While Friedreich's ataxia (FRDA) and ataxia telangiectasia (AT) are known to be the two most frequent forms of autosomal recessive cerebellar ataxia (ARCA), knowledge on the other forms of ARCA has been obtained only recently, and they appear to be rarer. Little is known about the epidemiological features and the relative frequency of the ARCAs and only few data are available about the comparative features of ARCAs. We prospectively studied 102 suspected ARCA cases from Eastern France (including 95 from the Alsace region) between 2002 and 2008. The diagnostic procedure was based on a sequential strategic scheme. We examined the clinical, paraclinical and molecular features of the large cohort of patients and compared features and epidemiology according to molecular diagnosis. A molecular diagnosis could be established for 57 patients; 36 were affected with FRDA, seven with ataxia plus oculomotor apraxia type 2 (AOA2), four with AT, three with ataxia plus oculomotor apraxia type 1 (AOA1), three with Marinesco–Sjögren syndrome, two with autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS), one with ataxia with vitamin E deficiency (AVED) and one with autosomal recessive cerebellar ataxia type 2 (ARCA2). The group of patients with no identified mutation had a significantly lower spinocerebellar degeneration functional score corrected for disease duration (SDFS/DD ratio; p = 0.002) and comprised a significantly higher proportion of cases with onset after 20 years (p < 0.01). Extensor plantar reflexes were rarer and cerebellar atrophy was more frequent in the group of patients with a known non-Friedreich ARCA compared to all other patients (p < 0.0001 and p = 0.0003, respectively). Lower limb areflexia and electroneuromyographic evidences of peripheral neuropathy were more frequent in the Friedreich ataxia group than in the group with a known non-Friedreich ataxia and were more frequent in the later group than in the group with no identified mutation (p = 0.0001 and p = 0.01, respectively). The overall prevalence of ARCA in Alsace is 1/19,000. We can infer the prevalence of FRDA in Alsace to be 1/50,000 and infer that AT is approximately eight times less frequent than FRDA. MSS, AOA2 and ARSACS appear only slightly less frequent than AT. Despite the broad variability of severity, Friedreich ataxia patients are clinically distinct from the other forms of ARCA. Patients with no identified mutation have more often a pure cerebellar degenerative disease or a spastic ataxia phenotype. It appears that ARCA cases can be divided into two major groups of different prognosis, an early-onset group with a highly probable genetic cause and an adult-onset group with better prognosis for which a genetic cause is more difficult to prove but not excluded. ARCAs are rare, early-disabling and genetically heterogeneous diseases dominated by FRDA. Several of the recently identified ARCAs, such as AVED, ARSACS, AOA1, AOA2 and MSS, have a prevalence close to AT and should be searched for extensively irrespective of ethnic origins. The strategic scheme is a useful tool for the diagnosis of ARCAs in clinical practice.

L’ataxie spastique autosomique récessive de Charlevoix-Saguenay (ARSACS) est une ataxie cérébelleuse de transmission autosomique récessive caractérisée par un syndrome pyramidal et une ataxie cérébelleuse débutant vers l’âge de deux ans. La paraparésie spastique s’aggrave progressivement pour dominer le tableau clinique souvent complété par une polyneuropathie sensitivomotrice axonale et démyélinisante et par la présence au fond d’œil de fibres myélinisées rétiniennes proéminentes. L’imagerie par résonance magnétique nucléaire met en évidence une atrophie cérébelleuse à prédominance vermienne. Des mutations dans le gène SACS, localisé en 13q11, sont responsables de l’ARSACS. Nous rapportons deux cas d’ARSACS, liés à deux mutations hétérozygotes composites, p.Ala2558Val et p.Pro536Leu, au sein d’une même famille française non consanguine. La présentation clinique de ces patients est assez fidèle à la description habituelle de la littérature, en dépit de l’existence d’un retard mental modéré, du caractère à prédominance démyélinisant de la neuropathie périphérique et de bouffées de pointe-ondes généralisées asymptomatiques chez les deux patients. De plus, nous décrivons l’hétérogénéité phénotypique de cette famille concernant notamment les modalités de début des symptômes et la rapidité d’aggravation de la pathologie. Nous présentons également une revue de la littérature sur cette pathologie rare décrite principalement, quoique non exclusivement, au Québec.

