X-linked Emery–Dreifuss muscular dystrophy caused by a novel FHL1 mutation: A case report

Abstract

This study characterizes a multigenerational family with X-linked Emery–Dreifuss muscular dystrophy associated with a novel FHL1 mutation (c.746G>A, p.Cys249Tyr). Among 21 family members, 5 were affected and 3 had died. The affected individuals exhibited progressive limb weakness and muscle atrophy; classical joint contractures were absent or minimal. The proband presented with mild muscle wasting and sinus tachycardia without structural cardiac abnormalities. Electromyography revealed myopathic changes with preserved nerve conduction. Thigh magnetic resonance imaging demonstrated bilateral reduction of muscle volume with fatty infiltration, and muscle biopsy confirmed variable fiber size, degeneration, and mild fibrosis consistent with a myogenic pattern. Genetic testing identified six affected members carrying the hemizygous FHL1 c.746G>A variant, resulting in a cysteine-to-tyrosine substitution at codon 249. These findings expand the genotypic and phenotypic spectrum of FHL1-related X-linked Emery–Dreifuss muscular dystrophy, highlight the marked clinical and genetic heterogeneity of the disorder, and provide important insights into early diagnosis, phenotype prediction, and genetic counseling of the affected families.

Introduction

Emery–Dreifuss muscular dystrophy (EDMD) is a rare inherited neuromuscular disorder, first described in 1902 ¹ and defined as a distinct clinical entity by Emery and Dreifuss in 1966. ² The classical clinical triad includes the following: (a) early-onset joint contractures, mainly affecting the elbows, ankles, and cervical spine; ³ (b) slowly progressive muscle weakness and atrophy, typically in a humeroperoneal distribution; ⁴ and (c) cardiac conduction abnormalities, ranging from sinus node dysfunction to atrioventricular block and life-threatening arrhythmias. ⁵

EDMD demonstrates considerable genetic heterogeneity, with X-linked, autosomal dominant, and autosomal recessive inheritance patterns. ⁶ X-linked EDMD (X-EDMD) is most commonly associated with mutations in the EMD and FHL1 genes. ⁷ The FHL1 gene generates three major protein isoforms—FHL1A, FHL1B, and FHL1C—through alternative splicing, which differ in their structural characteristics and tissue distribution. ⁸ FHL1A is the predominant isoform, containing four and a half Lin-11, Isl-1, and Mec-3 (LIM) domains, with high expression in skeletal muscles and moderate expression in cardiac muscles. ⁹ In contrast, FHL1B and FHL1C are expressed at lower levels. FHL1B shuttles between the nucleus and cytoplasm ¹⁰ and is predominantly expressed in the skeletal muscles and brain, ¹¹ while FHL1C is mainly expressed in the skeletal muscles and testes. ¹² FHL1A contributes to sarcomere stability via its interaction with myosin-binding protein C, while FHL1B and FHL1C regulate their subcellular localization via nuclear localization and export signals.

In this study, we describe a multigenerational family with X-EDMD carrying a hemizygous FHL1 c.746G>A (p.Cys249Tyr) mutation. Five affected male patients presented predominantly with proximal muscle weakness and atrophy, mild or absent joint contractures, and minimal cardiac involvement. Electromyography (EMG) revealed myopathic changes, and magnetic resonance imaging (MRI) showed symmetrical fatty infiltration of the thigh muscles. The variant was confirmed using Sanger sequencing and co-segregated with the disease phenotype.

This report delineates the clinical, pathological, and genetic features of FHL1-related X-EDMD caused by c.746G>A mutation, expanding the known genotype–phenotype correlations and providing insights that would aid early diagnosis, phenotype prediction, and development of targeted management strategies for the affected families.

Clinical data

Clinical presentation of the proband

The proband was a man in his early 20s; his height was 167 cm and weight was 83 kg. He had developed progressive bilateral lower limb weakness 5 years ago without any apparent precipitating factors and experienced difficulty while climbing stairs and walking uphill. His symptoms had gradually worsened, leading him to seek medical attention in early 2024. He had no history of chronic systemic or infectious diseases, and several family members had exhibited similar symptoms, suggesting a hereditary neuromuscular disorder.

