Spinal Muscular Atrophy: SMN1-negative variants resembling Infantile Onset SMA

Spinal Muscular Atrophy: SMN1-negative variants resembling Infantile 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 an expanding list of pathogenic gene variants associated with “non-5q”4 or “SMN1-negative” congenital SMAs.5,6 With expanded use of gene sequencing, more pathogenic mutations are sure to be found, and clinicians should note that the standard gene panels currently in use may not capture every potential known genetic cause.3

Atypical forms of SMA and SMA-like diseases with prenatal or infantile onset (SMA type 0 and SMA type 1) and a lethal phenotype are discussed below.

  • SMA with respiratory distress type 1, or SMARD-1, is an autosomal recessive lower motor neuron disorder that presents with global weakness and with often fatal early life respiratory distress due to diaphragmatic paralysis.7,8 The immunoglobulin μ-binding protein 2 (IGHMBP2) gene is implicated in SMARD1; the function of the IGHMBP2 protein is unclear.8 The clinical appearance of SMARD1 differs from that of SMA types 0 and 1 by affecting all muscles equally, involving sensory nerves, and presenting with lower extremity contractures and deformities.7 There are rare cases of SMARD1 with milder disease courses who survive out of infancy.8
  • X-linked SMA (SMAX2) is the only X-linked infantile onset SMA-like disease within the LCCS family. Infants born with SMAX2 will have the hypotonia and areflexia typical of SMA but will have deformities of the face, chest, and genitals to suggest a diagnosis other than SMA 0 or 1.5 SMAX2 is caused by mutations in the ubiquitin-like modifier-activating enzyme1 UBA1 gene; UBA1 interacts with SMN1 within neurons, a potential explanation for the close similarity of SMAX2 and classic SMA.9,10
  • Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD) is a prototype of the lethal congenital contracture syndromes (LCCS).5,11 LAAHD is caused by mutations in the gene GLE1 which encodes for a protein involved in the terminal step of mRNA transport via the nuclear pore into the cytoplasm.12,13 Some pathogenic variants in the TTN gene result in a phenotype that is similar to LAAHD.14 LAAHD presents prenatally with reduced or absent fetal movement leading to contractures that are evident at birth with death due to respiratory failure in early life.11 Though the weakness and anterior horn cell pathology of LAAHD grossly resembles those associated with SMA, LAAHD differs from SMA because the descending spinal tracts are preserved there are protean manifestations including pterygia, micrognathia, and pulmonary hypoplasia that are not found in any type of SMA.5
  • Infantile onset SMA associated with pontocerebellar hypoplasia is typified by congenital global hypotonia, microcephaly, intellectual disability and early life demise.5 Pontocerebellar hypoplasia with infantile SMA is caused by homozygous or compound heterozygous mutations in the genes EXOSC3 (part of the RNA exosome), or, more rarely, VRK1 (a kinase expressed in dividing cells).5 The brainstem abnormalities are obviously pathognomonic for this variant SMA.
  • SMA with progressive myoclonic epilepsy is an autosomal recessive inhertiance congenital weakness and neurodegenerative epilepsy syndrome that typically leads to death by age 2 years.5,15 Patients may have initial weakness and feeding difficulties that evolves into a refractory and often painful myoclonic epilepsy.5,15 Mutations in ASAH1,a lysosomal acid ceramase, are causal; the reported phenotypes associated with ASAH1 variants range from mild to very severe and overlaps with the Farber lipogranulomatosis disease.16,17


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. Messina MF, Messina S, Gaeta M, et al. Infantile spinal muscular atrophy with respiratory distress type I (SMARD 1): an atypical phenotype and review of the literature. Eur J Paediatr Neurol. 2012;16(1):90-94.

8. Wu S, Chen T, Li Y, et al. An atypical phenotype of a patient with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD 1). Eur J Med Genet. 2018.

9. Wishart TM, Mutsaers CA, Riessland M, et al. Dysregulation of ubiquitin homeostasis and beta-catenin signaling promote spinal muscular atrophy. J Clin Invest. 2014;124(4):1821-1834.

10. Balak CD, Hunter JM, Ahearn ME, Wiley D, D’Urso G, Baumbach-Reardon L. Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy. F1000Research. 2017;6:1636.

11. Vuopala K, Makela-Bengs P, Suomalainen A, Herva R, Leisti J, Peltonen L. Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus. Journal of medical genetics. 1995;32(1):36-38.

12. Nousiainen HO, Kestila M, Pakkasjarvi N, et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nature genetics. 2008;40(2):155-157.

13. Said E, Chong JX, Hempel M, et al. Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1. Am J Med Genet A. 2017;173(11):3098-3103.

14. Chervinsky E, Khayat M, Soltsman S, Habiballa H, Elpeleg O, Shalev S. A homozygous TTN gene variant associated with lethal congenital contracture syndrome. Am J Med Genet A. 2018;176(4):1001-1005.

15. Dyment DA, Bennett SAL, Medin JA, Levade T. ASAH1-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA): University of Washington, Seattle

University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993.

16. Filosto M, Aureli M, Castellotti B, et al. ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study. Eur J Hum Genet. 2016;24(11):1578-1583.

17. Yildiz EP, Yesil G, Bektas G, et al. Spinal muscular atrophy with progressive myoclonic epilepsy linked to mutations in ASAH1. Clinical neurology and neurosurgery. 2018;164:47-49.