M E Fruguglietti

Azienda Ospedaliera Niguarda Ca' Granda, Milano, Lombardy, Italy

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Publications (6)16.2 Total impact

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    ABSTRACT: Selenoprotein N-related myopathy (SEPN1-RM) is an early-onset muscle disorder that can manifest clinically as congenital muscular dystrophy with spinal rigidity and can result in specific pathological entities such as multiminicore disease, desmin-related myopathy with Mallory body-like inclusions, and congenital fiber-type disproportion. Here we describe the clinical, histopathological, muscle magnetic resonance imaging (MRI) and genetic findings of three Italian SEPN1-RM families. Proband 1 is a 31-year-old female who was floppy at birth and developed axial and mild lower limb-girdle weakness. The second proband is a 13-year-old boy with RSMD1. Probands 3 and 4 were brothers showing clinical phenotype of congenital myopathy. Muscle MRI demonstrated selective involvement of sartorius, gluteal muscles and distal gastrocnemius and sparing of rectus femoris and gracilis. Muscle histopathology showed in proband 1 myopathic changes with mild connective tissue increase and some fibres lacking the Z-line, while probands 2 and 3 had multiminicores. SEPN1 gene analysis revealed five mutations, three of which are novel. Proband 1 was a compound heterozygote for a 92-bp (exon 1) and a 1-bp deletion (exon 9); proband 2 had a 99-bp deletion and a 10-bp duplication in exon 1, and proband 3 presented a novel homozygous mutation in intron 10 acceptor splice site.
    Journal of the neurological sciences 10/2010; 300(1-2):107-13. · 2.32 Impact Factor
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    ABSTRACT: A 48-years old man was diagnosed an IgD-k multiple myeloma (MM) at age 38 years for which he successfully underwent chemotherapy and bone marrow transplant. He then developed a graft-versus-host disease (GVHD) whose manifestations included, three years later, a polymyositis, diagnosed at muscle biopsy and successfully treated with steroids. Few months after polymyositis remission, myeloma relapsed and the patient was treated with thalidomide for six years with good remission. Soon after thalidomide suspension, MM relapsed again and the patient came to our observation for a new onset of neuromuscular symptoms. He underwent both muscle and peripheral nerve biopsy to discriminate between myositis (paraproteinemia versus GVHD), amyloidosis, and thalidomide toxicity. The first muscle biopsy showed an inflammatory pattern with necrotic fibres, macrophagical invasion (CD68 positive), rare interstitial cellular infiltrates (CD8 positive and CD4 negative), widespread anti-HLA positivity and negative antiMAC. The second muscle biopsy showed the same inflammatory pattern plus an involvement of blood vessels. Direct immunofluorescence for IgD showed diffuse positivity along the sarcolemmal in both muscle biopsies. Sural nerve biopsy demonstrated both demyelinating and axonal aspects with no inflammatory infiltrates, but positivity for HLA and MAC. Congo Red was negative in both skeletal muscle and peripheral nerve.
    Neurology research international. 01/2010; 2010:808474.
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    ABSTRACT: Glycogen storage disease type IV (GSD IV, or Andersen disease) is an autosomal recessive disorder due to the deficiency of 1,4-alpha-glucan branching enzyme (or glycogen branching enzyme, GBE1), resulting in an accumulation of amylopectin-like polysaccharide in muscle, liver, heart and central and peripheral nervous system. Typically, the presentation is in childhood with liver involvement up to cirrhosis. The neuromuscular form varies in onset (congenital, perinatal, juvenile and adult) and in severity. Congenital cases are rare, and fewer than 20 cases have been described and genetically determined so far. This form is characterized by polyhydramnios, neonatal hypotonia, and neuronal involvement; hepatopathy is uncommon, and the babies usually die between 4 weeks and 4 months of age. We report the case of an infant who presented severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle haemorrhage, features consistent with the congenital form of GSD IV. He died at one month of life of cardiorespiratory failure. Muscle biopsy and heart and liver autoptic specimens showed many vacuoles filled with PAS-positive diastase-resistant materials. Electron-microscopic analysis showed mainly polyglucosan accumulations in all the tissues examined. Postmortem examination showed the presence of vacuolated neurons containing this abnormal polysaccharide. GBE1 biochemical activity was virtually absent in muscle and fibroblasts, and totally lacking in liver and heart as well as glycogen synthase activity. GBE1 gene sequence analysis revealed a novel homozygous nonsense mutation, p.E152X, in exon 4, correlating with the lack of enzyme activity and with the severe neonatal involvement. Our findings contribute to increasing the spectrum of mutation associated with congenital GSD IV.
