Striatal [123I] FP-CIT SPECT demonstrates dopaminergic deficit in a sporadic case of Creutzfeldt-Jakob disease.

BACKGROUND: The frequent occurrence of movement disorders such as myoclonus, parkinsonism and dystonia, strongly suggests an involvement of the dopaminergic system in sporadic Creutzfeldt-Jakob disease (sCJD), but this issue has not been specifically addressed yet. METHODS: We report a patient who after a sub-acute focal clinical onset, developed the full clinical picture of probable sCJD. Given the early unilateral right extrapyramidal rigidity, the patient was assessed by single-photon emission computed tomography of the dopamine transporter (DAT) using [123I] FP-CIT. RESULTS: DAT-scan demonstrated reduced values of presynaptic receptorial trace in the putamen, particularly on the left side, consistent with functional putaminal dopaminergic presynaptic alteration. CONCLUSIONS: The present observation emphasizes the possible role of DAT imaging studies in the investigation of the pathogenesis of movement disorders in CJD.

Broadened Friedreich's ataxia phenotype after gene cloning. Minimal GAA expansion causes late-onset spastic ataxia.

We describe three siblings from an Italian family affected by an autosomal recessive spinocerebellar degeneration. Gait ataxia, presenting between 38 and 45 years, was the first symptom in all three patients. Dysarthria, dysmetria, brisk tendon reflexes, extensor plantar response, and scoliosis were constant features. Disease progression was slow. Electrophysiologic studies demonstrated a slight reduction in sural nerve sensory action potential in only one patient. Analysis of GAA expansion within the X25 gene showed that patients were homozygous for the expansion, with the shorter expanded allele ranging from 120 to 156 triplets. The size of the GAA expansion may be smaller than we previously described. Such minimal expansions may result in atypical forms of Friedreich's ataxia.

Clinical and genetic study of a large Charcot-Marie-Tooth type 2A family from southern Italy.

The authors report a large pedigree from southern Italy with Charcot-Marie-Tooth disease type 2A (CMT2A). The clinical picture was uniform and characterized by distal muscular weakness and atrophy in the lower limbs, reduced or absent tendon reflexes mainly in the lower limbs, and mild sensory impairment in the feet. Significant linkage to the CMT2A locus on chromosome 1p35-p36 was detected. Based on informative recombination in affected individuals, the authors mapped the CMT2A gene between D1S160 and D1S170.

Hydrocephalus, skeletal anomalies, and mental disturbances in a mother and three daughters: a new syndrome.

We report on a family in which a mother and her 3 daughters have delayed psychomotor development and/or psychosis, hydrocephalus with white matter alterations, arachnoid cysts, skeletal anomalies consisting of brachydactyly, and Sprengel anomaly. Biochemical and cytogenetic analyses were normal on all 4 patients. The pattern of inheritance, clinical manifestations, and variability of expression suggest that this is a new hydrocephalus syndrome possibly transmitted as an X-linked dominant trait.

Androgen receptor gene (CAG)n repeat analysis in the differential diagnosis between Kennedy disease and other motoneuron disorders.

An increase in the number of (CAG)n repeats in the first coding exon of the androgen receptor (AR) gene has been strongly associated with Kennedy disease (KD) (spinal and bulbar muscular atrophy). This is an X-linked hereditary disorder characterized by motoneuron degeneration occurring in adults together with gynecomastia and hyperestrogenemia. We have performed AR gene molecular analysis in several members of a large family with KD as well as in 25 sporadic patients suffering from heterogeneous motoneuron disease (MND). An increase in the length of the (CAG)n repeats was detected, as expected, in all the affected males and in obligatory carrier females, some of which had minor signs of lower motoneuron involvement. There was only one possible exception, one young male with initial signs of the disease, who had an apparent normal length allele. An increased pathological allele was also found in 3 patients with MND. This indicates that the analysis of (CAG)n repeats of the AR gene plays a role in the differential diagnosis of this heterogeneous group of neurological diseases.

Biochemical and molecular consequences of ethidium bromide treatment on Drosophila cells.

