Clinical characterizations of three adults with genetically confirmed spinal muscular atrophy: a case series

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degenerations of anterior horn cells in the human spinal cord and subsequent loss of function in motor neurons leading into progressive muscular atrophy, muscle weakness, and muscle paralysis [1‐3]. The classifications of SMA are based on the age of onset and maximum motor function achieved. The first is SMA type I, with onset in the first month of life in which the patient is unable to sit/move unsupported and also needs breathing support, with a chance of survival only up to 2 years old. The second is SMA type II, with onset between 6 and 18 months old and with motor ability to sit alone without support. The third is SMA type III, with onset between 18 months–30 years old. The patients can stand and walk without support. The fourth is SMA type IV, which is the mildest type of SMA with onset in adulthood, in which the patient tends to have normal mobility with mild muscle weakness [4, 5].

The survival motor neuron (SMN) genes, SMN1 and SMN2, have been identified as the genes responsible for SMA. They exist in chromosome 5q13.2 as highly homologous gene copies. SMN1 is now considered as the primary gene responsible for SMA, because SMN1 is completely deleted in more than 95% of SMA patients and is deleteriously mutated (intragenic mutations) in the rest of patients [6]. SMN2 has been considered as a dispensable gene because absence of SMN2 is frequently found in control individuals, but it is now considered to be a modifying factor of the SMA phenotype, which is supported by the fact that a high copy number of SMN2may be related to the milder phenotype of SMA [7, 8]. According to recent research, the incidence of SMA cases owing to mutation of the SMN1 gene is approximately 1 in 10,000 newborns, with a prevalence of approximately 1–2 per 100,000 people [5].

In Indonesia, genetic neuromuscular diseases, including SMA, are commonly misdiagnosed owing to the similar clinical presentations with other neuromuscular disorders, such as Duchenne muscular dystrophy, Becker muscular dystrophy, multiple sclerosis, amyotropic lateral sclerosis, and even poliomyelitis. To establish the diagnosis of SMA, molecular genetic analysis is necessary to find the deletion or intragenic mutation in SMN1 [6]. Therefore, genetic diagnosis centers should be available to perform these genetic analyses.

Moreover, supporting examinations are not always available to further investigate the patients in local healthcare facilities, particularly in remote areas. To date, genetic diagnosis centers for SMA in Indonesia have been established mostly in Java Island. However, it is difficult to send patients from different islands of Indonesia for genetic analysis owing to the patients’ limited mobility, geographical landmarks, and financial problems. However, current technologies of genetic testing are rapidly developing, and there are many new methods that are much simpler, easier, and more efficient for examining genetic diseases [9].

In our case series, we report three patients with neuromuscular complaints who were found to have SMN1 deletions, thus confirming the diagnosis of SMA. All of them were Javanese and lived in remote rural areas in Indonesia. Patients 1 and 2 were related as cousins. Besides these two patients, there were no other family members who suffered from the same disease (Fig. 1). These case series focused on the disease courses, diagnosis difficulties, and clinical presentations of the three patients that lead to the SMA diagnosis.

All of the patients in the presented cases were diagnosed with SMA type III because their onsets were between 18 months and 30 years old. Patients with SMA type 3 usually develop more problems with back pain and can include disorders of the backbone such as scoliosis [10‐12]. Before we could reach the diagnosis of SMA type III, some considerations of other neuromuscular disorders were also taken into account. Although all the patients presented during adulthood, the disease onset started when they were children. Therefore, genetic neuromuscular disorders were suspected. Upon history taking and physical examinations, we eliminated Duchenne muscular dystrophy owing to the absence of Gower signs and the cardiomyopathy signs, as well as shortness of breath [13]. Kennedy disease often shows gynecomastia and decreased fertility, but these patients were not infertile and did not have gynecomastia. Another possible differential diagnosis was amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis presents with motor symptoms such as extensor plantar response, increase muscle tone, lower limbs pain, and muscle cramps that occur as the result of degeneration of both upper and lower motor neurons [14]. However, the three patients did not show any extensor plantar response and muscle cramps. The third patient is female and her clinical manifestations may also fit Becker muscular dystrophy (BMD). The patient had no history of speech disturbance, shortness of breath, or toe walking, which may support the diagnosis of BMD. BMD is a rare disease almost exclusively in males, female carriers may only present with cardiomyopathy. Sometimes carrier females may have mild muscle weakness with approximately 22% of carriers become symptomatic [15]. Owing to the limitation of genetic or molecular testing in our medical or research facilities, it is difficult to reach a definitive diagnosis of a genetic disease. In addition, if the testing is available, the cost is expensive and not covered by the national health care insurance. Clinicians should pay attention in the clinical details in history taking and physical examinations to narrow down the differential diagnoses and to plan further diagnostic testing. In our cases, effort was required to convince the patients to perform the genetic examinations despite the financial, geographical, and availability problems to establish a diagnosis.

