A 10 Mb duplication in chromosome band 5q31.3-5q33.1 associated with late-onset lipodystrophy, ichthyosis, epilepsy and glomerulonephritis

We report here a 44 years-old patient with late-onset partial lipodystrophy, mental retardation, epilepsy, ichtyosis and glomerulonephritis, carrying a 10 Mb duplication of the chromosome 5q31.3-5q32.1 region detected by array-CGH.     

Hepatic arterial embolization in patients with neuroendocrine tumors

Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques.TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases.     

Autosomal dominant Alzheimer's disease with early frontal lobe involvement associated with the Met239Ile mutation of Presenilin 2 gene

Mutations in the Presenilin 2 gene (PSEN2) represent the less frequent genetic cause of familial Alzheimer's disease (FAD). Only eight PSEN2 mutations, reported in approximately 27 families, satisfied strict criteria of pathogenicity. We reported a patient with early-onset FAD and the PSEN2 p.Met239Ile mutation, presenting with severe executive dysfunction and myoclonic tremor, associated with memory loss. Brain SPECT study showed an early hypoperfusion of the frontal cortex. We confirmed the pathogenicity of PSEN2 p.Met239Ile mutation and its heterogeneous phenotypic expression. The modulating effect of the Apolipoprotein E and Prion Protein gene polymorphisms on the phenotypic variability was not confirmed.     

Hypertension alone or related to the metabolic syndrome in postmenopausal women

Cardiovascular risk is poorly perceived by women, especially during the peri- and postmenopausal period when susceptibility to cardiovascular events increases. Nevertheless in Europe, 55% of women versus 43% of men currently die of cardiovascular disease. Blood pressure is one of the most powerful and accurate determinants of cardiovascular status and risk. Despite its importance, hypertension is often underestimated and undiagnosed, especially in women. Various mechanisms are implicated to play a role in the blood pressure increase in women at the time of menopause. Hypertension can be considered an isolated disease, more typical of elderly women, or part of the metabolic syndrome, more frequent in early postmenopausal women. The metabolic syndrome, a clustering of lipid and nonlipid cardiovascular risk factors, is estimated to affect approximately 20-30% of the middle-aged population and its prevalence appears to be increasing in the worldwide population.     

Italian version of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS): validation and longitudinal performance

Objective

To validate an Italian version of the Rasch-Built Overall ALS Disability Scale (ROADS) in a broad population of patients and assess its longitudinal performance over time.

Methods

270 ALS patients referring to the Motor Neuron Disease Clinic of the University of Padova and Modena (Italy) accepted to compile the Italian version of the ROADS and results were correlated with the ALSFRSr and ALSAQ-40 scores, FVC values, and creatinine or albumin blood levels. To verify test–retest reliability, patients were asked to fill in a second copy of the scale within 5–7 days. Thirty-nine patients compiled a further copy of questionnaire during the follow up visit (after 133 days on average) which allowed us a longitudinal assessment of the scale.

Results

We found a good external construct validity between ROADS and either ALSFRS-R (correlation coefficient = 0.85) or ALSAQ-40 (correlation coefficient = − 0.84). Test–retest reliability was excellent with a concordance-correlation coefficient of 0.93. Yet, we observed a significant correlation between changes over time of the ROADS normalised sum score (− 2.18 point loss per month) and those of both the ALSFRS-R (positive correlation; Rho = 0.64, p ≤ 0.0001) or the ALSAQ-40 (negative correlation; Rho = − 0.60, p = 0.014).

Conclusions

The Italian version of ROADS proved to be a reliable marker to monitor overall disability in ALS patients. Further studies are necessary to assess its longitudinal performance.

     

Tight skin and limited joint movements as early presentation of Hutchinson-Gilford progeria in a 7-week-old infant

We present a 7-week-old male infant with pseudoscleroderma as a primary manifestation of the Hutchinson-Gilford syndrome of premature aging. He had suffered intra-uterine growth retardation; micrognathism and a cleft palate were evident at birth. He presented with feeding difficulties and severe, diffuse scleroderma-like lesions, a faint peri-oral cyanosis and prominent scalp veins. With time, special facial features became more and more apparent: frontal bossing, prominent eyes, thin and fine nose and lips, microstomia, low-set ears and occipito-parietal alopecia. Histopathology of the skin showed an increased density and thickness of collagen in the dermis and hypodermis. Within the 1st year of life, typical skeletal characteristics were observed. The diagnosis of Hutchinson-Gilford syndrome was confirmed by analysis of the lamin A gene, revealing a heterozygous c.1824C>T (G608G) mutation. Conclusion:Hutchinson-Gilford syndrome is an extremely rare disorder of which the full clinical spectrum becomes evident with time. Sclerodermatous changes in the infant can be the first manifestation.     