The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a cerebellar ataxia autosomal recessively inherited characterized by an ataxic and pyramidal syndrome usually occurring near two years of age. The spastic paraparesis progressively worsens and becomes the prominent sign. Sensorial and motor axonal peripheral neuropathy is frequently reported as well as prominent retinal myelinated fibers on fundus examination. Brain magnetic resonance imaging reveals a predominantly vermian cerebellar atrophy. Mutations in SACS gene on 13q11 are responsible for ARSACS. We report two patients from a non-consanguineous French family, affected with ARSACS, due to the compound heterozygous mutations p.Ala2558Val and p.Pro536Leu. The clinical presentation is in accordance with the previously described ARSACS cases, despite the presence of mental retardation, the predominantly demyelinating peripheral neuropathy, and the evidence of asymptomatic generalized spikes and waves on electroencephalography. We described the clinical heterogeneity in this family including the age at onset of the disease and the first signs as well as the rapidity of the disease progression. We present a review of the literature on this rare disease mostly described in Quebec.

Le déficit en VLCAD est une erreur innée de la bêta-oxydation des acides gras, se manifestant par des hypoglycémies hypocétotiques, des troubles cardiaques ou des épisodes récurrents de rhabdomyolyses. Nous décrivons les caractéristiques cliniques, histopathologiques, biochimiques et moléculaires observées chez 12 patients dont le diagnostic a été porté en France. Les patients étaient tous suivis par un spécialiste de pathologie musculaire ou de maladies métaboliques. Une biopsie musculaire fut réalisée chez 9 patients. Les analyses biochimiques ont comporté un dosage de carnitine sérique dans 9 cas, un dosage des acylcarnitines plasmatiques dans 10 cas, une étude de l'oxydation des acides gras sur lymphocytes ou fibroblastes en culture dans 10 cas, et une étude du profil des acylcarnitines dans le sang par spectrométrie de masse en tandem chez tous les patients. Tous les patients ont présenté depuis l'enfance des épisodes de rhabdomyolyses après des efforts prolongés, lors de périodes de jeûne, ou dans un contexte fébrile, ou après exposition au froid. Une insuffisance rénale est survenue chez 3 patients. Il n'a pas été observé de complication cardiologique. La biopsie musculaire avait montré une surcharge lipidique dans 3 cas. Les taux de carnitine sérique étaient diminués dans 5 cas, et une accumulation anormale d'acylcarnitines C14 : 1 fut observée dans tous les cas. Un important retard au diagnostic est observé chez de nombreux patients. Les raisons de la méconnaissance de cette myopathie métabolique sont essentiellement l'absence d'anomalie significative sur la biopsie musculaire, et la nécessité de réaliser des analyses biochimiques approfondies pour aboutir au diagnostic. La diffusion récente de la technique de spectrométrie de masse a permis d'améliorer considérablement les possibilités de diagnostic. Le déficit en VLCAD est une cause de rhabdomyolyses récurrente après effort, sans intolérance à l'effort court, débutant dans l'enfance, dont le diagnostic peut être facilement orienté par l'étude du profil des acylcarnitines.

Premature termination of translation due to nonsense mutations is a frequent cause of inherited diseases. Therefore, many efforts were invested in the development of strategies or compounds to selectively suppress this default. Selenoproteins are interesting candidates considering the idiosyncrasy of the amino acid selenocysteine (Sec) insertion mechanism. Here, we focused our studies on SEPN1, a selenoprotein gene whose mutations entail genetic disorders resulting in different forms of muscular diseases. Selective correction of a nonsense mutation at the Sec codon (UGA to UAA) was undertaken with a corrector tRNA(Sec) that was engineered to harbor a compensatory mutation in the anticodon. We demonstrated that its expression restored synthesis of a full-length selenoprotein N both in HeLa cells and in skin fibroblasts from a patient carrying the mutated Sec codon. Readthrough of the UAA codon was effectively dependent on the Sec insertion machinery, therefore being highly selective for this gene and unlikely to generate off-target effects. In addition, we observed that expression of the corrector tRNA(Sec) stabilized the mutated SEPN1 transcript that was otherwise more subject to degradation. In conclusion, our data provide interesting evidence that premature termination of translation due to nonsense mutations is amenable to correction, in the context of the specialized selenoprotein synthesis mechanism.

