Spinal Muscular Atrophy (SMA)


Patients with spinal muscular atrophy (SMA) experience progressive muscular weakness with decreased endurance and mobility.1,2 Patients present with various motor function impairments, ranging from the inability to sit to the inability to perform routine daily tasks and engage in sports. Contractures of the hip and knee joints also can be associated with decreased motor ability.3

The identification of the genetic basis of SMA paved the way for the discovery of several new potential therapeutic options.4 The evaluation of motor function in patients with SMA and its evolution throughout the disease course, as well as the effectiveness of therapeutics, relies on the use of scales and tests that have been designed to consider not only the age of the patient but also specific motor behaviors.2

Hammersmith Infant Neurological Examination

The Hammersmith Infant Neurological Examination (HINE), which can be used to study children aged up to 2 years, includes 26 items grouped into 3 different sections to provide a complete neurological, developmental, and behavioral assessment.5 The neurological examination includes an assessment of cranial nerve function, posture, movements, and reactions. The developmental evaluation includes 8 milestones in motor function: head control, sitting, voluntary grasp, ability to kick in a supine position, rolling, crawling, standing, and walking.

In the HINE, each item is individually scored on a scale from 0 to 3, and the sum of the scores can range from 0 to 78. Scoring is based on observation of the child’s performance on each item. The HINE is a simple method to ascertain how severely a motor outcome is affected and at what age each milestone is achieved.5

CHOP INTEND

Patients with SMA type 1 have a very limited range of motor function and are typically unable to sit without assistance.6 These clinical features preclude a simple quantification of the motor abilities of a patient presenting with this severe form of the disease. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was developed to evaluate motor skills in children with SMA type 1 from infancy to 4 years of age.2,6 The 16 items are graded on a scale ranging from 0 (which corresponds to no response) to 4 (corresponding to a complete response), for a total possible score of 64.

HFMSE for Patients With SMA Type 2 or  3

The Hammersmith Functional Motor Scale–Expanded (HFMSE) was developed in 2003 to evaluate the physical abilities of ambulatory and nonambulatory patients with SMA type 2 or 3.7 This scale consists of 20 items that are scored from 0 to 2, depending on the patient’s ability to perform with or without assistance.7 Because the HFMSE score is positively correlated with the SMN2 gene copy number, compound muscle action potential (CMAP), and muscle strength, it has been implemented in studies of patients in clinical trials.8

The Upper Limb Module

The Upper Limb Module (ULM) was created to evaluate upper limb function in young nonambulatory children with a low score on the HFMSE.9 This module includes items from other scales as well as items appropriate for patients ranging in age from 30 months to adulthood.9 It was validated in a multicenter study10 and since then has undergone several revisions intended to improve its measurement capabilities.11,12 As the result of one of these revisions, the ULM is now applicable to patients with SMA type 3.12

Six Minute Walk Test

For the scales typically used in SMA staging, an observer evaluates the scaled items. However, the Six Minute Walk Test (6MWT) provides an objective evaluation of a patient’s exercise capacity. This test can be conducted in ambulatory patients with SMA in whom the disease later progresses. Because the intensity of the 6MWT is controlled by the patient and the test is sensitive to changes resulting from the patient’s fatigue, the 6MWT is an important measure of the functional capacity of a patient with SMA.1,13 This test has been accepted by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) as a primary endpoint in late-phase clinical trials.1

CMAP to Gauge Motor Neuron Loss

In addition to the existing scales for quantifying motor function, electrophysiologic measurements can be used to follow motor neuron loss.14 The compound muscle action potential (CMAP) measures the electrophysiologic response of a muscle or muscle group to nerve stimulus.15

CMAP amplitudes tend to decrease or stabilize with time in infants and individuals with types of SMA that have a later onset.16 However, the CMAP may fail to detect denervation changes, even when the patient exhibits a significant loss of motor neurons.17 