Neurological disorders in liver transplant candidates: Pathophysiology and clinical assessment

Compromised liver function, as a consequence of acute liver insufficiency or severe chronic liver disease may be associated with various neurological syndromes, which involve both central and peripheral nervous system. Acute and severe hyperammoniemia inducing cellular metabolic alterations, prolonged state of “neuroinflammation”, activation of brain microglia, accumulation of manganese and ammonia, and systemic inflammation are the main causative factors of brain damage in liver failure. The most widely recognized neurological complications of serious hepatocellular failure include hepatic encephalopathy, diffuse cerebral edema, Wilson disease, hepatic myelopathy, acquired hepatocerebral degeneration, cirrhosis-related Parkinsonism and osmotic demyelination syndrome. Neurological disorders affecting liver transplant candidates while in the waiting list may not only significantly influence preoperative morbidity and even mortality, but also represent important predictive factors for post-transplant neurological manifestations. Careful pre-transplant neurological evaluation is essential to define severity and distribution of the neurological impairment, to identify the abnormalities still responsive to current treatment, and to potentially predict the inherent post-operative prognosis. The preferred specific indices of neurological pre-transplant assessment may vary among centers, however, even with the aid of the current biochemical, neurophysiological, neuropsychological and neuroimaging diagnostic tools, the correct diagnosis and differential diagnosis of various syndromes may be difficult. In this article the relevant pathophysiological and clinical aspects of the most frequent brain and peripheral nervous system diseases affecting liver transplant candidates with acute or advanced chronic liver failure are briefly reported. The practical diagnostic findings useful for the preoperative assessment and treatment, as well as the expected neurological evolution after liver transplantation are also evaluated.     

A conserved splicing mechanism of the LMNA gene controls premature aging

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and leads to the production of a truncated protein (progerin) with a dominant negative effect. Here we show that HGPS mutation changes the accessibility of the 5'SS of LMNA exon 11 which is sequestered in a conserved RNA structure. Our results also reveal a regulatory role of a subset of serine-arginine (SR)-rich proteins, including serine-arginine rich splicing factor 1 (SRSF1) and SRSF6, on utilization of the 5'SS leading to lamin A or progerin production and a modulation of this regulation in the presence of the c.1824C>T mutation is shown directly on HGPS patient cells. Mutant mice carrying the equivalent mutation in the LMNA gene (c.1827C>T) also accumulate progerin and phenocopy the main cellular alterations and clinical defects of HGPS patients. RNAi-induced depletion of SRSF1 in the HGPS-like mouse embryonic fibroblasts (MEFs) allowed progerin reduction and dysmorphic nuclei phenotype correction, whereas SRSF6 depletion aggravated the HGPS-like MEF's phenotype. We demonstrate that changes in the splicing ratio between lamin A and progerin are key factors for lifespan since heterozygous mice harboring the mutation lived longer than homozygous littermates but less than the wild-type. Genetic and biochemical data together favor the view that physiological progerin production is under tight control of a conserved splicing mechanism to avoid precocious aging.     

Obstetric dilemma on the most appropriate management of Creutzfeldt–Jakob disease in pregnancy: seventh case presentation,literature review and new insight

Prion diseases (PDs) are fatal neurological disorders that are thought to be caused by the accumulation of an altered variant of a benign, widely expressed protein (PrPC) into a distinct pathological conformation(s) (PrPSc). The PDs are so rare but lethal pathologies that need an early diagnosis to adequately support the infected patient. A maternal–fetal transmission during pregnancy has been supposed to be on the basis of animal studies, but till now the effective vertical transmission in humans has not been proved. We present a case of infected pregnant woman with a peculiar pregnancy course and outcome. We also provided a systematic literature review to find the best obstetrical management of women affected by prionic disease during pregnancy.

The available data underline the potential risk of prenatal and postnatal transmission of the disease but do not permit to define the exact molecular mechanism of transmission, the best follow-up and recommendations that are useful in both obstetrical and neonatal practice.

At present awaiting for further clarifications about this topic, it is mandatory to personalize the management of this rare pregnancy complication according to the maternal–fetal well-being status.