    Journal of Inherited Metabolic Disease 05/2009; · 4.07 Impact Factor
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    ABSTRACT: Our objective was to investigate grey matter (GM) contraction in patients with amyotrophic lateral sclerosis (ALS) using tensor based morphometry (TBM). Using a 1.5 Tesla scanner, T1-weighted MRI scans were obtained at baseline and at follow-up (mean interval, 9 months) from 16 ALS and 10 controls. Standard TBM procedures in Statistical Parametric Mapping (SPM2) were used for image processing and statistical analyses. The frontotemporal cortex and basal ganglia were considered areas of interest, based on pathological studies. Eight patients showed rapid clinical progression of ALS during the follow-up period. Compared to controls, all ALS patients showed progression of GM atrophy in left premotor cortex and right basal ganglia. Patients with rapidly progressing ALS showed GM atrophy changes in a larger motor cortical-subcortical area and in extramotor frontal regions compared to both controls and to non-rapidly progressing cases. Thus, TBM detected longitudinal atrophy changes in the motor network in ALS occurring over less than one year. The faster the clinical progression, the greater was the GM loss in motor and prefrontal areas. Further advances in tracking longitudinal changes in cortical and subcortical regions in ALS may provide an objective marker for monitoring disease progression, and the disease-modifying effect of potential treatments.
    Amyotrophic Lateral Sclerosis 01/2009; 10(3):168-74. · 3.40 Impact Factor
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    ABSTRACT: The regeneration in the peripheral nervous system is often incomplete and the treatment of severe lesions with nerve tissue loss is primarily aimed at recreating nerve continuity. Guide tubes of various types, filled with Schwann cells, stem cells, or nerve growth factors are attractive as an alternative therapy to nerve grafts. In this study, we evaluated whether skin-derived stem cells (SDSCs) can improve peripheral nerve regeneration after transplantation into nerve guides. We compared peripheral nerve regeneration in adult rats with sciatic nerve gaps of 16 mm after autologous transplantation of GFP-labeled SDSCs into two different types of guides: a synthetic guide, obtained by dip coating with a L-lactide and trimethylene carbonate (PLA-TMC) copolymer and a collagen-based guide. The sciatic function index and the recovery rates of the compound muscle action potential were significantly higher in the animals that received SDSCs transplantation, in particular, into the collagen guide, compared to the control guides filled only with PBS. For these guides the morphological and immunohistochemical analysis demonstrated an increased number of myelinated axons expressing S100 and Neurofilament 70, suggesting the presence of regenerating nerve fibers along the gap. GFP positive cells were found around regenerating nerve fibers and few of them were positive for the expression of glial markers as S-100 and glial fibrillary acidic protein. RT-PCR analysis confirmed the expression of S100 and myelin basic protein in the animals treated with the collagen guide filled with SDSCs. These data support the hypothesis that SDSCs could represent a tool for future cell therapy applications in peripheral nerve regeneration.
    Glia 04/2007; 55(4):425-38. · 5.07 Impact Factor
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    ABSTRACT: We describe the clinicopathologic features of a 69-year-old man affected with acute onset Churg-Strauss syndrome with major peripheral nerve involvement. At admission the patient presented a one-week history of distal upper-limb asymmetrical paresthesias. Asthma had been present since the age of 55 and treated with leukotriene receptor antagonists (LTAs, Montelukast) for a few years. Multiple pulmonary infiltrates had been diagnosed during follow-up for melanoma. During hospitalization he showed rapidly progressive weakness worsening within a few hours; cerebrospinal fluid analysis, cervical MRI, head CT scan, nerve conduction studies and peripheral nerve and skeletal muscle biopsies were performed. Blood analysis showed leukocytosis and marked eosinophilia; p-ANCA were positive. Sural nerve biopsy showed a marked loss of myelinated fibers, thrombosed vessels surrounded by mononuclear and eosinophilic cells, necrotizing and hyaline degeneration. Eosinophilic infiltrates were shown in May-Grunwald-Giemsa stained sections. The eosinophils mostly occupied the outer zone of the adventitia at the margin of the active lesion. Perivascular cellular infiltrates within the epineurium were immunoreactive for T-lymphocytes and macrophages. Strong HLA-DR immunostaining was present in the perineurium and membrane attack complex deposition was present in a few endoneurial capillaries. Muscle biopsy showed neurogenic changes and one vessel surrounded by mononuclear cells. After a few days of corticosteroid therapy leukocytosis and eosinophilia normalized and the patient's clinical features stabilized.
    Clinical neuropathology 28(2):125-8. · 1.34 Impact Factor