A Case of a Patient With MYH2-Associated Myopathy Presenting With a Chief Complaint of Hand Tremor

Introduction

Tremor is defined as an involuntary, rhythmic, and oscillatory activity that can involve various parts of the body. The generation of rhythmic tremor activity necessitates the presence of “oscillators”, which are functional systems composed of interconnected body parts, including muscles, peripheral nerves, central nuclei, and neuronal networks. The intricate interactions within these oscillator systems can result in a wide range of tremor etiologies. Most tremor syndromes are associated with the central nervous system pacemakers, while peripheral nervous system pacemakers are less commonly implicated. Additionally, myogenic tremor stands out as a recently recognized and potentially under-characterized novel type of tremor, with the tremor pacemaker uniquely situated at the level of the myofibrils [1].

To date, myogenic tremor has only been reported in association with mutations in sarcomere-associated genes, mainly the thick filaments and the thin filaments. Myosin, a major structural component of the thick filaments, is crucial for bodily movement and cardiac contractility [2]. The conventional two-headed myosin is a hexamer formed by two identical myosin heavy chains (MyHCs) and two pairs of non-identical myosin light chains (MyLCs) [3]. In adult skeletal muscles, MyHC IIa, one of the three major MyHC isoforms, is encoded by MYH2 gene and expressed in fast-type 2 A and 2B muscle fibers. Mutations in the MYH2 gene lead to a rare group of hereditary myopathies with both autosomal dominant (AD) and recessive (AR) modes of transmission [4, 5, 6, 7].

Herein, we describe a male patient with MYH2-associated myopathy who exhibited high-frequency, postural tremor that was notably pronounced in his fingers and appeared in conjunction with muscle weakness and ophthalmoplegia. The diagnosis was confirmed by the identification of two novel compound heterozygous variants in MYH2 via whole-exome sequencing and a muscle biopsy that revealed a reduction in type 2 A fibers. The co-occurrence of tremor and muscle weakness strongly indicates a sarcomeric origin, offering a valuable clinical indicator for the differential diagnosis of complex tremor disorders.

Case report

The patient was a 21-year-old Chinese man who was the only child of healthy, non-consanguineous parents. He was born at 39 weeks’ gestation via spontaneous vaginal delivery, and exhibited normal motor development with no history of early joint contracture. During his middle school years, he reported involuntary bilateral hand tremor in specific postures, particularly noticeable when pouring water into a narrow-mouthed container. Despite the prior diagnosis of essential tremor and treatment with propranolol, there was no improvement in his symptoms. He later noticed a slight decrease in muscle strength, characterized by diminished explosive power, which became evident during sprint tests. At the age of 21, he had difficulty when lifting heavy objects and visited our clinic for the first time. He had no symptoms of prominent dysphagia. Examination revealed near-complete ophthalmoplegia, slight constant ptosis, and myopathic facial appearance. Muscle strength, graded using the Medical Research Council (MRC) scale, was 4/5 for neck flexor muscles, 4+/5 for shoulder abduction, 4+/5 for elbow flexion, and extension, and 4/5 for hand intrinsics muscles. Mild bilateral facial weakness was observed, characterized by a weak smile and normal eyelid closure strength. Tongue lateralization demonstrated normal agility and range of motion. The strengths of the bilateral hip abductor, knee extensor, and ankle dorsiflexor muscles were all rated as normal. Muscle atrophy was not apparent, except for mild atrophy of the tongue, and mild atrophy of both the thenar and hypothenar muscles. There was a mild, medium to high frequency postural tremor involving the fingers, and the tremor symptoms did not worsen upon the 3-year follow-up examination (Video 1). Spooning was present in both hands when the arms were extended forward, with the left hand showing a more pronounced effect in the wing-beat position. Additionally, there was a clear indication of dystonic flexion in the right fifth finger during the wing-beat position. Extremely mild tremors were observed on the left hand during the spiral drawing test. On the nose-finger-nose test, no intention tremors and dysmetria were observed. No signs of sensory impairment were observed. The patient had a normal gait, with no difficulty walking uphill or climbing stairs. Serum creatine kinase levels ranged between 444 and 812 IU/L (normal range: 50–310 IU/L). His resting-state lactate concentration ranged between 2.87 and 3.18 mmol/L (normal range: 1.42–1.9 mmol/L). Routine blood test, thyroid function tests and serum levels of ceruloplasmin, ferritin and vitamin B12 were within normal limits. Nerve conduction studies and electromyographic findings were unremarkable. The electrocardiogram and echocardiography were normal. Magnetic resonance imaging (MRI) revealed mild fatty infiltration of the deltoid muscle and triceps brachii in the upper arms and the biceps femoris, sartorius, semitendinosus, semimembranosus, and gracilis in the thigh (Figure 1). No abnormalities or atrophy were detected in the brain MRI. Serum creatine kinase levels were normal in both of the patient’s parents.

