Long-term Natural History Observations of FHL1-related Reducing Body Myopathy from Childhood to Adulthood

Topic:

Other

Poster Number: 290 T

Author(s):

Pitchamol Vilaisaktipakorn, MD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Payam Mohassel, MD, Department of Neurology, Johns Hopkins University School of Medicine, Pomi Yun, MD, Department of Neurology, Johns Hopkins University School of Medicine, Sandra Donkervoort, MS, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Healt, Wei Zhang, MD, Department of Neurology, Peking University First Hospital, Michael Leeson, MD, Division of Medical Genetics, Children's Hospital Los Angeles, Jachinta Rooney, PhD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Yaqun Zou, MD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, A. Reghan Foley, MD, MD(Res), Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health, Carsten G. Bönnemann, MD, habil., Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, National Institutes of Health

Reducing body myopathy (RBM) is a rare, X-linked dominant progressive myopathy, characterized by the presence of reducing bodies on muscle histopathology. While often severe and progressive in early childhood manifestations, its long-term natural history in comparatively milder familial cases is still poorly understood. Here, we report long-term natural history observations of RBM from childhood to adulthood in two unrelated families and review the literature on emerging genotype-phenotype correlations in RBM. Family 1 (P1: son; P2: mother) harbors FHL1: p.C150R, and Family 2 (P3: male proband) harbors FHL1: p.C132Y. Initial symptoms were elbow contractures noted in P1 at 9 years and toe-walking/gait difficulties noted in P3 at 8 years. P1, at 21 years, can take a few steps with support, has a forced vital capacity of 52% (upright) and 51% (supine), and has been fed entirely via G-J tube since age 17 years. P3, at 18 years, lost ambulation by 14 years, has required full-time ventilatory support since age 18 years, and (in the absence of a G-tube) has minimal intake by mouth. Muscle ultrasound in P1 demonstrates a progression of increased echogenicity in most muscles over time. P2 exhibits a milder clinical phenotype but shows clear progression of asymmetric muscle weakness, and strikingly asymmetric and patchy abnormal T1 signal on serial muscle MRIs. Cardiac function has remained normal in all patients. These findings emphasize the phenotypic variability in FHL1-RBM and highlight progression in comparatively milder familial cases. They also underscore the importance of proactive pulmonary and nutritional care and support and demonstrate the potential of muscle imaging to serve as a biomarker of disease progression in males and females. Following our discovery of FHL1 as the causative gene for RBM in 2008, gene-directed therapeutic strategies are now under development. Our clinical observations contribute to clinical trial readiness for this challenging condition.