Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Impact of music therapy before first-trimester instrumental termination of pregnancy: a randomised controlled trial.

OBJECTIVES: To evaluate the impact of preoperative Music Therapy (MT) on pain in first-trimester termination of pregnancy (TOP) under local anaesthesia. DESIGN: Randomised controlled trial comparing women undergoing a first-trimester TOP under local anaesthesia with or without a preoperative MT session. SETTING: University Hospital of Angers from November 2016 to August 2017. POPULATION: Women who underwent first-trimester TOP under local anaesthesia. METHODS: Women allocated to the MT group underwent a preoperative 20-minute session of MT. MAIN OUTCOME MEASURES: Pain was assessed using a visual analogue scale (VAS) just before the procedure, during the procedure, at the end of the procedure and upon returning to the ward. RESULTS: A total of 159 women were randomised (80 in the MT group, and 79 in the control group). Two women were excluded from the control group and six from the MT group. Therefore, 77 women were analysed in the control group and 74 in the MT group. The intensity of pain was similar in the two groups just before the procedure (VAS 4.0 ± 2.9 versus 3.6 ± 2.5; P = 0.78), during the procedure (VAS 5.3 ± 2.5 versus 4.9 ± 2.9; P = 0.78), at the end of the procedure (VAS 2.7 ± 2.4 versus 2.6 ± 2.4; P = 0.43) and upon returning to the ward (VAS 1.8 ± 2.0 versus 1.5 ± 2.0; P = 0.84). The difference in pain between entering the department and returning to the room after the procedure was similar between the MT and control groups (difference in VAS 0.3 ± 2.5 versus 0.3 ± 2.4; P = 0.92). CONCLUSION: An MT session before a TOP under local anaesthesia procedure resulted in no improvement in patient perception of pain during a first-trimester TOP. TWEETABLE ABSTRACT: Music therapy before first-trimester termination of pregnancy under local anaesthesia did not improve the perception of pain.

Pre-symptomatic diagnosis in ALS.

Pathophysiology of amyotrophic lateral sclerosis (ALS) remains partially understood even though it is accepted worldwide that motor neuron death results from a pluri-factorial process with a variable role of genetic factors. Although not distinguishable from a clinical point of view, familial forms of ALS (fALS, 10% of cases) and sporadic forms (sALS, 90% of cases) can be described. Since the identification of superoxide dismutase 1 gene (SOD1) mutations, more than 30 genes have been linked to fALS. Among these genes, five (C9ORF72, SOD1, TARDBP, FUS, TBK1) seem predominant with mutation frequencies of 40%, 20%, 5%, <5%, <5% in fALS and 6%, 3%, and <1% for the last three in sALS, respectively. The situation that classically leads to request genetic screening is the presence of a familial history of motor neuron disorders (MND) or fronto-temporal lobar dementia (FTLD). However, this dichotomy between fALS and sALS based on familial history can lead to mistakes since illegitimacy, ignorance of MND, FTD or psychiatric disorders within the family due to a familial censorship or lack of familial relationship, or a recessive autosomal inheritance could wrongly lead to failing to recognize a familial form. The significant development of genetic research and easier access to genetic tests in fALS increase the number of situations for which gene mutations are identified. The consequence is an increase in genetic requests from relatives of ALS patients who are eager to know their own genetic status and their own individual risk to develop ALS. Pre-symptomatic testing is thus becoming a daily issue in ALS Centers. This led us to propose a framework for such pre-symptomatic genetic testing for people at risk for developing ALS.

Surfactant-polymer interactions: molecular architecture does matter.

Polymer-surfactant mixtures are found in many industrial formulations, and hence there is a significant interest in understanding, at a molecular level, how the self-assembly of surfactant is affected by oppositely-charged polyelectrolytes (PEs). We use self-consistent field modeling and show that the modes of interaction of PEs strongly depend on the architecture of the PE on the segmental level. Hydrophilic cationic PEs with their charge proximal to the linear backbone are expected to bind electrostatically to the outsides of the coronas of the spherical micelles of anionic surfactants, such as sodium laureth sulphate (SLES). As a result, the surfactant aggregation number increases, but at the same time the colloidal stability deteriorates, due to bridging of the PEs between micelles. PEs with their charge somewhat displaced from the backbone by way of short hydrophobic spacers, are expected to be present inside a micelle at the core-corona boundary. In this case the aggregation number decreases, yet the colloidal stability is retained. Hence, SLES tends to remove hydrophilic PEs from an aqueous solution, whereas it solubilizes more hydrophobic ones. The binding isotherm shows that the uptake of PEs remains typically below charge compensation and in this case the spherical micelle topology remains the preferred state.

Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Autosomal dominant cerebellar ataxias.

