Cardiogenic shock in a woman with a mitochondrial cardiomyopathy: a case report.

Background: Mitochondrial cardiomyopathy (MCM) is an alteration in cardiac structure and function caused by gene mutations or deletions affecting components of the mitochondrial respiratory chain. We report a case of MCM presenting as cardiogenic shock, ultimately requiring left ventricular assist device (LVAD) placement. Case summary: A 35-year-old woman with chronic weakness and non-ischaemic cardiomyopathy, on home dobutamine, was referred to our institution for heart transplantation evaluation. She was admitted to the hospital for suspected cardiogenic shock after laboratory tests revealed a lactate level of 5.4 mmol/L (ref: 0.5-2.2 mmol/L). Her hospital course was complicated by persistently undulating lactate levels (0.2-8.6 mmol/L) that increased with exertion and did not correlate with mixed venous oxygen saturation measurements obtained from a pulmonary artery catheter. Electrodiagnostic testing demonstrated a proximal appendicular and axial myopathy. A left deltoid muscle biopsy was performed that demonstrated evidence of a mitochondrial disease on light and electron microscopy. Muscle genetic testing revealed two large-scale mitochondrial deoxyribonucleic acid sequence deletions, confirming the diagnosis of MCM. She subsequently underwent LVAD placement, which was complicated by significant right ventricular failure requiring early mechanical support. She was ultimately discharged home with chronic inotropic support. Discussion: Mitochondrial cardiomyopathy in adults is a diagnostic and therapeutic challenge. Prompt diagnosis should be made in patients with unknown causes of heart failure via skeletal muscle histopathology guided by electrodiagnostic studies, and targeted genetic testing in affected tissue. Outcomes in adult MCM patients who receive an LVAD are unknown and warrant further investigation.

A Novel Dynamin 2 Mutation Causing Dominant Intermediate Charcot-Marie-Tooth Neuropathy: Case Report.

Dynamin 2 mutations are associated with Charcot-Marie-Tooth neuropathy. We report two siblings with a novel missense heterozygous point mutation (c.1609 G>A) in the highly conserved pleckstrin homology domain in exon 15 of Dynamin 2 presenting with progressive length-dependent sensorimotor polyneuropathy with mixed demyelinating and axonal features on electrodiagnostic studies. The previously unrecognized missense point mutation, which was inherited from their symptomatic but previously undiagnosed mother, was determined to be likely pathogenic based on a non-conservative amino acid substitution (p.Gly537Ser) that is predicted to damage secondary protein structure or function. This report emphasizes the importance of recognizing inherited neuropathies in clinical practice and evaluating suspected pathogenic gene variants initially classified to be of undetermined clinical significance in family cohorts. These cases add to the spectrum of pathogenic Dynamin 2 mutations associated with dominant-intermediate Charcot-Marie-Tooth neuropathy.

Hereditary Transthyretin Amyloidosis: Clinical Presentation and Management Updates.

Hereditary transthyretin amyloidosis, once a rare progressive neuropathy and/or cardiomyopathy, is now recognized with increasing worldwide frequency, various phenotypes, and over 130 gene mutations identified to date. This inherited disorder develops as a result of mutated transthyretin amyloid aggregation and systematic deposition throughout the body. With increasing knowledge about the pathophysiology of this disease, new disease-modifying therapies are being developed. In addition to slowing progression, these new agents were found to improve quality of life and reduce the severity of neuropathic symptoms. Two new gene-modifying therapies recently received Food and Drug Administration approval following the positive results from phase III trials. These include an antisense oligonucleotide, inotersen, and small interfering RNA, patisiran, which were reported to reduce the production of transthyretin and had promising safety profiles. Additional novel therapies are being explored with hopes to prolong survival. Therefore, early diagnosis of this treatable disorder has become increasingly important in clinical practice.

Hereditary Sensory and Autonomic Neuropathies: Adding More to the Classification.

PURPOSE OF REVIEW: Hereditary sensory and autonomic neuropathies (HSANs) are a clinically heterogeneous group of inherited neuropathies featuring prominent sensory and autonomic involvement. Classification of HSAN is based on mode of inheritance, genetic mutation, and phenotype. In this review, we discuss the recent additions to this classification and the important updates on management with a special focus on the recently investigated disease-modifying agents. RECENT FINDINGS: In this past decade, three more HSAN types were added to the classification creating even more diversity in the genotype-phenotype. Clinical trials are underway for disease-modifying and symptomatic therapeutics, targeting mainly HSAN type III. Obtaining genetic testing leads to accurate diagnosis and guides focused management in the setting of such a diverse and continuously growing phenotype. It also increases the wealth of knowledge on HSAN pathophysiologies which paves the way toward development of targeted genetic treatments in the era of precision medicine.