L'inversion-duplication 15 (inv/dup15) est l'anomalie chromosomique extra-structurelle la plus fréquente (1/2 500). Elle associe un retard mental, des troubles du comportement et une épilepsie fréquente souvent au premier plan. À partir d'une étude rétrospective de 5 cas, et à la lumière de la littérature, nous tentons de définir les caractéristiques électrocliniques de cette épilepsie. L'analyse des dossiers a comporté un recueil des antécédents, des paramètres néonataux, des données cliniques générales, des types de crises et des données EEG ainsi que de la réponse aux traitements. Trois cas ont bénéficié d'enregistrements vidéo-EEG de longue durée. En association à un retard mental et l'absence de dysmorphie, les crises comportaient spasmes infantiles (1/5), crises myocloniques (2/5), absences atypiques, crises partielles complexes, crises toniques avec chute et crises tonico-cloniques (4/5). Sur le plan EEG, les anomalies intercritiques étaient généralisées ou focalisées mais les crises avaient toujours un pattern généralisé avec rythmes rapides ou polypointes. La pharmacorésistance était fréquente (4/5) et aucun nouvel antiépileptique n'a été efficace. En dehors des 2 cas du nourrisson, quand les crises débutent dans l'enfance (3/5), l'épilepsie est de type généralisée non idiopathique et associe des absences atypiques, des crises toniques ou tonico-automatiques, des crises avec chute et des crises tonico-cloniques. L'EEG retrouve toujours un pattern critique de décharge de rythmes rapides ou polypointes souvent au sommeil. Ces critères correspondent à un syndrome de Lennox-Gastaut (SLG). Devant une épilepsie généralisée cryptogénique ou un SLG avec un retard mental sans dysmorphie, le clinicien doit penser à demander un examen cytogénétique avec hybridation in situ à la recherche d'un syndrome inv/dup15.

Ullrich congenital muscular dystrophy (UCMD) is due to mutations in one of the three collagen VI genes. The disease course is very variable and optimization of management is required before therapeutic trials are considered. We analyzed motor, respiratory and orthopaedic data in a series of 16 UCMD patients (8M, 8F, mean age 14 years) to identify predictive parameters of severity and therapeutic interventions with an impact in the course of complications. All patients had at least one mutation in one of the COL6 genes: COL6A1 (7), COL6A2 (8), COL6A3 (2) including nine dominant de novo mutations. According to walking abilities and respiratory function, patients were classified as severe (2), moderate (9) and mild (5). Two patients never walked and nine either lost ambulation or had very limited ability. Signs of diaphragmatic failure were typically observed. Seven patients were mechanically ventilated (3 through tracheostomy). Nine patients had joint release surgery. Thirteen patients developed scoliosis, eight treated by orthopaedic bracing. Among six patients with early onset of scoliosis, two (without early bracing) developed a very severe scoliosis (70–105°), while four (treated by Garchois bracing) had stabilized scoliosis (<45°). Spinal fusion was performed in 80% of the patients older than 10 years. We identified several predictive parameters of severe or moderate course: proximal joint contractures at birth, not acquisition of walking before two years, early scoliosis or vital capacity (VC) lower than 70% in supine position in the first 7 years. Our study emphasizes the need for regular orthopaedic and respiratory follow-up in UCMD patients to identify parameters predictive of poor prognosis and propose early treatment of the complications. We found that Garchois bracing had a significant impact in the course of early-onset scoliosis without interference in the respiratory function and therefore was a main tool to manage scoliosis in UCMD patients.

