Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

Characteristics of EEG power spectrum during sleep spindle events in ADHD children.

The attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder that interferes with the typical development and both learning and motor functioning in a child's life. Most of the children with ADHD present also sleep problems like difficulties in falling asleep and maintaining sleep. Sleep spindles are characteristic waves of sleep stage 2 in humans and are characterized by a fusiform morphology. In the last years, the empirical evidence indicates that spindles are associated with cognitive faculties and intelligence as well as with several disease states. On the other hand, power spectral analysis of EEG represents a powerful noninvasive tool for examining cerebral behavior. The aim of this study is to evaluate the differences between ADHD and healthy children of the power spectral values in delta, theta, alpha, beta and gamma bands, before, during and after sleep spindles. Our results show significant differences concentrated in the period immediately after spindle epochs, in the left hemisphere of the brain, in almost all bands, with greater values in control than in ADHD children.

A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation.

PMM2-CDG (PMM2 gene mutations) is the most common congenital disorder of N-glycosylation. We conducted a nationwide survey to characterize the frequency, clinical features, glycosylation and genetic correlates in Italian patients with PMM2-CDG. Clinical information was obtained through a questionnaire filled in by the referral physicians including demographics, neurological and systemic features, neuroimaging data and genotype. Glycosylation analyses of serum transferrin were complemented by MALDI-Mass Spectrometry (MALDI-MS). Between 1996 and 2012, data on 37 Italian patients with PMM2-CDG were collected. All the patients with a severe phenotype were unable to walk unaided, 84 % had severe intellectual disability and 81 % microcephaly. Conversely, among 17 mildly affected patients 82 % had independent ambulation, 64 % had borderline to mild intellectual disability and 35 % microcephaly. Epilepsy and stroke-like events did not occur among patients with the mild phenotype. The rate and extent of systemic involvement were more pronounced in severely affected patients. The L32R misfolding mutation of the PMM2 gene occurred in 70 % of the patients with the mild phenotype and was associated with a less severe underglycosylation of serum Tf at MALDI-MS analyses. Despite their different disease severity, all patients had progressive (olivo)ponto-cerebellar atrophy that was the hallmark clinical feature for the diagnosis. A mild neurological phenotype of PMM2-CDG marked by preserved ambulatory ability and autonomy and associated with L32R mutation is particularly frequent in Italy. PMM2-CDG should be considered in patients with even mild developmental disability and/or unexplained progressive cerebellar atrophy.

The Tolosa-Hunt syndrome in children: a case report.

Tolosa-Hunt syndrome (THS) is characterized by unilateral painful ophthalmoplegia with oculomotor paresis, associated with an idiopathic granulomatous inflammation involving the cavernous sinus, with a typical relapsing-remitting course. We report a case of an 8-year-old girl who was admitted because of an ophthalmoplegia with exotropia and ptosis of the left eyelid, accompanied by diplopia and left sovraorbital pain. The clinical data, neuroradiological findings and response to steroid treatment suggested THS, as defined by the 2004 International Classification of Headache Disorders (ICHD)-II criteria. THS must be considered a possible cause of painful ophthalmoplegia in childhood, as well as in adults, and confirmed with a focused neuroradiological investigation. The few paediatric cases described in the literature that meet the 2004 ICHD-II criteria are not sufficient to identify possible differences between the paediatric and the adult forms. Every new paediatric case should therefore be reported in order to gather and compare further information.

Two novel cosegregating mutations in tRNAMet and COX III, in a patient with exercise intolerance and autoimmune polyendocrinopathy.

We report a 12-year-old patient with growth retardation, exercise intolerance, lactic acidosis (increasing after exercise) and autoimmune polyendocrinopathy type 2. Muscle biopsy shows abundant COX-negative fibers, subsarcolemmal mitochondrial aggregates and markedly reduced activities of all respiratory chain complexes. Genetic analysis identified two new cosegregating mutations in Met-tRNA (m.4415A>G) and Cox III (m.9922A>C), located in highly conserved regions of MtDNA. Both the mutations are heteroplasmics in multiple patients' tissues. Single-muscle fiber analysis showed significantly higher levels of both the mutations in COX-negative than in normal fibers. In addition, a possible link between the mitochondrial dysfunction and the autoimmune disease is suggested.

Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction.

BACKGROUND: Inherited mtDNA depletion syndromes (MDS) are a group of severe mitochondrial disorders resulting from defects in nucleus-encoded factors and often associated with severe or fatal liver failure. PATIENT: In this article, we describe the case of an 18-month-old patient with recurrent hypoketotic hypoglycaemia and fatal hepatic dysfunction with liver mtDNA depletion. METHODS: The assessment of mtDNA copy number was performed on leucocytes, liver and muscle biopsy by Quantitative Real Time PCR and total RNA from liver biopsy was used as a template to amplify the cDNA of the POLG1 gene. RESULTS: Sequence analysis identified two previously undescribed mutations (1868T>G and 2263A>G) located in the gene coding the catalytic subunit of mitochondrial DNA polymerase gamma (POLG), predicting an L623W and K755E amino acid change, respectively. Both mutations were located in the highly conserved linker region of the protein and were absent in more than 200 healthy unrelated control subjects. The identification of these two mutations allowed us to perform genetic counselling and prenatal diagnosis. CONCLUSION: Our data further expand the spectrum of POLG1 gene mutations and the unique phenotype reported (late onset isolated liver disease without lactic acidosis) increase the variability of clinical presentations associated with mutations in this gene.

Comorbidity of DCD and SLI: Significance of epileptiform activity during sleep.

