Gian Maria Fabrizi

Atypical McLeod syndrome manifested as X-linked chorea-acanthocytosis, neuromyopathy and dilated cardiomyopathy: report of a family

We report a family with three members affected by a typically X-linked McLeod syndrome. In the proband a very weak positivity for antigens of the Kell group was detected. His sister showed a normal antigenic pattern. We emphasize the prominent neurological picture characterized by a choreic syndrome with atrophy of the caudate nucleus on MRI, psychiatric disturbances, peripheral nerve and muscle biopsy findings indicating slight neuromuscular involvement, and cardiac abnormalities. The differential diagnosis is discussed.

Clinicopathological and genetic studies of two further Italian families with cerebral autosomal dominant arteriopathy

Abstract We report on two Italian families with an early-adult onset autosomal dominant disorder, characterized by leukoencephalopathy, migraine, psychiatric disturbances, stroke and dementia. These findings fulfill the diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) syndrome. Moreover, to confirm the CADASIL gene location to 19p12, we performed a linkage analysis with four microsatellite markers. The results of the genetic study gave positive but not significant lod scores, indicating only weak evidence of a linkage with 19p12. In one autopsy case, we found extensive ischemic changes due to the selective involvement of the small muscular arteries of the cerebral white matter. The lesions consisted of a thickening of the media with deposition of granular eosinophilic material. Ultrastructural examination of the arterial walls showed graded damage to smooth muscle cells, mostly of the longitudinal layer, and an abnormal proliferation of basal lamina components. Immunocytochemical analysis showed strong reactivity using antibodies to collagen IV and smooth myosin proteins. The results suggest a primary involvement of the smooth muscle cells of small cerebral arteries, with a secondary alteration of basal lamina components and elastic tissue.

Choreo-acanthocytosis like phenotype without acanthocytes: clinicopathological case report

Detailed clinical and neuropathological findings in two unrelated patients with a chorea-acanthocytosis-like phenotype (CA) are reported. One case met all the diagnostic criteria of CA and had a deceased brother with the same disease. The second case had a virtually identical phenotype to the former but without acanthocytes. These findings suggest that both patients are affected by the same disease and that acanthocytes are not essential to the diagnosis. Neuropathological autopsy studies on the brain of the second case showed selective atrophy of the caudate nucleus that seemed to correspond to the movement disorder and behavioural abnormalities prominent in this patient. In both subjects, morphometric and ultrastructural examination of the peripheral nerve showed loss of myelinated fibres, more accentuated distally, and cytoskeletal changes in the axoplasm. These findings support the hypothesis that peripheral neuropathy in CA is caused by distal axonopathy.

Ultrastructure and immunoreactivity of dystrophic axons indicate a different pathogenesis of Hallervorden-Spatz disease and infantile neuroaxonal dystrophy

An immunohistochemical and ultrastructural analysis of dystrophic axons (DAs) in the brain and peripheral nerve of a patient with familial infantile neuroaxonal dystrophy (INAD) and in the brain of a patient with familial Hallervorden-Spatz Disease (HSD) revealed prevalent membrano-tubular or granulo-vesicular profiles with a graded pattern of evolution in INAD, while dense bodies, vesicles and amorphous material were pressent in HSD. DAs immunoreactivity with τ-protein and 200 kDa-neurofilament antibodies was stronger in HSD than in INAD. In both cases immunohistochemistry was positive for ubiquitin and negative for β-tubulin and β-amyloid. Distinct ultrastructural features and immunoreactivity pattern of cytoskeletal components suggest different pathogenetic mechanisms.

Clinicopathological study of familial late infantile Hallervorden-Spatz disease: a particular form of neuroacanthocytosis

The cases of two sisters with late infantile Hallervorden-Spatz disease are reported, one of whom has died. Autopsy of the deceased patient showed typical pallidal lesions, such as axonal spheroids and iron deposits, without involvement of the substantia nigra. Ultrastructural examination revealed that pallidal axonal enlargements consisted of collecition of mitochondria, dense bodies, vesicles and amorphous material. In the living patient, brain MRI showed the classical “tigers eye” appearance of the globus pallidus. Retinitis pigmentosa, acanthocytosis and slight neuromuscular involvement with an increase in serum creatine kinase were observed in both subjects. The appearance of the globus pallidus on MRI was in line with the pathological abnormalities. Ultrastructural differences between the principal disorders characterized by neuroaxonal dystrophy are compared and the clinical spectrum and similarities of the different forms of neuroacanthocytosis analysed.

