Whole-exome sequencing of the mummified remains of Cangrande della Scala (1291-1329 CE) indicates the first known case of late-onset Pompe disease.

Mummified remains of relevant historical figures are nowadays an important source of information to retrace data concerning their private life and health, especially when historical archives are not available. Next-generation-sequencing was proved to be a valuable tool to unravel the characteristics of these individuals through their genetic heritage. Using the strictest criteria currently available for the validation of ancient DNA sequences, whole-genome and whole-exome sequencing were generated from the mummy remains of an Italian nobleman died almost 700 years ago, Cangrande della Scala.

Characterization of Repeat Expansion and Intragenic Variants by Indirect Sequence Capture.

Traditional methods for the analysis of repeat expansions, which underlie genetic disorders, such as fragile X syndrome (FXS), lack single-nucleotide resolution in repeat analysis and the ability to characterize causative variants outside the repeat array. These drawbacks can be overcome by long-read and short-read sequencing, respectively. However, the routine application of next-generation sequencing in the clinic requires target enrichment, and none of the available methods allows parallel analysis of long-DNA fragments using both sequencing technologies.

Oxidative stress biomarkers in Fabry disease: is there a room for them?

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder, caused by deficient activity of the alpha-galactosidase A enzyme leading to progressive and multisystemic accumulation of globotriaosylceramide. Recent data point toward oxidative stress signalling which could play an important role in both pathophysiology and disease progression.

Methods: We have examined oxidative stress biomarkers [Advanced Oxidation Protein Products (AOPP), Ferric Reducing Antioxidant Power (FRAP), thiolic groups] in blood samples from 60 patients and 77 healthy controls.

Pre-diagnosing and managing patients with GM1 gangliosidosis and related disorders by the evaluation of GM1 ganglioside content.

GM1 ganglioside, a monosialic glycosphingolipid and a crucial component of plasma membranes, accumulates in lysosomal storage disorders, primarily in GM1 gangliosidosis. The development of biomarkers for simplifying diagnosis, monitoring disease progression and evaluating drug therapies is an important objective in research into neurodegenerative lysosomal disorders. With this in mind, we established fluorescent imaging and flow-cytometric methods to track changes in GM1 ganglioside levels in patients with GM1 gangliosidosis and in control cells.

FAbry STabilization indEX (FASTEX): an innovative tool for the assessment of clinical stabilization in Fabry disease.

Two disease severity scoring systems, the Mainz Severity Score Index (MSSI) and Fabry Disease Severity Scoring System (DS3), have been validated for quantifying the disease burden of Fabry disease. We aimed to develop a dynamic mathematical model [the FASTEX (FAbry STabilization indEX)] to assess the clinical stability. A multidisciplinary panel of experts in Fabry disease first defined a novel score of severity [raw score (RS)] based on three domains with a small number items in each domain (nervous system domain: pain, cerebrovascular events; renal domain: proteinuria, glomerular filtration rate; cardiac domain: echocardiography parameters, electrocardiograph parameters and New York Heart Association class) and evaluated the clinical stability over time.

Mitochondrial DNA haplogroups may influence Fabry disease phenotype.

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls.

Aortic and Mitral Valve Involvement in Maroteaux-Lamy Syndrome VI: Surgical Implications in the Enzyme Replacement Therapy Era.

Open-heart operations in patients with mucopolysaccharidoses are exceedingly rare and pose distinct clinical challenges. Few reports exist of valve replacement in type VI mucopolysaccharidosis, mostly entailing combined mitral and aortic valve replacement. Here reported is the case of a young woman with mitral and aortic valve disease, in whom the surgical procedure was confined to the aortic valve.

Functional variations modulating PRKCA expression and alternative splicing predispose to multiple sclerosis.

The protein kinase C alpha (PRKCA) gene, encoding a Th17-cell-selective kinase, was repeatedly associated with multiple sclerosis (MS), but the underlying pathogenic mechanism remains unknown. We replicated the association in Italians (409 cases, 723 controls), identifying a protective signal in the PRKCA promoter (P = 0.033), and a risk haplotype in intron 3 (P = 7.

Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up.

An adult with Sandhoff disease presented with pure lower motor neuron phenotype. Twenty years later, he showed signs of upper motor neuron involvement. 25 years from the onset, his muscle weakness slightly worsened but he was fully independent in activities of daily living.