BACKGROUND: In children affected by specific language impairment (SLI), many authors have investigated a link between language and epileptiform discharges during sleep resembling the focal sharp waves typical of benign epilepsy with centro-temporal spikes (BECTS), the so-called rolandic spikes. On the other hand, the same electroencephalographic trait occurs in more than 50% of children affected by learning or behavioural disabilities without seizures, supporting the hypothesis of a common genetic disposition. The biological background of Developmental Coordination Disorder (DCD) is currently unknown, but a genetic liability may be assumed. The aims of our study were first to estimate the prevalence of sleep-related epileptiform discharges in children affected by DCD and second to investigate the occurrence of DCD in a population of children affected by BECTS. METHODS: We selected a group of eight children with severe DCD. In this group, the presence of epileptiform activity was investigated. We also searched for DCD among a group of 13 children affected by BECTS. RESULTS: We found rolandic spikes in more than 70% of the children with severe DCD and severe DCD in more than 30% of the children with BECTS. CONCLUSIONS: In children with severe DCD other disabilities are frequently associated. In these children, epileptiform activity during sleep is very frequently found and in our opinion, this represents a hallmark of 'Hereditary Impairment of Brain Maturation', a term only partially resembling 'Atypical Brain Development'.

Gaucher's disease with Parkinson's disease: clinical and pathological aspects.

The association between type 1 Gaucher disease and PD has been reported in the literature. The clinical picture is characterized by the predominance of bilateral akinetic-rigid signs and poor response to levodopa therapy. The authors describe four patients (two siblings) with type 1 Gaucher disease presenting with the following signs of typical PD: asymmetric onset of rigidity, resting tremor, bradykinesia, and a favorable response to Parkinson therapies.

Endozepine stupor in children.

Recurring episodes of stupor in adults have been shown to be related to increased levels of endozepines, which are endogenous ligands for the GABAA receptors. We report here two children presenting with recurrent episodes of stupor associated with fast EEG activity who had increased levels of endozepine-4 in plasma. Mass spectroscopy did not reveal commercially available benzodiazepines. Interictal endozepine-4 levels were normal. In one of the patients, administration of flumazenil (0.25 mg i.v.), a benzodiazepine inverse agonist, induced improvement of consciousness and attenuation of EEG fast activity. In conclusion, children presenting with recurrent episodes of stupor and EEG fast activity should be evaluated for endozepine levels and can be effectively treated with i.v. flumazenil.

Use of the fractal dimension for the analysis of electroencephalographic time series.

Electroencephalogram (EEG) traces corresponding to different physiopathological conditions can be characterized by their fractal dimension, which is a measure of the signal complexity. Generally this dimension is evaluated in the phase space by means of the attractor dimension or other correlated parameters. Nevertheless, to obtain reliable values, long duration intervals are needed and consequently only long-term events can be analysed; also much calculation time is required. To analyse events of brief duration in real-time mode and to apply the results obtained directly in the time domain, thus providing an easier interpretation of fractal dimension behaviour, in this work we optimize and propose a new method for evaluating the fractal dimension. Moreover, we study the robustness of this evaluation in the presence of white or line noises and compare the results with those obtained with conventional spectral methods. The non-linear analysis carried out allows us to investigate relevant EEG events shorter than those detectable by means of other linear and non-linear techniques, thus achieving a better temporal resolution. An interesting link between the spectral distribution and the fractal dimension value is also pointed out.

Enzyme replacement treatment in type 1 and type 3 Gaucher's disease.

The development of intravenous enzyme-replacement treatment for Gaucher's disease has changed life expectancy in cases without neurological involvement (type 1). The effects in patients with neurological involvement are unknown. We treated 12 Italian patients, types 1 (9) and 3 (3), with intravenous alglucerase: 70-120 IU/kg per month for type 3 and 30-60 IU/kg per month for type 1. Maintenance infusions were biweekly in patients without neurological symptoms, whereas in one symptomatic type 3 patient, infusion was weekly. All patients improved; a resumption of growth in children with growth retardation was observed and spleen and liver reduced in size. In one type 3 patient, a bone callus formed during treatment and enabled the patient to walk. Laboratory tests showed rapid increase of haemoglobin in anaemic patients, and a slower response in patients with thrombocytopaenia. In 4 patients there was temporary hypocalcaemia immediately after the beginning of treatment. Neurological symptoms were present in 1 of the type 3 patients, and electroencephalogram was abnormal in another. After 2 years of treatment, the patient with symptoms showed an improvement of psychomotor skills and of IQ from 50 to 60. Genotype analysis showed a high frequency of the 1448C mutation (54.5%). The 9 patients carrying this allele came from Italian regions which in the past had been invaded from north Europe and Scandinavia. Enzyme replacement in Gaucher's type 1 can also be effective at low doses and even with a 2-week interval between infusions. This makes treatment cheaper, and reduces hospital stay for patients.

Mutagenicity test of extracts of airborne dust from the municipal incinerator of Trieste.

The composition of the effluents from incineration plants has been studied by several authors, and some chemical compounds have been identified as hazardous to the health of the people living in the environs of such plants. On the other hand, very little is known about the chemical risks for the people working inside the incineration plants. In the present paper, an evaluation of these risks has been attempted by testing for the mutagenic activity of the extracts of airborne particulates collected inside the working area of the Municipal Incinerator of Trieste. Most samples of dust were proved to be mutagenic by the Ames test, indicating that the environment is heavily polluted with incompletely burnt materials. In fact, when a sample of settled dust was heated at high temperatures, its mutagenic activity disappeared. In addition, samples of solid residues collected at the end of the combustion process showed only weak, if any, mutagenic response.