Mari Mori

Severe Cardiomyopathy as the Isolated Presenting Feature in an Adult with Late-Onset Pompe Disease: A Case Report

Many inborn errors of metabolism can cause cardiomyopathy. Cardiomyopathy associated with glycogen storage includes PRKAG2-associated glycogen storage disease (GSD), Danon disease, infantile-onset Pompe disease (GSD II), GSD III, GSD IV, and phosphofructokinase deficiency (Tarui disease or GSD VII).We present a 35-year-old female who presented with cardiomyopathy after a pregnancy complicated by primary hyperparathyroidism. She had enjoyed excellent health until her first pregnancy at age 33. One week postpartum, she developed dyspnea and an echocardiogram revealed left ventricular ejection fraction (LVEF) of 35%. A cardiac MRI was consistent with nonischemic cardiomyopathy with an infiltrative process. Endomyocardial biopsy showed striking sarcoplasmic vacuolization, excess glycogen by PAS staining, and frequent membrane-bound glycogen by electron microscopy, consistent with lysosomal GSD. Acid alpha-glucosidase (GAA) activity in skin fibroblasts was in the affected range for Pompe disease. Sequencing of the GAA gene revealed a paternally inherited pathogenic c.525delT (p.Glu176Argfs*45) and a de novo c.309C>G (p.Cys103Trp) with unknown pathogenicity. Testing of the familial mutations in her daughter indicated that the variants in the proband were in trans. 26-gene cardiomyopathy sequencing panel had normal results thereby excluding GSD III, Danon disease, Fabry disease, and PRKAG2-associated cardiomyopathy. Therefore, results strongly suggest a diagnosis of Pompe disease.Pompe disease has a broad disease spectrum, including infantile-onset (IOPD) and late-onset (LOPD) forms. LOPD typically presents with proximal muscle weakness and respiratory insufficiency in childhood or late adulthood. Our case may represent a very unusual presentation of adult LOPD with isolated cardiomyopathy without skeletal muscle involvement or respiratory failure.

Anti-glomerular basement membrane disease treated with mycophenolate mofetil, corticosteroids, and plasmapheresis.

An 18-year-old woman presented with anemia, pulmonary hemorrhage, and necrotizing glomerulonephritis, and was diagnosed with anti-glomerular basement membrane (anti-GBM) disease. Treatment was undertaken with plasma exchange, mycophenolate mofetil and corticosteroids, due to patient refusal of cyclophosphamide. Clinical remission was successfully induced with this fertility-sparing regimen. A relapse due to therapy non-adherence was successfully treated with a second course of plasmapheresis, mycophenolate, and steroids. Thereafter, 6 months of directly observed therapy resulted in a favorable outcome with well-preserved pulmonary and renal function. This case suggests the possibility that mycophenolate may have a role in the treatment of anti-GBM disease.

Case series: Odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? – Call for a long-term follow-up of premature loss of primary teeth

Introduction Hypophosphatasia, a metabolic bone disease caused by a tissue-nonspecific alkaline phosphatase deficiency, leads to undermineralization of bone and/or teeth, impaired vitamin B6 metabolism, and a spectrum of disease presentation. At the mild end of the spectrum, it presents as pathologic fractures in later adulthood. Patients with isolated dental manifestations, typically presenting as premature loss of primary teeth, are classified as having odontohypophosphatasia (odontoHPP). A subset of patients diagnosed with odontoHPP in childhood can later develop extra-dental manifestations that constitute childhood- or adult-onset hypophosphatasia. Case reports: methods/results Retrospective data related to onset, detailed clinical course, and method of diagnosis were collected as part of a natural history of adult patients with hypophosphatasia. Of 9 initial patients, all had low serum alkaline phosphatase levels for their age and gender at adult presentation (Table 2). The majority (8/9) demonstrated childhood dental signs of hypophosphatasia as the initial clinical manifestation: premature loss of primary teeth (7/9), absent primary teeth (1/9), and delayed loss of primary teeth (1/9). Despite childhood dental presentation and/or other signs/symptoms, diagnosis of hypophosphatasia was delayed 20–54 years (median = 46) since the primary tooth problems and 8–45 years (median = 27) since the first fracture or onset of a major adult tooth problem. Conclusion Patients with primary tooth loss in childhood were often diagnosed with hypophosphatasia later in life. Pediatric patients classified as having odontoHPP under present practice can manifest significant disease burden later in life.

