- •
Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy.
- •
SMA subtypes are classified by severity of weakness: type I nonsitters, type II sitters, type III walkers, and type IV adult-onset patients with mild phenotype.
- •
The survival of motor neuron (SMN) gene is present in 2 copies on each chromosome 5, designated SMN1 and SMN2. A majority of cases are caused by homozygous deletions of exon 7 of the
Spinal Muscular Atrophies
Section snippets
Key points
Epidemiology
The incidence of SMA has been estimated at 1 in 6000 to 11,000 live births4, 5, 6, 7 or approximately 7.8 to 10 per 100,000 live births8, 9, 10 and at 4.1 per 100,000 live births for type I SMA.8 The estimated panethnic disease frequency is approximately 1 in 11,000.7 The carrier frequency for mutations in the SMN1 gene has been estimated from 1:38 to 1:70. Despite the high carrier frequency, the incidence of SMA is lower than expected. It has been postulated that this may reflect that some
Clinical characteristics
Although most patients with SMA have deletions or mutations involving the SMN1 gene, a range of phenotypic severity permits division into 4 broad clinical subtypes. It is recognized that the subtypes represent a phenotypic continuum extending from the very severe, with onset in utero, to the very mild, with onset during adulthood; there is also a spectrum of severity within each of these groups (Table 1).12, 13 For the purposes of clinical classification or of guidelines developed for standards
The Survival of Motor Neuron Gene
In 1995, Lefebvre and colleagues58 identified the SMN gene within the SMA chromosomal region, which was absent or interrupted in 98.6% of the patients in their group. The structure of this region is complex, with a large inverted duplication of a 500-kb element. This contains the SMN1 gene, which is deleted or interrupted in patients with SMA and is evolutionarily older, in the telomeric portion of the region; and the SMN2 gene, a duplication of SMN1 that differs from it by only 5 nucleotides,
Other diagnostic tests
In patients with SMA, the serum creatine kinase may be 2- to 4-fold elevated but not more than 10 times normal.22 Nerve conduction studies demonstrate normal sensory potentials but may show diminished compound motor action potential amplitudes.72 Needle electromyography (EMG) in patients with type II/III SMA demonstrates a neurogenic pattern with high-amplitude, long-duration motor unit potentials with reduced recruitment pattern. Needle EMG in patients with type I SMA shows denervation changes
Differential diagnosis
The differential diagnosis of 5q SMA is listed in Box 1.
Treatment
Currently, there is no cure for SMA. Despite the presence of homozygous deletions of SMN1 in a majority of patients with SMA,74 however, the unique structure of the 5q11.1-13.3 inverted duplication provides potential therapeutic targets. There has been great interest in identifying agents that can increase the amount of full-length SMN protein by up-regulating the expression of the SMN2 gene or promoting inclusion of exon 7. Researchers are also actively exploring several other approaches to
Care of patients with spinal muscular atrophy
Patients with SMA and their families benefit greatly from a multidisciplinary approach to care. This approach involves members from neurology/neuromuscular medicine, orthopedics, physical and occupational therapy, pulmonology, nutrition and gastroenterology. For severely affected patients with type I SMA, early involvement of the pediatric advanced care or palliative care team can provide parents with support and assistance in making decisions that are consonant with their values and help to
Summary
SMA is a chronic, inherited motor neuron disease for which there is no established treatment. Yet there is cause for optimism, because it is an area of active research, and knowledge about the molecular genetics and pathogenesis of SMA is ever increasing. Several groups are actively exploring pharmacologic treatments, whether through the use of approved drugs, identification of new agents via high-throughput screens, or development of novel pharmaceutical compounds. Consortia of clinicians and
References (116)
- et al.
Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2
Genet Med
(2002) - et al.
59th ENMC International Workshop: spinal muscular atrophies: recent progress and revised diagnostic criteria 17-19 April 1998, Soestduinen, The Netherlands
Neuromuscul Disord
(1999) Chaos in the classification of SMA: a possible resolution
Neuromuscul Disord
(1995)Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype
Eur J Paediatr Neurol
(1999)- et al.
An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients
Neuromuscul Disord
(2007) - et al.
The natural history of type I (severe) spinal muscular atrophy
Neuromuscul Disord
(1994) - et al.
Spinal muscular atrophy. 32nd ENMC International Workshop. Naarden, The Netherlands, 10-12 March 1995
Neuromuscul Disord
(1996) - et al.
Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy
Neuromuscul Disord
(2009) - et al.