KC167 Drosophila cells were incubated with low concentrations of ethidium bromide (200 ng/ml), causing changes in mitochondrial DNA (mtDNA) content (2-184% of that of controls). SSCP (single strand conformational polymorphism) analysis of mtDNA indicated that the incubation with ethidium bromide also generated mutations. Compared with controls, there were marked reductions in the activities of respiratory complexes III and IV measured in these cells, and in respiration and ATP synthesis capacities measured in isolated mitochondria. These reductions matched that in mtDNA content. In contrast, no link could be demonstrated between mtDNA content and steady-state concentrations of the transcripts of genes COIII and Cyt b.

A kindred affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A 2-year neuropsychological follow-up.

We report a 2-year prospective neuropsychological study of five asymptomatic subjects with magnetic resonance imaging (MRI) abnormalities from an Italian kindred affected by cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These subjects completed tests for attention capacities, processing speed, abstract thinking, short-term memory, learning and constructional praxis. Seven normal subjects matched for age and education, belonging to the same pedigree and not having MRI hyperintensities were examined as controls. The results did not show significant differences between asymptomatic subjects and normal controls. Cognitive performance of asymptomatic subjects did not deteriorate during a 2-year follow-up. Our findings suggest that, at this stage of the disease process, the presence of diffuse leukoencephalopathy does not imply subtle cognitive defects.

Patterns of motor control reorganization in a patient with mirror movements.

OBJECTIVE: To explore motor control reorganization in a 40-year-old, left-handed patient with perinatally acquired mirror movements. METHODS: We performed simultaneous bilateral recordings of motor evoked potentials (MEPs) following focal transcranial magnetic stimulation (fTMS) and of central silent period (cSP) during unilateral voluntary contraction in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. RESULTS: For both muscles the MEP study showed bilateral fast-conducting corticospinal projections from the right undamaged hemisphere, and residual contralateral projections from the left hemisphere. The cSP findings differed in the two muscles: the mirror phenomenon was bilateral in the ADM, but present only on the right side in the APB muscles; the mirror activity of right ADM and APB muscles was inhibited only by fTMS of the ipsilateral right motor cortex; the mirror phenomenon in the left ADM muscle was inhibited only by fTMS of the contralateral right motor cortex. CONCLUSIONS: Mirror movements of right APB and ADM muscles were sustained by the ipsilateral connections from the undamaged motor cortex, while the mirror phenomenon in the left ADM muscle could be explained by hypothesizing a bilateral activation of motor cortices. This previously unreported electrophysiological picture demonstrates that different patterns of motor control may realize after perinatal cerebral lesions, even in different distal muscles of the same patient.

Benign monomelic amyotrophy of lower limb: a rare entity with a characteristic muscular CT.

Six patients presented with amyotrophy confined to a single lower limb and characterized by insidious onset, slow progression and later stabilization. Wasting was out of proportion with disability and there were no sensory, pyramidal tract or bulbar signs. All cases were sporadic, and there was no history of poliomyelitis. CK, anti-ganglioside antibodies, motor and sensory conductions were normal. Quantitative EMG and muscle biopsy revealed neurogenic features also in clinically unaffected limbs. Muscular CT showed selective or predominant, asymmetrical involvement of posterior leg muscles and caput longus of biceps femoris. Monomelic amyotrophy of lower limb is a clinically localized variant of spinal muscular atrophy with a particularly benign course. Although in the early stage there are no clinical or laboratory findings which allow differential diagnosis with other motor neuron diseases, the history of an amyotrophy clinically localized for more than 3 years to a lower single limb and the characteristic muscular CT pattern suggest the diagnosis since the first observation and indicate a favorable prognosis.

Acute motor axonal neuropathy with high titer IgG and IgA anti-GD1a antibodies following Campylobacter enteritis.

We describe the first two European cases of acute axonal motor neuropathy with both IgG and IgA anti-GD1a antibodies following Campylobacter enteritis. Both patients acutely developed severe weakness without sensory involvement, had antibodies to Campylobacter jejuni and polyclonal IgG and IgA titers > or = 12,800 to GD1a at onset, which decreased during follow-up. Serial electrophysiologic studies showed: 1, normal or only slightly slowed motor conductions; 2, evidence of a progressive loss of excitability and conduction failure in nerve fibers undergoing axonal degeneration in intermediate nerve segments and evidence of distal axonal involvement in one nerve; 3, normal sensory conductions, sensory potential amplitudes and somatosensory evoked potentials. Although we cannot exclude that axonal degeneration followed demyelination, we think that anti-GD1a antibodies account for the axonal involvement because GD1a is present in the axolemma and exposed at the node of Ranvier and in nerve terminals. The exclusive motor involvement could be explained by the fact that GD1a has a different internal structure in motor and sensory fibers.

