Spinocerebellar ataxia (SCA) comprises a large group of heterogeneous neurodegenerative disorders inherited in an autosomal dominant fashion. It is characterized by progressive cerebellar ataxia with oculomotor dysfunction, dysarthria, pyramidal signs, extrapyramidal signs, pigmentary retinopathy, peripheral neuropathy, cognitive impairment and other symptoms. It is classified according to the clinical manifestations or genetic nosology. To date, 40 SCAs have been characterized, and include SCA1-40. The pathogenic genes of 28 SCAs were identified. In recent years, with the widespread clinical use of next-generation sequencing, the genes underlying SCAs, and the mutants as well as the affected phenotypes were identified. These advances elucidated the phenotype-genotype relationship in SCAs. We reviewed the recent clinical advances, genetic features and phenotype-genotype correlations involving each SCA and its differentiation. The heterogeneity of the disease and the genetic diagnosis might be attributed to the regional distribution and clinical characteristics. Therefore, recognition of the phenotype-genotype relationship facilitates genetic testing, prognosis and monitoring of symptoms.

Spinocerebellar ataxia: relationship between phenotype and genotype - a review.

Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection.

Elongation of Very Long chain fatty acids-4 (ELOVL4) protein is a member of the ELOVL family of fatty acid elongases that is collectively responsible for catalyzing formation of long chain fatty acids. ELOVL4 is the only family member that catalyzes production of Very Long Chain Saturated Fatty Acids (VLC-SFA) and Very Long Chain Polyunsaturated Fatty Acids (VLC-PUFA) with chain lengths ≥28 carbons. ELOVL4 and its VLC-SFA and VLC-PUFA products are emerging as important regulators of synaptic signaling and neuronal survival in the central nervous system (CNS). Distinct sets of mutations in ELOVL4 cause three different neurological diseases in humans. Heterozygous inheritance of one set of autosomal dominant ELOVL4 mutations that leads to truncation of the ELOVL4 protein causes Stargardt-like macular dystrophy (STGD3), an aggressive juvenile-onset retinal degeneration. Heterozygous inheritance of a different set of autosomal dominant ELOVL4 mutations that leads to a full-length protein with single amino acid substitutions causes spinocerebellar ataxia 34 (SCA34), a late-onset neurodegenerative disease characterized by gait ataxia and cerebellar atrophy. Homozygous inheritance of a different set of ELOVL4 mutations causes a more severe disease with infantile onset characterized by seizures, spasticity, intellectual disability, ichthyosis, and premature death. ELOVL4 is expressed widely in the CNS and is found primarily in neurons. ELOVL4 is expressed in cell-specific patterns within different regions of the CNS that are likely to be related to disease symptoms. In the retina, ELOVL4 is expressed exclusively in photoreceptors and produces VLC-PUFA that are incorporated into phosphatidylcholine and enriched in the light sensitive membrane disks of the photoreceptor outer segments. VLC-PUFA are enzymatically converted into "elovanoid" compounds that appear to provide paracrine signals that promote photoreceptor and neuronal survival. In the brain, the main ELOVL4 products are VLC-SFA that are incorporated into sphingolipids and enriched in synaptic vesicles, where they regulate kinetics of presynaptic neurotransmitter release. Understanding the function of ELOVL4 and its VLC-SFA and VLC-PUFA products will advance our understanding of basic mechanisms in neural signaling and has potential for developing novel therapies for seizure and neurodegenerative diseases.

/pdf/novel-cellular-functions-of-very-long-chain-fatty-acids-38wyfqj2zj.pdf

Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations.

Docosahexaenoic acid (DHA, 22:6 n-3) is abundant in the retina and is enzymatically converted into pro-homeostatic docosanoids. The DHA- or eicosapentaenoic acid (EPA)-derived 26 carbon fatty acid is a substrate of elongase ELOVL4, which is expressed in photoreceptor cells and generates very long chain (≥C28) polyunsaturated fatty acids including n-3 (VLC-PUFAs,n-3). While ELOVL4 mutations are linked to vision loss and neuronal dysfunctions, the roles of VLC-PUFAs remain unknown. Here we report a novel class of lipid mediators biosynthesized in human retinal pigment epithelial (RPE) cells that are oxygenated derivatives of VLC-PUFAs,n-3; we termed these mediators elovanoids (ELV). ELVs have structures reminiscent of docosanoids but with different physicochemical properties and alternatively-regulated biosynthetic pathways. The structures, stereochemistry, and bioactivity of ELVs were determined using synthetic materials produced by stereo-controlled chemical synthesis. ELVs enhance expression of pro-survival proteins in cells undergoing uncompensated oxidative stress. Our findings unveil a novel autocrine/paracrine pro-homeostatic RPE cell signaling that aims to sustain photoreceptor cell integrity and reveal potential therapeutic targets for retinal degenerations.

Elovanoids are novel cell-specific lipid mediators necessary for neuroprotective signaling for photoreceptor cell integrity.

