Sections

Sections Spinal Muscular Atrophy
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Medication
Follow-up
Questions & Answers
References

Presentation

History

The diagnosis of spinal muscular atrophies includes the following a detailed clinical history. Obtaining a complete family history facilitates genetic counseling.

Patients with spinal muscular atrophy present with weakness and muscle wasting in the limbs, respiratory, and bulbar or brainstem muscles. They have no evidence of cerebral or other CNS dysfunction. Patients with spinal muscular atrophy often have above-average intelligence quotients (IQs) and demonstrate high degrees of intelligence.

The clinical manifestations of each particular form of spinal muscular atrophy are discussed:^{[15, 2, 16, 17, 18]}

SMA type I - Acute infantile or Werdnig-Hoffman disease

Patients present before 6 months of age, with 95% of patients having signs and symptoms by 3 months. They have severe, progressive muscle weakness and flaccid or reduced muscle tone (hypotonia). Bulbar dysfunction includes poor suck ability, reduced swallowing, and respiratory failure. Patients have no involvement of the extraocular muscles, and facial weakness is often minimal or absent. They have no evidence of cerebral involvement, and infants appear alert.

Reports of impaired fetal movements are observed in 30% of cases, and 60% of infants with SMA type I are floppy babies at birth. Prolonged cyanosis may be noted at delivery. In some instances, the disease can cause fulminant weakness in the first few days of life. Such severe weakness and early bulbar dysfunction are associated with short life expectancy, with a mean survival of 5.9 months. In 95% of cases, infants die from complications of the disease by 18 months.

SMA type II - Chronic infantile form

This is the most common form of spinal muscular atrophy, and some experts believe that SMA type II may overlap types I and III.

Most children present between the ages of 6 and 18 months.

The most common manifestation that parents and physicians note is developmental motor delay. Infants with SMA type II often have difficulties with sitting independently or failure to stand by 1 year of age.

An unusual feature of the disease is a postural tremor affecting the fingers. This is thought to be related to fasciculations in the skeletal muscles.

Pseudohypertrophy of the gastrocnemius muscle, musculoskeletal deformities, and respiratory failure can occur.

The lifespan of patients with SMA type II varies from 2 years to the third decade of life. Respiratory infections account for most deaths.

SMA type III - Chronic juvenile or Kugelberg-Welander syndrome

This is a mild form of autosomal recessive spinal muscular atrophy that appears after age 18 months.

SMA type III is characterized by slowly progressive proximal weakness. Most children with SMA III can stand and walk but have trouble with motor skills, such as going up and down stairs.

Bulbar dysfunction occurs late in the disease.

Patients may show evidence of pseudohypertrophy, as in patients with SMA type II.

The disease progresses slowly, and the overall course is mild. Many patients have normal life expectancies.

SMA type IV - Adult-onset form

Onset is typically in the mid 30s.

In many ways, the disease mimics the symptoms of type III.

Overall, the course of the disease is benign, and patients have a normal life expectancy.

Physical

Patients with disease of the lower motor neurons present with flaccid weakness, hypotonia, decreased or absent deep tendon reflexes, fasciculations, and muscle atrophy.

SMA type I - Acute infantile or Werdnig-Hoffman disease

Diffuse muscle weakness and hypotonia can be demonstrated with a variety of bedside maneuvers, including the traction response, vertical suspension, and horizontal suspension tests.

In general, infants with SMA type I cannot hold their heads up when pulled to the sitting position, and they will slip through the examiner's hands when held vertically. They lay limp in the physician's hand when held under the abdomen and facing down.

Weakness is greater in proximal than distal muscles and may mimic muscle disease (myopathy).

Findings on sensory examination are normal. Deep tendon reflexes are absent, as are long-tract signs and sphincteral abnormalities.

Arthrogryposis, or deformities of the limbs and joints at birth, can be observed and results from in utero hypotonia. Skeletal deformities (scoliosis) may be present.