Since early 2024, the patient has been undergoing regular follow-up. At the initial assessment, mild proximal weakness (MRC 4/5) was observed in both upper limbs, with scapular girdle atrophy, mild atrophy of the supraspinatus and infraspinatus muscles, and pseudohypertrophy of the deltoid (Figure 1(a)). In the lower limbs, proximal strength was 4/5, with brisk tendon reflexes and bilateral calf muscle atrophy, more pronounced on the left, along with mild gastrocnemius hypertrophy (Figure 1(b)). No pathological reflexes were present, and coordination was intact. His 6-min walk distance was 470 m, and timed up-and-go (TUG) test time was 13.8 s. By mid-2024, his muscle strength had decreased to 4/5, 6-min walk distance had reduced to 450 m, and TUG test time had increased to 15.4 s. At follow-up in early 2025, his strength had further declined to 4/5, 6-min walk distance had reduced further to 420 m, and TUG test time had increased to 16.7 s. Throughout the follow-up period, the patient’s gait slowed progressively, with notable fatigue after walking >500 m or climbing up two flights of stairs.

Figure 1.

(a) Scapular girdle atrophy and deltoid pseudohypertrophy. (b) Bilateral calf muscle atrophy (more pronounced on the left) with mild gastrocnemius hypertrophy. (c) Proximal lower limb MRI showing atrophy with fatty infiltration in the adductor muscles, vastus intermedius, and vastus lateralis, with additional involvement of the vastus medialis, semitendinosus, gracilis, adductor longus, adductor magnus, and adductor brevis. (d–e) Biceps brachii biopsy: fibers of variable diameter, focal degeneration and necrosis, occasional opaque fibers, and mild connective tissue proliferation. (f) AMP staining showing normal enzymatic activity. ATP staining revealing a mosaic pattern of type I and II fibers, with type II predominance in some regions (acidic 200×, g; alkaline 200×, h). (i) SDH staining (200×) showing largely preserved myofibrillar network with focal mild activity changes; no moth-eaten or split fibers observed. (j) Genetic testing showing a hemizygous FHL1 variant NM_001449.4:c.746G>A (p.Cys249Tyr) in exon 8, affecting the fourth LIM domain of the FHL1A isoform. MRI: magnetic resonance imaging; AMP: adenosine monophosphate; ATP: adenosine triphosphate; SDH: succinate dehydrogenase; LIM: Lin-11, Isl-1, and Mec-3 domain.

Figure 1.

Continued.

From the patient’s perspective, progressive muscle weakness had significantly impacted his daily life. For instance, his walking endurance had reduced, he faced difficulty in stair climbing and prolonged standing, and had to rely on others for certain activities. The patient reported marked physical fatigability and experienced a degree of psychological stress, primarily related to uncertainty about disease progression and concerns regarding his future functional status. These observations highlight that beyond objective clinical assessments, quality of life and psychological well-being are also critical considerations in the management of patients with FHL1-related EDMD.

Ancillary examination results of the proband

The patient’s serum creatine kinase (CK) level was elevated (801.0 U/L, reference range, 50–310 U/L), and his myoglobin level was increased to 125.37 ng/mL (reference range, 25–72 ng/mL), whereas his CK-myocardial band (MB) and lactate dehydrogenase levels were normal. Cardiac ultrasonography and electrocardiography showed no abnormalities.

EMG of the left tibialis anterior and medial gastrocnemius showed no spontaneous activity at rest. During mild voluntary contraction, the duration and amplitude of motor unit potentials were slightly reduced, consistent with a myopathic pattern. Nerve conduction velocities were within normal limits.

Skeletal muscle MRI showed atrophy with fatty infiltration in the short and long heads of the adductor muscles, the vastus intermedius, and the vastus lateralis. Additionally, fatty infiltration with atrophy was observed in the vastus medialis, semitendinosus, gracilis, adductor longus, adductor magnus, and adductor brevis (Figure 1(c)). Magnetic resonance images were limited to the proximal lower limb muscles.

