Vincent Laugel

Three New BLM Gene Mutations Associated with Bloom Syndrome

Blooms syndrome (BS) is a rare autosomal recessive disease predisposing patients to all types of cancers affecting the general population. BS cells display a high level of genetic instability, including a 10-fold increase in the rate of sister chromatid exchanges, currently the only objective criterion for BS diagnosis. We have developed a method for screening the BLM gene for mutations based on direct genomic DNA sequencing. A questionnaire based on clinical information, cytogenetic features, and family history was addressed to physicians prescribing BS genetic screening, with the aim of confirming or guiding diagnosis. We report here four BLM gene mutations, three of which have not been described before. Three of the mutations are frameshift mutations, and the fourth is a nonsense mutation. All these mutations introduce a stop codon, and may therefore be considered to have deleterious biological effect. This approach should make it possible to identify new mutations and to correlate them with clinical information.

Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype

Abstract Background: Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population. Objectives: Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other mutations. Methods: We first compared fifteen non-ambulant DMD patients carrying deletions theoretically treatable by exon 53 skipping (DMD-53) with fifteen closely age-matched DMD patients with mutations not treatable by exon 53 skipping (DMD-all-non-53) then with fifteen DMD patients carrying deletions not treatable by exon 53 skipping (DMD-del-non-53). Results: We found that DMD-53 patients had a lower left ventricular ejection fraction, more contractures and they tend to have weaker grips and pinch strengths than other DMD patients. DMD-53 patients lost ambulation significantly younger than other DMD patients. This result was confirmed by comparing ages at loss of ambulation in all non-ambulant DMD patients of the DMD cohort identified in a molecular diagnostic lab. Conclusions: These prospective and retrospective data demonstrate that DMD-53 patients have clinically more severe phenotypes than other DMD patients.

Progressive demyelinating neuropathy correlates with clinical severity in Cockayne syndrome.

OBJECTIVE Cockayne syndrome (CS) is characterized by postnatal growth failure and progressive multi-organ dysfunctions. CSA and CSB gene mutations account for the majority of cases and three degrees of severity are delineated. A peripheral neuropathy is known to be associated with CS but the type, severity and correlation of the nerve involvement with CS subtypes remain unknown in genetically identified patients. METHODS Clinical and nerve conduction studies (NCS) in 25 CS patients with CSA (n=13) CSB (n=12) mutations. RESULTS NCS show a widespread decrease in motor and sensory conduction velocities (CV) in all severe and classical form of CS. In one patient, CV were normal at age 8months but severe slowing was detected at 2years. Conduction block and/or temporal dispersion were observed in 68% of patients. CONCLUSIONS CS is associated with a progressive sensory and motor neuropathy. Signs of segmental demyelination, including conduction blocks, may not be obvious before the age of 2years. CV slowing is correlated with the CS clinical severity. SIGNIFICANCE NCS should be performed in patients with suspected CS as an additional tool to guide the diagnosis before molecular studies. Further studies focused on NCS course are required in order to assess its relevance as a biomarker in research therapy projects.

Timed function tests, motor function measure, and quantitative thigh muscle MRI in ambulant children with Duchenne muscular dystrophy: A cross-sectional analysis

The development of new therapeutic agents for the treatment of Duchenne muscular dystrophy has put a focus on defining outcome measures most sensitive to capture treatment effects. This cross-sectional analysis investigates the relation between validated clinical assessments such as the 6-minute walk test, motor function measure and quantitative muscle MRI of thigh muscles in ambulant Duchenne muscular dystrophy patients, aged 6.5 to 10.8 years (mean 8.2, SD 1.1). Quantitative muscle MRI included the mean fat fraction using a 2-point Dixon technique, and transverse relaxation time (T2) measurements. All clinical assessments were highly significantly inter-correlated with p < 0.001. The strongest correlation with the motor function measure and its D1-subscore was shown by the 6-minute walk test. Clinical assessments showed no correlation with age. Importantly, quantitative muscle MRI values significantly correlated with all clinical assessments with the extensors showing the strongest correlation. In contrast to the clinical assessments, quantitative muscle MRI values were highly significantly correlated with age. In conclusion, the motor function measure and timed function tests measure disease severity in a highly comparable fashion and all tests correlated with quantitative muscle MRI values quantifying fatty muscle degeneration.

Loss of Proteostasis Is a Pathomechanism in Cockayne Syndrome

Retarded growth and neurodegeneration are hallmarks of the premature aging disease Cockayne syndrome (CS). Cockayne syndrome proteins take part in the key step of ribosomal biogenesis, transcription of RNA polymerase I. Here, we identify a mechanism originating from a disturbed RNA polymerase I transcription that impacts translational fidelity of the ribosomes and consequently produces misfolded proteins. In cells from CS patients, the misfolded proteins are oxidized by the elevated reactive oxygen species (ROS) and provoke an unfolded protein response that represses RNA polymerase I transcription. This pathomechanism can be disrupted by the addition of pharmacological chaperones, suggesting a treatment strategy for CS. Additionally, this loss of proteostasis was not observed in mouse models of CS.

Place de la neuropathie dans le diagnostic précoce du syndrome de Cockayne : à propos de deux cas dans une fratrie

Two siblings affected with Cockayne syndrome (CS) are described: this diagnosis was suggested by the finding of a demyelinating neuropathy on electromyography in both children and consistent clinical features. CS is a rare genetic disorder with severe prognosis and a highly varied phenotype, making early diagnosis difficult. Taking into account these two cases and the literature, the current diagnosis criteria are insufficiently specific and appear late: the diagnosis may be delayed because multi-organ involvement and sensorial impairment suggests more frequent neurometabolic disorders. Neuroradiologic abnormalities are suggestive but may occur later. The finding of a demyelinating peripheral neuropathy seems to be a more useful marker to suspect this disorder in the presence of other clinical features. Further studies are required to better define the chronology of the symptoms, not only for adequate genetic counseling and eventual prenatal diagnosis, but also to assess the efficacy of future therapies.

A European prospective study of the natural history of patients with type 2 and 3 spinal muscular atrophy

Revised Hammersmith scale for spinal muscular atrophy: Inter and intra-rater reliability and content validity from a patient perspective D. Ramsey *, M. Scoto , A. Mayhew , G. Ramdharry , A. Wallace , F. Muntoni 1 1 UCL & Great Ormond Street Hospital, Dubowitz Neuromuscular Centre, London, UK; 2 Newcastle University, Institute of Human Genetics, Newcastle, UK; 3 UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, London, UK