Hereditary myopathies associated with hematological abnormalities

Abstract

The diagnostic evaluation of a patient with suspected hereditary muscle disease can be challenging. Clinicians rely largely on clinical history and examination features, with additional serological, electrodiagnostic, radiologic, histopathologic, and genetic investigations assisting in definitive diagnosis. Hematological testing is inexpensive and widely available, but frequently overlooked in the hereditary myopathy evaluation. Hematological abnormalities are infrequently encountered in this setting; however, their presence provides a valuable clue, helps refine the differential diagnosis, tailors further investigation, and assists interpretation of variants of uncertain significance. A diverse spectrum of hematological abnormalities is associated with hereditary myopathies, including anemias, leukocyte abnormalities, and thrombocytopenia.Recurrent rhabdomyolysis in certain glycolytic enzymopathies co-occurs with hemolytic anemia, often chronic and mild in phosphofructokinase and phosphoglycerate kinase deficiencies, or acute and fever-associated in aldolase-A and triosephosphate isomerase deficiency. Sideroblastic anemia, commonly severe, accompanies congenital-to-childhood onset mitochondrial myopathies including Pearson marrowpancreas syndrome and mitochondrial myopathy, lactic acidosis, and sideroblastic anemia phenotypes. Congenital megaloblastic macrocytic anemia and mitochondrial dysfunction characterize SFXN4-related myopathy. Neutropenia, chronic or cyclical, with recurrent infections, infantile-to-childhood onset skeletal myopathy and cardiomyopathy are typical of Barth syndrome, while chronic neutropenia without infection occurs rarely in DNM2-centronuclear myopathy. Peripheral eosinophilia may accompany eosinophilic inflammation in recessive calpainopathy. Lipid accumulation in leukocytes on peripheral blood smear (Jordans' anomaly) is pathognomonic for neutral lipid storage diseases. Mild thrombocytopenia occurs in autosomal dominant, childhood-onset STIM1 tubular aggregate myopathy, STIM1 and ORAI1 deficiency syndromes, and GNE myopathy. Herein, we review these hereditary myopathies in which hematological features play a prominent role.

EHBP1L1 Frameshift Deletion in English Springer Spaniel Dogs with Dyserythropoietic Anemia and Myopathy Syndrome (DAMS) or Neonatal Losses

“…Hereditary diseases involving either congenital dyserythropoietic anemias [ 9 , 29 , 30 ] or congenital myopathies [ 10 , 11 , 31 , 32 , 33 ] have been described and associated with specific gene defects in humans and animals. In this study, we further characterize a dyserythropoietic anemia and myopathy syndrome (DAMS) in a large family of ESSP dogs as an autosomal recessive trait that is likely caused by an EHBP1L1 frameshift deletion.…”

“…In addition, siderocytic anemias in humans are microcytic [ 43 ]. Human patients with CDA frequently have splenomegaly [ 33 ], which was noted in some but not all affected ESSPs and in one of two Labrador retriever dogs with a similar syndrome [ 18 ].…”

“…As mentioned above, EHBP1L1 is an integral part of RAB8 and the BIN1–dynamin complex and could thus readily explain the myopathy [ 44 , 45 , 46 , 47 ]. Defects in BIN1 and dynamin 2 have been reported to cause CNM in humans and animals [ 12 , 13 , 14 , 31 , 32 , 33 , 47 ].…”

Acquired and hereditary bone marrow failure: A mitochondrial perspective

“…Patients present with pancytopenia sideroblastic anemia and exocrine pancreatic insufficiency. The Barth syndrome, which presents with neutropenia in addition to musculoskeletal defects and cardiomyopathy, is another mitochondrial disorder ( 22 , 60 ).The Barth syndrome is caused by a mutation in the gene TAZ. TAZ encodes for the mitochondrial phospholipid transacylase tafazzin.…”

GNE myopathy: Don't sleep on the platelets

“…Mori‐Yoshimura and colleagues highlight that GNE myopathy can now assuredly take its place among the expanding list of inherited myopathies associated with hematological abnormalities 19 . Further prospective evaluation of the significance of PA‐IgG in larger patient cohorts is needed, but PA‐IgG appears to be a promising biomarker in this disorder.…”