Figure 1

A biopsy of the biceps brachii muscle, conducted at age 21, revealed mild variability in fiber size with scattered atrophic or hypoplastic fibers (Figure 2A). No obvious inflammatory cell infiltration was observed in the endomysium or perimysium. The fiber types were identified as ATPases, indicating marked predominance of type 1 fibers and minimal type 2 fibers (Figure 2B, C). Neither ragged red nor ragged blue muscle fibers were observed via modified Gomori trichrome (Figure 2D) or succinic acid dehydrogenase (SDH) staining, respectively. No Cox-deficient fibers were observed by COX/SDH double-staining. The intermyofibrillar network was slightly disturbed (Figure 2E).

Figure 2

Total DNA was isolated from the patient’s biceps brachii muscle and from the peripheral blood lymphocytes of his parents. Whole-exome sequencing conducted on the proband identified two heterozygous MYH2 variants (NM_017534.6): c.505 + 2T>C and c.3565 del C (p. (L1189Yfs*10)). The patient’s entire mitochondrial DNA (mtDNA) genome was enriched by single-amplicon long-range PCR followed by massive parallel sequencing; no pathogenic mtDNA variants, large deletions, or duplications were detected. Sanger sequencing was performed for verification and segregation analysis in the patient and his parents. The mother and father were heterozygous for c.505 + 2T>C and c.3565 del C, respectively (Figure 3). Both variants were absent from all population databases, including gnomAD (version 2.1.1) and Exome Aggregation Consortium (ExAC) database. The maternally inherited variant (c.505 + 2T>C) occurs on a canonical splice donor site of exon 3, which was predicted to be a splice-altering variant with an extraordinary score of 0.9759 on the Splice AI tool (v1.3) (https://github.com/Illumina/SpliceAI) and 36 on CADD v1.7 (CADD: Combined Annotation-Dependent Depletion; https://cadd.gs.washington.edu) [8, 9, 10]. The thresholds are 0.2 for splice AI and 14.25 for CADD, respectively. The second MYH2 variant, c.3565 del C, was predicted to result in a frameshift and premature stop codon (p. (L1189Yfs*10)), resulting in truncation of the proximal coiled-coil rod domain—and was therefore predicted to be pathogenic. Both variants were categorized as pathogenic according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines [11]: for variant c.505 + 2T>C, PVS1, PM2, PP3, and PP4; for c.3565 del C, PVS1, PM2, and PP4. Given that the patient’s parents showed no symptoms of muscle weakness or tremor, and the genetic testing results were consistent with the principle of co-segregation, the patient was diagnosed with autosomal recessive MYH2-associated myopathy.

