Fabrizio Gaudiello

A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts.

The clinical and genetic findings are described for 16 patients from a large Italian family with a variant form of hereditary spastic paraplegia and congenital arachnoid cysts inherited as an autosomal dominant trait. A molecular study has revealed a novel missense mutation, T614I, in exon 17 of SPG4, which may play a role in both focal cortical dysgenesis and neurodegeneration of the motor neurons in the corticospinal tract.

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot–Marie–Tooth disease

Mutations in the ALS5/SPG11/ KIAA1840 gene cause autosomal recessive hereditary spastic paraplegia or autosomal recessive juvenile amyotrophic lateral sclerosis. Montecchiani et al . show that KIAA1840 mutations can manifest also as recessive Charcot-Marie-Tooth disease. They describe 12 kindreds with 15 different mutations, two of which have not been reported previously.

Silver syndrome variant of hereditary spastic paraplegia A locus to 4p and allelism with SPG4

Objective: To perform a clinical and genetic study of two large Italian families (RM-36 and RM-51) showing the cardinal clinical features of Silver syndrome (SS), a rare dominantly inherited form of hereditary spastic paraplegia (HSP) complicated by amyotrophy of the small hand muscles. Methods: Clinical assessment including neurophysiologic, neuropsychological, and neuroimaging evaluations. Genetic studies included linkage and sequence analyses. Results: Using a genome-wide survey in the RM-36 family, a novel locus (SPG38) has been identified and mapped within the 13.1-cM region on chromosome 4p16-p15 between markers D4S432 and D4S1599. The RM-51 family was linked to the SPG4 locus at 2p21-p24 and sequence analysis of SPG4 showed a novel frameshift mutation p.Asp321GlyfsX6. Clinical examination of the affected members carrying the mutation showed high frequency of additional clinical features including decreased vibration sense, pes cavus, temporal lobe epilepsy, and cognitive impairment. Conclusions: This study demonstrates evidence of a novel locus SPG38 for Silver syndrome (SS) and suggests that genetic defects in SPG4 might lead to broad clinical features overlapped with those of SS.

New locus for hereditary spastic paraplegia maps to chromosome 1p31.1-1p21.1

We have updated the clinical description of a large Scottish pedigree, in which patients were affected by spastic paraplegia complicated by hearing impairment and persistent vomiting due to hiatal hernia inherited as an autosomal dominant trait. Using a genome‐wide mapping approach, we identified a novel locus (SPG29) for this form of hereditary spastic paraplegia on chromosome 1p31.1‐21.1 and narrowed it to 22.3cM between markers D1S2889 and D1S248. Sequencing of one candidate gene in the region (sorting nexin 7, SNX7), involved in several stages of intracellular trafficking and protein transport, showed no disease‐causing mutations. Ann Neurol 2005;58:423–429

Sixty-four-section CT cerebral perfusion evaluation in patients with carotid artery stenosis before and after stenting with a cerebral protection device

BACKGROUND AND PURPOSE: Brain tissue viability depends on cerebral blood flow (CBF) that has to be kept within a narrow range to avoid the risk of developing ischemia. The aim of the study was to evaluate by 64-section CT (VCT) the cerebral perfusion modifications in patients with severe carotid stenosis before and after undergoing carotid artery stent placement (CAS) with a cerebral protection system. MATERIALS AND METHODS: Fifteen patients with unilateral internal carotid stenosis (≥70%) underwent brain perfusional VCT (PVCT) 5 days before and 1 week after the stent-placement procedure. CBF and mean transit time (MTT) values were measured. RESULTS: Decreased CBF and increased MTT values were observed in the cerebral areas supplied by the stenotic artery as compared with the areas supplied by the contralateral patent artery (P < .001). A significant normalization of the perfusion parameters was observed after the stent-placement procedure (mean pretreatment MTT value, 5.3 ± 0.2; mean posttreatment MTT value, 4.3 ± 0.18, P < .001; mean pretreatment CBF value, 41.2 mL/s ± 2.1; mean posttreatment CBF value, 47.9 mL/s ± 2.9, P < .001). CONCLUSIONS: PVCT is a useful technique for the assessment of the hemodynamic modifications in patients with severe carotid stenosis. The quantitative evaluation of cerebral perfusion makes it a reliable tool for the follow-up of patients who undergo CAS.

Late-onset hereditary spastic paraplegia with thin corpus callosum caused by a new SPG3A mutation

