Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance

Figures & data

Table 1 Classification of Spinal Muscular Atrophy

SMA Type	Copies SMN2	Percent of Cases	Onset	Motor Milestones	Clinical Features	Natural History Prior to Disease-Modifying Therapy
0	1	Rare, <1%	Prenatal, at birth	Non-sitter, no head control	Generalized weakness, hypotonia, respiratory failure, poor feeding, contractures	Death within weeks of birth
1	1–2	45%	0–6 mo	Non-sitter	Proximal predominant weakness, respiratory insufficiency, poor feeding, tongue fasciculations	Death by age 2
2	3	20%	6–18 mo	Sits independently, never stands or ambulates	Proximal predominant weakness, tongue fasciculations, minipolymyoclonus, scoliosis	Most alive at 25 years
3	3–4	30%	A: 18 mo −3yr B: 3–30 yr	Ambulates independently	Proximal, lower extremity predominant weakness, abnormal gait	Normal lifespan
4	4 or more	<5%	> 30 yr	Ambulates independently	Maintain ability to ambulate	Normal lifespan

Figure 1 Two genes are responsible for producing the survival motor neuron (SMN) protein, SMN1 and SMN2. SMN1 provides humans with the proper quantity of SMN protein necessary for a normal phenotype. SMN2 is an inverted duplicate of SMN1 lying closer to the centromere. A C>T transition in exon 7 of SMN2 causes the SMN2 gene to produce mostly (~90%) nonfunctional protein and a small amount (~10%) of the functional SMN protein.

Figure 2 (A) A chromosome carrying a normal copy of SMN1 and SMN2. (B) The blank box indicates a deleted gene. A deletion can remove part or all of the SMN1 gene. (C) The curved arrow represents a conversion. With the C>T transition in SMN1, the SMN1 copy now closely resembles SMN2 and is considered SMN2-like. (D) Point mutations occurring in any of the SMN1 exons prior to the last exon can affect the SMN protein.

Figure 3 (A) A wild type with 2 copies of SMN1 and SMN2 on each chromosome. (B) SMA carrier with only one copy of SMN1 on one chromosome and loss of SMN1 on the other. (C) A silent SMA carrier with a duplication of SMN1 on one chromosome and no SMN1 on the other chromosome. (D) SMA carrier with one normal copy of SMN1 on one chromosome and one copy that contains a point mutation on the other chromosome.

Table 2 SMA Treatments

Type of Treatment	Mechanism of Action	Drug	Route of Administration	Clinical Trials	Current Status
SMN dependent pathway
SMN1 gene delivery	SMN1 gene transfer via adenovirus vector	Onasemnogene abeparvovec	Single intravenous injection	START (Phase I) STRONG (Phase I) SPR1NT (Phase III)	FDA approved in May 2019
Act on SMN2 to increase SMN protein production	Antisense oligonucleotide that binds SMN2 mRNA to modify splicing	Nusinersen	Intrathecal injection every 4 months	NCT01494701 and NCT01780246 (Phase I) NCT01839656 (Phase II) ENDEAR (Phase III) CHERISH (Phase III) NURTURE (Phase II) SHINE (Phase III)	FDA approved in December 2016
	Small molecule that alters splicing of SMN2	Risdiplam	Oral daily medication	FIREFISH (Phase II, III) SUNFISH (Phase II, III) JEWELFISH (Phase II) RAINBOWFISH (Phase II)	FDA approved in August 2020
SMN independent pathways
Restores mitochondrial homeostasis	Cholesterol like molecule that enhances mitochondrial functioning and inhibits release of apoptotic factors	Olesoxime	Oral daily medication	2 Phase II trials	Development stopped
Enhance muscle function	Skeletal muscle troponin activator that acts to increase the skeletal muscle force response to nerve stimulation.	Reldesemtiv	Oral twice daily medication	Phase II trial	Phase III trial is planned
Promote muscle cell growth and division	Monoclonal antibody inhibits latent myostatin	SK-015	IV injection every 4 weeks	TOPAZ (Phase II)	Ongoing clinical trials
Improve muscle strength and fatigue	Acetylcholine esterase inhibitor	Pyridostigmine	Oral medication, can be taken multiple times per day	Currently trialed in types 2–4 SMA	Currently in clinical trials