The Spectrum of Childhood-Onset Lower Motor Neuron Disease of Spinal Muscular Atrophy Phenotype Associated with Survival Motor Neuron-2 Gene Deletion

Abstract

Pediatric lower motor neuron disease is clinically and genetically heterogeneous. We characterized disease progression among children with the spinal muscular atrophy (SMA) phenotype having 2:0 (group A) and 2:1 (group B) of the survival motor neuron 1/2 (SMN1:SMN2) genotype over 1 year. We included children aged 0 to 12 with the SMA phenotype between January 2018 and December 2021. Their demographic, clinical (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP-INTEND] scores), electrophysiological, radiological, and genetic data were collected from past medical records. The sequential CHOP-INTEND scores and the compound muscle action potential (CMAP) amplitudes were compared using an analysis of covariance test, controlling for age and sex. A linear regression was run to determine the association between the ages of the patients and the CHOP-INTEND scores. Among nine children in group A and six in group B, the decline of the mean (standard deviation) CHOP-INTEND score from the initial value to the 12th-month follow-up value was significant only in group A. CHOP-INTEND scores did not significantly differ between the two groups at the first admission but were significantly lower in group A at the subsequent visits. Group A patients had significantly lower CMAP amplitudes than patients in group B. There was a moderate, negative association between the age of patients and the CHOP-INTEND scores in group A. Group A patients had a significantly higher age-dependent decline in CHOP-INTEND scores and CMAP values than group B, although their age and the severity of weakness did not significantly differ at presentation.