In the infant or newborn, fasciculations are often restricted to the tongue, but tongue fasciculations can be difficult to distinguish from normal random movements unless atrophy is also present.

SMA type II - Chronic infantile form

Infants cannot get to a sitting position on their own, though they may stay upright if placed in that position.

As with SMA type I, SMA type II cause notable, symmetric proximal weakness, hypotonia, and fasciculations.

Findings on sensory examination are normal, and long-tract signs are absent. When the patient's hands are held out, a characteristic fine postural tremor may be observed.

SMA type III - Chronic juvenile or Kugelberg-Welander syndrome

Children can ambulate, but they have proximal muscle weakness and various degrees of muscle hypotonia and wasting.

The lower extremities are often more severely affected than the upper extremities.

SMA type IV - Adult-onset form

Patients are similar to those with SMA type III in presentation and clinical findings, though the overall degree of motor weakness is less severe in type IV than in type III.

Spinal muscular atrophy variants:

See the list below:

SMA type 0 (prenatal onset SMA or arthrogryposis multiplex congenita): This has been described in infants born with hypotonia, respiratory distress, and multiple arthrogryposis. Complete deletion of SMN and NAIP genes has been noted.^[19]
Juvenile bulbar palsy, or bulbar hereditary motor neuronopathy (HMN) types I and II: Bulbar HMN I (Vialletto-van Laere syndrome) is an autosomal recessive syndrome that begins in the second decade of life. It is characterized by facial weakness, dysphagia and dysarthria followed by facial weakness and compromised respiratory function. The distinguishing feature of this syndrome is the development of bilateral sensorineural hearing loss.
Bulbar HMN II (Fazio-Londe disease): This is characterized by progressive bulbar paralysis in the first decade of life. Patients present with stridor, dysarthria, and dysphagia. Cranial-nerve involvement leads to facial diplegia, ptosis, and ophthalmoplegia. Generalized weakness of the lower motor neurons and rare corticospinal-tract signs are sometimes observed. Median survival for patients with bulbar HMN II is 18 months.^[20]
Distal spinal muscular atrophy (spinal CMT or HMN type II): This may clinically mimic Charcot-Marie-Tooth (CMT) disease, otherwise known as hereditary motor and sensory neuropathy (HMSN) types 1 and 2: CMT is characterized by peroneal muscular atrophy, weakness, and wasting in the legs. High foot arches (pes cavus) are often present. Deep tendon reflexes are reduced or absent. Distal large fiber sensory loss is found on examination, although patients do not usually present with complaints of subjective sensory loss. Compared with CMT, patients with distal spinal muscular atrophy do not have sensory loss and the electrodiagnostic examination shows sparing of sensory nerves.^[4]
X-lined recessive bulbospinal muscular atrophy (Kennedy disease):^[21]Patients present with bulbar weakness, gynecomastia, and lower motor neuron weakness beginning at age 20-40 years. Muscles cramps often precede weakness, and facial and perioral fasciculations are seen in more than 90% of patients. Increased rates of type 2 diabetes, infertility, and hand tremor are associated with Kennedy disease. This condition results from a triple repeat mutation (cytosine-adenine-guanine [CAG]) in exon 1 of the androgen receptor gene on the X chromosome. Because of the X-linked nature of Kennedy disease, daughters of affected patients are obligated carriers; therefore, genetic counseling is indicated.
Scapuloperoneal spinal muscular atrophy: Type 1 (AD form) appears at age 14-26, with weakness, distal leg atrophy, and absent tendon reflexes and sparing of intrinsic foot muscles. Facial, bulbar, and pectoral muscles are rarely affected. Progression is slow, with survival into the seventh or eight decade of life.
Type 2 (AR form): Patients present between birth and age 5 years, with weakness and atrophy of the lower extremities and pectoral girdle. The course is variable, and patients can survive to the fourth decade.^[22]
X-linked form scapuloperoneal spinal muscular atrophy: This has been described with an onset before age 10 years. Patients present with weakness of the pectoral girdle and arms with contractures. Cardiac conduction defects and cardiomyopathy are noted. The syndrome is slowly progressive but stabilizes by age 20 years, and patients survive to the sixth decade.
Davidenkow syndrome: This is a form of scapuloperoneal SMA characterized by weakness of the pectoral girdle and distal leg muscles, pes equinovarus, and distal sensory loss and fasciculations. Autosomal dominant (age of onset, 15-30 y) and autosomal recessive (age of onset, < 15 y) forms have been described. The clinical course is slow in the autosomal dominant form, whereas the course of the autosomal recessive form is unknown.
Fascioscapulohumeral (FSH) SMA: Most reports of this disorder are from Japan. It is an autosomal dominant or sporadic disorder characterized by limb-girdle and facial weakness occurring before age 20 years. The phenotype of FSH SMA is similar to that of FSH dystrophy (FSHD), another unrelated muscular dystrophy. However, FSH SMA does not have the chromosome 4 gene deletion seen in FSHD. Progression is slow, and the overall prognosis is good.
Scapulohumeral spinal muscular atrophy: Described initially in a Dutch family, this autosomal dominant disorder is characterized by the onset of scapulohumeral weakness and atrophy between the fourth and sixth decades of life. Progression is rapid, with death from respiratory failure occurring within 3 years.
Oculopharyngeal spinal muscular atrophy: This disorder is seen mainly in people of French-Canadian descent and is characterized by bulbar and cranial-nerve weakness followed by myopathic weakness of the limbs. The pattern of inheritance is autosomal dominant with variable penetrance. The onset is usually in the fourth to fifth decades of life, and the disease is slowly progressive.
Ryukyuan spinal muscular atrophy: This is an autosomal recessive disorder described in men who live in the Japanese community on Ryukyu Islands. The onset is before age 5 years, and the disease is characterized by weakness and atrophy of the lower extremities, skeletal abnormalities (eg, scoliosis), and foot deformities (eg, pes cavus). Deep tendon reflexes are diminished or absent. The course of disease is unknown.^[23]
Spinal muscular atrophy with pontocerebellar hypoplasia (PCH1): This heterogeneous autosomal recessive disorder is characterized by generalized muscle weakness, global developmental delay, and early death. One study found that 30-40% of patients with milder disease course had protein EXOSC3 mutations.^[24]
Other: Other variants have been described, including multiple long-bone fractures at birth, diaphragmatic paralysis with early respiratory failure, congenital heart defects, arthrogryposis, segmental amyotrophy, vocal-cord paralysis (distal HMN type VII), and disease of the anterior horn cell with agenesis of the corpus callosum (SMA with respiratory distress).^{[25, 26, 27]}SMA with respiratory distress presents with rapid decline over 2 years, followed by a plateau, and is linked with mutation in the IGHMBP2 gene.^[28]An autosomal dominant late-onset lower motor neuronopathy was discovered in 2 Finnish families with linkage to a mutation on band 22q11.2-q13.2.^[29]A rare form of autosomal dominant proximal SMA has been identified with a possible linkage to an SETX gene mutation.^[30]

Causes

In 1995, the SMN gene, responsible for SMA types I-III, was mapped to the long arm of chromosome 5. (See Pathophysiology.)

Two copies of the SMN gene have been identified on the 5q arm: a telomeric SMN gene (SMNt, or SMN1) and a centromeric SMN gene (SMNc, or SMN2). These 2 genes are nearly identical except for base-pair changes in exons 7 and 8. About 95% of all cases of SMA involve a homozygous deletion of the SMN1 gene.^[31]

Expression of SMN1 produces the full-length SMN protein. In contrast, expression of SMN2 produces a truncated version of the SMN protein that is missing the 16 amino acids from the carboxy terminus. This truncated protein results from a base-pair switch in exon 7 of the SMN2 gene. This switch leads to alternative splicing of SMN2 mRNA, with removal of the exon 7 sequence. About 70-80% of the gene product is in the form of this truncated protein. Only about 10-25% of the protein produced is the full-length functioning form.^[31]

