Epidermal Nevi and Related Syndromes -- Part 1: Keratinocytic Nevi. / Nevus epidérmicos y síndromes relacionados. Parte 1: nevus queratinocíticos.

Epidermal nevi are hamartomatous lesions derived from the epidermis and/or adnexal structures of the skin; they have traditionally been classified according to their morphology. New variants have been described in recent years and advances in genetics have contributed to better characterization of these lesions and an improved understanding of their relationship with certain extracutaneous manifestations. In the first part of this review article, we will look at nevi derived specifically from the epidermis and associated syndromes.

[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]. / Überblick über die kongenitale stationäre Nachtblindheit mit überwiegend normalem Fundus.

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of non-progressive retinal disorder with largely normal fundus appearance. The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB). Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity. The Riggs and Schubert-Bornschein form of CSNB can be discriminated by electroretinography. While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form. The Schubert-Bornschein form can be further divided into incomplete (icCSNB) and complete (cCSNB) showing different electroretinograms (ERGs). While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well. Using classical linkage, candidate gene analyses and more recent next-generation sequencing approaches, to date, mutations in 13 different genes have been associated with this disease. In vitro and in vivo models showed a correlation of the phenotype of patients with the expression, protein localization and function of the respective molecules: genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade. Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors. Genes mutated in patients with cCSNB, code for proteins important for glutamate uptake and further signal transmission to the ON-bipolar cells. Preliminary in vivo studies showed that CSNB may be cured by gene therapy. These studies concerning CSNB are important for the precise diagnosis of patients with this disease, but are also helpful in deciphering key molecules essential for signal transmission from photoreceptors to bipolar cells. So far, it is a poorly understood field.

Depressive mixed states: A reappraisal of Koukopoulos' criteria.

BACKGROUND: Mixed states have been a fundamental part of Kraepelin׳s conceptualization of the manic-depressive illness. However, after Kraepelin, the study of mixed states was not of great interest, until the publication of the RDC criteria (1978) and then the DSM-III edition (1980), where criteria for mixed manic states were operationalized. The most notable victims of DSM nosology were depressive mixed states, in particular depression with flight of ideas and excited (agitated) depression. METHODS: We briefly review the clinical work of Athanasios Koukopoulos on depressive mixed states (in particular agitated depression) pointing out the diagnostic and therapeutic contributions, especially in the lights of Koukopoulos׳ first description of depressive mixed syndrome in 1992. RESULTS: The mixed depressive syndrome is not a transitory state but a state of long duration, which may last weeks or several months. The clinical picture is characterized by dysphoric mood, emotional lability, psychic and/or motor agitation, talkativeness, crowded and/or racing thoughts, rumination, initial or middle insomnia. Impulsive suicidal attempts may be frequent. The family observes incessant complaints, irritability, occasional verbal outbursts, occasional physical aggression, and occasional hypersexuality. Treatment with antipsychotics and ECT is very effective; antidepressants can worsen the clinical picture. LIMITATIONS: Selective but not systematic review of the literature on depressive mixed states. Relatively little research data is currently available for validation of the criteria proposed by Koukopoulos. CONCLUSIONS: Koukopoulos׳ proposal of mixed depression, besides its diagnostic implications, clearly identifying it as manifestations of bipolar disorder, allows for better clinical characterization of cases and improves treatment decisions.

Clinical features and management of hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Clinical features and management of hereditary spastic paraplegia / Aspectos clinicos e manejo das paraplegias espasticas hereditarias

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Paraplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.

Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review.

Most lysosomal diseases (LD) are inherited as autosomal recessive traits, but two important conditions have X-linked inheritance: Fabry disease and Mucopolysaccharidosis II (MPS II). These two diseases show a very different pattern regarding expression on heterozygotes, which does not seem to be explained by the X-inactivation mechanism only. While MPS II heterozygotes are asymptomatic in most instances, in Fabry disease most of female carriers show some disease manifestation, which is sometimes severe. It is known that there is a major difference among X-linked diseases depending on the cell autonomy of the gene product involved and, therefore, on the occurrence of cross-correction. Since lysosomal enzymes are usually secreted and uptaken by neighbor cells, the different findings between MPS II and Fabry disease heterozygotes can also be due to different efficiency of cross-correction (higher in MPS II and lower in Fabry disease). In this paper, we review these two X-linked LD in order to discuss the mechanisms that could explain the different rates of penetrance and expressivity observed in the heterozygotes; this could be helpful to better understand the expression of X-linked traits.

Amelogenesis imperfecta.

Amelogenesis imperfecta (AI) represents a group of developmental conditions, genomic in origin, which affect the structure and clinical appearance of enamel of all or nearly all the teeth in a more or less equal manner, and which may be associated with morphologic or biochemical changes elsewhere in the body. The prevalence varies from 1:700 to 1:14,000, according to the populations studied. The enamel may be hypoplastic, hypomineralised or both and teeth affected may be discoloured, sensitive or prone to disintegration. AI exists in isolation or associated with other abnormalities in syndromes. It may show autosomal dominant, autosomal recessive, sex-linked and sporadic inheritance patterns. In families with an X-linked form it has been shown that the disorder may result from mutations in the amelogenin gene, AMELX. The enamelin gene, ENAM, is implicated in the pathogenesis of the dominant forms of AI. Autosomal recessive AI has been reported in families with known consanguinity. Diagnosis is based on the family history, pedigree plotting and meticulous clinical observation. Genetic diagnosis is presently only a research tool. The condition presents problems of socialisation, function and discomfort but may be managed by early vigorous intervention, both preventively and restoratively, with treatment continued throughout childhood and into adult life. In infancy, the primary dentition may be protected by the use of preformed metal crowns on posterior teeth. The longer-term care involves either crowns or, more frequently these days, adhesive, plastic restorations.

BTKbase: the mutation database for X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). XLA patients have a decreased number of mature B cells and a lack of all immunoglobulin isotypes, resulting in susceptibility to severe bacterial infections. XLA-causing mutations are collected in a mutation database (BTKbase), which is available at http://bioinf.uta.fi/BTKbase. For each patient the following information is given (when available): the identification of the entry, a plain English description of the mutation followed by a reference, formal characterization of the mutation, and the various parameters from the patient. BTKbase is implemented with the MUTbase program suite, which provides an easy, interactive, and quality controlled submission of information to mutation databases. BTKbase version 8 lists mutation entries of 1,111 patients from 973 unrelated families showing 602 unique molecular events. The localization of the mutations on the gene and protein for BTK can be analyzed by clicking sequences on the web pages. The distribution of the mutations in the five structural domains is approximately proportional to the length of the domains, except for the Tec homology (TH) domain. The most frequently affected sites are CpG dinucleotides. The majority of the missense mutations are structural-disturbing Bruton tyrosine kinase (Btk) folding or decreasing stability. Many of the mutations affect functionally significant, conserved residues. The structural consequences of the mutations in all the domains have been studied based on crystallographic and nuclear magnetic resonance (NMR) structures as well as computer-aided molecular modeling.

Early-onset encephalopathy and cortical myoclonus in a boy with MECP2 gene mutation.

The authors report the unusual clinical and neurophysiologic features of a sporadic case of a boy carrying an 806delG mutation on the MECP2 gene. A 28-month-old boy was examined for severe developmental delay, seizures, microcephaly, breathing dysfunction, and spontaneous and evoked myoclonic jerks of upper limbs. Neurophysiologic study proved the cortical origin of myoclonus; however, it was not associated with signs of cortical hyperexcitability. 3-Methoxy-4-hydroxy-phenylethylene glycol and valine concentrations were low in CSF.