A 40-year-old male visited our clinic for asymmetric upper and lower extremity weakness. The patient reported that he had suffered bilateral shoulder weakness since the age of 10 years. When he was 13-years-old, he presented with a right winged scapula. In addition, he reported bilateral leg weakness since he was 24 years old. Physical examination revealed a transverse smile; winged scapula; “Popeye” arm appearance; facial weakness; and asymmetric, proximal dominant arm and leg weakness (right side more severe than the left). Serum creatinine kinase levels were mildly elevated at 319 unit/L. His father and elder brother had similar symptoms (). His elder brother had been visiting another hospital for similar symptoms since he was 10 years old, and his muscle pathology showed severe chronic myopathic changes (marked increased size variability, hypertrophic fibers, degenerating and atrophic fibers, endomysial fibrosis and mild fatty infiltration, disruption of intermyofibrillar network, and lobulated fibers) with normal dystrophin immunoreactivity. The elder brother was diagnosed with FSHD based on clinical phenotype, but refused a genetic study. However, our patient agreed to undergo genetic analysis for diagnosis. Therefore, we performed conventional Southern blot analysis with EcoRI and BlnI enzymes, but the D4Z4 repeat size was 12, which is normal. Next, whole exome sequencing revealed a novel frameshift mutation (c.3801delG, p.Glu1267Aspfs*5) in SMCHD1 [, upper (patient) and lower (mother) panels], a mutation that has not been described in previous reports or public databases (ExAC, ESP6500, 1000 genome). Finally, methylation-sensitive Southern blot analysis with FseI showed mildly reduced D4Z4 repeat size on 4q (41kb/39kb) and reduced D4Z4 methylation ratio (14.6%). Accordingly, we could report our case 1 as “pathogenic” and carrying a novel variant, as indicated in ACMG-AMP guidelines.
Patient 2 was a 36-yr-old man presenting with progressive limb muscle weakness, which developed at the age of 20. Initially, he began to have a difficulty in raising his arm above his head and climbing stairs. The weakness was slowly progressive. His mother was noted to have similar symptoms (). His 34-yr-old brother and 39-yr-old sister were not affected clinically. The neurological examination was remarkable for moderate facial weakness; mild (MRC grade 4) and minimal weakness of proximal and distal extremity muscles, respectively; and humeral and quadriceps atrophy. Other remarkable findings included winged scapulae, anterior axillary folds, waddling gait, and hypoactive deep tendon reflexes. The serum creatinine kinase (CK) was 610 IU/L. The forced vital capacity (FVC) was 3.2 L (71% of predicted). Electrocardiogram, echocardiogram, audiogram, and nerve conduction studies were normal. Needle electromyography demonstrated chronic myopathic changes.