A type IV spinal muscular atrophy with gastrocnemius pseudohypertrophy caused by SMN1 deletion: a case report and literature review

Abstract

Background

Spinal muscular atrophy (SMA) is a rare autosomal recessive genetic disorder characterized by severe neurological and muscular degeneration, often leading to severe disability or death. Its complex clinical manifestations frequently result in misdiagnosis or missed diagnosis. Type IV SMA primarily affects adults, rarely impacting normal lifespan or maximum motor capacity, and is clinically uncommon. However, SMA presenting with pseudohypertrophy of the gastrocnemius muscle and near-complete loss of motor function is extremely rare and has not been previously reported. We hereby report what we believe to be the first case of Type IV SMA caused by SMN1 deletion presenting with pseudohypertrophy of the gastrocnemius muscle.

Case presentation

A 51-year-old man presented with progressive weakness in all four limbs over 16 years, which worsened over the past two months, leaving him unable to walk. Examination strongly suggested a diagnosis of SMA type IV. He was found to have a homozygous deletion of the SMN1 gene at exon 7, located on 5q13.2. Muscle strength in the biceps brachii and triceps brachii of both upper limbs was grade IV, with weakened grip strength in both hands. Grade III muscle strength in the quadriceps of both lower limbs, Grade IV muscle strength in the tibialis anterior, gastrocnemius, and extensor hallucis longus muscles, bilateral knee reflexes and Achilles reflexes (+), right Hoffmann’s sign (+), bilateral Babinski signs (+), and Gower’s sign (+). Multiple disc herniations with degeneration in the cervical spine. Multiple muscle atrophy of the thoracic wall. Electromyography of the limbs shows neurogenic changes. However, symptoms such as pseudohypertrophy of the gastrocnemius muscle and almost complete loss of motor function are rare, suggesting a poor prognosis.

Conclusion

This rare case highlights that pseudohypertrophy of the gastrocnemius muscle may be a rare manifestation of type IV spinal muscular atrophy, and clinical differential diagnosis should be made with PMD and other diseases.

Background

Spinal muscular atrophy (SMA) is a rare, highly lethal autosomal recessive genetic neuromuscular degenerative disease caused by mutations or deletions in the survival motor neuron 1 gene (SMN1, OMIM #600354) located at 5q13.2 [1]. Epidemiological studies indicate that the incidence of the disease ranges from 1 in 10,000 to 1 in 6,000, with a carrier frequency of 1 in 70 to 1 in 40, primarily affecting infants, young children, and adolescents. The primary pathological feature is the degeneration of α-motor neurons in the anterior horn of the spinal cord. Clinical manifestations include proximal, symmetrical, progressive muscle weakness, skeletal muscle atrophy, and tongue fasciculations, often affecting the skeletal and respiratory systems [2]. Based on age of onset and symptoms, SMA is classified into five types: fetal, infantile, intermediate, juvenile, and adult [3]. Among these, type IV, which occurs in adults, is relatively rare, and cases presenting with pseudohypertrophy of the gastrocnemius muscle are even more uncommon, leading to misdiagnosis or missed diagnosis and posing challenges for newborn genetic counseling and the implementation of tertiary prevention. This article reports the first known case of Type IV SMA caused by SMN1 deletion, presenting with pseudohypertrophy of the gastrocnemius muscle. It reviews relevant literature to provide evidence for clinicians to accurately diagnose and treat Type IV SMA and provide genetic counseling for patients.