Keywords

lower motor neuron diseases - SMN2 - MLPA - CHOP-INTEND score - CMAP amplitudes

Publication History

Received: 21 December 2023

Accepted: 02 July 2024

Article published online:
30 July 2024

• References

• 1 van den Berg-Vos RM, Visser J, Franssen H. et al. Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 2003; 126 (Pt 5): 1036-1047
• 2 van Den Berg-Vos RM, van Den Berg LH, Visser J, de Visser M, Franssen H, Wokke JH. The spectrum of lower motor neuron syndromes. J Neurol 2003; 250 (11) 1279-1292
• 3 Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman OM. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch Neurol 2000; 57 (08) 1171-1176
• 4 Deng X, Hao Y, Xiao B, Tan EK, Lo YL. Prognostic factors of key outcomes for motor neuron disease in a multiracial Asian population. J Clin Neurosci 2020; 72: 63-67
• 5 Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet 2021; 14: 11-25
• 6 Kim J, Lee SG, Choi YC. et al. Association between survivor motor neuron 2 (SMN2) gene homozygous deletion and sporadic lower motor neuron disease in a Korean population. Ann Clin Lab Sci 2010; 40 (04) 368-374
• 7 Lee JB, Lee KA, Hong JM, Suh GI, Choi YC. Homozygous SMN2 deletion is a major risk factor among twenty-five Korean sporadic amyotrophic lateral sclerosis patients. Yonsei Med J 2012; 53 (01) 53-57
• 8 Moulard B, Salachas F, Chassande B. et al. Association between centromeric deletions of the SMN gene and sporadic adult-onset lower motor neuron disease. Ann Neurol 1998; 43 (05) 640-644
• 9 Echaniz-Laguna A, Guiraud-Chaumeil C, Tranchant C, Reeber A, Melki J, Warter JM. Homozygous exon 7 deletion of the SMN centromeric gene (SMN2): a potential susceptibility factor for adult-onset lower motor neuron disease. J Neurol 2002; 249 (03) 290-293
• 10 Veldink JH, van den Berg LH, Cobben JM. et al. Homozygous deletion of the survival motor neuron 2 gene is a prognostic factor in sporadic ALS. Neurology 2001; 56 (06) 749-752
• 11 Corcia P, Camu W, Halimi JM. et al; French ALS Study Group. SMN1 gene, but not SMN2, is a risk factor for sporadic ALS. Neurology 2006; 67 (07) 1147-1150
• 12 Gamez J, Barceló MJ, Muñoz X. et al. Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients. Neurology 2002; 59 (09) 1456-1460
• 13 Cobben JM, de Visser M. SMN2 deletion in childhood-onset spinal muscular atrophy. Am J Med Genet 2002; 109 (03) 246 , author reply 247
• 14 Ogino S, Van Deerlin VM, Wilson RB. Comment on SMN2 deletion in childhood-onset spinal muscular atrophy. Am J Med Genet 2002; 109 (03) 243-244 , author reply 245
• 15 Moisse M, Zwamborn RAJ, van Vugt J. et al; Project MinE Sequencing Consortium. The Effect of SMN gene dosage on ALS risk and disease severity. Ann Neurol 2021; 89 (04) 686-697
• 16 Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron 2005; 48 (06) 885-896
• 17 Srivastava S, Mukherjee M, Panigrahi I, Shanker Pandey G, Pradhan S, Mittal B. SMN2-deletion in childhood-onset spinal muscular atrophy. Am J Med Genet 2001; 101 (03) 198-202
• 18 Liping L, Hongwei M, Lin W. Homozygous survival motor neuron 2 gene deletion and sporadic lower motor neuron disease in children: case report and literature review. J Child Neurol 2013; 28 (04) 509-516
• 19 Chidambaram AG, Jhawar S, McDonald CM, Nandalike K. Sleep disordered breathing in children with neuromuscular disease. Children (Basel) 2023; 10 (10) 1675
• 20 Pechmann A, Langer T, Schorling D. et al. Evaluation of children with SMA type 1 under treatment with Nusinersen within the expanded access program in Germany. J Neuromuscul Dis 2018; 5 (02) 135-143
• 21 Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. 4th ed.. London: Elsevier Saunders; 2020
• 22 Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve 2015; 51 (02) 157-167
• 23 García A, Calleja J, Antolín FM, Berciano J. Peripheral motor and sensory nerve conduction studies in normal infants and children. Clin Neurophysiol 2000; 111 (03) 513-520
• 24 Pierzchlewicz K, Kępa I, Podogrodzki J, Kotulska K. Spinal muscular atrophy: the use of functional motor scales in the era of disease-modifying treatment. Child Neurol Open 2021; 8: 2329048-X211008725
• 25 Pechmann A, König K, Bernert G. et al. SMArtCARE - A platform to collect real-life outcome data of patients with spinal muscular atrophy. Orphanet J Rare Dis 2019; 14 (01) 18
• 26 Stępień A, Gajewska E, Rekowski W. Motor function of children with SMA1 and SMA2 depends on the neck and trunk muscle strength, deformation of the spine, and the range of motion in the limb joints. Int J Environ Res Public Health 2021; 18 (17) 9134
• 27 Mercuri E, Lucibello S, Perulli M. et al. Longitudinal natural history of type I spinal muscular atrophy: a critical review. Orphanet J Rare Dis 2020; 15 (01) 84
• 28 Swoboda KJ, Prior TW, Scott CB. et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol 2005; 57 (05) 704-712
• 29 Veldink JH, Kalmijn S, Van der Hout AH. et al. SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology 2005; 65 (06) 820-825
• 30 Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N. Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next. Annu Rev Genomics Hum Genet 2020; 21: 231-261
• 31 Monani UR, Sendtner M, Coovert DD. et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet 2000; 9 (03) 333-339
• 32 Gavrilina TO, McGovern VL, Workman E. et al. Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum Mol Genet 2008; 17 (08) 1063-1075
• 33 Gabanella F, Butchbach MER, Saieva L, Carissimi C, Burghes AHM, Pellizzoni L. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS One 2007; 2 (09) e921
• 34 Coovert DD, Le TT, McAndrew PE. et al. The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 1997; 6 (08) 1205-1214
• 35 Niba ETE, Nishio H, Wijaya YOS. et al. Stability and oligomerization of mutated SMN protein determine clinical severity of spinal muscular atrophy. Genes (Basel) 2022; 13 (02) 205
• 36 Harada Y, Sutomo R, Sadewa AH. et al. Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity. J Neurol 2002; 249 (09) 1211-1219
• 37 Mitani AA, Haneuse S. Small data challenges of studying rare diseases. JAMA Netw Open 2020; 3 (03) e201965
• 38 Althouse AD. Posthoc power analysis: not empowering, just misleading. J Surg Res 2021; 259: A3-A6
• 39 Jangi M, Fleet C, Cullen P. et al. SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage. Proc Natl Acad Sci U S A 2017; 114 (12) E2347-E2356