Revisiting genotype-phenotype overlap in neurogenetics: triplet-repeat expansions mimicking spastic paraplegias.

Hereditary spastic paraplegias (HSPs) constitute a heterogeneous group of neurological disorders, characterized primarily by progressive spasticity and weakness of the lower limbs. HSPs are caused by mutations in multiple genes (at least 48 loci and 28 causative genes). The clinical spectrum of HSPs is wide and important differences have been reported between patients with distinct mutations in the same gene, or even between different family members bearing the same mutation. Many patients with HSP present clinical deficits related to the involvement of neuronal systems other than corticospinal tracts, namely, peripheral nerves, sensory, or cerebellar pathways. These cases may be difficult to differentiate from other neurological diseases (e.g., hereditary ataxias), also genetically and clinically heterogeneous. As an illustration of how overlapping this genotype-phenotype relationship is, and the difficulties that it brings upon the development of neurogenetic algorithms and databases, we review the main clinical and genetic features of HSPs, and summarize reports on cases of triplet-repeat spinocerebellar ataxias that can mimic HSP phenotypes. This complex scenario makes the necessity of high-quality, curated mutation databases even more urgent, in order to develop adequate diagnostic guidelines, correct interpretation of genetic testing, and appropriate genetic counseling.

[Renal cyst infected by Brucella]. / Quiste renal infectado por Brucela.

OBJECTIVES: To report one case of renal cyst infected by Brucella, an exceptional pathology in our environment. METHODS: 82-year-old patient who was referred from his primary care physician for persistent microhematuria and piuria without evidence of infection. RESULTS: Radiological studies (XR+US+CTscan) showed a left renal cyst with parietal calcifications. Pathologic study was compatible with complicated cyst, with cultured (+) to Brucella spp. CONCLUSIONS: Renal involvement by Brucella is exceptional, and the cystic renal involvement is by far one of the more exceptional manifestations.

Risk factors for dementia of Alzheimer type and aging-associated cognitive decline in a Spanish population based sample, and in brains with pathology confirmed Alzheimer's disease.

We investigated the environmental and genetic factors for Alzheimer's disease (AD) in Spain and performed a door to door study of a cohort of more than 500 subjects, over 70 years old, from Leganés, a suburban area near Madrid. The cohort was followed for 6 years by neurologists and other health workers and was divided in three groups: normal controls, subjects with aging-associated cognitive decline (AACD) and probable AD or dementia of Alzheimer's type (DAT). Biological variables and polymorphisms of different genes, important in neurodegeneration or reported to be associated with AD, were investigated as putative risk modifiers. These polymorphisms have also been analyzed in 94 brains, 39 from patients with pathologically confirmed AD and 55 controls. The statistical investigation included the evaluation of different individual risks and a multinomial logistic regression analysis to detect predictive factors. The risk of AACD and AD increased with age, feminine gender and history of stroke and decreased with education. The allele ApoE4 increased the risk of AD but not of AACD. When the impact of ApoE4 was added to the model, the effect of education and stroke disappeared as risk modifiers.

Parkin polymorphisms in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a mostly sporadic disorder of unknown pathogenesis. Familial PSP have been reported related to mutations of microtubule-associated protein tau (MAPT). Mutations of the Park2 gene cause autosomal recessive parkinsonism with neuropathological findings consistent with neurofibrillary tangles and tau immunoreactive lesions. We analysed the presence of MAPT and Park2 mutations and polymorphisms in sporadic and familial PSP. No patients had mutations of Park2 or MAPT but there was genetic association for the polymorphism Val380Leu in sporadic and familial PSP. Leu380 is associated with less risk of familial or sporadic PSP.

Variability of age at onset in siblings with familial Alzheimer disease.