Mutations in the SPG3A gene cause the most frequent autosomal dominant (AD) type of pure hereditary spastic paraplegia (HSP) with very early onset [1, 2]. Here, we report a novel disease-associated mutation in the SPG3A gene in an immigrant South African Zulu family with ADHSP and atypical clinical characteristics. Individuals were clinically evaluated by two neurologists with a proven experience in HSPs (A.O., G.B.). The proband (Fig. 1a, II:3) was a 68-year-old male. He had had progressive walking disturbance from the age of 56 years and a hoist had been required from the age of 66 years. A recent neurological examination disclosed moderate disease severity (SPRS [3] score 35/52) and mild mental retardation (WAIS-R IQ [4] score 62). Furthermore, the patient reported urinary incontinence due to sphincter incompetence. Brain MRI showed a thin corpus callosum (TCC) without cerebellar involvement or white matter abnormalities (Fig. 1b). The spinal cord MRI demonstrated no abnormal signal intensity or atrophy. Similar clinical features, including a late-onset of the disease (55 ± 5.6 years, mean ± SD), mental impairment and the occurrence of TCC, were observed in the other family members (Table 1). After informed consent was given by participants, genomic DNA was isolated from blood samples and subject to linkage analyses at all currently known ADHSP loci (OMIM web site: http://www.ncbi.nlm.nih.gov/omim). HSP gene sequences were studied by direct sequencing. The PCR-RFLP method was used for segregation analysis as described previously [5]. Significant two-point lod scores were obtained at the microsatellite markers of the SPG3A region (Zmax = 4.11 for D14S269 at h = 0.0), while linkage to the other known ADHSP loci was excluded. Sequence analysis of SPG3A demonstrated a novel heterozygous change in exon 12 (c.1246 C[T), resulting in the change of amino acid arginine to cysteine at codon 416 (R416C). The PCR-RFLP analyses showed that all affected family members carried the mutation in SPG3A, while the unaffected members did not (Fig. 1). The mutation was absent in 400 control chromosomes from unrelated South African Zulu individuals. In addition, sequence analyses of the known genes causing HSP with mental retardation and TCC (SPG1, SPG7, SPG11, SPG15 and SPG21) showed no pathological nucleotide changes. We detected a novel R416C missense mutation in a South African Zulu family with ADHSP. The genetic variation fell on exon 12, in accordance with the literature indicating a frequency of 35% for SPG3A mutations in this exon [2], and the R416C amino acid change could exert its pathogenic effect by generating an aberrant secondary A. Orlacchio (&) P. Montieri C. Babalini F. Gaudiello G. Bernardi Laboratorio di Neurogenetica, Centro Europeo di Ricerca sul Cervello (CERC), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia, 64 Via del Fosso di Fiorano, 00143 Rome, Italy e-mail: a.orlacchio@hsantalucia.it

Clinical and genetic study of a large SPG4 Italian family.

A novel SPG4 906delT frame‐shift mutation in exon 6 was identified in a large Italian family with an autosomal dominant form of hereditary spastic paraplegia (ADHSP). Intrafamilial phenotypic variations observed in the pedigree included spasticity and additional clinical features, such as peripheral sensory–motor neuropathy, cognitive impairment, and urological dysfunction. Severe clinical features were found predominantly in the men who were affected, and there was no statistically significant correlation of disability and time since onset of symptoms, suggesting the existence of other genetic/nongenetic modifier(s), including gender.

Advances in neuroimaging of the visual pathways and their use in glaucoma

Recently developed neuroimaging techniques such as diffusion tensor (DT) magnetic resonance (MR) imaging, functional MR imaging (fMRI), and MR spectroscopy can be used to evaluate the microstructural integrity of white-matter fibers and the functional activity of gray matter. They have been widely employed to investigate various diseases of the central nervous system, and they can be useful tools for assessing the integrity and functional connections of the visual pathways and areas that play key roles in glaucoma. In vivo degeneration of the optic nerves can be noninvasively demonstrated by DT MR imaging. DT fiber tractography provides valuable information on the axonal density of postgeniculate fibers (optic radiation), and fMRI studies of patients with primary open-angle glaucoma (POAG) have demonstrated alterations involving the human visual cortex that are consistent with clinically documented losses of visual function. This article reviews some of the more recent data supporting the use of MR imaging techniques as reliable, noninvasive tools for monitoring the progression of human glaucoma.

Hereditary spastic paraplegia: a novel mutation and expansion of the phenotype variability in SPG10

of 3 per year (range 0–48.3). A literature review of UK medical meetings during a similar time period revealed variable rates of eventual publication. Weale et al found publication rates of 24–54% across four surgical meetings. A study of emergency medicine identified a publication rate of 30%, with platform presentations more likely to be published. Oral and maxillofacial surgery abstracts from 2001 to 2007 were published in 24% of cases, with scientific versus clinical presentations more likely to achieve eventual publication. Urology abstracts from 2001 to 2002 were published in 42% cases. Strengths of our study include surveying a large number of abstracts, a relatively long follow-up time and a robust search methodology consistent with previous work on this subject. A potential limitation is that we were unable to determine how many abstracts were submitted for full publication but eventually rejected, or never submitted at all, as this would have required extensive surveying of all authors presenting at the ABN. Our findings emphasise the importance of collaborative work in achieving high-quality research and publication. However, it is possible that this represents a surrogate of other factors, for example case reports may be likely to be single-centre work. While impact factors are a controversial metric of research quality, the majority of eventually published work following presentation at the ABN contributed to the scientific literature in the form of subsequent citations.

Evaluation of basal ganglia haemodynamic changes with perfusion-weighted magnetic resonance imaging in patients with Parkinson's disease.

Purpose.The aim of our study was to assess the regional cerebral blood flow (rCBF) of basal ganglia and thalami in patients with Parkinson’s disease (PD) using perfusion–weighted magnetic resonance imaging (PW–MRI).Material and methods.Twenty subjects affected by idiopathic PD according to the United Kingdom Brain Bank criteria were enrolled in the study. Twenty normal subjects matched for age and gender were included as controls. After 20–day therapy withdrawal, the PD patients underwent PW–MRI. The rCBF was calculated both in patients and in controls. The regions of interest were manually positioned on rCBF maps over the caudate nucleus, the putamen, the external and internal globus pallidus, and over the ventrolateral nucleus of the thalamus. Data were normalised with those obtained from parieto–occipital white matter (POWM). Statistical analysis was performed using a parametric ANOVA test.Results.Patients showed a significant (p<0.01) interhemispheric asymmetry; rCBF values were higher on the more severely affected side. Controls showed no interhemispheric asymmetry.Conclusion.Our study suggests that PW–MRI is a valuable tool for assessing haemodynamic changes in PD patients. Haemodynamic change pattern may be useful in the early diagnosis of PD.