F. Hentati

A comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism

Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.

Characterization of DCTN1 genetic variability in neurodegeneration

Objective: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. Methods: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. Results: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case–control series did not identify any variants segregating with disease or associated with increased disease risk. Conclusions: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

PINK1 mutations and parkinsonism

Background: PINK1 loss-of-function causes recessive, early-onset parkinsonism. In Tunisia there is a high rate of consanguineous marriage but PINK1 carrier frequency and disease prevalence have yet to be assessed. Objectives: The frequency of PINK1 mutations in familial parkinsonism, community-based patients with idiopathic Parkinson disease (PD) (non-familial PD), and control subjects was determined. Demographic and clinical characteristics of individuals with PINK1 homozygous or heterozygous variants, or without PINK1 mutations, were compared. Methods: A total of 92 kindreds (with 208 affected and 340 unaffected subjects), 240 nonfamilial PD, and 368 control participants were recruited from the Institut National de Neurologie, Tunis. Clinical examinations included Hoehn &Yahr, UPDRS, and Epworth scales. PINK1 sequencing and dosage analysis was performed in familial index patients, the variants identified screened in all subjects. Parkin and LRRK2 genes were also examined. Results: Four PINK1 homozygous mutations, three novel (Q129X, Q129fsX157, G440E, and one previously reported; Q456X), segregate with parkinsonism in 46 individuals in 14 of 92 families (15%). Six of 240 patients with nonfamilial PD were found with either homozygous Q456X or Q129X (2.5%) substitutions. In patients with familial disease, PINK1 homozygotes were younger at disease onset (36 ± 12 years) than noncarriers (57 ± 15 years) and more often had an akinetic-rigid presentation at examination and slow progression. Conclusions: Segregation of PINK1 mutations with parkinsonism within families, and frequency estimates within population controls, suggested only four PINK1 mutations were pathogenic. Several PINK1 sequence variants are potentially benign and there was no evidence that PINK1 heterozygosity increases susceptibility to idiopathic Parkinson disease.

Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I.

The authors mapped an autosomal recessive form of limb-girdle MD on chromosome 19q13.3 (LGMD2I), further narrowed down the candidate region to 1.1 Mb, and identified one new homozygous mutation in the fukutin-related protein (FKRP) gene on patients of the original Tunisian family. Immunohistochemical and immunoblot analysis showed abnormal expression of α-dystroglycan and laminin-α2 supporting the hypothesis that FKRP has a role in the interaction between the extracellular matrix components.

An independent replication of park16 in asian samples

Parkinson disease (PD) is the most common neurodegenerative movement disorder with age-related prevalence. Approximately 1% of the population is affected at 65 years, which increases to 4%–5% in 85-year-olds.1 To date, several loci containing pathogenic or risk variants have been identified; the most recent, PARK16 , was nominated through 2 genome-wide association studies (GWAS) using samples of Japanese and European ancestry.2,3 This new locus, located in 1q32, was originally identified in the Asian study with p values ranging from 10 −7 to 10 −12 . PARK16 did not reach significance level in the European GWAS or its replication ( p value >10 −4 ); however, combining samples from stage I and II indicated an association. The most significant SNP in the European study (rs823128) showed a 1% difference in minor allele frequency (MAF) between patients with PD (4%) and control subjects (3%), resulting in an odds ratio (OR) of 0.66 ( p value = 7.3 × 10 −8 ) (of note, the allele frequencies seem to have been mistakenly switched in the combined analysis).3 In contrast, the MAF of rs823128 appears to be more common in the Japanese population, with a lower frequency in patients with PD (10%) …

Neuropathie périphérique au cours de la maladie de Behçet

Resume Introduction A l’inverse de l’atteinte du systeme nerveux central, l’atteinte du systeme nerveux peripherique au cours de la maladie de Behcet a ete rarement decrite. Nous rapportons une observation de neuropathie peripherique survenant chez un patient atteint d’une maladie de Behcet. Observation Un homme âge de 47 ans, atteint d’une maladie de Behcet diagnostiquee en 1997, a recu un traitement par prednisolone et colchicine jusqu’a janvier 2001. Deux mois plus tard, il a presente des paresthesies des deux membres inferieurs d’evolution ascendante atteignant secondairement les membres superieurs, associes a une faiblesse musculaire. En janvier 2003, il s’est plaint d’une diarrhee motrice et d’une dysfonction erectile. L’electromyogramme avec mesure des vitesses de conduction nerveuse a montre une polynevrite avec atteinte neurogene peripherique sensitivomotrice. La biopsie neuromusculaire a revele une neuropathie axonale moderee. La fibroscopie œsogastroduodenale etait normale et la coloscopie avec biopsie colique n’a pas montre d’aspect en faveur d’un entero-Behcet. Le patient a ete traite par prednisone, colchicine et carbamazepine avec une diminution des paresthesies. Conclusion Cette observation est particuliere par l’association chez un sujet atteint d’une maladie de Behcet d’une polyneuropathie sensitivomotrice, d’une diarrhee d’origine dysautonomiques et d’une dysfonction erectile. La neuropathie peripherique peut etre secondaire a une vascularite des vasa nervorum ou a la prise de colchicine.

