Imed Feki

Exon Deletions of SPG4 are a Frequent Cause of Hereditary Spastic Paraplegia

Background: Point mutations in SPG4, the gene encoding spastin, are a frequent cause of autosomal dominant hereditary spastic paraplegia (AD-HSP). However, standard methods for genetic analyses fail to detect exonic microdeletions. Methods: 121 mutation-negative probands were screened for rearrangements in SPG4 by multiplex ligation-dependent probe amplification. Results: 24 patients with 16 different heterozygotic exon deletions in SPG4 (20%) were identified, ranging from one exon to the whole coding sequence. Comparison with 78 patients with point mutations showed a similar clinical picture but an earlier age at onset. Conclusions: Exon deletions in SPG4 are as frequent as point mutations, and SPG4 is responsible for 40% of AD-HSP.

Alteration of Ganglioside Biosynthesis Responsible for Complex Hereditary Spastic Paraplegia

Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origins. Five homozygous truncating (n = 3) and missense (n = 2) mutations were identified in B4GALNT1. After this finding, we analyzed the entire coding region of this gene in 65 additional cases, and three mutations were identified in two subjects. All mutated cases presented an early-onset spastic paraplegia, with frequent intellectual disability, cerebellar ataxia, and peripheral neuropathy as well as cortical atrophy and white matter hyperintensities on brain imaging. B4GALNT1 encodes β-1,4-N-acetyl-galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis. These findings confirm the increasing interest of lipid metabolism in HSPs. Interestingly, although the catabolism of gangliosides is implicated in a variety of neurological diseases, SPG26 is only the second human disease involving defects of their biosynthesis.

REEP1 mutations in SPG31: Frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction†

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized at least by slowly progressive spasticity of the lower limbs. Mutations in REEP1 were recently associated with a pure dominant HSP, SPG31. We sequenced all exons of REEP1 and searched for rearrangements by multiplex ligation‐dependent probe amplification (MLPA) in a large panel of 175 unrelated HSP index patients from kindreds with dominant inheritance (AD‐HSP), with either pure (n = 102) or complicated (n = 73) forms of the disease, after exclusion of other known HSP genes. We identified 12 different heterozygous mutations, including two exon deletions, associated with either a pure or a complex phenotype. The overall mutation rate in our clinically heterogeneous sample was 4.5% in French families with AD‐HSP. The phenotype was restricted to pyramidal signs in the lower limbs in most patients but nine had a complex phenotype associating axonal peripheral neuropathy (= 5/11 patients) including a Silver‐like syndrome in one patient, and less frequently cerebellar ataxia, tremor, dementia. Interestingly, we evidenced abnormal mitochondrial network organization in fibroblasts of one patient in addition to defective mitochondrial energy production in both fibroblasts and muscle, but whether these anomalies are directly or indirectly related to the mutations remains uncertain. Hum Mutat 32:1118–1127, 2011. ©2011 Wiley‐Liss, Inc.

Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity

Hereditary spastic paraplegias (HSP) constitute a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. We performed the first clinical, epidemiological and genetic study of HSP in Southern Tunisia. We investigated 88 patients belonging to 38 unrelated Tunisian HSP families. We could establish the minimal prevalence of HSP in the district of Sfax at 5.75/100,000. Thirty‐one percent of the families had a pure HSP, whereas 69% had a complicated form. The mode of inheritance was almost exclusively compatible with an autosomal recessive trait (97%, 37/38). Taking into account previously published results and new data generated in this work, genetic studies revealed significant or putative linkage to known HSP loci in 13 families (34.2%) to either SPG11 (7/38, 18.4%), SPG15 (4/38, 10.5%) or to SPG4 and SPG5 in one family each. The linkage results could be validated through the identification of two recurrent truncating mutations (R2034X and M245VfsX246) in the SPG11 gene, three different mutations (Q493X, F683LfsX685 and the novel S2004T/r.?) in the SPG15 gene, the recurrent R499C mutation in the SPG4 gene as well as the new R112X mutation in the SPG5 gene. SPG11 and SPG15 are the major responsible HSP genes in Tunisia.