Deletions or mutations in the SMN1 gene substantially decrease expression of the SMN protein. Expression of SMN2 alone does not appear to produce sufficient amounts of SMN protein to permit normal mRNA processing in the lower motor neurons. A correlation between SMN2 copy number and disease phenotype has been proposed, with increased copy associated with milder disease.^[32]Additionally, low SMN protein levels are associated with more severe disease forms.^[33]Inefficient or abnormal mRNA processing appears to have a toxic effect on the lower motor neurons and results in cellular degeneration.^[34]

SMN protein is part of a multimeric protein complex that plays a critical role in the assembly of snRNPs. These snRNPs are essential for early pre-mRNA splicing. The hypothesis is that impaired or reduced formation of snRNPs impairs mRNA splicing, with a toxic effect on normal cellular function. Why this mutation results in such selective degeneration of lower motor neurons is unclear, though the SMN protein is expressed in many types of neurons and organ systems.^[35]

Neuronal apoptosis inhibitory protein (AIP), NAIP, gene was also identified in 1995. Homozygous deletions of this gene are found in 45% of patients with SMA type I and in 18% of patients with SMA types II or III. This gene belongs to a class of highly conserved AIPs that help to regulate programmed cell death. Deletion of this gene appears to be associated with severe phenotypes of SMA.^[36]

Mutations in BFT2p44 have been found in 15% of patients with SMA.^[37]