Case presentation

The patient is a 51-year-old male with progressive weakness in all four limbs for more than 16 years, which has worsened over the past two months. At the age of 35, the patient noticed weakness in both lower limbs during daily activities without any apparent cause, which gradually worsened and later affected the upper limbs. At the age of 51, the symptoms worsened significantly, with numbness in the skin of both forearms and the ulnar side of both hands, affecting his ability to care for himself and walk. Abdominal and calf muscle hypertrophy, quadriceps muscle atrophy. (Fig. 1A-C) Previous hospital examinations revealed multiple cervical disc herniations with degenerative changes (Fig. 1D, E). Multiple muscle atrophy of the thoracic wall (Fig. 1G-I). Electromyography of the limbs showed neurogenic changes, suggesting anterior horn cell lesions of the spinal cord (tibialis anterior muscle, medial head of the gastrocnemius muscle: insertion -, fasciculation +, positive sharp wave +, fasciculation -). Some of the muscles examined showed spontaneous electrical activity, prolonged MUP latency, and weakened active recruitment response. Preliminary diagnosis: “muscular dystrophy.” Treatment with neurotrophic agents was administered, but symptoms did not improve. The patient later presented at our hospital. Physical examination revealed muscle strength of grade IV in the biceps brachii and triceps brachii muscles of both upper limbs, weakened grip strength in both hands, muscle strength of grade III in the quadriceps femoris muscles of both lower limbs, muscle strength of grade IV in the tibialis anterior, triceps surae, and extensor hallucis longus muscles, bilateral knee reflexes and Achilles reflexes (+), right Hoffmann’s sign (+), bilateral Babinski sign (+), and Gower’s sign (+). Serum creatine kinase 161 U/L (normal range 50–310 U/L), serum creatine kinase isoenzyme 14.8 U/L (normal range < 19 U/L). No family history of the disease (Fig. 1J). Whole-exome sequencing revealed a homozygous deletion of the SMN1 gene in exon 7 at 5q13.2. All other test results were as previously reported (Fig. 1K).

Fig. 1.

Integrated clinical and molecular profile. A The patient has fat accumulation in the abdomen. B gastrocnemius pseudohypertrophy. C and quadriceps atrophy. D The MRI of the patient’s neck before surgery. E at the C3/C4 and C5/C6 levels. F one month after surgery, and eight months after surgery. G-I The patient’s pectoralis major muscle is atrophied, Chest CT image layer 19, chest CT image layer 20, chest CT image layer 21. J Genetic mapping of families of patients with spinal muscular atrophy, with II-4 as a pre-documented person, showing the results: Ruling out concomitant X- and Y-chromosome genetic disorders. K Patient WES-CNV test results show a homozygous deletion of the SMN1 gene at 7q13.2. (Graphic description: 0F2 × 025718 inspected person) The red arrows indicate herniated cervical intervertebral discs, and the yellow arrow points to the pectoralis major muscle

Preliminary diagnosed: (1) Cervical Spondylotic Myelopathy (CSM) (2) intervertebral disc herniation with degeneration. However, cervical spondylosis with myelopathy primarily involves compression of the spinal cord, leading to damage to the upper motor neurons. This condition typically presents with hyperactive tendon reflexes, spastic atrophy, and weakness of the lower limbs, and electromyography (EMG) often shows regular muscle activity or segmental damage to the spinal cord [4], which does not fully align with the findings in this case. Based on the medical history, physical examination, and auxiliary tests, the initial consideration was lower motor neuron damage in SMA. However, the patient exhibited pseudohypertrophy of the gastrocnemius muscle and a positive Gower sign, which do not align with the typical manifestations of the disease. There is no family history of genetic disorders. Whole exome sequencing and copy number variation gene testing were conducted, revealing a homozygous deletion in the SMN1 gene in exon 7 at 5q13.2. According to the SMA diagnostic guidelines [5, 6], in addition to the above diagnosis, the patient was definitively diagnosed with the relatively rare Type IV SMA. Disease-modifying therapy for SMA [7] was recommended, but the patient refused. Subsequently, the patient underwent spinal decompression surgery at another hospital (Fig. 1F), but symptoms continued to worsen, with a poor prognosis progressively.

