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Background and aims Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. Methods Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. Results LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. Conclusions This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene. © 2017

Autosomal recessive spastic paraplegia with thinning of corpus callosum (ARHSP-TCC) is a complex form of HSP initially described in Japan but subsequently reported to have a worldwide distribution with a particular high frequency in multiple families from the Mediterranean basin. We recently showed that ARHSP-TCC is commonly associated with mutations in SPG11/KIAA1840 on chromosome 15q. We have now screened a collection of new patients mainly originating from Italy and Brazil, in order to further ascertain the spectrum of mutations in SPG11, enlarge the ethnic origin of SPG11 patients, determine the relative frequency at the level of single Countries (i.e., Italy), and establish whether there is one or more common mutation. In 25 index cases we identified 32 mutations; 22 are novel, including 9 nonsense, 3 small deletions, 4 insertions, 1 in/del, 1 small duplication, 1 missense, 2 splice-site, and for the first time a large genomic rearrangement. This brings the total number of SPG11 mutated patients in the SPATAX collection to 111 cases in 44 families and in 17 isolated cases, from 16 Countries, all assessed using homogeneous clinical criteria. While expanding the spectrum of mutations in SPG11, this larger series also corroborated the notion that even within apparently homogeneous population a molecular diagnosis cannot be achieved without full gene sequencing.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat. METHODS: The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if

Gaucher disease (GD) is caused by an enzyme deficiency that leads to the accumulation of glycolipids in various organs. Although the signs and symptoms of GD emerge in childhood in the majority of patients, the disease often remains unrecognized for many years with delay of benefits of therapy or development of irreversible complications. Based on published data and data from the International Collaborative Gaucher Group Registry, an algorithm has been drafted for early diagnosis of GD in pediatric patients. It will help hematologists in promoting a timely diagnosis and early access to therapy for pediatric patients with GD.

Intellectual disability (ID) is frequently due to the synergic action of environmental and genetic factors. Here we describe the particular case of three Gipsy Italian siblings, fifteen, twelve and eleven years old, with ID. Genetic analysis stated that the parents are not consanguineous, and no human leukocyte antigen (HLA) alleles related to autism and/or other neurological disorders are present in the 3 ID patients. Instead, a positive association of ID with brain derived neurotrophic factor (BDNF) (Val66Met and C270T), IL6 (-174) and interleukin 1receptor antagonist (IL1RA) mspa 11100 polymorphisms was demonstrated in these three ID patients. Moreover, serum levels of interleukin 1beta (IL1?), interleukin 6 (IL6) were significantly different between the three patients and controls.

The authors sought to define the prevalence of Fabry disease and to establish the incidence and its natural history in Italy. The aim of this study was to point out the first clinical signs and symptoms to perform an early diagnosis and hence to start a specific therapeutic treatment. Fabry disease is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme alpha-galactosidase A. Fabry disease is a severe X-linked disorder presenting with a higher morbidity between the third and the fourth decade of life. Fabry disease may be confused with other diseases or completely misdiagnosed: its frequency is estimated worldwide to be 1:117000. In Italy, 65 patients have been identified by several specialized institutions; age, sex, onset of first clinical signs and symptoms were analyzed and reported. In conclusion, this is the first Italian collaborative study that allows to delineate and point out the clinical signs of Fabry disease to perform a correct and early diagnosis. Enzyme replacement therapy is now available and its early beginning can prevent renal and cardiac failure, improve the quality of life and life expectancy in these patients.

This deliverable (D1.2) describes the work carried out in the Task 1.2 Integration of Robotic Components and WSAN. In particular, T1.2 concerns the integration of previously existing robotic devices and software components to satisfy the requirements posed by Task 1.1, which involves the generic integration of pre-existing robotic com- munication tools (Part of the PEIS-ROS bridge) and the integration of specific PEIS Ecology functionalities to non-PEIS side of Communication Layer. This latter task includes the routing between islands and the access to non-WSN sensors inside WSN network.

