There is a range of phenotypes associated with pathogenic variants in the FHL1 gene, including X-linked dominant scapuloperoneal myopathy, X-linked myopathy with postural muscle atrophy, reducing body myopathy, Emery-Dreifuss muscular dystrophy, rigid-spine syndrome, and hypertrophic cardiomyopathy. This gene encodes the four-and-a-half LIM domain protein 1 which is highly expressed in skeletal and cardiac muscle. The function of this protein includes influencing cellular architecture, myoblast differentiation, mechanotransduction, and skeletal muscle fiber size. We report a case of a 6-year-old boy with a novel FHL1 gene mutation who presented to the neuromuscular clinic for evaluation of stiffness, joint contractures, and mild proximal weakness. Symptoms first noted in the newborn period have been slowly progressive. The child's presentation has not been described before and represents a new clinical phenotype within the spectrum of FHL1-related disorders.

It has been known for long that females carrying pathogenic variants in the DMD gene often report symptoms and/or exhibit signs of the disease. However, a notable knowledge gap exists concerning the signs and symptoms of female carriers of other X-linked neuromuscular diseases (XLNMDs). This scoping review aims to provide a comprehensive outline of existing literature regarding the signs and symptoms of carriers of non-DMD XLNMDs to raise awareness among both researchers and clinicians. Three electronic databases were used for the literature search (PubMed, Embase, Web of Science). Studies on the signs and symptoms of carriers of non-DMD XLNMDs were included. We included 44 articles for this review with a total of 354 carriers of non-DMD XLNMDs (mean age 43.9 years, std. deviation 17.4). Muscular signs and symptoms were reported for 125 carriers (X-linked myotubular myopathy (XLMTM): n = 96 (65%); Kennedy's disease (KD): n = 25 (32%); X-linked recessive Charcot-Marie-Tooth disease (CMTXR): n = 2 (15%); Uruguay faciocardiomusculoskeletal syndrome (FCMSU): n = 1 (33%); Barth syndrome (BS): n = 1 (100%)). In terms of ancillary investigations, abnormalities in histopathology and imaging were the most frequent with 44 carriers having abnormalities found by these testing (XLMTM: n = 36 (24%); Emery-Dreifuss muscular dystrophy 1 (EDMD1): n = 4 (5%); KD: n = 4 (5%) / XLMTM: n = 18 (12%); EDMD1: n = 1 (1%); KD: n = 5 (6%); X-linked myopathy with postural muscle atrophy (XMPMA): n = 19 (83%); BS: n = 1 (100%)). A difference between the number of EDMD1 carriers with cardiovascular signs and symptoms (n = 2 (1%)) and the number of carriers with abnormal electrocardiography tests (n = 20 (23%)) was also noted. Carriers of non-DMD XLNMDs exhibit a variety of signs and symptoms that could impact quality of life, making it vital for clinicians to be aware of these patients.

Mutations in the FHL1 gene have been associated with a diverse spectrum of X-linked diseases affecting skeletal and cardiac muscle. Six clinically distinct human myopathies can be recognized, including reducing body myopathy (RBM), X-linked dominant scapuloperoneal myopathy (SPM), X-linked myopathy with postural muscle atrophy (XMPMA), rigid spine syndrome (RSS), hypertrophic cardiomyopathy (HCM) and type 6 Emery- Dreifuss muscular dystrophy (EDMD). The core features of all described FHL1opathies are mostly scapuloperoneal muscle weakness, rigid spine, cardiac involvement, and cytoplasmic bodies in the muscle biopsy. We systematically reviewed the medical literature between the years 2000 and 2024 regarding the phenotype and genotype description of FHL1-associated myopathies. Here, we report two novel patients presenting with an X-linked myopathy with postural muscle atrophy (XMPMA) caused by the c.672 C > G FHL1 gene mutation. When encountering these features in a patient, one may consider screening for an FHL1 mutation. The course ranges from a severe fatal course with early onset to very mild features with late onset. Once a dystrophinopathy has been excluded, increased CK values in male subjects with possible X-linked inheritance should always trigger FHL1 gene screening.

FHL1-related myopathies, including reducing body myopathy (RBM), X-linked scapulo-axio-peroneal myopathy, rigid spine syndrome, X-linked myopathy with postural muscle atrophy (XMPMA), X-linked Emery-Dreifuss muscular dystrophy and hypertrophic cardiomyopathy, are clinically and pathologically heterogeneous disorders caused by FHL1 gene mutations. According to previous reports, the first three types are myopathies with reducing bodies observed in biopsies, and the last three are myopathies without reducing bodies. We report four FHL1-related myopathy patients, including an XMPMA patient and a RBM family with three patients. Clinical information, muscle biopsies, electromyograms and genetic testing were obtained. Muscle weakness and atrophy, spinal rigidity, and joint contracture were present in the RBM family. The XMPMA patient showed a pseudoathletic appearance with muscle weakness and atrophy, spinal rigidity and deformity. The index patient of the RBM family underwent two muscle biopsies to find reducing bodies. Interestingly, these muscle biopsies revealed reducing bodies and rimmed vacuoles not only in the RBM family but also in the XMPMA patient. Next-generation sequencing identified a reported single missense mutation c.448 C>T (p. C150R) in the RBM family and a novel mutation c.814T>C (p. S272P) in the XMPMA patient. Therefore, FHL1-related myopathies overlap substantially and may not be simply classified into subtypes depending on reducing bodies. Biopsies of additional affected muscles can aid in finding reducing bodies. We report the first XMPMA patient with a novel FHL1 mutation and reducing bodies in a muscle biopsy in China.

FHL1-related myopathies are clinically heterogeneous, involving skeletal and cardiac muscles. Overlapping clinical features include joint contractures, rigid spine, scapuloperoneal weakness and cardiac diseases. Histopathologically, reducing bodies are the most characteristic finding, but not present in all FHL1-related cases. Non-specific dystrophic pathology without reducing body is usual in the forms of X-linked myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy and isolated hypertrophic cardiomyopathy. Here, we describe a patient with mild weakness with ankle contracture. We finally concluded he has a FHL1-related myopathy at an extreme end of phenotypic spectrum of FHL1 myopathy, which one might miss to recognize as a form of myopathy. The genetic variant was detected by whole exome sequencing, and its pathogenicity was clearly confirmed with pathological and biochemical studies. This is the first FHL1 case with a mildest phenotype backed by biochemical/genetic evidence. This report will help clinicians hesitating to further evaluate mild cases to better correlate the genotype to the phenotype.