Selective upregulation of p66-Shc gene expression in the liver and brain of aged rats

The phosphotyrosine signaling followed by various receptor activations conforms a unique signaling platform during metazoan evolution, and is crucial for animal development, maturation, and aging. Shc is the most versatile bipartite phosphotyrosine signal adaptor harboring phosphotrosine-biding (PTB) and Src-homology2 (SH2) domains. Among the Shc adaptor family members, p66-Shc is of potential interest in aging studies, since its deletion in mice resulted in a longer lifespan and/or higher quality of life in later stages of life. However, a few studies have examined the gene expression profiles of p66-Shc in aging tissues. Here, we quantified the expression levels of transcripts of Shc-related isoforms in the liver and brain of young adult, middle-aged, and aged rats, and found that p66-Shc gene expression is specifically up-regulated in the aged liver and brain. In the aged liver tissue, p66-Shc expression was also evident at the protein level, and accumulated in the soluble fraction of the aged tissue. These results indicate that p66-Shc is not only related to animal longevity but also affected during aging, and thus the repression of p66-Shc could become a potential target for an anti-aging strategy.

Neuronal Shc: a gene of longevity in the brain?

Aging is inevitable to all multi-cellular organisms, and each organism has its own lifespan. The species-specific lifespan seems determined genetically; however little is known about how the lifespan determined. During the last decades accumulative evidence indicates that there is certainly a set of genes that are involved in the lifespan determination. Among those dozens of genes, the Shc gene encoding a phosphotyrosine signal adaptor is of potential interests in mammalian aging and/or longevity determination. Shc is merely one form of a gene family, and accumulative evidence demonstrates the presence of additional Shc homologues that are strongly expressed in the nervous system. We hypothesize that lifespan is regulated primarily by the nervous system and/or brain, and neurally expressed Shc homologues play pivotal roles in relation to the evolution of longevity with quality of life. We discuss herein the recent progress of our understanding of the neuronally expressed Shc genes in comparision with p66-Shc as a candidate for the evolution of long life with higher quality of life in mammals.

Complex III deficiency due to an in-frame MT-CYB deletion presenting as ketotic hypoglycemia and lactic acidosis ☆

Complex III deficiency due to a MT-CYB mutation has been reported in patients with myopathy. Here, we describe a 15-year-old boy who presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency. Electron transport chain analysis and mitochondrial DNA sequencing on muscle tissue lead to the eventual diagnosis of complex III deficiency. This case demonstrates the critical role of muscle biopsies in a myopathy work-up, and the clinical efficacy of supplement therapy.

Sensitivity of whole exome sequencing in detecting infantile- and late-onset Pompe disease

Pompe disease is a metabolic myopathy with a wide spectrum of clinical presentation. The gold-standard diagnostic test is acid alpha-glucosidase assay on skin fibroblasts, muscle or blood. Identification of two GAA pathogenic variants in-trans is confirmatory. Optimal effectiveness of enzyme replacement therapy hinges on early diagnosis, which is challenging in late-onset form of the disease due to non-specific presentation. Next-generation sequencing-based panels effectively facilitate diagnosis, but the sensitivity of whole-exome sequencing (WES) in detecting pathogenic GAA variants remains unknown. We analyzed WES data from 93 patients with confirmed Pompe disease and GAA genotypes based on PCR/Sanger sequencing. After ensuring that the common intronic variant c.-32-13T>G is not filtered out, whole-exome sequencing identified both GAA pathogenic variants in 77/93 (83%) patients. However, one variant was missed in 14/93 (15%), and both variants were missed in 2/93 (2%). One complex indel leading to a severe phenotype was incorrectly called a nonsynonymous substitution c.-32-13T>C due to misalignment. These results demonstrate that WES may fail to diagnose Pompe disease. Clinicians need to be aware of limitations of WES, and consider tests specific to Pompe disease when WES does not provide a diagnosis in patients with proximal myopathy, progressive respiratory failure or other subtle symptoms.