Association of vitamin D status with multiple sclerosis in a case-control study from Morocco.

BACKGROUND: Growing evidence suggests that hypovitaminosis D contributes to the pathogenesis of multiple sclerosis (MS). OBJECTIVE: This study aimed to evaluate whether vitamin D levels are associated with having MS and some of its characteristics in the Moroccan population. METHODS: Using liquid chromatography-tandem mass spectrometry, the 25(OH)D3 metabolite was measured to quantify vitamin D serum levels (DSLs) in 113 patients with MS and 146 healthy controls matched for gender and age. DSLs were then compared between patients and controls, with correlations sought between DSLs and gender, age at onset, disease duration, MS type, degree of disability (EDSS score) and disease severity (MSSS) in patients. RESULTS: Hypovitaminosis D (DSL<30ng/mL) was observed in 97.3% of MS patients and in 98.6% of controls. Although the mean DSL was slightly lower in patients (11.69±6.97ng/mL) than in controls (12.98±6.58ng/mL), there was no significant association between DSL and MS status (P=0.131). Similarly, among patients, no apparent association was found between DSL and MS type (P=0.214), EDSS score (P=0.076) or MSSS (P=0.772). CONCLUSION: Our study suggests that DSL is not associated with having MS nor with MS type, degree of disability or disease severity in the Moroccan population. On the other hand, DSL was lower in women and decreased with age.

Inhabitual autosomal recessive form of dentin dysplasia type I in a large consanguineous Moroccan family.

Dentin dysplasia is a rare autosomal dominant genetic disease characterized by defect of dentin development and the causal gene is DSPP (Dentin Sialophosphoprotein gene). We report in the present study a large Moroccan family in which dentin dysplasia is clearly transmitted as an autosomal recessive trait. Four males and females family members born from healthy consanguineous parents are carriers of the typical features of the dentin dysplasia type I. Polymorphic markers that span the DSPP gene, allowed us to show that this locus is not linked to dentin dysplasia in our family. We also excluded in our family the SMOC2 gene (Sparc Related Modular Calcium Binding Protein 2) which was recently identified as a causal gene in dentin dysplasia type I with microdontia and misshapen teeth. This family represents, a new description of autosomal recessive pattern of inheritance of dentin dysplasia type I. Moreover, this form of dentin dysplasia is not allelic to the autosomal dominant dentin dysplasia and the genetic cause is to be discovered.

Spine deformities in Charcot-Marie-Tooth 4C caused by SH3TC2 gene mutations.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked, and autosomal recessive (AR) CMT. A locus responsible for the demyelinating form of ARCMT was assigned to the 5q23-q33 region (CMT4C) by homozygosity mapping. Recently, 11 mutations were identified in the SH3TC2 (KIAA1985) gene in 12 families with demyelinating ARCMT from Turkish, Iranian, Greek, Italian, or German origin. OBJECTIVE: To identify mutations in the SH3TC2 gene. METHODS: The authors searched for SH3TC2 gene mutations in 10 consanguineous CMT families putatively linked to the CMT4C locus on the basis of haplotype segregation and linkage analysis. RESULTS: Ten families had mutations, eight of which were new and one, R954X, recurrent. Six of the 10 mutations were in exon 11. Onset occurred between ages 2 and 10. Scoliosis or kyphoscoliosis and foot deformities were found in almost all patients and were often inaugural. The median motor nerve conduction velocity values (

Autosomal-recessive forms of demyelinating Charcot-Marie-Tooth disease.

Autosomal-recessive forms of Charcot-Marie-Tooth (ARCMT) account for less than 10% of the families in the European CMT population but are more frequent in the Mediterranean basin and the Middle East because of more widespread consanguinity. Until now, demyelinating ARCMT was more extensively studied at the genetic level than the axonal form. Since 1999, the number of localized or identified genes responsible for demyelinating ARCMT has greatly increased. Eight genes, EGR2, GDAP1, KIAA1985, MTMR2, MTMR13, NDRG1, PRX, and CTDP1, have been identified and two new loci mapped to chromosomes 10q23 and 12p11-q13. In this review, we will focus on the particular clinical and/or neuropathological features of the phenotype caused by mutations in each of these genes, which might guide molecular diagnosis.

Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia.

BACKGROUND: Mutilating sensory neuropathy with spastic paraplegia is a very rare disease with both autosomal dominant and recessive modes of inheritance. We previously mapped the locus of the autosomal recessive form to a 25 cM interval between markers D5S2048 and D5S648 on chromosome 5p. In this candidate interval, the Cct5 gene encoding the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (CCT) was the most obvious candidate gene since mutation in the Cct4 gene encoding the CCT delta subunit has been reported to be associated with autosomal recessive mutilating sensory neuropathy in mutilated foot (mf) rat mutant. METHODS: A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated. To identify the disease causing gene, the 11 coding exons of the Cct5 gene were screened for mutations by direct sequencing in all family members including the four patients, parents, and six at risk relatives. RESULTS: Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4 that results in the substitution of a highly conserved histidine for arginine amino acid 147. Interestingly, R147 was absent in 384 control matched chromosomes tested. CONCLUSION: This is the first disease causing mutation that has been identified in the human CCT subunit genes; the mf rat mutant could serve as an animal model for studying these chaperonopathies.

High incidence of SMN1 gene deletion in Moroccan adult-onset spinal muscular atrophy patients.

