TMEM5-associated dystroglycanopathy presenting with CMD and mild limb-girdle muscle involvement

The dystroglycanopathies, which are caused by reduced glycosylation of alpha-dystroglycan, are a heterogeneous group of neurodegenerative disorders characterized by variable brain and skeletal muscle involvement. Recently, mutations in TMEM5 have been described in severe dystroglycanopathies. We present the clinical, molecular and neuroimaging features of an Italian boy who had delayed developmental milestones with mild limb-girdle muscle involvement, bilateral frontotemporal polymicrogyria, moderate intellectual disability, and no cerebellar involvement. He also presented a cochlear dysplasia and harbored a reported mutation (p.A47Rfs*42) in TMEM5, detected using targeted next-generation sequencing. The relatively milder muscular phenotype and associated structural brain abnormalities distinguish this case from previously reported patients with severe dystroglycanopathies and expand the spectrum of TMEM5-associated disorders

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease

Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle diseasegenes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T > G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy

<div><p>Objective</p><p>Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the <i>SPP1</i> promoter, rs10880 and the VTTT/IAAM haplotype in <i>LTBP4</i>) also modify DCM onset.</p><p>Methods</p><p>A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m² as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.</p><p>Results</p><p>Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at <i>SPP1</i> rs28357094 and recessive T allele at <i>LTBP4</i> rs10880, which was statistically significant in steroid-treated patients for <i>LTBP4</i> rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).</p><p>Conclusions</p><p>We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.</p></div

Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.

<p>*Significant difference between genotypes (log-rank p<0.05).</p><p>§DCM onset was observed in less than 50% of patients, so no median value can be calculated.</p><p>Total n for <i>LTBP4</i> differs due to limited DNA availability in a few patients. For <i>SPP1</i>, patients included in the previous report about loss of ambulation (Pegoraro et al, 2011) were also excluded. <i>SPP1</i>: Secreted PhosphoProtein 1. <i>LTBP4</i>: latent transforming growth factor beta binding protein 4. DCM: dilated cardiomyopathy.</p><p>Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.</p

Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).

<p>Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).</p

Kaplan-Meier plots of LoA by genotypes and steroid treatment.

<p>Triangles indicate censoring. (A) <i>SPP1</i> rs28357094 genotype: T/T red, T/G-G/G blue; (B) <i>LTBP4</i> rs10880: T/T red, C/C-C/T blue; (C) LTBP4 haplotype: IAAM/IAAM red, VTTT/VTTT grey, other blue; (D) rs28357094 genotype and steroid treatment: T/T red, T/G-G/G blue, solid treated (>1 year before LoA), dashed untreated; (E) rs10880 and steroid treatment: T/T red, C/C-C/T blue, solid treated, dashed untreated; (F) LTBP4 haplotype and steroid treatment: IAAM/IAAM red, other (including VTTT) grey, solid treated, dashed untreated.</p