Publications (104) View all
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Article: Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy.
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ABSTRACT: BACKGROUND: To review the descriptive epidemiological data on neuronal ceroid lipofuscinoses (NCLs) in Italy, identify the spectrum of mutations in the causative genes, and analyze possible genotype-phenotype relations. METHODS: A cohort of NCL patients was recruited through CLNet, a nationwide network of child neurology units. Diagnosis was based on clinical and pathological criteria following ultrastructural investigation of peripheral tissues. Molecular confirmation was obtained during the diagnostic procedure or, when possible, retrospectively. RESULTS: One hundred eighty-three NCL patients from 156 families were recruited between 1966 and 2010; 124 of these patients (from 88 families) were tested for known NCL genes, with 9.7% of the patients in this sample having not a genetic diagnosis. Late infantile onset NCL (LINCL) accounted for 75.8% of molecularly confirmed cases, the most frequent form being secondary to mutations in CLN2 (23.5%). Juvenile onset NCL patients accounted for 17.7% of this cohort, a smaller proportion than found in other European countries. Gene mutations predicted severe protein alterations in 65.5% of the CLN2 and 78.6% of the CLN7 cases. An incidence rate of 0.98/100,000 live births was found in 69 NCL patients born between 1992 and 2004, predicting 5 new cases a year. Prevalence was 1.2/1,000,000. CONCLUSIONS: Descriptive epidemiology data indicate a lower incidence of NCLs in Italy as compared to other European countries. A relatively high number of private mutations affecting all NCL genes might explain the genetic heterogeneity. Specific gene mutations were associated with severe clinical courses in selected NCL forms only.Orphanet Journal of Rare Diseases 02/2013; 8(1):19. · 5.83 Impact Factor -
Article: Axonal dystrophies.
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ABSTRACT: The Neuroaxonal Dystrophies (NADs) are a group of clinically and genetically heterogeneous neurodegenerative conditions. These disorders show the unique pathological feature of neuroaxonal dystrophy (NAD): axonal swelling (spheroids) localized throughout the central nervous and peripheral nervous systems. NADs are also morphologically characterized by iron accumulation in the basal ganglia; and are now included in the group of diseases called neurodegeneration with brain iron accumulation (NBIA). NADs comprise two main diseases: pantothenate-kinase associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy (INAD). PKAN in caused by mutation in the PANK-2 gene. In classic PKAN onset of disease is in the first decade and patients show dystonia, rigidity and dysarthria; course is progressive leading to loss of autonomous gait within 15 years. In atypical PKAN age at onset is later and progression slower. Psychiatric symptoms, obsessive-compulsive disorder, and tourettism may be prominent. In classic INAD patients present with psychomotor regression between 6 months-3 years, followed by neurological deterioration leading to tetraparesis, optic atrophy, and dementia. Atypical NAD refers to all patients who differ from the classical phenotype in term of age at onset and disease progression. Mutations in PLA2G6 gene are found both in classic and atypical INAD patients.Handbook of Clinical Neurology 01/2013; 113:1919-24. -
Article: Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA.
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ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.The American Journal of Human Genetics 11/2012; · 10.60 Impact Factor -
Article: Error-enhancing robot therapy to induce motor control improvement in childhood onset primary dystonia.
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ABSTRACT: BACKGROUND: Robot-generated deviating forces during multijoint reaching movements have been applied to investigate motor control and to tune neuromotor adaptation. Can the application of force to limbs improve motor learning? In this framework, the response to altered dynamic environments of children affected by primary dystonia has never been studied. METHODS: As preliminary pilot study, eleven children with primary dystonia and eleven age-matched healthy control subjects were asked to perform upper limb movements, triangle-reaching (three directions) and circle-writing, using a haptic robot interacting with ad-hoc developed task-specific visual interfaces. Three dynamic conditions were provided, null additive external force (A), constant disturbing force (B) and deactivation of the additive external force again (C). The path length for each trial was computed, from the recorded position data and interaction events. RESULTS: The results show that the disturbing force affects significantly the movement outcomes in healthy but not in dystonic subjects, already compromised in the reference condition: the external alteration uncalibrates the healthy sensorimotor system, while the dystonic one is already strongly uncalibrated. The lack of systematic compensation for perturbation effects during B condition is reflected into the absence of after-effects in C condition, which would be the evidence that CNS generated a prediction of the perturbing forces using an internal model of the environment. The most promising finding is that in dystonic population the altered dynamic exposure seems to induce a subsequent improvement, i.e. a beneficial aftereffect in terms of optimal path control, compared with the correspondent reference movement outcome. CONCLUSIONS: The short-time error-enhancing training in dystonia could represent an effective approach for motor performance improvement, since the exposure to controlled dynamic alterations induces a refining of the existing but strongly imprecise motor scheme and sensorimotor patterns.Journal of NeuroEngineering and Rehabilitation 07/2012; 9(1):46. · 3.26 Impact Factor -
Article: Therapeutic advances in neurodegeneration with brain iron accumulation.
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ABSTRACT: Neurodegeneration with brain iron accumulation (NBIA) includes a heterogeneous group of genetically defined disorders characterized by progressive extrapyramidal deterioration and iron accumulation in the basal ganglia. Current medical options for these disorders remain largely unsatisfactory and do not prevent the disease from progressing to a severe and disabling state. In select cases, surgical techniques, such as deep brain stimulation, may be effective in ameliorating some of the symptoms of the disease. The availability of chelating agents with specific properties that have been demonstrated to be effective in other disorders with regional iron accumulation as well as magnetic resonance imaging techniques that allow for quantitative assessment of iron have stimulated interest in the use of chelating agents in NBIA. This review aims to describe the role of surgical therapies in NBIA, discuss the use of chelating agents in NBIA, and presents new therapeutic approaches under consideration.Seminars in pediatric neurology 06/2012; 19(2):82-6.