Microscopic polyangiitis presenting with peripheral and central neurological manifestations

Although peripheral neuropathy is a common complication of microscopic angiitis, manifestations involving the muscle and the central nervous system have been rarely reported. We describe a 48-year-old man who rapidly developed a clinical picture of mononeuritis multiplex. A month after the appearance of the primary symptoms, he became comatose and had left hemiplegia in relation with a massive cerebral haematoma. Laboratory data revealed signs of inflammation, glomerular dysfunction with microhaematuria, and positive myeloperoxidase-antineutrophil cytoplasmic antibodies. The neuromuscular biopsy disclosed a small-vessel vasculitis, consisting with microscopic angiitis, associated with myositis and extensive axonal loss. The patient had surgical evacuation of the haematoma and received immunosuppressive therapy with good outcome. Thus, microscopic angiitis should be considered as a differential diagnosis in cases of myositis and intracerebral haemorrhage.

LRRK2 parkinsonism in Tunisia and Norway: A comparative analysis of disease penetrance

In recent years, the molecular etiology of parkinsonism has yielded to genetic analysis.1 Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have the highest genotypic and population attributable risk. Disparate penetrance estimates have been reported using a variety of statistical analyses, ethnic populations, and sample sizes.2 We compared the age-associated cumulative incidence (penetrance) of LRRK2 p.G2019S patients from Tunisia and Norway.

The role of SNCA and MAPT in Parkinson disease and LRRK2 parkinsonism in the Tunisian Arab‐Berber population

Parkinson’s disease (PD) is a progressively debilitating neurodegenerative disease for which current treatments help with symptoms but fail to slow or halt progression [1]. SNCA variability contributes to PD susceptibility, and possibly also to age at onset (AAO); but there is limited evidence that it contributes to disease progression or outcomes [2]. The influence of MAPT appears limited to Caucasians in which an ancestral paracentric inversion resulted in non-recombining H1/H2 alleles [3]. Recently, SNCA rs356219 and MAPT rs11079727 were proposed as modulators of disease onset in patients with LRRK2 p.G2019S parkinsonism [4,5]. Hence, we tested whether SNCA/MAPT genetic variability influences susceptibility and AAO in idiopathic PD and LRRK2 p.G2019S parkinsonism. The population cohort consisted of 315 unrelated Arab-Berber patients: 101 LRRK2 p.G2019S carriers with parkinsonism (50.3% female, mean AAO 55.9 14.7 years, mean age 70.4 12.9 years) and 214 with idiopathic PD (50.9% female, mean AAO 54.9 14.5 years, mean age 68.1 12.8 years); there were 321 age-matched controls (48.5% female, 62.4 11.0 years). Physical examinations and diagnoses were performed at the Institut National de Neurologie, Tunis, by neurologists specialized in movement disorders [6]. The LRRK2 p.G2019S (rs34637584), SNCA rs356219 and MAPT rs11079727 variants were genotyped by TaqMan on ABI7900 (Applied Biosystems, Foster City, CA, USA). Patients harboring other pathogenic mutations were excluded. Single nucleotide polymorphisms (SNPs) in SNCA and MAPT were assessed using Affymetrix 500K arrays. Genotypes were extracted from CEL intensity files using BBRML, JAPL and CHIAMO [7]. All genotype distributions were in Hardy Weinberg equilibrium. Pairwise linkage disequilibrium (LD) was calculated for all SNCA and MAPT SNPs. JMP Software (SAS Institute Inc., Cary, NC, USA) was employed for statistical analysis of regression models. Susceptibility to PD is associated with intronic SNPs in SNCA and most notably rs7661330 (P = 1.40 9 10 , Fig. 1, Table 1, Table S1). Pairwise LD analyses show that alleles at rs7661330 are highly associated with rs3857059, rs3756054, rs356168 (r > 0.98) and more marginally with rs17016168 (r = 0.68). These intronic SNPs are in a 31 kb LD block. (block 1; Fig. 1). Other significant SNPs include rs3756057 which is in high LD with rs3775461, rs1442143 and rs1837890 (r > 0.98) (Table S1). These intronic

Sténose urétérale au cours de la granulomatose de Wegener: Une observation

INTRODUCTION Ureteral stenoses in Wegeners granulomatosis are rare. They usually involve the pelvic portion of the ureter and are caused by vasculitic lesions or granulomatous inflammation. CASE A 38-year-old woman with Wegeners granulomatosis was treated with corticosteroids and monthly intravenous cyclophosphamide pulses. After 4 months, urinary retention developed, accompanied by lumbar pain, associated with protenuria and hematuria, and related to bilateral ureteral stenoses. Treatment by endoscopic dilatation and double J stents led to with clinical and radiological improvement, while the medical treatment continued. CONCLUSION Hematuria in patients with Wegeners granulomatosis suggests renal involvement, but ureteral stenoses must also be considered when these patients present hematuria or urinary tract infections. Surgery should be reserved for those patients in whom medical treatment is not rapidly effective.Recu le 8 aout 2005 Accepte le 20 juin 2006 ■ Summary Ureteral stenosis in Wegeners granulomatosis: Case report Introduction > Ureteral stenoses in Wegeners granulomatosis are rare. They usually involve the pelvic portion of the ureter and are caused by vasculitic lesions or granulomatous inflammation. Case > A 38-year-old woman with Wegeners granulomatosis was treated with corticosteroids and monthly intravenous cyclophospha- mide pulses. After 4 months, urinary retention developed, accompa- nied by lumbar pain, associated with protenuria and hematuria, and related to bilateral ureteral stenoses. Treatment by endoscopic dila- tation and double J stents led to with clinical and radiological impro- vement, while the medical treatment continued. Conclusion > Hematuria in patients with Wegeners granulomatosis suggests renal involvement, but ureteral stenoses must also be consi- dered when these patients present hematuria or urinary tract infec- tions. Surgery should be reserved for those patients in whom medi- cal treatment is not rapidly effective.