Mutations in the SEPN1 gene, which encodes the selenium-containing protein N (SelN), were first identified in Rigid Spine Muscular Dystrophy (RSMD1) and more recently in multiminicore disease (MmD) and desmin-related myopathy with Mallory Body-like inclusions (MB-DRM). These phenotypes, now collectively classified as SEPN1-related myopathies, are characterized by an early onset generalized hypotonia and weakness, with predominant axial muscle impairment leading to neck weakness and scoliosis, a variable degree of spinal rigidity and life-threatening respiratory failure. As a member of the selenoprotein family, SelN contains the peculiar amino acid selenocysteine (Sec), which is co-transitionally incorporated at a reprogrammed UGA codon within the coding sequence. Here, we present an ex vivo rescue approach based on our knowledge of the specificities of the selenocysteine translation machinery, that successfully restored expression of SelN in cultured skin fibroblasts from a previously described case of RSMD1 with a homozygous nonsense mutation in exon 10 (c.1385G > A; U462X) thereby transforming the Sec codon (UGA) in a stop codon (UAA). This peculiar amino acid was shown to play an important catalytic role and is thought to be located within the active site of the protein. In addition, the occurrence of this premature termination codon induces destabilization of the SelN mRNA in the patient-derived fibroblasts, and as a consequence no protein could be detected by immunoblotting. A plasmid encoding a mutated form of the tRNASec was engineered to accommodate the novel UAA codon at position 462 of SelN. Transfection into cultured fibroblasts of this construction enforced the renewed incorporation of a Sec residue at its normal position thereby allowing expression of detectable amounts of full-length protein. On the contrary, transfection of the wild-type tRNASec was unable to induce re-expression of SelN. Additional experiments demonstrated that the correction was indeed specific for this UAA codon. Our results constitute the first report of a targeted rescue approach for a specific SEPN1 mutation.

Background: Epileptic syndromes with continuous spikes and waves during sleep (CSWS) represent a wide spectrum of epileptic conditions associated with cognitive dysfunctions that have the EEG pattern of CSWS as a common feature. Reported are the results of voxel-based analyses of brain glucose metabolism performed in a group of 18 children with CSWS. Methods: Voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping (SPM). First, each patient was compared with a control group and the influence of age, epileptic activity, and corticosteroid treatment on metabolic abnormalities was studied. Also, disease-related changes in the contribution of a brain area to the level of metabolic activity in another brain area were investigated using pathophysiologic interactions in groups of patients compared with the control group. Results: Individual SPM analyses identified three metabolic patterns: association of hypermetabolic and hypometabolic areas, hypometabolic areas only, and normal pattern. Age and intensity of awake interictal spiking did not significantly differ in patients showing focal hypermetabolism compared with the other ones. Treatment with corticosteroids was associated with absence of focal hypermetabolism. In the group of patients with hypermetabolic areas, analyses of pathophysiologic interactions showed disease-related altered functional connectivity between the parietal and frontal cortices. Conclusions: Cerebral metabolic patterns are heterogeneous among patients with CSWS. This metabolic heterogeneity could be related to the use of corticosteroid treatment before PET. The parietofrontal altered connectivity observed in patients with hypermetabolism is interpreted as a phenomenon of remote inhibition of the frontal lobes induced by highly epileptogenic and hypermetabolic posterior cortex.

Marinesco–Sjögren syndrome (MSS), first described in 1931, is an autosomal recessive condition characterised by somatic and mental retardation, congenital cataracts and cerebellar ataxia. Progressive myopathy was later reported to be also a cardinal sign of MSS, with myopathic changes on muscle biopsies. Hypergonadotrophic hypogonadism and skeletal deformities related to pronounced hypotonia were also reported. The major differential diagnosis of MSS is the syndrome defined by congenital cataracts, facial dysmorphism and peripheral neuropathy (CCFDN), which is localised to 18qter. Using homozygosity mapping strategy in two large consanguineous families of Turkish and Norwegian origin, respectively, we have identified the MSS locus on chromosome 5q31. LOD score calculation, including the consanguinity loops, gave a maximum value of 2.9 and 5.6 at θ =0 for the Turkish and the Norwegian families, respectively, indicating linkage between the disease and the D5S1995-D5S436 haplotype spanning a 9.3 c M interval. Patients of the two families presented with the strict clinical features of MSS. On the other hand, the study of two smaller French and Italian families, initially diagnosed as presenting an atypical MS syndrome, clearly excluded linkage from both the MSS locus on 5q31 and the CCFDN locus in 18qter. Patients of the two excluded families had all MSS features (but the myopathic changes) plus peripheral neuropathy and optic atrophy, and various combinations of microcornea, hearing impairment, seizures, Type I diabetes, cerebral atrophy and leucoencephalopathy, indicating that only the pure MSS syndrome is a homogeneous genetic entity.