Intelligence and cognitive function in children and adolescents with spinal muscular atrophy
Neuromuscul Disord
(2002) - et al.
A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients
J Neurol Sci
(1997)
Prenatal onset spinal muscular atrophy
Eur J Paediatr Neurol
Unusual clinical features in infantile Spinal Muscular Atrophies
Brain Dev
93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) - clinical picture (6-8 April 2001, Naarden, The Netherlands)
Neuromuscul Disord
Clinical and mutational characteristics of spinal muscular atrophy with respiratory distress type 1 in The Netherlands
Neuromuscul Disord
Interfamilial phenotypic heterogeneity in SMARD1
Neuromuscul Disord
Brown-Vialetto-van Laere and Fazio-Londe overlap syndromes: a clinical, biochemical and genetic study
Neuromuscul Disord
Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene
Am J Hum Genet
Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy
Am J Hum Genet
Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene
Neuromuscul Disord
Identification and characterization of a spinal muscular atrophy-determining gene
Cell
Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy
Am J Hum Genet
Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number
Am J Hum Genet
Spinal muscular atrophy: a clinical and research update
Pediatr Neurol
The effect of hydroxyurea in spinal muscular atrophy cells and patients
J Neurol Sci
Daily salbutamol in young patients with SMA type II
Neuromuscul Disord
A placebo-controlled trial of gabapentin in spinal muscular atrophy
J Neurol Sci
Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice
Am J Hum Genet
Two early infantile hereditary cases of progressive muscular atrophy simulating dystrophy, but on a neural basis [article in German]
Arch Psychiat Neurol
Ueber chronische spinale Muskelatrophie im Kindesalter, auf familiärer Basis
Dtsch Z Nervenheilkd
A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2
Hum Mol Genet
Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy
J Med Genet
Genetic risk assessment in carrier testing for spinal muscular atrophy
Am J Med Genet
New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations
Eur J Hum Genet
Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens
Eur J Hum Genet
Epidemiology of spinal muscular atrophies in a sample of the Italian population
Neuroepidemiology
Epidemiological data on Werdnig-Hoffmann disease in Germany (West-Thuringen)
Hum Genet
Newborn and carrier screening for spinal muscular atrophy
Am J Med Genet A
Prospective analysis of strength in spinal muscular atrophy. DCN/Spinal Muscular Atrophy Group
J Child Neurol
Consensus statement for standard of care in spinal muscular atrophy
J Child Neurol
Paralysie flasque de quatre membres et des muscles du tronc (sauf le diaphragme) chez un nouveau-ne
Bull Soc Pediatr Paris
A case of congenital spinal muscular atrophy (family type) and a case of hemorrhage into the spinal cord at birth, giving similar symptoms
Brain
Infantile muscular atrophy
Arch Neurol
Spinal muscular atrophies
Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications
Arch Neurol
The changing natural history of spinal muscular atrophy type 1
Neurology
Observational study of spinal muscular atrophy type I and implications for clinical trials
Neurology
Congenital heart defects in spinal muscular atrophy type I: a clinical report of two siblings and a review of the literature
Am J Med Genet A
Digital necroses and vascular thrombosis in severe spinal muscular atrophy
Muscle Nerve
Vascular perfusion abnormalities in infants with spinal muscular atrophy
J Pediatr
Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy
Neurology
Cited by (112)
Survival in patients diagnosed with SMA at less than 24 months of age in a population-based setting before, during and after introduction of nusinersen therapy. Experience from Sweden
2022, European Journal of Paediatric NeurologyCitation Excerpt :Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is characterized by progressive muscle atrophy and weakness. Most of the infants who are born with SMA have the severe type 1 disease, which is characterized by onset of symptoms at 6 months of age or younger and a median life expectancy of less than 2 years without respiratory support [1–3]. New developmental motor milestones are, for this subgroup of SMA, rarely achieved after diagnosis [4].
Estimating mortality in rare diseases using a population-based registry, 2002 through 2019
2023, Orphanet Journal of Rare DiseasesSpinal muscular atrophy in Ghanaian children confirmed by molecular genetic testing: a case series
2023, Pan African Medical JournalA Mixed-method Approach to Develop an Ambulatory Module of the SMA Independence Scale
2023, Journal of Neuromuscular Diseases
Disclosures: Dr. Darras receives research support from PTC Therapeutics and ISIS Pharmaceuticals.
This article was funded in part by the SMA Foundation (New York, NY).