Differential Diagnoses

Katirji B, Kaminski HJ, Preston DC. Spinal muscular atrophies. Katirji B, Kaminski HJ, Preston DC, Ruff RL, Shapiro BE, eds. Neuromuscular Disorders in Clinical Practice. Boston: Butterworth-Heinemann; 2002. 445-53.
Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice. 2nd ed. Boston: Butterworth-Heinemann; 1996. 1829-43.
Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990 Apr 5. 344(6266):540-1. [QxMD MEDLINE Link].
Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature. J Neurol Sci. 1980 Mar. 45(2-3):337-48. [QxMD MEDLINE Link].
Burlet P, Burglen L, Clermont O, et al. Large scale deletions of the 5q13 region are specific to Werdnig- Hoffmann disease. J Med Genet. 1996 Apr. 33(4):281-3. [QxMD MEDLINE Link].
Emery AE. The nosology of the spinal muscular atrophies. J Med Genet. 1971 Dec. 8(4):481-95. [QxMD MEDLINE Link].
Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26. 1(8174):919-22. [QxMD MEDLINE Link].
Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992. 2(5-6):423-8. [QxMD MEDLINE Link].
Burglen L, Lefebvre S, Clermont O, et al. Structure and organization of the human survival motor neurone (SMN) gene. Genomicx. 1996. 32:479-482.
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008 Jun 21. 371(9630):2120-33. [QxMD MEDLINE Link].
Harding AE. Inherited neuronal atrophy and degeneration predominantly of lower motor neurons. Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 3rd ed. Philadelphia: WB Saunders; 1993. 1051-64.
Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002 Jul 15. 110(4):301-7. [QxMD MEDLINE Link].
Awater C, Zerres K, Rudnik-Schöneborn S. Pregnancy course and outcome in women with hereditary neuromuscular disorders: comparison of obstetric risks in 178 patients. Eur J Obstet Gynecol Reprod Biol. 2012 Jun. 162(2):153-9. [QxMD MEDLINE Link].
Hausmanowa-Petrusewicz I, Zaremba J, Borkowska J, Szirkowiec W. Chronic proximal spinal muscular atrophy of childhood and adolescence: sex influence. J Med Genet. 1984 Dec. 21(6):447-50. [QxMD MEDLINE Link].
Walton JN. The limp child. J Neurol Neurosurg Psychiatry. 1957 May. 20(2):144-54. [QxMD MEDLINE Link].
Rudnik-Schoneborn S, Forkert R, Hahnen E, et al. Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropediatrics. 1996 Feb. 27(1):8-15. [QxMD MEDLINE Link].
Fenichel GM. Clinical Pediatric Neurology. 3rd ed. WB Saunders: Philadelphia; 1997. 151-74.
Joynt R, Griggs R. Clinical Neurology. Philadelphia: Lippincott; 1997. Vol 4: 11-5.
Okamoto K, Saito K, Sato T, Ishigaki K, Funatsuka M, Osawa M. [A case of spinal muscular atrophy type 0 in Japan]. No To Hattatsu. 2012 Sep. 44(5):387-91. [QxMD MEDLINE Link].
McShane MA, Boyd S, Harding B, et al. Progressive bulbar paralysis of childhood. A reappraisal of Fazio-Londe disease. Brain. 1992 Dec. 115 ( Pt 6):1889-900. [QxMD MEDLINE Link].
Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968 Jul. 18(7):671-80. [QxMD MEDLINE Link].
Kaeser HE. Scapuloperoneal muscular atrophy. Brain. 1965 Jun. 88(2):407-18. [QxMD MEDLINE Link].
Kondo K, Tsubaki T, Sakamoto F. The Ryukyuan muscular atrophy. An obscure heritable neuromuscular disease found in the islands of southern Japan. J Neurol Sci. 1970 Oct. 11(4):359-82. [QxMD MEDLINE Link].
Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, et al. Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology. 2013 Jan 29. 80(5):438-46. [QxMD MEDLINE Link]. [Full Text].
Young ID, Harper PS. Hereditary distal spinal muscular atrophy with vocal cord paralysis. J Neurol Neurosurg Psychiatry. 1980 May. 43(5):413-08. [QxMD MEDLINE Link].
Bertini E, Gadisseux JL, Palmieri G, et al. Distal infantile spinal muscular atrophy associated with paralysis of the diaphragm: a variant of infantile spinal muscular atrophy. Am J Med Genet. 1989 Jul. 33(3):328-35. [QxMD MEDLINE Link].