Cerebellar ataxias with autosomal dominant transmission (ADCA) are far rarer than sporadic cases of cerebellar ataxia. The identification of genes involved in dominant forms has confirmed the genetic heterogeneity of these conditions and of the underlying mechanisms and pathways. To date, at least 28 genetic loci and, among them, 20 genes have been identified. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes more complex multisystemic neurological deficits. Seven ADCA (SCA1, 2, 3, 6, 7, 17, and dentatorubro-pallido-luysian atrophy) are caused by repeat expansions in the corresponding proteins; phenotype-genotype correlations have shown that repeat size influences the progression of the disease, its severity and clinical differences among patients, including the phenomenon of anticipation between generations. All other ADCA are caused either by non-coding repeat expansions, conventional mutations or large rearrangements in genes with different functions. This review will focus on the genetic features of ADCA and on the clinical differences among the different forms.

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients.

INTRODUCTION: Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI). OBJECTIVE: To characterise in more detail the mutation spectrum associated with Dravet syndrome. METHODS: A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened. RESULTS: SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients. CONCLUSION: These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.

Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work.

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p = 0.001) and more frequently parkinsonism (p < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

[Melanoma within naevus spilus: 5 cases]. / Mélanome sur naevus spilus: 5 observations.

BACKGROUND: Nevus spilus is defined as café-au-lait macules with dark maculopapular speckles. Histologically, it has the aspect of lentigo associated with nevocellular nevus. There are 3 types of nevus spilus: small or medium-sized (<20 cm), giant and zosteriform. Malignant transformation of nevus spilus is rare. PATIENTS AND METHODS: We analyzed the cases of 5 patients presenting melanoma within nevus spilus as well as 20 published cases. The evaluation criteria were: for nevus spilus: size, type, topography, age of onset and presence of dysplastic nevi within the nevus spilus; for melanoma: clinical aspect, histological type, thickness, level and age at diagnosis. The presence of other risk factors for melanoma was noted. RESULTS: The 14 women and 11 men had a mean age of 49 years at melanoma diagnosis. Type of nevus spilus was: small or medium-sized (15 cases), zosteriform (6 cases) and giant (4 cases). Only 3 nevi spili were<4 cm in diameter. Nevus spilus was present since birth (11 cases), childhood (7 cases), after the age of 20 years (3 cases) and was unspecified in 4 cases. Three of our five patients had other risk factors for melanoma. Two patients were presenting 2 melanomas within nevus spilus. The histological type of melanoma was not specified in 8 cases but SSM was the most common type (13 cases). Median Breslow thickness was 1.25 mm (0.27 to 8 mm) for the 19 cases in which it was specified. CONCLUSION: The following criteria appeared to be associated with risk of developing melanoma in nevus spilus patients: nevus spilus present since birth, nevus spilus over 4 cm in diameter, and giant or zosteriform nevus spilus. Development of melanoma within nevus spilus is a rare event. Consequently, guidelines for follow-up of nevus spilus cannot be defined. However, follow-up is recommended, and in particular, self-examination.

Methodology to study polymers interaction by surface plasmon resonance imaging.

The surface plasmon resonance (SPR) technique has been primarily used in the field of biology, in particular for the study of antibody-antigen interactions. Recently, polymers were introduced to form inclusion complexes. We describe here, a methodology based on surface plasmon resonance imaging to study water-resistant and reversible inclusion complexes using systems which are compatible with a cosmetic use. The purpose of this study is to follow in real time the interaction between two polymers. To carry out this study: •A biochip based on a covalent binding of one "host polymer" on a gold-activated surface was developed.•The binding of the host polymer to a guest polymer was monitored.•The presence of interactions between the ß-cyclodextrins groups of the host polymer and the adamantyl functional groups of the guest polymer and the possibility of dissociating the complex were established. This technique allowed carrying out parallel assays for optimizing the amount of complexes formed, the host polymer being spotted at five concentrations. It was then possible to study the influence of the concentration in host system for two concentrations of the guest polymer. The concentration in the host polymer yielding the highest immobilization of the guest system was further determined.

NF1 gene analysis focused on CpG-rich exons in a cohort of 93 patients with neurofibromatosis type 1.

We studied the NF1 gene in 93 unrelated patients with neurofibromatosis type1, focusing the analysis on four exons that contain the highest number of possible mutations occurring at CpG sites. We used denaturing gradient gel electrophoresis to analyse exons 16, 28, 29 and 49, which contain 45 (25%) of the 183 possible mutations that could occur at the 120 CpG dinucleotides of the coding sequence. Six different mutations were identified, five of which are novel: two truncating mutations, W1810X and 5448insG, located in exon29; two splice defects leading to exon29 skipping, 5206-2A>G and 5546G>A; and one missense mutation, L844F, located in exon16. The already described R1748X mutation located in exon29 was found in two unrelated patients. The 5546G>A and R1748X mutations are located at CpG sites, whereas the W1810X involves a CpNpG site. Four novel polymorphisms, which may be helpful for family studies, were also identified. Overall, all but one mutations were found in exon29, a result which suggests that all the CpG sites of the NF1 coding sequence do not have the same mutability, and that exon29, the most CpG-rich exon, contains mutational hotspots associated with NF1.

