Clinical and Genetic Profiles of 5q- and Non-5q-Spinal Muscular Atrophy Diseases in Pediatric Patients

Abstract

Background: Spinal muscular atrophy (SMA) is a genetic disease characterized by loss of motor neurons in the spinal cord and lower brainstem. The term "SMA" usually refers to the most common form, 5q-SMA, which is caused by biallelic mutations in SMN1 (located on chromosome 5q13). However, long before the discovery of SMN1, it was known that other forms of SMA existed. Therefore, SMA is currently divided into two groups: 5q-SMA and non-5q-SMA. This is a simple and practical classification, and therapeutic drugs have only been developed for 5q-SMA (nusinersen, onasemnogene abeparvovec, risdiplam) and not for non-5q-SMA disease.

Methods: We conducted a non-systematic critical review to identify the characteristics of each SMA disease.

Results: Many of the non-5q-SMA diseases have similar symptoms, making DNA analysis of patients essential for accurate diagnosis. Currently, genetic analysis technology using next-generation sequencers is rapidly advancing, opening up the possibility of elucidating the pathology and treating non-5q-SMA.

Conclusion: Based on accurate diagnosis and a deeper understanding of the pathology of each disease, treatments for non-5q-SMA diseases may be developed in the near future.

Keywords: 5q-SMA; SMA-JI; SMA-LED1; SMA-LED2; SMA-PME; SMARD1; SP-SMA; XL-SMA; non-5q-SMA.

Figure 1

Outline of 5q-SMA. Patients with SMA types 0 and I are unable to sit, and often present with arthrogryposis (multiple joint contractures) and respiratory failure. Patients with SMA type II are able to sit, but unable to stand or walk, and almost always present with scoliosis. Patients with SMA type III are able to stand and walk, but they lose these abilities as the disease progresses. People with SMA Type IV can stand and walk, and because the disease progresses slowly, they can maintain these abilities for long periods of time. The protein encoded by the responsible gene has two main domains, Tudor domain and C-terminal domain [50]. The Tudor domain has binding sites to Sm proteins, which are components of snRNPs. The C-terminal domain contains a tyrosine/glycine-rich region (YG box) that plays a role in oligomerization of SMN. Oligomerization is an essential step for the various functions of SMN [51,52]. Defects in snRNP biogenesis, axonal transport and NMJ maturation are thought to be involved in the pathogenesis.

Figure 2

Outline of SMARD1. The illustration of clinical features was drawn based on a diagram provided by Perego et al. [81]. Causative mutations occur mainly in the helicase domain [82,83,84,85]. Mutations in the helicase domain of IGHMBP2 may lead to impairment of translation. However, the exact molecular mechanism of IGHMBP2-related disorders remains largely unknown. The illustration here focuses on the reduced RNA helicase activity of mutated IGHMBP2.

Figure 3

Outline of SMA-JI. Infants with this disease present with respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Juvenile-onset patients may present with muscle weakness in the hands and legs (as in the typical peroneal muscular atrophy with foot drop and a high steppage gait). GARS is a tRNA synthetase gene, which encodes both cytosolic and mitochondrial isoforms of the protein. These forms differ by a 54 amino acid N-terminal mitochondrial targeting sequence. WHEP-TRS domain may play a role in the association of tRNA-synthetases into multienzyme complexes. GARS normally forms a homodimer. GARS mutation (or GARS dysfunction) may lead to defects of sensory-motor connectivity and impairment of axonal transport in the spinal cord [97].

Figure 4

Outline of XL-SMA. The molecular pathogenesis involves the impairment of adenylation and thiolation of ubiquitin (Ub) by UBA1. However, it remains unknown how mutations in the active adenylation domain (AAD) domain (UBA1 exon 15) cause the disease. Here, the canonical pathway of ubiquitylation is shown, but regulation of GARS by UBA1 occurred through a non-canonical pathway independent of ubiquitylation, as mentioned in Section 5.

Figure 5

Outline of SP-SMA. Infantile-onset patients show arthrogryposis, systemic muscle weakness, vocal cord paralysis and bone abnormalities. Juvenile- and adult-onset patients present with atrophy of the shoulders, and peroneal and small hand muscles resulting in distal weakness. Causative mutations occur in the ankyrin repeat domain (ARD) of the TRLV4 channel in the cell/mitochondrial membrane. Disrupted TRPV4-RhoA interaction may lead to an abnormal influx of calcium ions.

Figure 6

Outline of SMA-PME. Myoclonic epilepsy may occur after muscle weakness appear. Acid ceramidase is a heterodimeric protein composed of a non-glycosylated alpha-subunit and a glycosylated beta-subunit. The beta-subunit of the enzyme catalyzes ceramide to sphingosine and fatty acid. Of the recorded mutations leading to the diagnosis of Farber disease, the majority are located within the beta-subunit. In contrast, a larger number of mutations in SMA-PME have been identified within the alpha-subunit. Accumulation of ceramide may also cause an imbalanced activation of pathways and mediators in microglia, leading to neurodegeneration and neuroinflammation.

Figure 7

Outline of SMA-LED1. Early reports asserted that causative mutations are located exclusively in the tail domain. However, some causative mutations in the motor domain were later reported. DYNC1H1 is a molecular motor protein required for the retrograde transport of cargo along microtubules in axons and dendrites, and thus is involved in neuronal development, morphology, and survival.

Figure 8

Outline of SMA-LED2. Cytoplasmic dynein is a molecular motor protein required for the retrograde transport of cargo along microtubules in axons and dendrites, as described in the previous Section (Section 9). The BICD2 protein is an adaptor protein for linking the cargo to the motor protein.