Autosomal dominant cerebellar ataxia type I: multimodal electrophysiological study and comparison between SCA1 and SCA2 patients.

A multimodal electrophysiological study was performed on 41 patients from 24 families with autosomal dominant cerebellar ataxia type I (ADCA I). Upper- and lower-limb motor evoked potentials (MEPs) to transcranial magnetic stimulation, median and tibial nerve somatosensory evoked potentials (Mn and Tn-SSEPs), orthodromic sensory (SCV) and motor conduction (MCV) velocity along median and tibial nerve, brainstem auditory evoked potentials (BAEPs), and visual evoked potentials (VEPs) were examined. Molecular analysis showed 2 SCA1 families and 2 families linked to the SCA2 locus. A sural nerve biopsy was performed in 5 patients. Brainstem damage of the auditory pathway was observed in 79% of patients examined. VEP abnormalities possibly of central origin were found in 52% of patients. MEP and SSEP abnormalities were differently distributed along the pathways examined: the longer the pathway, the higher the occurrence and severity of impairment. Peripheral dying-back neuropathy (confirmed by nerve bioptic data) was a frequent finding (56%). A progressive degenerative process involving first the longest tracts of the central motor and central and peripheral branches of somatosensory pathways is hypothesized in ADCA I. MEP abnormalities were more frequent in SCA1, and the sensory-motor neuropathy was more severe in SCA2.

Autosomal dominant cerebellar ataxia type I. Clinical and molecular study in 36 Italian families including a comparison between SCA1 and SCA2 phenotypes.

We studied 83 patients from 36 Italian families with autosomal dominant cerebellar ataxia type I. Mean onset age +/- SD was 34.2 +/- 12.8 years with a mean anticipation of 12.8 +/- 15.1 in 52 parent-offspring pairs. Onset age anticipation occurred predominantly through paternal transmission. Mean age at death was at 56.5 +/- 15.5 years. The most common associated features were supranuclear ophthalmoplegia, corticospinal signs, peripheral neuropathy and cognitive impairment. Cerebellar atrophy was constant at MRI and usually associated with shrinkage of the pons and degeneration of the pontine transverse fibres. Direct mutation analysis in 29 families showed two families with SCA1 and none with Machado-Joseph/SCA3 mutation. We performed linkage analysis in the ten largest families. Two of them showed linkage to SCA2 locus and none to SCA4 and SCA5 loci. SCA2 patients showed higher occurrence of peripheral neuropathy and slow saccades, rarer corticospinal signs and a milder course of the disease in comparison with SCA1 patients.

Evidence that Charcot-Marie-tooth disease with tremor coincides with the Roussy-Levy syndrome.

We report data on 3 members of a family affected by a dominantly inherited disorder closely resembling Roussy-Levy syndrome (RLS). Electrophysiological findings showed a marked decrease of motor and sensory conduction velocities and EMG signs of mild neurogenic damage. Light and electron microscopy of sural nerve biopsy showed a hypertrophic neuropathy with diffuse onion-bulb formations and marked decrease of large size fibers. Teased fiber preparations evidenced reduced internodal lengths and segmental demyelination. Other data from the literature on RLS are reviewed and discussed. The hypothesis that RLS is not a disease entity but a hypertrophic-type of Charcot-Marie-Tooth disease with essential tremor (HMSN type 1) is strongly supported.

A family with tomaculous neuropathy mimicking Charcot-Marie-Tooth disease.

The appearance of Guillain-Barré syndrome in a 9-year-old girl led to the detection of a hereditary neuropathy in her family. This neuropathy showed clinical and electrophysiological characteristics of Charcot-Marie-Tooth disease. Only nerve biopsy performed in a sister of the proband allowed diagnosis of tomaculous neuropathy which presented unusual clinical, electrophysiological and bioptic aspects.

