SMN1-negative variants resembling Childhood Onset SMA

Spinal Muscular Atrophy (SMA) is a congenital motor neuron degenerative disorder typically resulting from loss of the SMN1 gene on chromosome 5q13.1 While homozygous loss of SMN1 has been reported to account for anywhere from 95%2 to approximately 50%3 of cases with SMA, there are patients with lower motor neuron presentations resembling SMA who are found to have disease-causing mutations in genes other than SMN1, leading to a growing list of pathogenic gene variants associated with “non-5q”4 or SMN1-negative congenital SMAs.5,6 but with expanded use of gene sequencing, more pathogenic mutations are sure to be found, and clinicians should not that the standard gene panels currently in use may not capture every potential genetic cause.3

Atypical forms of SMA and SMA-like diseases with childhood onset (SMA types 1 through 3) are discussed below.

  • Riboflavin Transporter Deficiency, formerly known as Brown-Vialetto-Van Laere Syndrome, presents on average at age 4 years old with progressive weakness and low tone resembling SMA.5,7 Weakness due to Riboflavin Transporter Deficiency occurs because of pathogenic changes in the SLC52A2 or SLC52A3 genes that code for riboflavin transporters; this disease is amenable to dietary riboflavin supplementation.7 Features of these riboflavin deficiency syndromes include sensorineural and cranial neuropathies.7 Most notably hearing loss occurs making Riboflavin Transporter Deficiency a very different presentation than SMA types 1-3 which do not have sensory components and spare the cranial nerves.8
  • Scapuloperoneal SMA can present soon after birth or in early childhood.5 This atypical SMA features progressive atrophy of the scapular and lower extremity (below the knee) muscles, respiratory stridor, and laryngeal palsy.5 This disease is inherited in an autosomal dominant pattern and is caused by missense mutations in the transient receptor potential cation channel gene TRPV4.9 There is variable penetrance of this gene leading to a diverse array of muscle involvement and weakness, and skeletal dysplasias associated with variants in TRPV45,9 that can differentiate it from SMA types 1-3.
  • One form of an autosomal dominant form of SMA with lower extremity predominance (termed “SMALED-1”) can present in infancy or early childhood as lower extremity weakness and muscle wasting.5 SMA LED-1 is associated with pathogenic variants in one of the component chains of the muscle protein dynein, specifically, the dynein cytoplasmic 1, heavy chain 1 DYNC1H1 gene.10 Unlike SMA types 1-3, SMALED-1 is slowly progressive or static5 and is confined to the lower extremities, and can be associated with cortical brain malformations and intellectual disability.11
  • A second form of an autosomal dominant form of SMA with lower extremity predominance (SMALED-2) is described in association with pathogenic variants in the bicaudal D homolog 2 or BICD2 gene.12 Patients have delayed acquisition of motor milestones due to largely static proximal leg weakness.5,12 The lack of progression with preserved ambulation and confinement to lower extremities differentiate SMALED-2 from SMA types 1-3,1 and an onset in childhood would not be consistent with SMA type 4.13


1. Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurologic clinics. 2015;33(4):831-846.

2. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165.

3. Karakaya M, Storbeck M, Strathmann EA, et al. Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies. Human mutation. 2018.

4. Zerres K, Rudnik-Schoneborn S. 93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) – clinical picture (6-8 April 2001, Naarden, The Netherlands). Neuromuscular disorders : NMD. 2003;13(2):179-183.

5. Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014;137(Pt 11):2879-2896.

6. Darras BT. Spinal muscular atrophies. Pediatric clinics of North America. 2015;62(3):743-766.

7. Jaeger B, Bosch AM. Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience. Journal of inherited metabolic disease. 2016;39(4):559-564.

8. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet journal of rare diseases. 2011;6:71.

9. Dai J, Cho TJ, Unger S, et al. TRPV4-pathy, a novel channelopathy affecting diverse systems. Journal of human genetics. 2010;55(7):400-402.

10. Harms MB, Ori-McKenney KM, Scoto M, et al. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology. 2012;78(22):1714-1720.

11. Scoto M, Rossor AM, Harms MB, et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy. Neurology. 2015;84(7):668-679.

12. Peeters K, Litvinenko I, Asselbergh B, et al. Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. American journal of human genetics. 2013;92(6):955-964.

13. Piepers S, van den Berg LH, Brugman F, et al. A natural history study of late onset spinal muscular atrophy types 3b and 4. J Neurol. 2008;255(9):1400-1404.