second-line therapy is not convincingly supported by highly powered studies [1]. As this case illustrates, the treatment of KD is neither universal nor intuitive. The efficacy of infliximab in this population would perhaps be enhanced if administered at an earlier time point, especially in children who are at high risk for resistance to therapy. Children who are resistant to first-line treatment with IVIG carry a higher risk for development of coronary artery aneurysms [4]. Therefore, to avoid such devastating outcomes, should infliximab be used as an adjunct to IVIG in the treatment of children with KD who are at high risk? These high-risk patients (male, young age, recurrence of fever) could possibly be identified with a risk stratification algorithm and may benefit from more aggressive early therapy. It has been shown that tumor-necrosis factor (TNF)-alpha inhibitors decrease inflammation and endoarteritis in murine models, specifically the inhibition of neutrophil adhesion to endothelial cells, which is seen in the early phase of vasculitis [2]. This proof of concept experiment further elucidates the role of TNF-alpha inhibitors in the treatment of panvasculitis. Based on the mechanism of endoarteritis and the success of other patients treated with infliximab, we believe that high-risk KD patients may benefit from early treatment with infliximab in conjunction with conventional IVIG therapy [3,4]. In keeping with this hypothesis, researchers at The University of California at San Diego recently completed a phase III placebo-controlled, multicenter, randomized clinical trial of infliximab plus standard therapy versus placebo plus standard therapy in children with acute KD to determine if the addition of infliximab to primary therapy can decrease the percentage of children who are resistant to therapy. Results of this study will perhaps further guide our primary management of KD.

Cushing Syndrome from Topical Foam Steroid Use in an Adolescent Male

Cushing syndrome (CS) is suspect in the presence of the clinical phenotype: centripetal obesity, cervical or posterior fat pad, purple striae, proximal muscle weakness, hypertension, glucose intolerance, acne, fatigue, chronic obstructive pulmonary disease, hirsutism, and menstrual irregularity. Depression, emotional lability, anxiety, sleep disturbance, and cognitive deficits are also frequently obser ved.1 If CS is suspected, there should be comprehensive questioning regarding any prior condition, including dermatologic, that may require use of corticosteroids. Although exogenous steroid use is the most common etiology, the source can be elusive and proper diagnosis can be missed. Excessive use of glucocorticoids, nonsystemic (topical and inhaled) and systemic, can result in suppression of the hypothalamic-pituitary-adrenal (HPA) axis.2 However, we think our patient is the first reported pediatric case of CS secondary to the use of the scalp foam (Olux®, clobetasol propionate foam 0.05%; Connetics Corp., Palo Alto, CA) commonly prescribed for treatment of psoriasis.

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.

Teaching Translational Research to Medical Students: The New York University School of Medicine's Master's of Science in Clinical Investigation Dual‐Degree Program

To develop the next generation of translational investigators, New York University School of Medicine (NYUSOM) and the NYU‐NYC Health and Hospitals Corporation Clinical and Translational Science Institute (NYU‐HHC CTSI) developed the Masters of Science in Clinical Investigation dual‐degree (MD/MSCI) program. This 5‐year program dedicates 1 year to coursework and biomedical research, followed by a medical school/research overlap year, to prepare students for academic research careers. This paper details the MD/MSCI programs curriculum and approach to mentorship, describes the research/professional interests of students, and reports student productivity. In the first 4 years of the program (2010–2014) 20 students were matriculated; 7 (35%) were women, and 12 (60%) research projects were in surgical specialties. To date, 14 students have applied to residency, and half pursued surgical residency programs. Our students have produced 68 accepted abstracts, 15 abstracts in submission, 38 accepted papers, and 24 papers in submission. Despite the time‐limited nature of this program, additional training in research design and implementation has promoted a high level of productivity. We conclude that dual‐degree training in medicine and translational research is feasible for medical students and allows for meaningful participation in valuable projects. Follow‐up is warranted to evaluate the academic trajectory of these students.