BACKGROUND: Variability of age at onset (AO) of Alzheimer disease (AD) among members of the same family is important as a biological clue and because of its clinical effects. OBJECTIVE: To evaluate which clinical variables influence the discrepancy in AO among affected relatives with familial AD. SETTING: Clinical genetic project of Spanish kindred with AD conducted by 4 academic hospitals in Madrid, Spain. METHODS: Age at onset of AD in 162 families and discrepancy in AO in intragenerational and intergenerational affected pairs were analyzed in relation to age, sex, maternal or paternal transmission, pattern of inheritance, and apolipoprotein E genotype. RESULTS: Maternal transmission of AD was significantly more frequent than paternal transmission (P < .001). In 27% of the affected individuals, AO occurred before the patient was 65 years old. Discrepancy in AO among siblings was within 5 years in 44% of the families, 6 to 10 years in 29%, and more than 10 years in 27% (range, 0-22). This discrepancy was independent of the sex of the sibling pairs and was significantly lower with maternal transmission of AD (P = .02). Segregation analysis showed no differences in the inheritance pattern between families with low (< or =5 years) or high (>5 years) AO discrepancy. Age at onset in carriers of the apolipoprotein E epsilon4 allele was slightly younger. However, among siblings, an extra apolipoprotein E epsilon4 allele was not consistently associated with earlier onset of AD. Eighty percent of patients, independent of sex or mode of transmission, were already affected at their parents' reported AO. CONCLUSIONS: There is a wide discrepancy in AO in affected siblings that is not clearly explained by a single clinical variable or apolipoprotein E genotype. The interaction of many factors probably determines AO in each affected individual. However, maternal transmission of AD seems to result in a similar AO in offspring, and the risk of developing dementia after the parent's reported AO decreases significantly.

Progressive nonfluent aphasia associated with a new mutation V363I in tau gene.

Reported here is a new missense mutation V363I in exon 12 of the microtubule-associated protein tau (MAPT) gene associated with progressive nonfluent aphasia, with onset at the age of 69 years in a woman. Although near mute, she maintained complex activities and had no discernible deficits outside of language until the age of 75 years, when progressive gait and swallowing disturbances appeared. There was a history of late-onset aphasia and apraxia in her father. All of her children were asymptomatic adults, but psycholinguistic abnormalities were detected in those bearing the mutation, consisting of difficulties in comprehension, both reading (symbol discrimination and comprehension of oral spelling) and oral (matching sentences to pictures and comprehension of locative relationships). A mutation-bearing sibling showed no abnormalities at 70 years old, consistent with the limited penetrance expected in late-onset disease. The mutation, corresponding to a highly conserved residue in the fourth tubulin-binding repeat, was not present in 194 normal individuals with the same genetic background.

A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy (PSP) is a clinicopathological syndrome related to tau deposits and in linkage disequilibrium with tau polymorphisms. Some rare familial PSP cases have been related to tau gene mutations. OBJECTIVE: To present the clinical, pathological, and molecular data of one family with early-onset autosomal dominant PSP. DESIGN: We performed clinical examinations, quantitative neurological tests, positron emission tomographic scans with fluorodopa F 18 and raclopride C 11, analysis of tau mutations, neuropathological examinations, and protein analyses on brain specimens. RESULTS: Three family members had PSP confirmed by pathological features in the proband. A novel mutation of tau, G303V, was found in the proband and other family members. tau Isoforms with 4 microtubule-binding repeats were overexpressed in the proband brain. CONCLUSIONS: The G303V mutation of tau is associated with autosomal dominant PSP. Expression of 4 microtubule-binding repeat tau isoforms is increased in the proband.

Transcript diversity of Machado-Joseph disease gene (ATXN3) is not directly determined by SNPs in exonic or flanking intronic regions.

Alternative splicing (AS) of pre-mRNA is an important regulatory mechanism that enables one gene to produce multiple mature transcripts and, therefore, multiple protein isoforms. Besides the information content of core splicing signals, additional cis-regulatory elements (splicing enhancers and silencers) are needed to precisely define exons. AS is well documented in ATXN3 gene, which encodes for ataxin-3 and, when mutated, is responsible for Machado-Joseph disease (MJD). By studying MJD patients and controls, we have previously identified 56 alternative transcript variants for this gene; some were predicted to encode "protective" ataxin-3 isoforms, making then pertinent to understand AS regulation. The present study aims to investigate the relationship between variation in ATXN3 cis-regulatory motifs and AS variants found for each individual. We have sequenced exonic and flanking intronic ATXN3 regions, in genomic DNA from MJD patients and controls previously studied. None of the 10 single nucleotide polymorphisms (SNPs) that were found was located in core splicing signals. In silico analysis showed those SNPs implied losses and gains of recognition motifs for splicing factors. Each particular allele was not directly reflected in alterations of the resulting splicing variants, indicating that AS cannot be determined solely by these cis-elements, but should result from a more complex mode of regulation.