Epidemic West Nile Virus Encephalitis in Tunisia

West Nile fever (WNF) is a mosquito-borne flavivirus infection. It is epidemic in Africa and Asia. In autumn 1997, a WNF epidemic occurred in the Sfax area (southeastern Tunisia). Fifty-seven patients were hospitalized with aseptic meningitis and/or encephalitis. Search for specific anti-West Nile virus (WNV) antibodies in serum and cerebrospinal fluid (CSF) was performed using an ELISA test. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect the WNV genome in CSF and brain specimens. Recent central nervous system (CNS) infection by WNV was confirmed in 30 patients, probable infection in 17 and it was excluded in 10. In the confirmed subgroup, patients with encephalitis were older than those with meningitis. CSF showed pleocytosis, high protein (47%) and normal glucose levels. Brain computed tomography-scan (CT-scan) and magnetic resonance imaging (MRI) were normal. RT-PCR disclosed WNV genome in the CSF in two cases and in a brain specimen in one. Three patients died rapidly, the remaining cases had favorable prognosis. Autopsy was performed in two cases and showed nonspecific lesions of encephalitis. No viral inclusions were seen with light microscopy. Seropositivity rate in patients’ proxies for WNV was 23.4%. Prognosis of CNS involvement during WNF seemed to be poor in older patients. This is the first WNV encephalitis epidemic report in the Sfax area of Tunisia.

Spastic paraplegia 15: linkage and clinical description of three Tunisian families.

Hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower limbs. The locus designated spastic paraplegia 15 (SPG15), located in a 16‐Mb interval on chromosome 14q, is associated with a rare autosomal recessive complicated form of HSP known as Kjellins syndrome. In this study, we describe three additional families, of Tunisian origin, linked to the SPG15 locus, one of which had a significant multipoint LOD score of 3.46. In accordance with previous reports, the phenotype of our patients consisted of early onset spastic paraparesis associated with mental impairment and severe progression. Retinal degeneration was not observed, however, but we extended the phenotype of this form to include peripheral neuropathy and white matter abnormalities on MRI. Interestingly, like retinal degeneration, thin corpus callosum is not a constant feature in this entity.

Three-dimensional neuronal brain activity estimation using shrinking smooth weighted-minimum-norm focal underdetermined-system solver methods

A new nonparametric method, based on the smooth weighted-minimum-norm (WMN) focal underdetermined-system solver (FOCUSS), for electrical cerebral activity localization using electroencephalography measurements is proposed. This method iteratively adjusts the spatial sources by reducing the size of the lead-field and the weighting matrix. Thus, an enhancement of source localization is obtained, as well as a reduction of the computational complexity. The performance of the proposed method, in terms of localization errors, robustness, and computation time, is compared with the WMN-FOCUSS and nonshrinking smooth WMN-FOCUSS methods as well as with standard generalized inverse methods (unweighted minimum norm, WMN, and FOCUSS). Simulation results for single-source localization confirm the effectiveness and robustness of the proposed method with respect to the reconstruction accuracy of a simulated single dipole.

Nouvelle mutation du gène ATP7B responsable d’une maladie de Wilson avec atteinte neurologique sévère

Fig. 1 – Arbre généalogique. Le symbole d’individu noir correspond au sujet atteint (flèche : cas index ; carré hachuré : frère probablement atteint ; * : sujets prélevés). Family pedigree (black symbol: affected member; arrow: index case; hatched square: probable affected brother; *: individuals for whom DNA was available). Nouvelle mutation du gène ATP7B responsable d’une maladie de Wilson avec atteinte neurologique sévère

Paraplégie spastique familiale avec amyotrophie sévère des mains (syndrome de Silver

Resume Les paraplegies spastiques familiales (PSF) avec amyotrophie severe des mains et des pieds sont exceptionnelles. Des formes de transmission autosomique dominante ont ete initialement decrites par Silver en 1966. Nous rapportons 2 cas d’une famille tunisienne de PSF avec amyotrophie severe des mains. Il s’agit d’un frere et d’une sœur âges respectivement de 37 et 36 ans et presentant pratiquement le meme tableau clinique. Leurs parents etaient cousins germains. Les troubles de la marche sont apparus vers l’âge de trois ans. Une amyotrophie des mains etait constatee plus tardivement vers l’âge de 20 ans. L’examen neurologique mettait en evidence une paraplegie spastique avec une amyotrophie severe des mains et moderee des pieds. La sensibilite etait conservee et il n’y avait pas de fasciculations. L’imagerie par resonance magnetique (IRM) medullaire et cerebrale etait normale. L’electromyogramme (EMG) montrait un trace neurogene et la stimulation respective des nerfs medians, cubitaux, sciatique poplite externe et interne (SPE et SPI) etait inefficace. Les potentiels evoques somesthesiques (PES) etaient alteres. Le liquide cephalo-rachidien (LCR) renfermait un element blanc/mm 3 et la proteinorachie etait a 0,10 g/l. Le diagnostic de syndrome de Silver a ete retenu apres avoir elimine une malformation de la charniere cervico-occipitale, une syringomyelie et une sclerose laterale amyotrophique (SLA) juvenile familiale.

A generalization to the Hardy-Sobolev spaces

The main purpose of this article is to give a generalization of the logarithmictype estimate in the Hardy-Sobolev spaces Hk,p(G); k ∈ N*, 1 ≤ p ≤ ∞ and G is the open unit disk or the annulus of the complex |space^C.