Neuronal intranuclear inclusion disease: polymerase chain reaction and ultrastructural study of rectal biopsy specimen in a new case.

We report the case of a boy with neuronal intranuclear inclusion disease in whom the diagnosis was made by examination of a rectal biopsy specimen. Intranuclear inclusions were observed in the Auerbach and Meissner plexuses. In an attempt to understand the physiopathology of this very rare disease, we performed polymerase chain reaction (PCR) and reverse transcriptase-PCR analysis for viral nucleic acids of human immunodeficiency virus type 1 (HIV-1), HIV-2, human cytomegalovirus and measles virus. No viral nucleic acids were detected in the biopsy specimen.

Autosomal dominant limb girdle myopathy with ragged-red fibers and cardiomyopathy A pedigree study by in vivo 31P-MR spectroscopy indicating a multisystem mitochondrial defect

We describe a late-onset autosomal dominant limb girdle myopathy, associated with dilated cardiomyopathy and mental deterioration. In two affected members of the pedigree with histochemical (ragged-red and cytocrome c oxidase - negative fibers) and ultrastructural abnormalities of muscle mitochondria, in vivo muscle phosphorus MR spectroscopy disclosed a slow rate of phosphocreatine resynthesis after exercise. Brain phosphorus MR spectroscopy revealed a defect of the energy metabolism in the two patients and in a third asymptomatic member, as shown by a significantly low phosphocreatine, increased ADP and decreased phosphorylation potential. Molecular analysis of muscle mitochondrial DNA failed to reveal any known mutation, including multiple deletions of the mtDNA which have been associated with some autosomal dominant mitochondrial diseases. The multisystem clinical involvement, the presence of ragged-red fibers and the alterations revealed by in vivo brain and muscle 31P-MRS suggest that this limb-girdle syndrome represents an unusual phenotype of mitochondrial cytopathy.

Congenital lactic acidosis due to a defect of pyruvate dehydrogenase complex (E1). Clinical, biochemical, nerve biopsy study and effect of therapy.

We report an 8-year-old patient with clinical features suggesting Leighs syndrome and with a decreased activity of the E1 component of the pyruvate dehydrogenase complex in cultured skin fibroblasts. A nerve biopsy showed the presence of severe peripheral neuropathy, rarely described in the literature. The partial correction of lactic acidosis with oral sodium bicarbonate chronic therapy may result in a slow evolution of the clinical symptoms.

Juvenile Leigh syndrome with protracted course presenting as chronic sensory motor neuropathy, ataxia, deafness and retinitis pigmentosa: a clinicopathological report.

We herein describe a male patient who died at 37 years of age, after having suffered from a slowly progressive syndrome of chronic sensory motor neuropathy, deafness, retinitis pigmentosa and ataxia. The neuropathological study showed symmetric areas of necrosis and demyelination affecting the cerebellum and brainstem. The type of lesion was consistent with the characteristics of Leigh Syndrome. On the basis of the histology of the lesions, we believe that they appeared only a few months before the death of the patient. We underline the atypical clinical picture and suggest that, in certain cases, brain MRI may not be a reliable diagnostic tool.

Early-onset benign limb-girdle myopathy with contractures and facial involvement affecting a father and daughter

We describe a father and daughter with early-onset benign limb-girdle myopathy and contractures of elbows and hands, resembling Bethlem disease. Muscle biopsy showed a pattern of dystrophy with non specific mitochondrial changes. In both patients there was unusual facial muscle weakness. We discuss the nosologic position of Bethlem myopathy and suggest that facial involvement may be an additional feature of this disease.