Motor fibers in human sural nerve.

Two cases of anomalous innervation of the abductor digiti quinti muscle of the foot via sural nerve are described. This anatomical variation can be discovered only when antidromic sensory conduction is investigated. The possibility that the abnormality could explain some reports of degenerated myelinated fibers in sural nerve biopsies of patients with amyotrophic lateral sclerosis is underlined.

Mutational and haplotype map of NOTCH3 in a cohort of Italian patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of familial vascular dementia, is caused by mutations of the NOTCH3 gene. Approximately two hundred pathogenic mutations have been reported within five exons (exons 3, 4, 6, 11 and 19) which accounted for 78% of known mutations in worldwide series. We reported twenty-one NOTCH3 pathogenic mutations (including five novel ones) identified in 53 index Italian patients. Exons 4 (28%), 7 (21%) and 19 (24%) were the most frequently involved. To dissect genetic heterogeneity, we analyzed five haplotyped tagging single nucleotide polymorphisms (rs1044009, rs4809030, rs10426042, rs10423702 and rs3815188) in 95 patients, 39 unaffected pedigree members and 50 healthy controls. SNPs were analyzed using the Illumina VeraCode Universal Capture Beads technology by Allele Specific Primer Extension (ASPE). We identified ten different haplotypes named H1-H10; H1 was the most common haplotype in patients and controls and it was associated with at least twelve out of the twenty-one mutations. Detected mutations were not associated to specific haplotypes while genotyping was compatible with a possible founder effect for the novel p.S396C mutation which clustered in a restricted geographical area of northeast Italy. The results added on to the genetic heterogeneity of CADASIL and emphasized difficulties in designing algorithms for molecular diagnosis.

Clinical presentation of CADASIL in an Italian patient with a rare Gly528Cys exon 10 NOTCH3 gene mutation.

CADASIL is an autosomal dominant arteriopathy characterised by diffuse white matter lesions and small subcortical infarcts on neuroimaging and a variable combination of recurrent cerebral ischaemic episodes, cognitive deficits, migraine with aura and psychiatric symptoms. It is caused by mutations in the NOTCH3 gene encoding a NOTCH3 receptor protein. Here, we describe the genetical, clinical, neuropsychological and neuroimaging findings in an Italian CADASIL patient with a rare mutation in exon 10 leading to a Gly528Cys substitution.

Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene.

Here we describe clinical, neuropsychological and neuroradiological findings in 6 subjects belonging to two unrelated Italian cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) kindreds from the same geographic area who shared a common Arg1006Cys mutation. Subjects from Family A were virtually asymptomatic, and yet showed MRI pathological findings and a cluster of sub-clinical neuropsychological defects mainly centred on the visuospatial domain; patients from Family B had presented several clinically relevant episodes and showed a general cognitive impairment compatible with the clinical picture of vascular dementia. The present clinical observations are consistent with the hypothesis of a geographical clustering for CADASIL, and highlight that sub-clinical cognitive impairment may help to identify this syndrome in families presenting with only migraine.

Multimodal electrophysiologic follow-up study in 3 mutated but presymptomatic members of a spinocerebellar ataxia type 1 (SCA1) family.

The objective was to determine the progression of nervous system involvement in spinocerebellar ataxia type 1 (SCA1). Three presymptomatic members of an Italian SCA1 family underwent molecular analysis and showed the SCA1 mutation. They were defined as "at risk/mutated" individuals. A clinical and electrophysiologic 7-9 year follow-up was performed. The Inherited Ataxia Progression Scale was used for clinical staging. Sensory and motor conduction velocities, somatosensory evoked potentials and transcranial magnetic stimulation were performed at least three times in each subject. Clinical examination showed the early corticospinal pathway involvement. Electrophysiologic investigations confirmed that at the asymptomatic stage only magnetic motor cortex stimulation was abnormal and rapidly worsened with time. Somatosensory pathway studies showed a later involvement and a light sensory-motor neuropathy was the last electrophysiologic abnormality to be recognised. These data confirm that SCA1 phenotype is characterised by early and prevalent pyramidal tract involvement and that peripheral neuropathy is a late and moderate complication.