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuropathy characterized by selective degeneration of anterior horn cells of the spinal cord. Childhood SMA is divided into three types (I-III) on the basis of age of onset and severity. These disorders have been linked to the 5q13 region, where mutations in the Survival Motor Neuron 1 (SMN1) gene have been found in affected individuals. In the case of adult-onset SMA (type IV), on the other hand, reports of homozygous absence of SMN1 gene have been rare. We conducted deletion analysis of SMN and a neighboring gene, NAIP (neuronal apoptosis inhibiting protein). Among 54SMA patients (types I-IV), all of Moroccan origin, Exon 7 of the SMN1 gene was homozygously absent in 100% of type I, 90% of type II, 74% of type III and 80% of type IV SMA patients. Deletion of SMN1 exon 8 was detected in 100% of type I, 53% of type II, 53% of type III and 80% of type IV patients. NAIP exon 5 was homozygously deleted in 67% of type I, 32% of type II, 5% of type III and 20% of type IV SMA patients. Thirty control individuals who were studied had normal SMN1 and NAIP genes. Our results show a high incidence of SMN1 gene deletion in adult-onset SMA patients indicating that SMN1 is the autosomal recessive adult SMA-causing gene. While NAIP is commonly deleted in SMA, this is unlikely to affect disease severity; it was deleted in two adult SMA patients with mild phenotypes.

Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma.

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.

Genetic, cytogenetic and physical refinement of the autosomal recessive CMT linked to 5q31-q33: exclusion of candidate genes including EGR1.

Charcot-Marie-Tooth disease is an heterogeneous group of inherited peripheral motor and sensory neuropathies with several modes of inheritance: autosomal dominant, X-linked and autosomal recessive. By homozygosity mapping, we have identified, in the 5q23-q33 region, a third locus responsible for an autosomal recessive form of demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricted the candidate region to a 4 cM interval. A physical map of the candidate region was established by screening YACs for microsatellites used for genetic analysis. Combined genetic, cytogenetic and physical mapping restricted the locus to a less than 2 Mb interval on chromosome 5q32. Seventeen consanguineous families with demyelinating ARCMT of various origins were screened for linkage to 5q31-q33. Three of these seventeen families are probably linked to this locus, indicating that the 5q locus accounts for about 20% of demyelinating ARCMT. Several candidate genes in the region were excluded by their position on the contig and/or by sequence analysis. The most obvious candidate gene, EGR1, expressed specifically in Schwann cells, mapped outside of the candidate region and no base changes were detected in two families by sequencing of the entire coding sequence.

A locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 1q21.2-q21.3.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of disorders that affect the peripheral nervous system. Three loci are known for the autosomal dominant forms of axonal CMT (CMT2), but none have yet been identified for autosomal recessive axonal CMT (ARCMT2). We have studied a large consanguineous Moroccan ARCMT2 family with nine affected sibs. The onset of CMT was in the 2d decade in all affected individuals who presented with a severe motor and sensory neuropathy, with proximal muscle involvement occurring in some patients. After exclusion of known loci for CMT2 and for demyelinating ARCMT2, a genomewide search was performed. Evidence for linkage was found with markers on chromosome 1q. The maximum pairwise LOD score was above the threshold value of 3.00, for markers D1S514, D1S2715, D1S2777, and D1S2721, and it reached 6.10 at the loci D1S2777, D1S2721, and D1S2624, according to multipoint LOD-score analysis. These markers defined a region of homozygosity that placed the gene in a 4.4-cM interval. Moreover, a recombination event detected in an unaffected 48-year-old individual excludes the D1S506 marker, thereby reducing the interval to 1.7 cM. In addition, the P0 gene, an attractive candidate because of both its location on chromosome 1q and its role in myelin structure, was excluded by physical mapping and direct sequencing.

[The role of quinine chlorhydrate in the conditioned inhibition of the tarsal reflex in Drosophila melanogaster]. / Le rôle du chlorhydrate de quinine dans l'inhibition conditionnée du réflexe tarsal chez Drosophila melanogaster.

The proboscis extension reflex (PER) can be elicited by applying a sucrose stimulation to the tarsus of a walking fly. This reflex decreases in frequency with repetition, presumably habituation, a nonassociative learning. If each sucrose stimulation is followed by a bitter stimulation, quinine chloride, the PER declines more rapidly, probably the result of conditioning, an associative learning. The present work shows that quinine chloride does not always inhibit PER suppressions but depends on the moment of delivery, being most effective when presented immediately after a sucrose stimulation. A bitter stimulus presented before, or simultaneously with a sucrose stimulation is less effective than habituation to sucrose alone. This experiment provides evidence for an interpretation in terms of cognitive association. The model of learning is not a Pavlovian conditioning as advanced by Medioni and Vaysse (1975), but corresponds to the punishment paradigm of Dyal and Corning (1973).

Immunocytochemical and learning studies of a Drosophila melanogaster neurological mutant, no-bridgeKS49 as an approach to the possible role of the central complex.

no-bridgeKS49 (nob) has been shown to have a disturbed protocerebral bridge (pb). Using monoclonal antibodies that stain selectively some central complex regions we found that the protocerebral pridge defect is accompanied by a loss of certain inputs and outputs of the central complex. Mutant nob flies have a reduced climbing activity due to a reduced average walking speed and to a spastic state. Their mean longevity is drastically reduced, suggesting that nob is a pleiotropic gene. The nob mutant is impaired in habituation and in Pavlovian conditioning of the proboscis extension reflex (PER), although its initial reactivity to the sucrose stimulus is normal. Tested in habituation of the PER by ipsi- and contralateral stimulations, the nob mutant shows some difficulties in the "data exchange" between the two brain hemispheres, suggesting that the central complex may coordinate information processing in the two hemispheres.