Predictive testing for Huntington disease over 24 years: Evolution of the profile of the participants and analysis of symptoms

Abstract Background Huntington disease (HD) is a devastating neurodegenerative autosomal dominant genetic condition. Predictive testing (PT) is available through a defined protocol for at‐risk individuals. We analyzed the over‐24‐years evolution of practices regarding PT for HD in a single center. Methods We gathered data from the files of all individuals seeking PT for HD in Lyon, France, from 1994 to 2017. Results 448 out of 567 participants had exploitable data. Age at consultation dichotomized over 24 years toward an eightfold increase in individuals aged >55 (2/94 vs. 30/183; 2% to 16%; p < .0001) and twice as many individuals aged 18–20 (3/94 vs. 12/183; 3%–7%; p < .05). Motives for testing remained stable. The rate of withdrawal doubled over 24 years (9/94 vs. 38/183; 9%–21%; p < .02). Independently of the time period, less withdrawal was observed for married, accompanied, at 50% risk, and symptomatic individuals, and in those able to explicit the motives for testing or taking the test to inform their children. We also assessed the consistency between the presence of subtle symptoms compatible with HD found before the test by the team's neurologist, and the positivity of the molecular test. The concordance was 100% (17/17) for associated motor and cognitive signs, 87% (27/31) for isolated motor signs, and 70% (7/10) for isolated cognitive signs. Furthermore, 91% (20/22) of individuals who requested testing because they thought they had symptoms, were indeed found carriers. Conclusion This over‐24 years study underlines an increasing withdrawal from protocol and a dichotomization of participants’ age. We also show a strong concordance between symptoms perceived by the neurologist or by the patient, and the subsequent positivity of the predictive molecular test

Congenital hypomyelinating neuropathy due to the association of a truncating mutation in PMP22 with the classical HNPP deletion

International audienceCongenital hypomyelinating neuropathy appears early in life, resulting in a delay of motor and sensory development. Mutations involve genes such as myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), and early growth response 2 (EGR2). We present a patient with two compound mutations in PMP22: a point mutation causing a premature STOP codon in exon 3 was inherited from the mother on the first allele, and the "typical" PMP22 deletion in the 17p11.2-p12 region was inherited from the father on the other allele. A sural biopsy was performed at age four. The patient has been followed from 28 months to 21 years of age; he presented significant sensory disturbances, with a slight motor deficit. PMP22 mRNA quantitation showed a severe decrease of PMP22 protein. No myelin sheaths were observed in the biopsy; mesaxons failed to form. The absence of PMP22 provides new insights into the role of this protein

Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds

International audienceBackground: At least 28 loci have been linked to autosomal dominant spinocerebellar ataxia (ADCA). Causative genes have been cloned for ten nucleotide repeat expansions (SCA1, 2, 3, 6, 7, 8, 10, 12, 17, and 31) and six genes with classical mutations (SCA5, 13, 14, 15/16, 27, adn 28). Recently, a large British pedigree linked to SCA11 has been reported to carry a mutation in the TTBK2-gene. In order to assess the prevalence and phenotypic spectrum of SCA11, we screened 148 index patients of predominantly German (n=69) and French (n=79) descents with ADCA tested negative for a panel of SCA mutations (SCA1, 2, 3, 6, 7, and 17), for mutations in TTBK2. Methods: In the German ADCA cohort the complete coding sequence of the TTBK2-gene was PCR-amplified and screened for mutations by high-resolution-melting (HRM) analysis. In the French cohort, exons known to carry mutations were directly sequenced. For both cohorts, the gene-dosage alterations were assessed using a customized multiplex ligation probe amplification (MLPA) assay. Results: In two of 148 ADCA families – one German and one French - we identified a potentially disease-causing SCA11 mutation. Interestingly, both carried an identical two basepair deletion (c.1306_1307delGA, p.D435fs448X in exon 12) leading to a premature stop codon. Gene dosage alterations were not detected in the TTBK2-gene. Clinically, our SCA11 patients had phenotypic characteristics as described before presenting with slowly progressive almost pure cerebellar ataxia with normal life expectancy. Conclusion: SCA11 presented as ADCA III according to Harding's classification and is a rare cause of spinocerebellar ataxia in Caucasians accounting for less than 1% of dominant ataxias in central Europe

Analysis of the DYSF mutational spectrum in a large cohort of patients

International audienceDysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc

Motor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials

International audienceOur objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD)

Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

International audiencePatients with SPG7 had a mean age of 35.5 ± 14.3 years (n = 233) at onset and presented with spasticity (n = 89), ataxia (n = 74), or both (n = 45). At the first visit, patients with a longer disease duration (>20 years, n = 62) showed more cerebellar dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle wasting (p < 0.01), ophthalmoplegia (p < 0.05), and sphincter dysfunction (p < 0.05) than those with a shorter duration (<10 years, n = 93). Progression, measured by Scale for the Assessment and Rating of Ataxia evaluations, showed a mean annual increase of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for loss of function (LOF) variants (n = 65) presented significantly more often with pyramidal signs (p < 0.05), diminished visual acuity due to optic atrophy (p < 0.0001), and deep sensory loss (p < 0.0001) than those with at least 1 missense variant (n = 176). Patients with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs 32.8 ± 14.6 years, p < 0.05) and showed ataxia at onset (p < 0.05). Neuropathologic examination revealed reduction of the pyramidal tract in the medulla oblongata and moderate loss of Purkinje cells and substantia nigra neurons

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes

International audienceImportance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Design, Setting, and Participants: Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Main Outcomes and Measures: Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. Results: The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Conclusions and Relevance: Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease

Coarelli et al., Table 4

Table 4. New SPG7 variants found in the analyzed cohort