On the diagnosis of CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic arteriopathy related to Notch3 mutations, is difficult to diagnosis. The goal of this study was to determine the value of clinical, immunohistochemical, and molecular techniques for the diagnosis of CADASIL. Clinical features and the immunohistochemical and molecular findings in 200 subjects with suspected CADASIL in whom 93 biopsies and 190 molecular studies are reported. Eighteen pathogenic mutations of the Notch3 gene, six of them previously unreported, were detected in 67 patients. The clinical features did not permit differentiation between CADASIL and CADASIL-like syndromes. The sensitivity and specificity of the skin biopsies was 97.7% and 56.5%, respectively, but increased to 100% and 81.5%, respectively, in cases with proven family history. In conclusion, a clinical diagnosis of CADASIL is difficult to determine and confirmatory techniques should be used judiciously.

Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1.

Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.

Quiste renal infectado por brucela / Renal cyst infected by brucella

Objetivos: Presentar un caso clínico de quiste renal infectado por Brucela, patología excepcional en nuestro medio. Método: Paciente de 82 años remitido desde Atención primaria por microhematuria y piuria persistentes sin evidencia de infección de orina. Resultado: El estudio radiológico (Rx+ECO+TAC) demuestra una imagen sugestiva de quiste renal izquierdo con calcificación depared. El estudio anatomopatológico se demostró compatible con quiste renal complicado y el cultivo fue positivo para Brucella spp. Conclusiones: La afectación renal por Brucela es excepcional, siendo aún más extraordinaria la infección de un quiste renal, motivo por el cual presentamos el caso (AU)

Objetives: To report one case of renal cyst infected by Brucella, an exceptional pathology in our environment. Methods: 82-year-old patient who was referred from his primary care physician for persistent microhematuria and piuria without evidence of infection. Results: Radiological studies (XR+US+CTscan) showed a left renal cyst with parietal calcifications. Pathologic study was compatible with complicated cyst, with cultured (+) to Brucella spp. Conclusions: Renal involvement by Brucella is exceptional, and the cystic renal involvement is by far one of the more exceptional manifestations (AU)

Steele-Richardson-Olszewski syndrome in a patient with a single C212Y mutation in the parkin protein.

Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed.

The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.

Genética molecular del cáncer renal: utilidad en pronóstico y posibilidades terapéuticas / Molecular genetics of renal cancer: usefulness in prognosis and therapeutic possibilities

El cáncer renal tiene una incidencia del 3% del total de las neoplasias en adultos, y puede ser tanto de origen hereditario como esporádico. Histológicamente se clasifica en 5 tipos principales. Las técnicas actuales de citogenética y biología molecular han permitido conocer con más detalle algunos de los sucesos genéticos iniciales que causa la patogenia de los tipos mayoritarios como, por ejemplo, que un defecto en el cromosoma 3p está implicado en el desarrollo del carcinoma de células claras (ccRCC) o que en un 13% de los RCC de tipo papilar está mutado el gen c-MET (cromosoma 7), y en el resto de cánceres de este tipo existe duplicación de este mismo cromosoma, o que, en los oncocitomas la pérdida de los cromosomas 1 y/o 14 podría representar el suceso inicial. Aparte de estos defectos, el conocimiento de otros genes y alteraciones cromosómicas implicados, junto con otros factores, permite definir de manera aproximada el pronóstico en cada caso. Debido a que este tipo de cáncer desarrolla metástasis rápidamente, las terapias actuales, como la cirugía y el uso de interleucina (IL) 2, son poco eficaces y sólo consiguen alargar en unos meses la supervivencia del paciente. Aunque se están ensayando nuevas terapias, es necesario un conocimiento más profundo de los procesos moleculares implicados para obtener el éxito deseado tanto en el diagnóstico precoz como en el pronóstico y el tratamiento de la enfermedad(AU)

Renal cancer has a 3% incidence of all neoplasms in adults and it can be of hereditary or sporadic origin. Histologically, it is classified into 5 main types. The current cytogenetic and molecular biology techniques allow some of the initial genetic events responsible for the main types of pathogenesis to be studied in more detail, such as the implication of a defect in chromosome 3p in the development of clear cell renal cell carcinoma (ccRCC), or the presence of the mutated c-MET gene (chromosome 7) in 13% of papillary RCCs and the presence of the same chromosome duplication in the rest of these types of cancer, or the loss of chromosomes 1 and/or 14 which could represent the initial event in oncocytomas. Apart from these defects, knowledge other genes involved and chromosomic defects, as well as other factors, may enable an approximate prognosis to be made in each case. As the metastatic process in this cancer type develops very early, the current therapies, such as surgery and the use of IL-2, are not very effective and they only manage to extend patient survival by a few months. Although newer therapies are being assessed, a deeper knowledge about the molecular processes involved is necessary to obtain the desirable success both in the early diagnosis, as well as the prognosis and treatment of the disease(AU)