Early onset demyelinating Charcot‐Marie‐Tooth disease caused by a novel in‐frame isoleucine deletion in peripheral myelin protein 2

Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot‐Marie‐Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in‐frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT‐associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic‐addressing additional features.     

Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis

Journal of Neurology - TK2 deficiency (TK2d) is a rare mitochondrial disorder that manifests predominantly as a progressive myopathy with a broad spectrum of severity and age of onset. The rate of...     

Onconeural antibodies: improved detection and clinical correlations

Onconeural antibodies are found in many patients with paraneoplastic neurological syndromes (PNS) and define the disease as paraneoplastic. The study describes the presence of onconeural antibodies and PNS in 555 patients with neurological symptoms and confirmed cancer within five years, and compares the diagnostic accuracy of different antibody assays (immunoprecipitation, immunofluorescence and immunoblot). Onconeural antibodies were found in 11.9% of the patients by immunoprecipitation, in 7.0% by immunofluorescence and in 6.3% by immunoblot. PNS were present in 81.8% of the cancer patients that were seropositive by immunoprecipitation. Immunofluorescence and immunoblot failed to detect onconeural antibodies in almost one third of the PNS cases.     

Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis

Synaptic dysfunction triggers neuronal damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). While excessive glutamate signaling has been reported in the striatum of EAE, it is still uncertain whether GABA synapses are altered. Electrophysiological recordings showed a reduction of spontaneous GABAergic synaptic currents (sIPSCs) recorded from striatal projection neurons of mice with MOG_(35−55)-induced EAE. GABAergic sIPSC deficits started in the acute phase of the disease (20-25 days post immunization, dpi), and were exacerbated at later time-points (35, 50, 70 and 90 dpi). Of note, in slices they were independent of microglial activation and of release of TNF-α. Indeed, sIPSC inhibition likely involved synaptic inputs arising from GABAergic interneurons, because EAE preferentially reduced sIPSCs of high amplitude, and was associated with a selective loss of striatal parvalbumin (PV)-positive GABAergic interneurons, which contact striatal projection neurons in their somatic region, giving rise to more efficient synaptic inhibition. Furthermore, we found also that the chronic persistence of pro-inflammatory cytokines were able, per se, to produce profound alterations of electrophysiological network properties, that were reverted by GABA administration.The results of the present investigation indicate defective GABA transmission in MS models depending from alteration of PV cells number and, in part, deriving from the effects of a chronic inflammation, and suggest that pharmacological agents potentiating GABA signaling might be considered to limit neuronal damage in MS patients.     

Static and pulsatile intracranial pressure in idiopathic intracranial hypertension

Objective

The aim of this observational study was to characterize the static and pulsatile intracranial pressure (ICP) in conservatively (medically) treated idiopathic intracranial hypertension (IIH) patients in need of shunt surgery, and also in patients with chronic daily headache (CDH) without visual disturbances.

Methods

The material includes 14 IIH patients and 7 CDH patients in whom ICP was monitored continuously over-night. Static ICP was characterized by mean ICP, pulsatile ICP was characterized by the wave amplitude, rise time, and rise time coefficient.

Results

In the IIH group all 14 had headache and visual disturbances. Mean ICP was high (>15 mmHg) in only 7 patients (50%), while mean ICP wave amplitude was high (≥4 mmHg) in all 14 (100%). All IIH patients were shunted and improved clinically thereafter (i.e., relief from visual disturbances and/or headache). None in the CDH group had high mean ICP or mean ICP wave amplitude, and none were shunted.

Conclusions

In this cohort of 14 conservatively treated IIH patients with lasting and shunt-responsive headache and visual disturbances, the mean ICP wave amplitude was elevated (≥4 mmHg) in all patients despite normal mean ICP (<15 mmHg) in 7 patients (all but one on medication). Therefore, the pulsatile ICP may be more relevant than the static ICP in the diagnostic setting for patients with IIH. Further prospective standardized approaches are warranted.     

A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family

We report the clinical, electrophysiological, and skin biopsy findings of an Italian Charcot-Marie-Tooth disease type 2 (CMT2) family with a novel heterozygous GDAP1 mutation. We observed a marked intra-familial phenotypic variability, in age at onset and disease severity which ranged from a typical CMT phenotype to an asymptomatic status. Electrophysiological study, consistent with an axonal sensory-motor neuropathy, confirmed a different degree of severity and disclosed minimal electrophysiological abnormalities also in the asymptomatic subjects. Skin biopsy findings showed a variable loss of large and small somatic nerve fibers. Molecular analysis identified a novel heterozygous missense mutation (Arg120Gly) in the GDAP1 gene which co-segregated with the disease within the pedigree. In conclusion, our findings confirm that the GDAP1 autosomal dominant mutations underlie a pronounced phenotypic variability, mimicking the effects of reduced penetrance. Notably, electrophysiological study in this family allowed to reveal hidden positive family history and assess a dominant inheritance pattern, revealing subclinical neuropathy in asymptomatic mutation carriers.     

In silico prediction and ex vivo evaluation of potential T-cell epitopes in glycoproteins 4 and 5 and nucleocapsid protein of genotype-I (European) of porcine reproductive and respiratory syndrome virus

T-cell epitopes of porcine reproductive and respiratory syndrome virus (PRRSV) glycoproteins 4 (GP4), 5 (GP5) and nucleocapsid (N) were predicted using bioinformatics and later tested by IFN-γ ELISPOT in pigs immunized with either a modified live vaccine (MLV) or DNA (open reading frames 4, 5 or 7). For MLV-vaccinated pigs, immunodominant epitopes were found in N but T-epitopes were also found in GP4 and GP5. For DNA-immunized pigs, some peptides were differently recognized. Using a large set of PRRSV sequences it was shown that N contains a conserved epitope and that for GP5, the genotype-I counterparts of previously reported epitopes of genotype-II strains were also immunogenic.     

Psychosomatic correlates of coronary heart disease during the socio-economic crisis of post-communist Bulgaria

Post-communist Bulgaria has experienced the full impact of a socioeconomic disaster. Under prolonged and powerful stress the human body may exhaust its adaptive potential and a variety of pathophysiological symptoms may occur. The cardiovascular system is most vulnerable to stress. The aim of this study is to analyze the role of psychological factors correlating with Acute Myocardial Infarction (AMI) during the transition period in post-communist Bulgaria. A case-control epidemiological study was performed. 306 cases of acute myocardial infarction (AMI) and 210 controls were studied. Analysis of patients’ records was made and a direct face-to-face interview was carried out. The study covers a 15-year transition period lasting from 1989 until 2005. The interview questions are based on W. Zung’s standardized self-evaluation tests of anxiety and depression (Self Rating Depression Scale — SDS, 1965, SAS-Self Rating Anxiety Scale, 1976) and on a test of aggression, as a part of the Minnesota Multiphase personality inventory, adapted from A.A. Krilov and F. Korozi’s FPI test. Average levels of anxiety and depression appear to be higher among patients suffering from coronary heart diseases than in control group members. Levels of aggression do not show a direct correlation with coronary heart disease. Both groups demonstrate symptoms of psychological disturbances caused, most probably, by the socio-economic instability of the transition period. In conclusion, certain socioeconomic factors significantly increase the level of anxiety and depression in the respondents. The AMI patients are considerably more anxious and depressed than the controls. The results provide evidence that high levels of anxiety and depression may correlate to and be interpreted as a potential risk factor for coronary heart disease.