Kamoshita S, Takei Y, Miyao M, Yanagisawa M, Kobayashi S, Saito K. Pontocerebellar hypoplasia associated with infantile motor neuron disease (Norman's disease). Pediatr Pathol. 1990. 10(1-2):133-42. [QxMD MEDLINE Link].
Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, et al. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Pediatrics. 2012 Jan. 129(1):e148-56. [QxMD MEDLINE Link].
Penttilä S, Jokela M, Hackman P, Maija Saukkonen A, Toivanen J, Udd B. Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2. Eur J Hum Genet. 2012 Nov. 20(11):1193-6. [QxMD MEDLINE Link]. [Full Text].
Rudnik-Schöneborn S, Arning L, Epplen JT, Zerres K. SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy. Neuromuscul Disord. 2012 Mar. 22(3):258-62. [QxMD MEDLINE Link].
Frugier T, Nicole S, Cifuentes-Diaz C, Melki J. The molecular bases of spinal muscular atrophy. Curr Opin Genet Dev. 2002 Jun. 12(3):294-8. [QxMD MEDLINE Link].
Chen WJ, He J, Zhang QJ, Lin QF, Chen YF, Lin XZ, et al. Modification of phenotype by SMN2 copy numbers in two Chinese families with SMN1 deletion in two continuous generations. Clin Chim Acta. 2012 Nov 20. 413(23-24):1855-60. [QxMD MEDLINE Link].
Finkel RS, Crawford TO, Swoboda KJ, Kaufmann P, Juhasz P, Li X, et al. Candidate proteins, metabolites and transcripts in the Biomarkers for Spinal Muscular Atrophy (BforSMA) clinical study. PLoS One. 2012. 7(4):e35462. [QxMD MEDLINE Link]. [Full Text].
Anderson K, Talbot K. Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol. 2003 Oct. 16(5):595-9. [QxMD MEDLINE Link].
Hausmanowa-Petrusewicz I, Vrbova G. Spinal muscular atrophy: a delayed development hypothesis. Neuroreport. 2005 May 12. 16(7):657-61. [QxMD MEDLINE Link].
Roy N, Mahadevan MS, McLean M, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell. 1995 Jan 13. 80(1):167-78. [QxMD MEDLINE Link].
Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med. 1996 Oct. 74(10):555-62. [QxMD MEDLINE Link].
[Guideline] Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol. 2012 May. 11(5):443-52. [QxMD MEDLINE Link].
Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015 Feb. 51 (2):157-67. [QxMD MEDLINE Link].
Palladino A, Passamano L, Taglia A, D'Ambrosio P, Scutifero M, Cecio MR, et al. Cardiac involvement in patients with spinal muscular atrophies. Acta Myol. 2011 Dec. 30(3):175-8. [QxMD MEDLINE Link]. [Full Text].
Hausmanowa-Petrusewicz I, Karwanska A. Electromyographic findings in different forms of infantile and juvenile proximal spinal muscular atrophy. Muscle Nerve. 1986 Jan. 9(1):37-46. [QxMD MEDLINE Link].
Krivickas LS. Electrodiagnosis in neuromuscular disease. Phys Med Rehabil Clin N Am. 1998 Feb. 9(1):83-114, vi. [QxMD MEDLINE Link].
Buchthal F, Olsen PZ. Electromyography and muscle biopsy in infantile spinal muscular atrophy. Brain. 1970. 93(1):15-30. [QxMD MEDLINE Link].
Dubowitz V. Muscle disorders in childhood. Major Probl Clin Pediatr. 1978. 16:iii-xiii, 1-282. [QxMD MEDLINE Link].
Spinraza (nusinersen) [package insert]. Cambridge, MA: Biogen Inc. 2016 December. Available at [Full Text].
A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Infantile-onset Spinal Muscular Atrophy - ENDEAR trial. Presented at the British Paediatric Neurology Association (BPNA) Annual Conference in January 2017. Clinical Trials.gov identifier: NCT02193074.
A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Later-onset Spinal Muscular Atrophy – CHERISH trial. Clinical Trials.gov identifier: NCT02292537.
Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2. 377 (18):1713-1722. [QxMD MEDLINE Link]. [Full Text].