Figure 3

Discussion

MyHC IIa myopathies are rare diseases with high levels of clinical and histological heterogeneity. To date, 7 AD and 23 AR mutations in MYH2 have been reported worldwide. Our patient carried two novel heterozygous variants, and there are several lines of evidence that these two variants are the cause of the congenital myopathy observed in this family: (1) The clinical and pathological phenotypes of the patient matched the typical characteristics of AR-MYH2 myopathy; (2) Both variants are not reported in any public population database, while non-pathogenic variants in MYH2 are very rare, considering the strong selective pressure against mutations in this gene as demonstrated by Tajshargi et al. [12]; (3) Fifteen out of 17 in silico analyses predicted the c.505 + 2T>C to be pathological, including SpliceAI and CADD; (4) The c.3565 delC variant shifts the reading frame and leads to a premature stop codon p.(L1189Yfs*10)—and a similar recessive single nucleotide deletion variant (c.4352 Adel;p. K1451Sfs*40), which is distal to the current MYH2 variant, has been previously reported to cause a severe phenotype [13]; (5) Whole-exome sequencing and optimized human mitochondrial genome sequencing did not reveal any other pathogenic variants that could explain the patient’s clinical phenotype.

In accordance with the previous reports, nonsense-mediated decay (NMD) leading to reduced transcript expression is one of the pathogenic mechanisms mediated by the nonsense mutations in MYH2 [4, 6, 13]. The two variants identified in our patient are predicted to potentially produce premature termination codons (PTCs), suggesting that transcripts from both mutated alleles might be degraded by NMD. To verify this hypothesis, the cDNA of MYH2 should be amplified and sequenced to confirm the presence of aberrant transcripts. Additionally, the proportion of each MyHC isoform in skeletal muscle should be quantified. The truncated and potentially non-functional or partially functional protein should also be detected using the MyHC IIa antibody by western blot.

It is worth noting that the chief complaint of our patient is hand tremor related to both posture and action. The tremor is localized to the distal joints (fingers) rather than the more proximal (wrist and elbow) tremor which is typically seen in essential tremor. In some cases, patients may not notice muscle weakness or ocular dysmotility without diplopia, since the clinical presentation is typically mild or static for prolonged periods—particularly among patients with a recessive pattern—resulting in delayed diagnosis. Although hand tremor is not a common clinical feature of MYH2-associated myopathy, it has been reported in patients with four distinct MYH2 gene mutations, encompassing both recessive and dominant types [5, 14, 15, 16]. Furthermore, tremors have frequently been associated with mutations in genes encoding sarcomeric proteins, such as those affecting MyHC and MyLC, components of the thick filament, as well as slow myosin binding protein-C (sMyBP-C), and the thin filament proteins troponin, tropomyosin, and nebulin [1, 17]. Consequently, in the differential diagnosis of tremors, myogenic causes should be considered, particularly in cases without prominent myopathic features.

The mechanism of tremor generation in our patient remains unclear. Tremors can arise from both neurogenic and myogenic foci, and both are thought to result from oscillations within the servomechanism γ-loop associated with the stretch reflex. Central to this mechanism are the innervated intrafusal muscle fibers, whose activation in response to the magnitude and rate of changes in muscle length regulates the reflex arc. Given that MYH2 expression is muscle sarcomere-specific, we hypothesize that variants in MYH2 could cause structural and/or contractile abnormalities at the sarcomere level, thereby inducing oscillations within the reflex arc and generating tremors.

Our case expands the clinical and mutational spectrum of MYH2-related myopathy and highlights that hand tremor, while rare, is a clinical feature that should not be overlooked in this disease. This insight underscores the importance of a comprehensive clinical evaluation and suggests that future research should focus on the under-recognized manifestations of MYH2-associated myopathy to improve early diagnosis and treatment strategies.

Ethics and Consent

This study received approval from the Ethics Committee of Xiangya Hospital, Central South University. We obtained written informed consent from the patient for the publication of this case report. We have thoroughly reviewed and adhere to the guidelines for ethical publication as outlined by the Journal, and we affirm that this work complies with these ethical standards.

Funding Information

This study was supported by the National Natural Science Foundation of China (Grant number: 82171256, Qiying Sun) and the Natural Science Foundation of Hunan Province, China (No. 2023 JJ40792, Xinxin Liao).

Competing Interests

The authors have no competing interests to declare.