Contributions to the study of spinocerebellar ataxia type 38 (SCA38).

OBJECTIVE: To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38). PATIENTS AND METHODS: Five family members spanning two generations developed gait ataxia and intermittent diplopia. On examination, a cerebellar syndrome accompanied by downbeat nystagmus and a saccadic head impulse test (HIT) were found. RESULTS: Whole-exome sequencing demonstrated a heterozygous variant in ELOVL5, c.779A > G (p.Tyr260Cys), in four tested patients. Intermittent concomitant esotropia and hypertropia caused transient diplopia in one individual each. Saccadic HIT responses were found in four subjects. Sensorineural hypoacusis was present in every case. Electrophysiological studies demonstrated a sensory neuronopathy in patients from the first generation, with prolonged disease duration. Baseline serum docosahexaenoic acid (DHA) percent was diminished in four individuals. Oral 26-week dietary DHA supplementation, 650 mg/day, raised serum DHA percent and induced a statistically significant reduction in Scale for the Assessment and Rating of Ataxia (SARA) total scores, and in stance and heel-shin slide item scores. CONCLUSION: The mentioned ELOVL5 variant segregated with disease in this kindred. Downbeat nystagmus, intermittent heterotropia causing transient diplopia, vestibular impairment demonstrated by abnormal HIT, and sensory neuronopathy were part of the clinical picture in this series. DHA supplementation raised serum DHA percent in cases with diminished levels, and induced a clinical amelioration and a statistically significant reduction in SARA scores in the study group. Further studies are needed to investigate the role of these findings in SCA38, and to determine the response to prolonged DHA supplementation.

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere's Disease.

Meniere's disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case-control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661-2.627); p = 1.39 × 10-09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10-11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD.

Ontogenetic explanation for tegmen tympani dehiscence and superior semicircular canal dehiscence association. / Explicación ontogénica para la asociación entre dehiscencia del tegmen tympani y dehiscencia del canal semicircular superior.

OBJECTIVES: To analyze the ontogeny of the superior semicircular canal and tegmen tympani and determine if there are common embryological factors explaining both associated dehiscence. METHODS: We analyzed 77 human embryological series aged between 6 weeks and newborn. Preparations were serially cut and stained with Masson's trichrome technique. RESULTS: The tegmental prolongation of tegmen tympani and superior semicircular canal originate from the same structure, the otic capsule, and have the same type of endochondral ossification; while the extension of the squamous prolongation of tegmen tympani runs from the temporal squama and ossification is directly of intramembranous type. The nuclei of ossification of the superior and external semicircular canals and accessory of tegmen collaborate in the ossification of the tegmental extension and by growth extend to the tegmental prolongation. This fact plus the fact that both structures share a common layer of external periosteum could explain the coexistence of lack of bone coverage in tegmen and superior semicircular canal. CONCLUSION: The development of the semicircular canal and tegmen tympani could explain the causes of the association of both dehiscences.

Mitochondrial ribosome and Ménière's disease: a pilot study.

Ménière's disease patients experience vestibular disability. When most of medical treatments fail, a chemical labyrinthectomy using aminoglycosides is indicated. However, this process frequently causes hearing damage. Aminoglycosides, interacting with mitochondrial rRNAs, alter mitochondrial protein synthesis and the oxidative phosphorylation system, which provide most of the energy in sensory hair cells. For this reason, we hypothesized that genetic variation in mitochondrial rRNA genes and in two nuclear genes coding for proteins that also modify the susceptibility to aminoglycosides might affect the risk of hearing loss in Ménière's disease patients suffering chemical labyrinthectomy. However, there were no differences in mitochondrial rRNA, TFB1M or MRPS12 genetic variation between those patients that experienced or did not experience hearing loss. This is only a pilot study and larger studies are required to use this therapeutic approach in a rational way and decrease the risk of hearing damage.

[Ontogenic development of the incudostapedial joint]. / Desarrollo ontogénico de la articulación incudoestapedial.

OBJECTIVE: To study the development of the incudostapedial joint in human embryos and foetuses. MATERIAL AND METHOD: 46 temporal bones with specimens between 9 mm and newborns were studied. The preparations were sliced serially and dyed using the Martins trichrome technique. RESULTS: The incudostapedial joint takes on the characteristics of a spheroidal joint at 16 weeks of development. The cartilage covering the articular surfaces is formed by different strata that develop in succession: the superficial stratum at 19 weeks, the transitional between 20 and 23 weeks, and the radial from 24 weeks on. The subchondral bone develops after 29 weeks by the mechanisms of apposition and extension of the periosteal and endosteal bones, but it is not until week 34 that it completely covers the articular surfaces, following constitution of the bone fascicles transmitting the lines of force. The articular capsule is formed from the inter-zone, the surface zone develops the capsular ligament, and the internal surface develops the synovial membrane. CONCLUSIONS: At the time of birth, the incudostapedial joint is completely developed.

[Subacute necrotizing histiocytic lymphadenitis. An almost unknown condition]. / Linfadenitis histiocitaria necrotizante subaguda. Una entidad poco conocida.

The etiology of neck masses is multifactorial, including genetical troubles, infections or tumoral lesions. A detailed medical history and a thorough physical check-up with the aid of analyses and imaging pictures properly selected, provide the doctor with the needle information in order to establish a correct diagnosis (table 1). We present the case of a young woman with lateral neck and supraclavicular adenopathies which diagnosis although sporadic must be keep in mind in daily clinic owing its growing incidence in last years.

Otorhinolaryngologic manifestations in Chiari malformation.

The Chiari malformation causes herniation of the cerebellar amygdalae through the foramen magnum, resulting in the descent of the brain stem and/or traction on the lower cranial pairs. It is important for otolaryngologists to recognize Chiari malformations as part of the differential diagnosis of balance disorders, because patients may initially exhibit symptoms related to the vestibular system, including ataxia, nystagmus, or vertigo. We report 2 cases.