Late-onset Krabbe disease may have variable misleading clinical manifestations and be a puzzling problem for physicians. We report clinical and peripheral nerve studies of three patients with adult-onset Krabbe disease. Two cases had a predominantly spastic paraparesis; in one case, the symptoms mimicked a cerebrovascular disorder. Predominantly, demyelinating neuropathy was observed in one case and axonal neuropathy in two cases. In all cases, no typical intracytoplasmic inclusions were found. These observations suggest that peripheral neuropathy in adult-onset Krabbe disease has variable clinical and pathological characteristics, different from those described in the classic form.

Congenital myopathies are a heterogeneous group of disorders characterized by muscle weakness and typical histopathological changes at muscle biopsy. In spite of recent advances on molecular genetics, their classification is still based on morphological criteria. Phenotypical and genetic heterogeneicity are common findings. The clinical symptoms usually appear in infancy, but adult-onset cases have been described. In this review, we focus on the current knowledges on congenital myopathies and we report our experience on adult-onset cases.

Clinical GeneticsVolume 71, Issue 1 p. 93-94 Inheritance of a novel RYR1 mutation in a family with myotonic dystrophy type 1 S Gambelli, Corresponding Author S Gambelli Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySimona Gambelli, MDUnit of Neurometabolic DiseasesDepartment of Neurological and Behavioural SciencesUniversity of SienaViale Bracci, 253100 SienaItalyTel.: +39 0577 233474Fax: +39 0577 40327e-mail: [email protected]Search for more papers by this authorA Malandrini, A Malandrini Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorG Berti, G Berti Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorC Gaudiano, C Gaudiano Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorE Zicari, E Zicari Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorP Brunori, P Brunori Unit of Neurophysiopatology, Silvestrini Hospital, Perugia, ItalySearch for more papers by this authorG Perticoni, G Perticoni Unit of Neurophysiopatology, Silvestrini Hospital, Perugia, ItalySearch for more papers by this authorA Orrico, A Orrico Unit of Molecular Medicine, Department of OncologySearch for more papers by this authorL Galli, L Galli Unit of Molecular Medicine, Department of OncologySearch for more papers by this authorV Sorrentino, V Sorrentino Unit of Molecular Medicine, Department of Oncology Section of Molecular Medicine, Department of Neuroscience, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorJ Lunardi, J Lunardi Laboratory of Genetic and Molecular Biochemistry, INSERM U607 and CHU-Grenoble, FranceSearch for more papers by this authorA Federico, A Federico Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorMT Dotti, MT Dotti Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this author S Gambelli, Corresponding Author S Gambelli Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySimona Gambelli, MDUnit of Neurometabolic DiseasesDepartment of Neurological and Behavioural SciencesUniversity of SienaViale Bracci, 253100 SienaItalyTel.: +39 0577 233474Fax: +39 0577 40327e-mail: [email protected]Search for more papers by this authorA Malandrini, A Malandrini Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorG Berti, G Berti Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorC Gaudiano, C Gaudiano Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorE Zicari, E Zicari Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorP Brunori, P Brunori Unit of Neurophysiopatology, Silvestrini Hospital, Perugia, ItalySearch for more papers by this authorG Perticoni, G Perticoni Unit of Neurophysiopatology, Silvestrini Hospital, Perugia, ItalySearch for more papers by this authorA Orrico, A Orrico Unit of Molecular Medicine, Department of OncologySearch for more papers by this authorL Galli, L Galli Unit of Molecular Medicine, Department of OncologySearch for more papers by this authorV Sorrentino, V Sorrentino Unit of Molecular Medicine, Department of Oncology Section of Molecular Medicine, Department of Neuroscience, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorJ Lunardi, J Lunardi Laboratory of Genetic and Molecular Biochemistry, INSERM U607 and CHU-Grenoble, FranceSearch for more papers by this authorA Federico, A Federico Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this authorMT Dotti, MT Dotti Unit of Neurometabolic Diseases, Department of Neurological and Behavioural Sciences, University of Siena, Siena, Tuscany, ItalySearch for more papers by this author First published: 28 November 2006 https://doi.org/10.1111/j.1399-0004.2006.00725.xCitations: 3Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Monnier N, Romero NB, Lerale J et al. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum Mol Genet 2001: 10: 2581–2592. 2 Shepherd S, Ellis F, Halsall J, Hopkins P, Robinson R. RYR1 mutations in UK central core disease patients: more than just the C-terminus transmembrane region of the RYR1 gene. J Med Genet 2004: 41 (3): e33. 3 Bruno C, Minetti C. Congenital myopathies. Current Neurol Neurosci Rep 2004: 4: 68–73. 4 Taratuto AL. Congenital myopathies and related disorders. Curr Opin Neurol 2002: 15 (5): 553–561. Citing Literature Volume71, Issue1January 2007Pages 93-94 ReferencesRelatedInformation