The Marinesco-Sjogren syndrome (MSS) (MIM 248800) is an autosomal recessive condition characterised by cataracts, ataxia, and growth and mental retardation. Chronic myopathy is a common feature. Peripheral neuropathy and acute rhabdomyolysis have been described occasionally in MSS. To date, no gene for it has been localised. Congenital cataracts-facial dysmorphism-neuropathy syndrome (CCFDN) (MIM 604168) is a recently delineated autosomal recessive condition,1 so far only described in a specific gypsy group originating from Bulgaria. This disorder was localised by linkage analysis to 18qter, telomeric to the marker D18S1141.2 CCFDN alleles showed a highly conserved haplotype in the region D18S1141-D18S70-D18S1268 consistent with genetic homogeneity and a single founder mutation. Since then, the disease locus has been reduced to the interval located between markers D18S1095 and D18S1390.3,4 MSS and CCFDN share common clinical features and are considered to be differential diagnoses. Recently, Merlini et al 4 proposed that the CCFDN syndrome and one subtype of MSS (Marinesco-Sjogren/myoglobinuria), also only described in gypsy patients, are genetically identical. We report here the clinical and linkage analysis of one gypsy family and one Turkish family in which patients presented with congenital or juvenile cataracts and ataxia. Both families were initially diagnosed as MSS. However, our study shows that they are clinically and genetically distinct. We found that the gypsy family had CCFDN features and was linked to 18qter whereas the Turkish family had typical MSS features and was not linked to 18qter. Here, we confirm the clinical overlap between the CCFDN and MS syndromes and show that they are distinct genetic entities. ### Family 1 A sister (patient 1) and a brother (patient 2) of Turkish origin were referred to the neuropaediatric clinic because of failure to thrive, psychomotor delay, major ataxia, and hypotonia. They were the fourth and fifth children of healthy, consanguineous parents (fig …

Annals of NeurologyVolume 47, Issue 6 p. 839-840 Letter Clinical heterogeneity in pedigrees with 2q-linked febrile seizures Bruno Moulard MD, PhD, Bruno Moulard MD, PhD Division de Neuropsychiatrie, Unité de Biochimie Génétique, Hôpital Belle Idée, Hôpitaux Universitaires de Genève, Chêne-Bourg, SwitzerlandSearch for more papers by this authorDenys Chaigne MD, Denys Chaigne MD Clinique Sainte-Odile, Strasbourg, FranceSearch for more papers by this authorAlain Malafosse MD, PhD, Alain Malafosse MD, PhD Division de Neuropsychiatrie, Unité de Biochimie Génétique, Hôpital Belle Idée, Hôpitaux Universitaires de Genève, Chêne-Bourg, SwitzerlandSearch for more papers by this author Bruno Moulard MD, PhD, Bruno Moulard MD, PhD Division de Neuropsychiatrie, Unité de Biochimie Génétique, Hôpital Belle Idée, Hôpitaux Universitaires de Genève, Chêne-Bourg, SwitzerlandSearch for more papers by this authorDenys Chaigne MD, Denys Chaigne MD Clinique Sainte-Odile, Strasbourg, FranceSearch for more papers by this authorAlain Malafosse MD, PhD, Alain Malafosse MD, PhD Division de Neuropsychiatrie, Unité de Biochimie Génétique, Hôpital Belle Idée, Hôpitaux Universitaires de Genève, Chêne-Bourg, SwitzerlandSearch for more papers by this author First published: 09 May 2001 https://doi.org/10.1002/1531-8249(200006)47:6<839::AID-ANA27>3.0.CO;2-SCitations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume47, Issue6June 2000Pages 839-840 RelatedInformation