Biceps brachii biopsy showed fibers of variable diameter with focal degeneration and necrosis, occasional opaque fibers, and mild connective tissue proliferation (Figure 1(d) and (e)). Adenosine monophosphate (AMP) staining demonstrated normal enzymatic activity (Figure 1(f)). Adenosine triphosphatase (ATP) staining revealed a mosaic pattern of type I and II fibers, with type II fibers predominating in some regions (ATP acidic 200×, Figure 1(g); ATP alkaline 200×, Figure 1(h)). Succinate dehydrogenase (SDH) staining 200× showed a largely preserved myofibrillar network, with focal mild increases or decreases in activity; no moth-eaten or split fibers were observed (Figure 1(i)).

Results of genetic testing of the proband (Figure 1(j)): a hemizygous variant was identified in the FHL1 gene: NM_001449.4:c.746G>A, resulting in a missense substitution p.(Cys249Tyr), located at exon 8 at genomic position chrX:135,292,087 (GRCh37/hg19), affecting the fourth LIM domain of the FHL1A isoform. This variant is found in the FHL1A isoform, which is highly expressed in skeletal and cardiac muscles and is most relevant to the clinical phenotype observed in this case. Exon 8 is shared by all three major FHL1 isoforms; however, structural differences in their transcripts may result in the variant affecting cysteine residues at different positions in other isoforms. Computational prediction analysis indicated that this variant was likely pathogenic: rare exome variant ensemble learner (REVEL) = 0.898, combined annotation-dependent depletion (CADD) = 25, sorting intolerant from tolerant (SIFT) was “deleterious” (0.02), polymorphism phenotyping (PolyPhen)-2 was “probably damaging” (0.85), and MutationTaster2 predicted it to be “disease-causing.” Additionally, this variant is absent from the gnomAD v2.1.1 database (allele count =0), further supporting its pathogenicity.

Pedigree analysis

As detailed in Figure 2, the proband (III:1) has three maternal uncles (II:5, II:7, II:9) who developed muscle weakness at approximately 10 years of age, consistent with progressive muscular dystrophy. All three reportedly died of respiratory failure at approximately 40 years of age; however, none underwent genetic testing. The proband’s maternal cousin (III:2), the son of his maternal aunt, is suspected to have progressive muscular dystrophy, presenting with limited right scapular mobility and right upper limb weakness, while remaining ambulatory. This clinical information was obtained from the proband’s medical history rather than via direct evaluation, and III:2 has not undergone formal assessment or Sanger sequencing due to limited medical access. Additionally, five female family members (I:2, II:2, II:4, IV:2, IV:3) were tested and found to be heterozygous carriers of the FHL1 variant, all without overt clinical symptoms. No other family members with negative genetic testing were identified.

Figure 2.

Pedigree analysis: male, female, proband, patient, X-linked carrier, and deceased individual.

The genetic testing results of family members presented in Figure 2 are detailed in Figure 3 (a) to (e): I:2 (Figure 3(a)), II:2 (Figure 3(b)), II:4 (Figure 3(c)), IV:2 (Figure 3(d)), and IV:3 (Figure 3(e)) carry the heterozygous c.746G>A point mutation. All carriers were asymptomatic.

Figure 3.

Genetic testing results of family members: (a) I:2, (b) II:2, (c) II:4, (d) IV:2, (e) and IV:3 are heterozygous carriers of the c.746G>A mutation. (a) (I:2) (early 80s): heterozygous variant. (b) (II:2) (early 50s): heterozygous variant. (c) (II:4) (early 60s): heterozygous variant. (d) (IV:2) (toddler): heterozygous variant. (e) (IV:3) (early 20s): heterozygous variant.

Figure 3.

Continued.

Treatment

The patient received Coenzyme Q10 (10 mg thrice daily after meals) and symptomatic supportive therapy during hospitalization. No other treatments were used, and no significant adverse reactions occurred. However, the symptoms did not improve.