We report the case of a 64-year-old female patient with hepatitis C infection (HCV), who developed Sjögren's disease and sensory peripheral neuropathy. Clinical conditions worsened over three years with central nervous system involvement characterised by transient third cranial nerve paresis and mild selective impairment of attention and memory. Brain magnetic resonance imaging showed diffuse periventricular and lobar white matter hyperintensity. Laboratory findings included mixed cryoglobulinaemia (type II), cryocrit 1.47%, low serum levels of complement C4 and high levels of rheumatoid factor, HCV 1b genotype, high HCV mRNA levels in serum and cerebrospinal fluid. Skin biopsy showed evidence of vasculitis. After one year of plasmapheresis, immunosuppressant therapy and occasional corticosteroid treatment, neurological symptoms improved, skin biopsy changed and inflammation parameters normalised, suggesting that neurological symptoms might be related to the high levels of mixed cryoglobulins.

derstood, dysphagia had worsened, cognitive function had deteriorated and the patient was no longer self-sufficient. On hospitalization in our department at age 28 years, neurological examination showed severe mental retardation (IQ 48), ataxic gait, diffuse hypotonia and mild muscle hypotrophy, unintelligible speech and hypernasal voice, dysphagia, slight upward gaze palsy, strabismus, anisocoria with unreactive pupils, slight dysmetria, and hypoactive deep tendon reflexes. Routine blood chemistry, including CK, LDH, pyruvic and lactic acid, carnitine, vitamin E, and thyroid hormones, was normal. Electrocardiography showed partial right branch block. Echocardiography and chest x-ray were normal. Tilting test showed significantly reduced heart rate variability and very high vagal tonus. Brain MRI confirmed severe cerebellar atrophy ( fig. 1 A) and small areas of signal hyperintensity in the olivary nuclei. EMG showed myopathic alterations. Peripheral nerve conduction velocities were in the normal range. Two years later, the patient was readmitted to our department for recurrent episodes of severe constipation lasting 2–3 weeks. Neurological examination was substantially unchanged apart from absent deep tendon reflexes. Abdominal x-ray and intestinal transit studies showed marked slowing (96 h to reach sigma and 148 h to reach rectum). The patient was successfully treated with intravenous Dear Sir, The presence of rimmed vacuoles and intranuclear tubulofilamentous inclusions in muscle fibers is characteristic of disorders such as inclusion body myopathies (IBM) [1–3] , oculopharyngeal muscular dystrophy [4] and distal myopathies [5] . Autosomal recessive and dominant forms of the above syndromes, in which the central nervous system (CNS) is not usually involved, have been reported [1–3, 5] . Here we describe an apparently autosomal dominant syndrome of mental retardation, cerebellar atrophy and abnormal pupils, associated with muscle biopsy evidence of rimmed vacuoles and tubulofilamentous inclusions.

Mutations of the Cav-3 gene are associated with distinct, sometimes overlapping muscle disease phenotypes. We report a new Italian family with autosomal dominant rippling muscle disease. Immunocytochemical analysis of muscle showed a deficit of caveolin-3 protein and molecular genetic analysis showed a novel mutation of the Cav-3 gene.

Minifascicle neuropathy (MN) is a rare developmental malformation of the peripheral nerve characterized by many small fascicles.1 Two unrelated cases, in which the disorder was associated with 46XY pure gonadal dysgenesis (GD),1,2 have been reported. We report a 28-year-old woman with healthy unrelated parents. Two siblings of the father had walking difficulties, but they were not available for examination. Developmental milestones were normal. From age of 2 to 3 years, walking difficulty was noted. At 3 years, the patient was hospitalized and “hypotonic syndrome” was diagnosed. Symptoms were slowly progressive. At 28 years, neurologic examination suggested hereditary motor-sensory polyneuropathy (HMSN): difficulty in walking with bilateral stepping; weakness and hypotrophy of the distal muscles of the four limbs, especially tibialis anterior; reduced superficial sensation; more accentuated distally and absent deep tendon reflexes. EKG showed sinus bradycardia. Gynecological and pelvic ultrasound examinations were normal; sexual characteristics and 46XX caryotype were both normal. EMG showed neurogenic changes with denervation at rest (positive sharp waves …

Clinical and biopsy study of nine patients on statin therapy suffering from various myopathic syndromes is reported. Biopsy findings showed non specific myopathic signs and mitochondrial changes, such as subsarcolemmal accumulation, morphological alterations, lipid increase and Cox-negative fibers. These findings confirm that statins may cause muscle damage and impair oxidative metabolism.