Discussion and conclusions

SMA was first clearly defined by Lefebvre and his team in France in 1955. It is more common in infants and young children and is the second leading cause of death among infants and young children [8]. The SMN protein is encoded by the SMN1 and SMN2 genes, which are homologous genes widely expressed throughout the human body, particularly in the lower motor neurons of the cervical and lumbar spinal cord regions. Due to a mutation in exon 7 of the SMN2 gene (C > T), it can only be expressed in an inactive state and is rapidly degraded, accounting for approximately 10%–15% of total SMN protein in the human body. Therefore, homozygous deletions or mutations in exon 7 or exons 7 and 8 of the SMN1 gene remain the primary cause of SMA [9]. Carriers have 1 to 4 copies of the SMN1 gene, which are classified into heterozygous deletions and compound heterozygous mutations based on the number of copies and their relationship with chromosome 5. Both have normal clinical phenotypes. Heterozygous deletions, where one chromosome lacks the SMN1 allele (“1 + 0”/“2 + 0” type), account for approximately 95%, while compound heterozygous mutations are relatively rare, involving an SMN1 allele on one chromosome paired with an SMN1 allele with a minor mutation on another chromosome or both SMN1 alleles on two chromosomes having minor mutations (“0 + 1d”/“1d + 1d” type), accounting for approximately 5%. The “1d + 1d” type with both alleles currently has no reported cases in China [10]. The number of SMN2 gene copies ranges from 0 to 8, and no correlation between SMN2 gene copy number and clinical phenotype has been identified to date. However, some studies have included it as a key biomarker for preclinical diagnosis and treatment [11].

SMN1 biallelic mutations or deletions result in reduced expression of the SMN protein, leading to degeneration and damage of lower motor neurons. Due to the damage to neurons, there are changes in the function and morphology of neuronal synapses and neuromuscular junctions, resulting in typical neurogenic degenerative changes in muscles throughout the body [12]. Existing reports indicate that the carrier rate in the Chinese population is approximately 1.56–2.0% [13, 14]. Based on age of onset and clinical symptoms, SMA is classified into five subtypes [15]. Patients with Type 0, Type I (Werdnig-Hoffmann, OMIM #253300), and Type II (Dubowitz, OMIM #253550) typically have a shorter life expectancy, poorer maximal motor function, and difficulty maintaining normal daily activities, resulting in low survival rates and poor quality of life [16, 17]. Type III (Kugelberg-Welander, OMIM #253400) and Type IV generally do not affect patients’ normal life expectancy. However, Type III typically presents between 2 and 10 years of age with poor quality of life. At the same time, Type IV is clinically rare, often presenting in adulthood, rarely involving respiratory muscles, and typically not affecting patients’ normal lifespan [18, 19]. In addition to the above classifications, there are also some rare clinical subtypes, such as lower limb-dominant SMA [20], characterized by limited mobility of the scapular muscles and congenital developmental abnormalities such as scoliosis, and scapulo-fibular muscle type SMA [21], which accounts for approximately 4% of all cases. Currently, the mechanism underlying SMA caused by SMN protein deficiency is still under investigation, and the complex clinical manifestations pose ongoing challenges for early, precise treatment of SMA.

Pseudohypertrophy of the gastrocnemius muscle and a positive Gower sign are typical clinical symptoms of progressive muscular dystrophy, a neuromuscular degenerative disease caused by defects in the dystrophin gene located at Xp21.2, which is inherited in an X-linked recessive manner [22] and commonly occurs in adolescents. Clinically, PMD is further classified into two subtypes: Duchenne muscular dystrophy (DMD; OMIM #310200) and Becker muscular dystrophy (BMD; OMIM #300376). EMG findings in PMD are typically indicative of myogenic damage, with only a small number of cases showing neurogenic or mixed damage. In DMD, the degree of dystrophin mutation is greater than in BMD, leading to earlier onset, faster progression, and a significant reduction in oxidative respiratory chain proteins, resulting in a higher rate of severe disease. Often leading to death due to organ failure, such as cardiac or pulmonary failure [23]. Therefore, in PMD, serum creatine kinase and creatine kinase isoenzyme levels are persistently and significantly elevated, typically reaching 20–100 times the normal range, whereas in SMA, these levels are often normal or only mildly elevated, with increases normally less than five times the normal range [24]; aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels are elevated to approximately 5 times the normal range during the early to mid-stages of the disease, while in SMA, these levels are typically normal [25].