Al-Zaidy S, Pickard AS, Kotha K, Alfano LN, Lowes L, Paul G, et al. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr Pulmonol. 2019 Feb. 54 (2):179-185. [QxMD MEDLINE Link]. [Full Text].
Novartis. AveXis data reinforce effectiveness of Zolgensma in treating spinal muscular atrophy (SMA) Type 1. 2019 Apr 16. Available at https://www.novartis.com/news/media-releases/avexis-data-reinforce-effectiveness-zolgensma-treating-spinal-muscular-atrophy-sma-type-1.
Servais L, Baranello G, Masson R, et al. FIREFISH Part 2: efficacy and safety of risdiplam (RG7916) in infants with spinal muscular atrophy (SMA) (1302). Neurology. April 14, 2020;94 (15 suppl). Presented at the 72nd Annual meeting of the American Academy of Neurology, April 25-May 1, 2020. [Full Text].
Evrysdi (risdiplam) [package insert]. South San Francisco, CA: Genentech. August 2020. Available at [Full Text].
Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, et al. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011. 6(7):e21296. [QxMD MEDLINE Link]. [Full Text].
Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, et al. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010 Aug 19. 5(8):e12140. [QxMD MEDLINE Link]. [Full Text].
Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST, et al. Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev. 2012 Apr 18. 4:CD006282. [QxMD MEDLINE Link].
Wadman RI, Bosboom WM, van der Pol WL, van den Berg LH, Wokke JH, Iannaccone ST, et al. Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev. 2012 Apr 18. 4:CD006281. [QxMD MEDLINE Link].
Fernandez-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011 Feb. 10(2):140-7. [QxMD MEDLINE Link].
van Bruggen HW, van den Engel-Hoek L, van der Pol WL, de Wijer A, de Groot IJ, Steenks MH. Impaired mandibular function in spinal muscular atrophy type II: need for early recognition. J Child Neurol. 2011 Nov. 26(11):1392-6. [QxMD MEDLINE Link].
Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families and friends. 3rd ed. Loma Linda, Calif: 2000. 18. [Full Text].
Mesfin A, Sponseller PD, Leet AI. Spinal muscular atrophy: manifestations and management. J Am Acad Orthop Surg. 2012 Jun. 20(6):393-401. [QxMD MEDLINE Link].
Birnkrant DJ, Pope JF, Martin JE, et al. Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding. Pediatr Neurol. 1998 May. 18(5):407-10. [QxMD MEDLINE Link].
Montes J, McIsaac TL, Dunaway S, Kamil-Rosenberg S, Sproule D, Garber CE, et al. Falls and spinal muscular atrophy: exploring cause and prevention. Muscle Nerve. 2013 Jan. 47(1):118-23. [QxMD MEDLINE Link].
Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012 Jan. 20(1):27-32. [QxMD MEDLINE Link]. [Full Text].
Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995 May. 52(5):518-23. [QxMD MEDLINE Link].
Ge X, Bai J, Lu Y, Qu Y, Song F. The natural history of infant spinal muscular atrophy in China: a study of 237 patients. J Child Neurol. 2012 Apr. 27(4):471-7. [QxMD MEDLINE Link].
Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr. 2013 Jan. 162(1):155-9. [QxMD MEDLINE Link].
Lemoine TJ, Swoboda KJ, Bratton SL, Holubkov R, Mundorff M, Srivastava R. Spinal muscular atrophy type 1: are proactive respiratory interventions associated with longer survival?. Pediatr Crit Care Med. 2012 May. 13(3):e161-5. [QxMD MEDLINE Link].
Manson JI, Thong YH. Immunological abnormalities in the syndrome of poliomyelitis-like illness associated with acute bronchial asthma (Hopkin's syndrome). Arch Dis Child. 1980 Jan. 55(1):26-32. [QxMD MEDLINE Link].
Brichta L, Holker I, Haug K, Klockgether T, Wirth B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann Neurol. 2006 Jun. 59(6):970-5. [QxMD MEDLINE Link].
Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology. 2006 Aug 8. 67(3):500-1. [QxMD MEDLINE Link].