CFTR gene mutations in adults with disseminated bronchiectasis.

The severity and type of clinical manifestations are variable in patients with cystic fibrosis (CF). The respiratory syndromes in these patients consist of lung infections associated with disseminated bronchiectasis (DB), asthma, and chronic obstructive pulmonary disease. To investigate the possible involvement of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in chronic pulmonary disease in adults, we studied 32 DB patients with a clinically isolated respiratory syndrome. Careful analysis of all the CFTR gene exons and their flanking regions revealed a significantly increased frequency of CFTR gene mutations in these patients. Thirteen CFTR gene mutations were identified in sixteen different alleles. Six of these mutations, which have previously been reported as CF defects, were found on nine alleles. A further four, two of which had not previously been described (D192N and 406-2 AdeltaC), are potentially disease-causing mutations. We also identified three rare substitutions (R31C, L997F, T1220I), which could be involved in mild CFTR gene disease. Four patients were compound heterozygotes, one carried two CFTR gene mutations (possibly allelic) and six were heterozygous for a mutation. These results indicate that CFTR gene mutations may play a role in bronchiectatic lung disease, possibly in a multifactorial context. These findings have implications for genetic counselling of DB patients and their families.

Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.

Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever.

Familial Mediterranean fever (FMF) is an autosomal recessively inherited disease affecting patients of the Mediterranean basin. FMF is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop a renal amyloidosis associated (AA) amyloidosis. The administration of colchicine is an effective preventive treatment of both the attacks and amyloidosis. The FMF gene (MEFV) was cloned and missense mutations were found to be responsible for the disease. We investigated a large series of 303 unselected and unrelated patients of various ethnic backgrounds with a clinical suspicion of FMF to confirm or invalidate the diagnosis of FMF and to determine the spectrum of MEFV mutations. Molecular analysis focused on all the most frequent mutations identified so far, and an exhaustive analysis of exon 10, containing the mutational hotspot, was performed through DNA sequencing. Sixty-two percent of Sephardic, North African Arabs, Armenian and Turkish patients were either homozygous or compound heterozygous for MEFV mutations. In other populations surrounding the Mediterranean Sea such as Greek, Italian, Portuguese, Kurdish and Lebanese populations, mutations were also found. In general, patients without Mediterranean origin had no mutations in the MEFV gene. Two new mis-sense mutations were identified in exon 10 of the MEFV gene: the S675N in an Italian patient and the M680L in a French patient without any known at-risk ethnic ancestry.

Clinical versus genetic diagnosis of familial Mediterranean fever.

The diagnosis of familial Mediterranean fever (FMF) has until recently been based on clinical signs alone. Discovery of the MEFV gene has enabled a molecular approach to diagnosis, which is already well established for diagnosing typical clinical forms of FMF. We evaluated the utility of this molecular approach in a large series of patients with various clinical presentations and ethnic origins. We looked for mutations in the MEFV gene in 303 unselected consecutive patients with a variable (from high to low) clinical suspicion of FMF. Two mutations were found in 133 patients (44%). In 22 patients (7%), the clinical diagnosis of FMF was unlikely according to the Tel Hashomer clinical criteria. Our results suggest that the spectrum of FMF-associated signs is broader than previously believed. Wider indications for genotyping should lead to more frequent diagnosis of FMF.

[Conjoined omphalopagous twins separated at fifteen days of age]. / Jumelles conjointes omphalopages séparées à 15 jours de vie.

BACKGROUND: Conjoined (siamese) twins represent a rare situation which may occur in 1 of every 50,000 births. A prenatal diagnosis usually leads to stopping pregnancy. We report a case with successful surgical separation at the age of 15 days. CASE REPORT: Ultrasonographic examination at 20 weeks of gestation showed omphalopagus siamese joined at the abdomen from the xiphoid process to the umbilicus. Conjoined structures included liver. There was a multicystic right kidney in one twin, without other malformation. Karyotype was normal, 46XX. The mother refused interruption of her pregnancy. Both girls were born by cesarean section. Angiography, magnetic resonance imaging and intravenous urography confirmed the ultrasound examination. There was no cross circulation into the liver and the gastrointestinal tract was not conjoined. The twins were separated at 15 days of age with right heminephrectomy of the multicystic kidney. The girls are now 16 months old and are in very good health. CONCLUSION: Prognosis of siamese twins depends on the nature of joined structures and presence of malformations. Ultrasonographic examination during pregnancy shows the possibility of surgical separation, which is performed by a double anesthetic and surgical pediatric team. Preoperative investigations must include MRI.