OBJECTIVE AND IMPORTANCE: Sinus histiocytosis or Rosai-Dorfman disease (RDD) is a rare but well-recognized disorder characterized by an unusual proliferation of histiocytic cells. Intracranial localization is a rare manifestation of RDD. Only three cases of localization in the posterior fossa have been reported in the literature. The present report describes the first case, to our knowledge, of cerebellar localization of RDD. CLINICAL PRESENTATION: A 67-year-old woman was admitted to our institution with a 5-month history of cerebellar ataxia. Her medical history was unremarkable. The patient was alert and cooperative. No cranial nerve deficits were evident; Romberg positivity to the left side was recorded. No cutaneous abnormalities, lymphadenopathy, or hepatosplenomegaly were revealed by physical examination. Routine hematological and biochemical studies were normal except for the erythrocyte sedimentation rate, which was elevated. Radiologically, the lesion appeared as a well-defined and avascular mass in the right cerebellar lobe. Meningioma was considered the most likely diagnosis. TECHNIQUE: The patient underwent a suboccipital craniotomy with complete excision of the lesion. Microscopic examination of the operative specimen revealed the presence of a mixed cellular population with predominant mature histiocytes. A peculiar feature was the presence of lymphocytes and monocytes within the cytoplasm of histiocytes (emperipolesis). Immunohistochemical study of the histiocytes revealed strong positivity for S-100, CD-68 antigen, and vimentin. CONCLUSION: Involvement of the central nervous system in RDD appears to have a benign prognosis, especially in the absence of nodal diseases. Surgery is essential for diagnosis, and, when total removal is achieved, the outcome is generally good without risk of recurrence.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE. © 2009 The American Society of Human Genetics.

Background. The nature and the cell of origin of lesions variously described as inflammatory pseudotumour (IP), pseudosarcomatous proliferation or inflammatory myofibroblastic tumour (IMT) are still debated. Most cases behave as benign, reactive lesions, but rarely may have an aggressive course. We analysed the clinicopathological and molecular features of a series of IMTs of the respiratory tract, with the aim to verify if they represent a single entity or a heterogeneous group of lesions. Methods. Histological features of thirty-eight cases diagnosed as IMT or IP in various Institutions were reviewed. Immunohistochemistry was performed for the following antibodies: CAM 5.2, MNF116, CD34, CD21, CD35, betacatenin, CD68, HHV8 and 6, smooth muscle actin, desmin, ALK, ki67, IgG4. Molecular investigations included in situ hybridization for EBV and DNA sequencing for c-kit, cmet, EGFR, PDGFR alpha and beta. Results. Histologically, tumours were subdivided in two groups: type A (8 cases) included lesions with a predominance of inflammatory cells and no prominent spindle cell proliferation; type B (27 cases) included lesions composed of uniform proliferation of spindled cells, sometimes with myxoid features. Three cases had borderline features between type A and B and were classified as “type AB”. All cases were negative for cytokeratins, HHV8, HHV6 and CD21 and beta-catenin. Cases from all subtypes were variously positive with muscular markers, CD34, CD68 and IgG4. ALK antibody stained only 4 cases of B type. No cases showed mutations in the genes studied.Conclusions. Under the designation of IMT or IP are actually included different lesions. In the present series, we identify histologically two main groups: one which represents more likely true myofibroblastic tumoral proliferations, and a group which is represented by non-tumoural, reactive lesions. At moment, however, it appears that there are no immunohistochemical or molecular markers to distinguish the two types of lesions.

Glycogen storage disease type II has a broad continuous clinical spectrum in terms of onset, involvement of organs and life expectancy. Infantile onset is the most severe form, presenting with prominent cardiomyopathy, hypotonia, hepatomegaly and death before 12 months of life. Late onset form has onset at any age, lack of severe (or absence of) cardiac involvement, progressive skeletal muscle dysfunction and less dismal short-term prognosis. In addition to muscle and heart involvement, other tissues are affected liver, spleen, endothelium, lung, brain, anterior horns, peripheral nerves. In fact some patients with infantile form have hearing loss, abnormal brain myelination and central fever and some adult patients show aneurysms of brain arteries due to accumulation of glycogen in vessels. As for other treatable lysosomal diseases, the advent of enzyme replacement therapy will change the natural history of this disease and also will increase our knowledge concerning clinical heterogeneity.