We report the case of a 41-year-old patient with bilateral hemorrhage of the thalamus, leading to death. Post-mortem examination showed acute myocarditis. Neuropathological study showed perivascular infiltrates in affected thalamic regions. Laboratory investigation failed to find any causal agent. We hypothesize an infective agent, affecting the heart and thalamus, as the cause of this syndrome. Diaschisis due to the strategic anatomical position of the thalamus may have been responsible for coma state and death.

Neuropathological study of a 3K year old girl with familial Leigh syndrome who also harboured a rare ATPase gene mutation disclosed extensive and unusual lesions in the cerebral cortex, despite a typical histological pattern. Early lesions in the periacqueductal grey matter of the brainstem, characterised by capillary congestion and initial regressive neuronal changes, were also observed, along with TUNEL reactive neuronal cells showing morphological signs typical of apoptosis in cortical areas with neuronal cell loss. The finding of lesions in atypical brain areas and for the first time, very early regressive neuronal phenomena, suggest that early changes in crucial brain areas may have been a cause of death. The abundance of TUNEL positive nuclei in cortical areas in the present case suggests that the apoptosis may be involved in the mechanism of neuronal death in Leigh syndrome.

We report a family with a clinical diagnosis of oculopharyngeal muscular dystrophy in which muscle biopsy showed mitochondrial changes such as cytochrome-c-oxidase-negative fibers and aggregates of mitochondria containing paracrystalline inclusions. Molecular analysis demonstrated a GCG expansion in the poly(A)-binding protein 2 (PABP2) gene and failed to demonstrate multiple deletions of mtDNA. We hypothesize that mitochondrial abnormalities may be a secondary phenomenon. This observation may suggest that the PABP2 gene could interfere in the posttranscriptional regulation of genes involved in mitochondrial function.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset familial disease with prominent myelinated fibers in the optic fundus. ARSACS is frequent in the Charlevoix-Saguenay region of Quebec but rare elsewhere. Mutations in SACS, encoding sacsin, a protein of unknown function, are associated with ARSACS. The authors identified three new SACS mutations in two Italian patients whose phenotype closely matches that of Quebec cases, but without retinal striation.

We report the case of a 51-year-old woman with anosmia and chronic sensory ataxic neuropathy. Olfactory tests suggested neurosensory anosmia. Immunocytochemical analysis showed serum antibodies against dorsal root ganglion (DRG) cells and olfactory neurons, in the absence of other known causes of anosmia and sensory neuropathy. Clinical and laboratory data suggested a slow autoimmune process affecting dorsal root ganglion and olfactory cells.

Statins are chemical agents useful in preventing vascular cerebral and heart diseases. They are able to reduce the serum level of cholesterol via the inhibition of HMG-CoA enzyme, so, they interrupt the metabolic chain leading to cholesterol synthesis. Statins also improve the endothelial function and increase the production of nitroxide (NO) and other factors involved in neo-angiogenesis. Additional beneficial effects include anti-aggregation and anti-trombotic actions.In case of ischemic event, they have protective function reducing citokines production (inflammatory activity); furthermore, they can reduce the damage caused by free radicals (antioxidant activity).Statins may be used successfully in other CNS diseases such as Alzheimer and Parkinson, trauma and malignant tumors.This drugs may also have variable side effects consisting in liver toxicity and skeletal muscle damage ranging from slight myopathy to acute rabdomyolisis. The pathogenesis of these complications is still unclear; most authors hypothesize a derangement of the mitochondrial metabolism; a reduction of CoQ10 synthesis has been demonstrated.

Nemaline myopathy is a rare congenital muscle disease, with neonatal or adult onset. We report clinical and ultrastructural study of a 73-year-old woman whose symptoms manifested at age 40 years with proximal muscle weakness, nocturnal cramps, muscle pain and walking impairment. Muscle biopsy showed rods and other typical findings suggesting nemaline myopathy. This myopathy should be taken into account in the differential diagnosis of adult onset myopathies. Only ultrastructural examination allows an exact diagnosis.