Discussion

This study reports a rare familial case of EDMD with a novel FHL1 mutation, c.746G>A (p.Cys249Tyr), in a male proband. Although EDMD classically presents with progressive muscle weakness, joint contractures, and cardiac involvement, this proband lacked contractures and cardiac abnormalities, underscoring the disease’s phenotypic heterogeneity. FHL1-related myopathies show broad clinical variability and overlap with other muscular dystrophies, complicating diagnosis. ¹³ Thus, building genotype–phenotype databases, accumulating more case reports, and fostering international collaboration are vital for improving diagnosis and understanding pathogenesis. Genetic counseling is also essential for risk assessment and reproductive guidance. ¹⁴

Although the proband did not show cardiac involvement at the time of this study, cardiac manifestations are common and represent the most severe feature of EDMD. ⁵ These primarily include conduction defects, atrial fibrillation/flutter, and atrial standstill. ¹⁵ Sudden cardiac death and heart failure due to left ventricular dysfunction are leading mortality causes. However, some FHL1 mutation carriers present with skeletal muscle involvement ¹⁶ and contractures without detectable cardiac abnormalities, highlighting the phenotypic variability associated with FHL1-related myopathies. ¹⁷ Treatment mainly focuses on symptomatic and supportive care; pacemaker implantation is necessary for severe conduction block or bradyarrhythmia. ¹⁸ Thus, long-term cardiac monitoring and annual follow-up are crucial for EDMD patients.

This pedigree is suggestive of an X-linked mode of inheritance. Five female family members (I:2, II:2, II:4, IV:2, and IV:3) were identified as heterozygous carriers and remained clinically asymptomatic. Three maternal uncles of the proband (II:5, II:7, and II:9) reportedly developed adolescent-onset progressive proximal muscle weakness and died of respiratory failure in mid-adulthood. Although this distribution may be compatible with X-linked inheritance, the possibility of incomplete clinical information and limited family size should be considered.

Muscle MRI demonstrated symmetrical fatty degeneration of the bilateral thigh muscles. This imaging pattern is not specific to FHL1-related myopathies and can be observed in several neuromuscular disorders, including limb-girdle muscular dystrophies, myofibrillar myopathies, and congenital muscular dystrophies. In this patient, MRI provided valuable information regarding the distribution of muscle involvement; however, the severity of clinical functional impairment was not fully reflected on imaging. ¹⁹ Therefore, MRI results should be interpreted in conjunction with clinical and functional assessments to provide a more comprehensive evaluation of disease severity and progression.

The FHL1 protein contains several highly conserved LIM domains, each composed of two zinc finger motifs, whose conformation depends on the coordination of zinc ions by cysteine and histidine residues. Substitutions in these critical residues, particularly cysteine, can impair zinc binding, cause protein misfolding, and disrupt interactions with sarcomeric proteins. ²⁰ Mutations affecting the distal LIM domains, especially the fourth LIM domain, are primarily associated with the EDMD6 phenotype, while mutations in other domains are more commonly linked to reducing body myopathy or X-linked postural muscular atrophy (XMPMA). ²¹ Literature reports indicate that disruptions in conserved residues of LIM3/4 domains lead to reduced protein expression or functional impairment, further supporting their significance in genotype–phenotype correlations. The p.Cys249Tyr variant identified in this study lies within the fourth LIM domain, directly affecting the key zinc-binding cysteine residue, consistent with the EDMD6 phenotype.

Currently, no specific therapies exist for FHL1-related myopathies; management remains supportive, focusing on symptom relief and preservation of functional capacity.

Conclusion

The FHL1 c.746G>A (p.Cys249Tyr) variant identified in this family expands the mutational and phenotypic spectrum of FHL1-related X-EDMD. This case highlights the clinical variability associated with FHL1 mutations and underscores the importance of integrating clinical findings, imaging features, and genetic analysis in the affected families. Long-term follow-up remains essential, particularly for monitoring potential cardiac involvement in patients with FHL1-related EDMD. The reporting of this study conforms to the Case Report (CARE) guidelines.