Bilateral foot drop as presenting feature of facioscapulohumeral muscular dystrophy type 1

Highlights

• •FSHD1 may present with bilateral foot drop in adulthood.
• •Clinical examination, EMG and muscle MRI may additionally guide genetic testing.
• •Targeted genetic testing is crucial in atypical cases, particularly in light of new therapies.

Dear Editor,

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is a comparatively common genetic myopathy in adults with an estimated prevalence of 12 per 100,000 individuals [1]. The condition is caused by a dominantly inherited pathogenic contraction of the D4Z4 repeat array located on chromosome 4 [2].

Affected individuals usually exhibit an asymmetric and descending pattern of muscle weakness, that is that facial muscles and upper extremities are initially affected, subsequently followed by leg muscle weakness [3]. However, the clinical expression may vary significantly both in terms of severity and the pattern of muscle weakness. Previous studies have outlined atypical disease manifestations, including facial-sparing variants, predominant ophthalmoplegic features, focal as well as isolated lower limb weakness [[4], [5], [6]].

In this report, we describe a currently 39-year-old male patient who had developed left-sided foot drop at the age of 37 years. The patient underwent multiple evaluations, including neurology, nerve conduction studies (NCS), and orthopedic assessments, but no definitive explanation for his symptoms was identified. Approximately one year later, he had also developed foot drop on the right side. The degree of weakness was reported to remain unchanged over the course of a day. He did not report any muscle pain. Upper limb strength was normal, allowing him to continue working as an event technician. His general medical history was also unremarkable, and the family history was negative with respect to neuromuscular disorders. His father is reported to have Parkinson's disease, his mother has no known health issues at the age of 60, and he has three healthy siblings.

A neurological examination at the age of 38 years showed bilateral weakness in foot dorsiflexion (Medical Research Council [MRC] grade 1–2), with a preserved muscle strength (MRC grade 5) in all upper limb and proximal leg muscles. In addition, significant atrophy of the tibialis anterior muscles was noted on both sides. The ankle jerk reflex was also reduced bilaterally, while all other deep tendon reflexes were normal. Although truncal weakness was not reported by the patient, a positive Beevor's sign was evident upon clinical examination. Lastly, while there was no overt “myopathic facies”, he also had difficulties blowing up his cheeks, though he could whistle.

Laboratory tests showed elevated serum creatine kinase (CK) activity levels in the range between 300 and 400 U/l. Furthermore, electromyography (EMG) indicated marked myopathic changes, i.e. shortened mean motor unit action potential duration, in the clinically affected tibialis anterior muscles. Notably, increased resistance during needle insertion in this muscle was suggestive of fibrosis. EMG of the right gastrocnemius and right quadriceps femoris muscles was unremarkable. Additionally, NCS of the peroneal nerves, including motor, sensory, and F-wave assessments, were normal on both sides.

Magnetic resonance imaging (MRI) of the lower limb muscles revealed bilateral muscle edema and fatty atrophy of the tibialis anterior and extensor muscles of the foot. The edema was more pronounced on the right side, whereas fatty atrophy, especially in the extensor muscles, was more severe on the left side, aligning with the patient's clinical history. MRI of the lower spine demonstrated fatty atrophy of the iliocostalis lumborum muscle bilaterally (Fig. 1). The findings of subtle asymmetry of muscle involvement are in line with previous reports describing asymmetric muscle involvement in approximately 45 % of cases with FSHD [7].

Fig. 1.

Magnetic resonance imaging (MRI) demonstrates muscle edema and fatty atrophy of the tibialis anterior (TA) and extensor muscles (asterisk), as well as atrophy of the iliocostalis lumborum muscle (star) bilaterally. Tibia (T) and Fibula (F) are also labeled.

Despite the atypical history with bilateral foot drop developing in adulthood, FSHD was suspected as differential diagnosis based on subtle yet characteristic examination and electrophysiological findings with normal NCS and myopathic EMG changes. Subsequently performed targeted genetic testing using Southern blot revealed a pathogenic contraction of the D4Z4 repeat array (23 kb, normal range: ≥43 kb) along with a permissive haplotype, consistent with FSHD1.

Diagnosing FSHD1 can be challenging, from both a clinical and genetic point of view. Clinically, our case might have been misinterpreted as polyneuropathy or distal myopathy. Here, a thorough electrophysiological workup provided the initial clue towards a myopathic cause. Nonetheless, the absence of overt upper limb weakness (MRC 5) may rather lead to the suspicion of less common distal myopathies, mainly affecting the leg muscles. Eventually, the focus on subtle clinical signs (e.g., Beevor's sign) following the thorough electrophysiological assessment corroborated FSHD as the primary differential diagnosis, leading to targeted single-gene testing.

From a genetic viewpoint, many patients receive unbiased next-generation sequencing (NGS) as a first-tier diagnostic test. Although comprehensive NGS applications have outperformed targeted approaches for most indications, there are important technical limitations that need to be considered [8]. Notably, most NGS analyses do not depict pathogenic repeat expansions or contractions, which is the type of genetic variation underlying FSHD1, which typically requires targeted testing. Recent technological advancements, particularly optical genome mapping, may represent more refined methods for measuring D4Z4 repeats and offer additional insights into genotype-phenotype correlations [9].

Overall, our case description underscores the relevance of a thorough clinical examination, accompanied by conventional diagnostic applications such as MRI and EMG to eventually obtain a correct genetic diagnosis. Achieving an accurate molecular diagnosis is crucial for genetic counselling, prognostication and screening for comorbidities. In the near future, this may even become more important, given the recent development of specific treatments [10].

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used the ChatGPT (version GPT-4) language model for language optimization. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Ethics committee approval

Ethics committee approval was not required for this letter, as only anonymized data of one single case are reported.

Consent for publication

Informed consent was obtained from the patient.

CRediT authorship contribution statement

Martin Krenn: Writing – original draft, Formal analysis, Data curation, Conceptualization. Veronika Vetchy: Writing – review & editing, Visualization, Formal analysis, Data curation. Gregor Kasprian: Writing – review & editing, Supervision, Formal analysis, Data curation. Wolfgang Grisold: Writing – review & editing, Supervision, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no conflicts of interest related to this article.