Aging affects every sensory system in the body, including the vestibular system. Although its impact is often difficult to quantify, the deleterious impact of aging on the vestibular system is serious both medically and economically. The deterioration of the vestibular sensory end organs has been known since the 1970s; however, the measurable impact from these anatomical changes remains elusive. Tests of vestibular function either fall short in their ability to quantify such anatomical deterioration, or they are insensitive to the associated physiologic decline and/or central compensatory mechanisms that accompany the vestibular aging process. When compared with healthy younger individuals, a paucity of subtle differences in test results has been reported in the healthy older population, and those differences are often observed only in response to nontraditional and/or more robust stimuli. In addition, the reported differences are often clinically insignificant insomuch that the recorded physiologic responses from the elderly often fall within the wide normative response ranges identified for normal healthy adults. The damaging economic impact of such vestibular sensory decline manifests itself in an exponential increase in geriatric dizziness and a subsequent higher prevalence of injurious falls. An estimated $10 to $20 billion dollar annual cost has been reported to be associated with falls-related injuries and is the sixth leading cause of death in the elderly population, with a 20% mortality rate. With an estimated 115% increase in the geriatric population over 65 years of age by the year 2050, the number of balanced-disordered patients with a declining vestibular system is certain to reach near epidemic proportions. An understanding of the effects of age on the vestibular system is imperative if clinicians are to better manage elderly patients with balance disorders, dizziness, and vestibular disease.

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype–phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

Background Based on pre‐clinical and clinical activity in adult refractory tumors, and absence of significant neuro‐, nephro‐, or oto‐toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. Procedure Satraplatin was administered orally once daily on days 1–5 of a 28‐day cycle at dose level (DL) 1 (60 mg/m²/dose), and DL2 (80 mg/m²/dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. Results Nine patients received 1–15 cycles (median = 2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose‐limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non‐DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro‐, nephro‐, or oto‐toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (­­­6–15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. Conclusions The MTD of oral satraplatin in children with solid tumors was 60 mg/m²/dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80–120 mg/m²/dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro‐, nephro‐ or oto‐toxicities were observed. Pediatr Blood Cancer 2015;62:603–610.

Purpose:Progressive decline of psychophysical cone-mediated measures has been reported in type 1 (USH1) and type 2 (USH2) Usher syndrome. Conventional cone electroretinogram (ERG) responses in USH demonstrate poor signal-to-noise ratio. We evaluated cone signals in USH1 and USH2 by recording microvolt level cycle-by-cycle ERG (CxC). Methods:Responses of molecularly genotyped USH1 (n = 18) or USH2 (n = 24) subjects (age range: 15-69 years) were compared with those of controls (n = 12). A subset of USH1 (n = 9) and USH2 (n = 9) subjects was examined two to four times over 2 to 8 years. Photopic CxC ERG and conventional 30-Hz flicker ERG were recorded on the same visits. Results:USH subjects showed considerable cone flicker ERG amplitude losses and timing phase delays (p < 0.01) compared with controls. USH1 and USH2 had similar rates of progressive logarithmic ERG amplitude decline with disease duration (-0.012 log μV/year). Of interest, ERG phase delays did not progress over time. Two USH1C subjects retained normal response timing despite reduced amplitudes. The CxC ERG method provided reliable responses in all subjects, whereas conventional ERG was undetectable in 7 of 42 subjects. Conclusions:CxC ERG showed progressive loss of amplitude in both USH1 and USH2 subjects, comparable to that reported with psychophysical measures. USH subjects showed abnormal ERG response latency, but this changed less than amplitude with time. In USH syndrome, CxC ERG is more sensitive than conventional ERG and warrants consideration as an outcome measure in USH treatment trials.

Objectives/Hypothesis: To define the audiologic and otologic phenotype of Hutchinson‐Gilford progeria syndrome (HGPS).Study Design: Prospective case series.Methods: Fifteen patients with HGPS were enrolled in a prospective natural history study; 14 were evaluated in the neurotology clinic, and 11 received audiologic evaluations. The physical exam and audiologic findings of these patients were reviewed to define an otologic and audiologic phenotype for HGPS in the largest series of subjects in the literature.Results: All patients were noted to have stiff auricular cartilages, small or absent lobules, and hypoplasia of the lateral soft‐tissue portion of the external ear canal leading to a shortened canal. Ten of 14 patients (71%) had dry cerumen impaction, and four of 14 patients (29%) reported a history of recurrent otitis media. Nineteen of 22 ears (86.4%) demonstrated low‐frequency conductive hearing loss in the 250 to 500 Hz range. Sixteen of 22 ears (73%) had type A tympanograms; three of 22 ears (14%) displayed bimodal or “W” peaked tympanograms; two of 22 ears (9%) had type B tympanograms; one of 22 ears (4%) had a type C tympanogram. Nine of 10 patients had distortion product otoacoustic emissions consistent with normal peripheral hearing sensitivity.Conclusions: HGPS is caused by a mutation in the LMNA gene resulting in the production of an abnormal nuclear protein; this in turn affects nuclear structure and function. Patients with HGPS have characteristic otologic features due to cartilaginous and subcutaneous tissue abnormalities and typically demonstrate low‐frequency conductive hearing loss despite largely normal tympanometry. It is important to be aware of these conditions in managing these patients.