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Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke. [ABSTRACT FROM AUTHOR]

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common form of autoimmune encephalitis, caused by the interaction between an antibody and its target, located on glutamate receptor type N-methyl-D-aspartate (NMDA) of neuronal surface. There is a wide spectrum of clinical features starting by a viral-like prodrome, followed by symptoms such as psychosis, aggressive behaviour, memory loss, seizures, movement disorders, and autonomic instability. Up to 50% of the affected young female patients have germ-cells tumours as ovarian teratoma, making it essential to establish an early diagnosis through detection of specific antibodies in serum and cerebrospinal fluid (CSF). This retrospective observational study was performed in patients whom positive anti-NMDA receptor antibodies have been tested, associated with clinical manifestations that suggest autoimmune encephalitis and a germ-cell tumour confirmed by pathology. Six patients have tested positive for anti-NMDA receptor antibodies associated with a germ-cell tumour and clinical manifestations of autoimmune encephalitis. Management includes aggressive immunosuppression and surgical removal. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to describe a new mutation in the LMNA gene diagnosed by whole exome sequencing. Methods: A two-generation kindred with recessive limb-girdle muscular dystrophy was evaluated by exome sequencing of the proband's DNA. Results: Exome sequencing disclosed 194,618 variants (170,196 SNPs, 8482 MNPs, 7466 insertions, 8307 deletions, and 167 mixed combinations); 71,328 were homozygotic and 123,290 were heterozygotic, with 11,753 non-synonymous, stop-gain, stop-loss, or frameshift mutations occurring in the coding region or nearby intronic region. The cross-referencing of these mutations in candidate genes for muscular dystrophy showed a homozygote mutation c.G674A in exon 4 of LMNA causing a protein change R225Q in an arginine conserved from human to Xenopus tropicalis and in lamin B1. Conclusions: This technique will be preferred for studying patients with muscular dystrophy in the coming years. Muscle Nerve, 2012 [ABSTRACT FROM AUTHOR]

Background and purpose: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the CYP27A1 gene resulting in sterol-27-hydroxylase deficiency. Current information about CTX is based mainly on case reports, with only few large series reported. Although perceived as a potentially treatable condition, efficacy of chenodeoxycholic acid plus statin therapy remains unclear. To perform a nationwide survey of confirmed cases, with a thorough analysis of genotype-phenotype data and prognostic factors. Methods: Retrospective review of the clinical and epidemiological aspects and mutations of all the patients diagnosed since 1992 in the main reference centers for genetic testing of CTX in Spain. Results: Twenty-five patients from 19 families were identified. An average delay of 19 years was observed between symptom onset and clinical diagnosis. Two main clinical subgroups were recognizable: a classic form (cerebellar and other supratentorial symptoms) and a spinal form (chronic myelopathy). Cholestanol levels did not correlate with clinical presentation, severity or response to therapy. Despite treatment, five patients died during follow-up, one to 4 years after diagnosis. Thirteen different mutations were identified, with a higher frequency of p.R395C in Northwestern Spain and p.R405W in Southern Spain. None of the mutations could be associated with a particular clinical feature combination or prognosis. Conclusions: This is the first nationwide extensive series of CTX reported in Spain. The higher number of cases in some areas suggests a possible founder effect. Spinal forms had a less severe prognosis. A delayed diagnosis could contribute to the lack of significant response to treatment. [ABSTRACT FROM AUTHOR]

The article discusses a neurophysiological study of cerebrotendinous xanthomatosis (CTX), a rare, autosomal disease manifested by the appearance of cataracts, xanthomas, and neurological symptoms. The study involved clinical and neurophysiological examinations of 13 patients from Spain suffering from CTX. Results revealed that all patients demonstrated symptoms of peripheral neuropathy, 67% had lower limb somatosensory evoked potentials (SSEPs), and 43% had affected visual evoked potentials.

Cerebrotendinous xanthomatosis is an inherited autosomal recessive lipid storage disease caused by a 27-hydroxylase enzyme deficiency, characterised clinically by tendon xanthomas, premature cataracts, chronic diarrhoea and progressive neurologic dysfunction. The disease is very uncommon and there are very few pathological descriptions. We report a 52-year-old male who presented with a neuropsychiatric disorder and cognitive decline. Despite treatment the patient developed optic atrophy, parkinsonism and dementia and died. The autopsy revealed a nonspecific brain and cerebellar atrophy.Under microscopic examination, lipid crystal clefts, neuronal loss, demyelination, reactive astrocytosis and perivascular macrophages were found. These findings suggest the limited reversibility of the disease, and its poor prognosis, specially if treatment is not started early. [ABSTRACT FROM AUTHOR]

In this report, we present the clinical and pathological details of a kindred of four individuals with a novel missense mutation (V272A) of the presenilin 1 gene (PSEN1) that experienced a subcortical dementia. The age of onset of symptoms ranged 26–36-year old, with an age at death of 36–46 years. Initial symptom was a marked mood disorder, with prominent parkinsonism in one case. The neuropsychological study, as well as the neuroimaging and PET in the proband were concordant with a subcortical dementia. The cerebral pathology showed in this patient, aside from the classical lesions of Alzheimer disease, Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. This clinical pattern and pathology expands the clinical spectrum of familial Alzheimer's disease and compel to include mutations of PSEN1 gene in the genetic study of subcortical dementia. [ABSTRACT FROM AUTHOR]

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) and leads to the generation of potent pro-inflammatory cytokines. The protein "apoptosis-associated speck-like protein containing a caspase recruitment domain" (ASC) modulates IF activation but has also other functions which are crucial in AD. We intended to characterize immunohistochemically ASC and pattern recognition receptors (PRR) of IF in the hippocampus (HP) of the transgenic mouse model Tg2576 (APP), in which amyloid-beta (Aβ) pathology is directly dependent on age. We show in old-aged APP a significant amount of ASC in microglia and astrocytes associated withAβ plaques, in the absence of PRR described by others in glial cells. In addition, APP developed foci with clusters of extracellular ASC granules not spatiallyrelated to Aβ plaques, which density correlated with the advanced age of mice and AD development. Clusters were associated withspecific astrocytes characterized by their enlarged ring-shaped process terminals, ASC content, and frequent perivascular location. Their possible implication in ASC clearance and propagation of inflammation is discussed. [ABSTRACT FROM AUTHOR]

The article reports on the case of a family with frontotemporal dementia caused by a novel progranulin gene mutation whose proband presented with impaired musical appreciation as an early symptom of the disease. The proband was a 53 year-old woman with degrees in music and journalism whose complaint was trouble assessing the quality of a musical performance accompanied by depression. Results of her brain magnetic resonance imaging showed asymmetric frontotemporal atrophy. Details of the case of her sister with progressive speech disorder are provided.