PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is norma

Peripartum Cardiomyopathy as a Part of Familial Dilated Cardiomyopathy

BACKGROUND-: Anecdotal cases of familial clustering of peripartum cardiomyopathy (PPCM) and familial occurrences of PPCM and idiopathic dilated cardiomyopathy (DCM) together have been observed, suggesting that genetic factors play a role in the pathogenesis of PPCM. We hypothesized that some cases of PPCM are part of the spectrum of familial DCM, presenting in the peripartum period. METHODS AND RESULTS-: We reviewed our database of 90 DCM families, focusing specifically on the presence of PPCM patients. Then, in a reverse approach, we reviewed 10 PPCM patients seen in our clinic since the early 1990s and performed cardiological screening of the first-degree relatives of 3 PPCM patients who did not show a full recovery. Finally, we analyzed the genes known to be most commonly involved in DCM in the PPCM patients. We identified a substantial number (5 of 90, 6%) of DCM families with PPCM patients. Second, cardiological screening of first-degree relatives of 3 PPCM patients who did not show full recovery revealed undiagnosed DCM in all 3 families. Finally, genetic analyses revealed a mutation (c.149A>G, p.Gln50Arg) in the gene encoding cardiac troponin C (TNNC1) segregating with disease in a DCM family with a member with PPCM, supporting the genetic nature of disease in this case. CONCLUSIONS-: Our findings strongly suggest that a subset of PPCM is an initial manifestation of familial DCM. This may have important implications for cardiological screening in such families

Peripartum Cardiomyopathy: Euro Observational Research Program

Peripartum cardiomyopathy is a rare but potentially life-threatening form of heart failure affecting women late in pregnancy or in the first months after delivery. Peripartum cardiomyopathy is difficult to diagnose and its onset and progression are variable between individuals. The pathophysiology remains poorly understood, hence treatment options are limited and possibly harmful to the foetus. Furthermore, geographical incidence varies greatly and little is known about the incidence in Western countries. To gain further understanding of the pathophysiology and incidence of peripartum cardiomyopathy, the European Society of Cardiology initiated a study group to implement a registry. This review provides an overview of current insights into peripartum cardiomyopathy, highlights the need for such a registry and provides information about this Euro Observational Research Program

Recurrent and founder mutations in the Netherlands: the cardiac phenotype of DES founder mutations p.S13F and p.N342D

Background Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac myopathy, mainly caused by dominant mutations in the desmin gene (DES).We describe new families carrying the p.S13F or p.N342D DES mutations, the cardiac phenotype of all carriers, and the founder effects. Methods We collected the clinical details of all carriers of p. S13F or p.N342D. The founder effects were studied using genealogy and haplotype analysis. Results We identified three new index patients carrying the p.S13F mutation and two new families carrying the p.N342D mutation. In total, we summarised the clinical details of 39 p. S13F carriers (eight index patients) and of 21 p.N342D carriers (three index patients). The cardiac phenotype of p.S13F carriers is fully penetrant and severe, characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement. Although muscle weakness is a prominent and presenting symptom in p.N342D carriers, their cardiac phenotype is similar to that of p.S13F carriers. The founder effects of p.S13F and p.N342D were demonstrated by genealogy and haplotype analysis. Conclusion DRM may occur as an apparently isolated cardiological disorder. The cardiac phenotypes of the DES founder mutations p.S13F and p.N342D are characterised by cardiac conduction disease and cardiomyopathy, often with right ventricular involvement

Relevance of Titin Missense and Non-Frameshifting Insertions/Deletions Variants in Dilated Cardiomyopathy

Recent advancements in next generation sequencing (NGS) technology have led to the identification of the giant sarcomere gene, titin (TTN), as a major human disease gene. Truncating variants of TTN (TTNtv) especially in the A-band region account for 20% of dilated cardiomyopathy (DCM) cases. Much attention has been focused on assessment and interpretation of TTNtv in human disease; however, missense and non-frameshifting insertions/deletions (NFS-INDELs) are difficult to assess and interpret in clinical diagnostic workflow. Targeted sequencing covering all exons of TTN was performed on a cohort of 530 primary DCM patients from three cardiogenetic centres across Europe. Using stringent bioinformatic filtering, twenty-nine and two rare TTN missense and NFS-INDELs variants predicted deleterious were identified in 6.98% and 0.38% of DCM patients, respectively. However, when compared with those identified in the largest available reference population database, no significant enrichment of such variants was identified in DCM patients. Moreover, DCM patients and reference individuals had comparable frequencies of splice-region missense variants with predicted splicing alteration. DCM patients and reference populations had comparable frequencies of rare predicted deleterious TTN missense variants including splice-region missense variants suggesting that these variants are not independently causative for DCM. Hence, these variants should be classified as likely benign in the clinical diagnostic workflow, although a modifier effect cannot be excluded at this stage.Peer reviewe