Media Gallery

of 0

Author

Jeffrey Rosenfeld, MD, PhD, FAAN Professor of Neurology, Associate Chairman, Department of Neurology, Director, Neuromuscular ALS/MND Program, Medical Director, The Center for Restorative Neurology, Loma Linda University Health Systems

Jeffrey Rosenfeld, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association, Society for Neuroscience

Disclosure: Nothing to disclose.

Coauthor(s)

Carmel Armon, MD, MSc, MHS Chair, Department of Neurology, Assaf Harofeh Medical Center, Tel Aviv University Sackler Faculty of Medicine, Israel

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Received research grant from: Neuronix Ltd, Yoqnea'm, Israel<br/>Received income in an amount equal to or greater than $250 from: JNS - Associate Editor. UpToDate - Author Royalties.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, American Medical Association, American Neurological Association, Association of Military Surgeons of the US, Child Neurology Society, Southern Pediatric Neurology Society

Disclosure: Nothing to disclose.

Additional Contributors

Bryan Tsao, MD Associate Professor, Department of Neurology, Loma Linda University; Chair and Service Chief, Department of Neurology, Loma Linda University Medical Center

Bryan Tsao, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine

Robert J Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society

Disclosure: Nothing to disclose.

Theresa L LaBarte, DO Resident Physician, Department of Neurology, Loma Linda University Medical Center

Theresa L LaBarte, DO is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.