As in other forms of SMA, muscle fatigue, weakness, and atrophy start in lower limbs, then there is proximal predominance, and spreading into the upper limbs and trunk in an ascending manner [4, 12]. When children start to walk, run, or even climb stairs they usually fall and show slow disease progression. Falls are increasingly frequent as their body changes during puberty when they will typically gain more weight. As they get older, the symptoms also get more progressive, with muscle weakness and complaints of fatigue as the most common [12]. From this brief explanation, it can be seen that all of the patients reported here had a similar progression of SMA type 3. Muscle weakness and inability to stand and walk independently are the most progressive symptoms that appeared. Some patients with SMA may also complain about general pain that mostly is from the back. Scoliosis occurs in almost all non-ambulant individuals with SMA. When untreated, scoliosis can cause chest deformities with subsequent respiratory restriction [1]. In this report, one of the patients had severe scoliosis but it did not affect her respiratory function. SMA type 3 usually has a slow progression. However, deformities including those in the vertebral column and lower limbs are frequent, and may lead to wheelchair use [16]. With this variety of clinical symptoms and presentations of SMA type 3, it may helpful that the patient knows about their condition as soon as they can. An early diagnosis may be helpful to involve a neurologist for confirming the diagnosis of SMA, but this genetic testing technology is still not available in every country, especially in developing countries such as Indonesia, where it is only available in only a few central hospitals. This may prevent early detection and cause a delay in diagnosing any genetic disorders, including SMA.

The confirmed SMA diagnosis of the three patients, shown by genetic testing, was identified from the deletion of SMN1 exon 7, and in addition, the third patient also had deletion in SMN1 exon 8 (Fig. 2). An isolated deletion in SMN1 exon 7 usually occurs in patients with SMA type II and type III, and deletion in SMN1 exon 8 gene is also associated with SMA [17]. Some authors argue that exon 8 is untranslated, therefore, an SMN gene containing such a mild mutation could be fully functional [18]. Accordingly, it has been argued that the untranslated sequences of genes may have regulatory function at the transcriptional level, thus, mutations on this region may impair these biological functions. One report found that two SMA patients with deletion of SMN1 exon 8 gene, but who retained the exon 7 gene had no significant clinical features [17]. Of interest, genotype/phenotype correlations in SMA found that the type of genes deleted markedly affected the severity of the disease [18, 19].

To establish the diagnosis of SMA, it is necessary to find the deletion or intragenic mutation in SMN1. Various polymerase chain reaction (PCR) technologies have been developed to separate SMN1 and SMN2 amplification, for example, PCR and single-strand conformation polymorphism (PCR–SSCP), PCR and restriction fragment length polymorphism (PCR–RFLP), radio-isotope competitive PCR and RFLP, PCR and denaturing high-performance liquid chromatography (DHPLC), real-time PCR with gene-specific primers, multiplex ligation probe amplification (MLPA), tetra-primer PCR, high-resolution melting analysis, and modified competitive oligonucleotide primers PCR [9, 20]. In Indonesia, SMA and other genetic neuromuscular disorders often become the last differential diagnosis to be considered owing to their rarity, the similarity of the clinical presentations with other neuromuscular disorders, and the difficulty in further investigating by molecular genetic analysis. None of the aforementioned PCR technologies are readily available and easily accessible for general practitioners and patients in Indonesia. In addition, the lack of national health insurance for genetic testing, the shortage of standardized operational procedures for genetic molecular testing, and the inadequacy of community knowledge and awareness of genetic diseases, in addition to the scarcity of the genetic experts for genetic consultation make the situation more difficult in Indonesia to establish genetic disease diagnoses, including SMA. Through publishing this case series, we also want to inform and describe three SMA cases that can hopefully lead more scientists, researchers, and doctors to be more aware and pay more attention to these problems of genetic diseases and the difficulty in their diagnoses, especially in developing countries such as Indonesia. Many genetic diseases are often neglected in developing countries owing to the difficulty in diagnosis and unavailable treatments. However, the new era for the screening, diagnosis, and treatment of SMA has come. This new science should be introduced to every clinician, researcher, and policy maker who deals with genetic diseases, such as spinal muscular atrophy.