Pseudohypertrophy of the gastrocnemius muscle is primarily caused by the non-functional compensation of atrophied muscle fibers with fat and connective tissue due to the degeneration and necrosis of gastrocnemius muscle cells. In addition to SMA and PMD, one should be highly vigilant for progressive muscle atrophy, Kennedy’s disease, congenital myopathies, and other hereditary neuromuscular diseases [26], as well as common neurological disorders such as CSM, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy, which present with muscle weakness and atrophy. However, by analyzing the location, nature, and progression of the disease, each condition can be distinguished. Therefore, the patient was diagnosed with type IV spinal muscular atrophy caused by SMN1 deficiency, presenting as pseudohypertrophy of the gastrocnemius muscle. Currently, there is no specific treatment for SMA. Patients are recommended to use disease-modifying therapies aimed at increasing SMN1 protein expression and enhancing muscle contraction. Several drugs have been developed, such as intrathecal injections of nusinersen and zolgensma, oral medications like risdiplam and reldesemtiv, and intravenous injections of zolgensma and apitegromab. The high expression of the SMN1 protein is primarily studied through mechanisms such as increasing the transcription of the intact SMN2 gene and replacing the SMN1 gene. Related research has achieved inevitable progress and effects [27–30]. Currently, there are also studies on drugs related to reducing SMN protein degradation, nourishing neurons, and stem cell therapy, but these are still in the preclinical stage.

In summary, SMA presents with a wide range of clinical phenotypes and is often misdiagnosed or overlooked in clinical practice. A thorough medical history should be obtained, relevant examinations should be conducted, and genetic testing should be performed when necessary. The goal is to achieve early identification, diagnosis, and treatment to slow disease progression and reduce the burden on patients and their families.

Abbreviations

BMD

Becker muscular dystrophy

CSM

Cervical Spondylotic Myelopathy

DMD

Duchenne muscular dystrophy

EMG

electromyography

SMA

Spinal muscular atrophy

SMN1

survival motor neuron 1 gene

Authors’ contributions

Hu XI: case collection, article writing, article revision; Wenming YANG and Hao LI: research idea guidance, paper review and proofreading, financial support; Wangsheng HE and Hailin JIANG: case organization, feasibility analysis of article writing; Wenting XIE and Yue YANG: case organization, analysis of imaging data; Yulong YANG, and Ke DIAO: case organization, analysis of neurophysiological data.

Funding

This work funded by Study on mechanism of Xin ‘an Medical Gubenpeiyuan prescription treating Wilson’s disease based on enterohepatic axis and enterobrain axis pathway (No. U22A20366), National Science and Technology Major Project (No.2023ZD0505801).

Data availability

The datasets generated and presented in this manuscript are available from National Center for Biotechnology Information: SUB15356778( [https://www.ncbi.nlm.nih.gov/clinvar/variation](https:/www.ncbi.nlm.nih.gov/clinvar/variation) ), for further information you can inquire with the corresponding author Wenming Yang.

Declarations

Ethics approval and consent to participate

Not applicable. This manuscript strictly follows the declaration of Helsinki, etc. The review opinion of the Medical ethics committee of The first affiliated hospital of Anhui university of Chinese Medicine(Anhui Provincial Hospital of Chinese Medicine): Based on international ethical standards and Chinese laws and regulations, case reports are not classified as clinical studies and, consequently, do not necessitate ethical review. Therefore, this case report was exempt from ethical. Written informed consent has been provided by the patient.

Consent for publication

The patient has granted written informed consent for the publication of this case report and any associated photos.

Competing interests

The authors declare no competing interests.