The extracellular matrix (ECM) plays a key role in tissue formation, homeostasis and repair, mutations in ECM components have catastrophic consequences for organ function and therefore, for the fitness and survival of the organism. Collagen, fibrillin and elastin polymers represent the architectural scaffolds that impart specific mechanic properties to tissues and organs. Fibrillin assemblies (microfibrils) have the additional function of distributing, concentrating and modulating local transforming growth factor (TGF)-β and bone morphogenetic protein (BMP) signals that regulate a plethora of cellular activities, including ECM formation and remodeling. Fibrillins also contain binding sites for integrin receptors, which induce adaptive responses to changes in the extracellular microenvironment by reorganizing the cytoskeleton, controlling gene expression, and releasing and activating matrix-bound latent TGF-β complexes. Genetic evidence has indicated that fibrillin-1 and fibrillin-2 contribute differently to the organization and structural properties of non-collagenous architectural scaffolds, which in turn translate into discrete regulatory outcomes of locally released TGF-β and BMP signals. Additionally, the study of congenital dysfunctions of fibrillin-1 has yielded insights into the pathogenesis of acquired connective tissue disorders of the connective tissue, such as scleroderma. On the one hand, mutations that affect the structure or expression of fibrillin-1 perturb microfibril biogenesis, stimulate improper latent TGF-β activation, and give rise to the pleiotropic manifestations in Marfan syndrome (MFS). On the other hand, mutations located around the integrin-binding site of fibrillin-1 perturb cell matrix interactions, architectural matrix assembly and extracellular distribution of latent TGF-β complexes, and lead to the highly restricted fibrotic phenotype of Stiff Skin syndrome. Understanding the molecular similarities and differences between congenital and acquired forms of skin fibrosis may therefore provide new therapeutic tools to mitigate or even prevent disease progression in scleroderma and perhaps other fibrotic conditions.

/pdf/fibrillin-assemblies-extracellular-determinants-of-tissue-3qqexdz9hf.pdf

Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis

A New ELOVL4 Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia Spinocerebellar ataxia with erythrokeratodermia (SCA34; OMIM 133190) is an autosomal dominant complex form of ataxia. This condition was first described in 1972 with the report of a French-Canadian family with multiple affected individuals.1 Four decades later, a segregating locus was identified through linkage analysis of 32 individuals from this family. Subsequent whole-exome sequencing of 3 individuals revealed a mutation in the elongation of very long-chain fatty acids–like 4 gene (ELOVL4) (NM_022726.3 c.504G>C); this mutation produced a defective protein (p.Leu168Phe).2 We report here the identification of a different ELOVL4 mutation in a single case who had signs consistent with SCA34. To our knowledge, our findings are the first to confirm ELOVL4 as the cause of SCA34.

https://jamanetwork.com/journals/jamaneurology/articlepdf/2411313/nld150003.pdf

A New ELOVL4 Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia.

BACKGROUND: Skin cancer is the most common malignancy and can be treated in various ways. One treatment modality is Mohs micrographic surgery. Due to the increasing incidence of skin cancer in the last decades, there is a need for improvement of the Mohs technique to optimize its effectiveness. OBJECTIVE: The aim of this study was to evaluate the use of dermoscopy to guide demarcation of Mohs micrographic surgery margins and ascertain whether this method can reduce operative time and, therefore, reduce surgical morbidity and cost. METHODS AND MATERIALS: The sample comprised 44 patients who underwent Mohs micrographic surgery, allocated into two groups: the control group and the intervention group. In the latter, surgical margins were guided by dermoscopy. RESULTS: There were no statistically significant differences between the two groups by chi-square analysis (p = 0.399). CONCLUSION: Although outcomes were similar in the two groups, demonstrating that dermoscopy does not help in the demarcation of surgical margins for Mohs micrographic surgery, the study provides a practical proposal for improvement of the Mohs technique.

Utility of dermoscopy for demarcation of surgical margins in Mohs micrographic surgery

Stiff skin syndrome is a rare cutaneous disease, scleroderma-like disorder that presents in infancy or early childhood with rock-hard skin, limited joint mobility, and mild hypertrichosis. Normally, it occurs in the absence of visceral or muscle involvement. Patients do not present immunologic abnormalities or vascular hyperactivity. We describe two adults who initially were diagnosed suffering from scleroderma but fit criteria for stiff skin syndrome. A review of the clinical range of this disorder and discussion of the differential diagnosis with scleroderma is presented.

Stiff skin syndrome versus scleroderma: a report of two cases

Erosive adenomatosis of the nipple is a complex benign mammary proliferation that can be misdiagnosed as a malignant mammary neoplasm. The most common clinical presentation includes discharge, erythema, erosion and crusting. The process is usually asymptomatic. It resembles benign conditions such as contact dermatitis, psoriasis and infections, but its main differential diagnosis is Paget's disease. Treatment is usually surgical and the prognosis is excellent.

http://www.scielo.br/pdf/abd/v86n4s1/en_v86n4s1a03.pdf

Erosive adenomatosis of the nipple

Acquired perforating dermatosis is characterized by transepithelial elimination of degenerated dermal substances. It occurs in many conditions, such as: diabetes mellitus, chronic renal failure and sclerosing cholangitis. This article describes a 17-year-old Caucasian female with type I glucogenosis and acquired perforating dermatosis due to chronic hepatic failure caused by hepatic complication of liver transplant.

https://www.scielo.br/pdf/abd/v82n1/v82n01a07.pdf

Sergio Zuneda Serafini

Papers

A New ELOVL4 Mutation in a Case of Spinocerebellar Ataxia With Erythrokeratodermia.

Utility of dermoscopy for demarcation of surgical margins in Mohs micrographic surgery

Stiff skin syndrome versus scleroderma: a report of two cases

Erosive adenomatosis of the nipple

Dermatose perfurante adquirida associada à insuficiência hepática em paciente transplantado de fígado