Anti-N-methyl-d-aspartate receptor encephalitis causing a prolonged depressive disorder evolving to inflammatory brain disease.

Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rapidly evolving condition that combines psychiatric and neurologic manifestations. Much remains unclear about its clinical onset and subsequent course. Although successful treatment depends on diagnosing the disorder early and therefore minimizing long-term complications, this is a difficult task owing to the atypical onset of this condition and the prolonged clinical course that has been observed in some patients.

No evidence for a role of rare CYP27B1 functional variations in multiple sclerosis.

Association studies have implicated common variants in the 12q14.1 region containing CYP27B1 in multiple sclerosis (MS). Rare CYP27B1 mutations cause autosomal recessive vitamin D-dependent rickets type 1, and it has recently been reported that heterozygous CYP27B1 mutations are associated with increased MS susceptibility and lower active vitamin D levels.

Prevalence of multiple sclerosis in Verona, Italy: an epidemiological and genetic study.

Background And Purpose: Recent multiple sclerosis (MS) prevalence studies classify Italy as a high-risk area without intra-regional latitude effect.

Objectives: To determine MS prevalence in Verona, Italy, and frequency of myelin oligodendrocyte glycoprotein (MOG) gene G511C polymorphism and HLA-DRB1*15 locus in a sample of cases and healthy controls.

Methods: The study area population on the prevalence date (31 December 2001) was 253208 (133508 women, 119700 men).

Genetic association and altered gene expression of mir-155 in multiple sclerosis patients.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance. In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology.

GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings.

GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature.

Nervous system and Fabry disease, from symptoms to diagnosis: damage evaluation and follow-up in adult patients, enzyme replacement, and support therapy.

The X-linked genetic Fabry disease causes multiorgan lesions due to intracellular storage of the substrate globotriaosylceramide. Neurological involvement ranges from painful, small fiber neuropathy to cerebrovascular disorders to multifocal aggressive forms. Disease identification through proper differential diagnosis and timely assessment of organ damage should guide a careful treatment planning.

Unusual renal presentation of Fabry disease in a female patient.

Background: A 29-year-old white woman with a family history of Fabry disease was referred to a nephrology clinic with hypertension and nephropathy. Her renal function was below normal (serum creatinine level 141 micromol/l; estimated glomerular filtration rate 41 ml/min/1.73 m2) with no proteinuria or albuminuria.

A case of Fabry disease with central nervous system (CNS) demyelinating lesions: a double trouble?

We present the case of a 36-year-old woman affected with Fabry disease (FD), with neuroradiologic and laboratory tests suggestive of a coexistent inflammatory demyelinating disease. Since the age of 23, she presented recurrent neurologic deficits, such as right limb paresthesias, diplopia, and right leg weakness. Magnetic resonance imaging revealed multiple demyelinating lesions in periventricular areas, corpus callosum, and spinal cord.

COX-2 promoter region polymorphisms in multiple sclerosis: lack of association of -765G>C with disease risk.

Cyclooxygenase-2 (COX-2) is extensively expressed in multiple sclerosis lesions suggesting that regulatory variants of the COX-2 gene could be implicated in multiple sclerosis (MS). Screening of the proximal 5' regulatory region and genotyping of -765G>C and -62C>G showed that polymorphisms in this COX-2 region are unlikely to be involved in MS susceptibility.

Could mitochondrial haplogroups play a role in sporadic amyotrophic lateral sclerosis?

Mitochondrial impairment has been implicated in the pathogenesis of the amyotrophic lateral sclerosis (ALS). Furthermore, mitochondrial-specific polymorphisms were previously related to other neurodegenerative diseases, such as Parkinson, Friedreich and Alzheimer disease. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of sporadic ALS (sALS), we have genotyped predefined European mtDNA haplogroups in 222 Italian patients with sALS and 151 matched controls.

Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene.

Metachromatic leukodystrophy (MLD) rarely has its clinical onset in young adults, with a combination of cognitive and behavioural symptoms and peripheral neuropathy. Here we present an exceptional case with very late onset at 42 years of age and no clinical or neurophysiological sign of peripheral neuropathy. Molecular analysis revealed compound heterozygosity for two novel missense mutations affecting conserved residues in the arylsulphatase A (ASA) sulphatase and carboxyterminal domains, resulting in an 89% loss of enzymatic activity.

Neuropathology of cognitively normal elderly.

Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years).