Disease progression is slower in older patients, who may benefit from a CMAP scan. A CMAP scan is generally superior to CMAPmax, in which all the motor units that innervate a specific muscle are stimulated.18

Motor Unit Number Estimation

The motor unit number estimation (MUNE) is an electrophysiologic technique that allows a clinician to estimate the number of motor neurons that innervate a muscle group and are involved in muscle contraction.19 The MUNE is calculated as the ratio of the CMAP to the average single motor unit potential (SMUP).19

Reviewed by Michael Sapko, MD on 7/1/2021

References

1. Montes J, McDermott MP, Martens WB, et al. Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology. 2010;74(10):833-8. doi:10.1212/WNL.0b013e3181d3e308

2. Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-61. doi:10.1016/j.nmd.2009.11.014

3. Salazar R, Montes J, Dunaway Young S, et al. Quantitative evaluation of lower extremity joint contractures in spinal muscular atrophy: implications for motor function. Pediatr Phys Ther. 2018;30(3):209-15. doi:10.1097/PEP.0000000000000515

4. Sumner CJ. Therapeutics development for spinal muscular atrophy. NeuroRx. 2006;3(2):235-45. doi:10.1016/j.nurx.2006.01.010

5. De Sanctis R, Coratti G, Pasternak A, et al. Developmental milestones in type I spinal muscular atrophy. Neuromuscul Disord. 2016;26(11):754-9. doi:10.1016/j.nmd.2016.10.002

6. Finkel RS, Hynan LS, Glanzman AM, et al. The test of infant motor performance: reliability in spinal muscular atrophy type I. Pediatr Phys Ther. 2008;20(3):242-6. doi:10.1097/PEP.0b013e318181ae96

7. Main M, Kairon H, Mercuri E, Muntoni Fl. The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol. 2003;7(4):155-9. doi:10.1016/s1090-3798(03)00060-6

8. Glanzman AM, O’Hagen JM, McDermott MP, et al. Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol. 2011;26(12):1499-1507. doi:10.1177/0883073811420294

9. Mazzone ES, Mayhew A, Montes J, et al. Revised upper limb module for spinal muscular atrophy: Development of a new module. Muscle Nerve. 2017;55(6):869-74. doi:10.1002/mus.25430

10. Mazzone E, Bianco F, Martinelli D, et al. Assessing upper limb function in nonambulant SMA patients: development of a new module. Neuromuscul Disord. 2011;21(6):406-12. doi:10.1016/j.nmd.2011.02.014

11. Krosschell KJ, Scott CB, Maczulski JA, et al. Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy. Muscle Nerve. 2011;44(2):246-51. doi:10.1002/mus.22040 

12. O’Hagen JM, Glanzman AM, McDermott MP, et al. An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord. 2007;17(9-10):693-97. doi:10.1016/j.nmd.2007.05.009

13. Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic overview of the measurement properties of functional walk tests used in the cardiorespiratory domain. Chest. 2001;119(1):256-70. doi:10.1378/chest.119.1.256

14. McComas AJ. 1998 ISEK Congress Keynote Lecture: Motor units: how many, how large, what kind? International Society of Electrophysiology and Kinesiology. J Electromyogr Kinesiol. 1998;8(6):391-402. doi:10.1016/s1050-6411(98)00020-0

15. Arnold WD,Sheth KA, Wier CG, et al. Electrophysiological motor unit number estimation (MUNE) measuring compound muscle action potential (CMAP) in mouse hindlimb muscles J Vis Exp. 2015(103):e52899. doi:10.3791/52899

16. Darras BT, Chiriboga CA, Iannaccone ST, et al. Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies. Neurology. 2019;21;92(21):e2492-506. doi:10.1212/WNL.0000000000007527. 

17. Daube JR. Motor unit number estimates–from A to Z J Neurol Sci. 2006;242(1-2):23-35. doi:10.1016/j.jns.2005.11.01

18. Wadman RI, Wijngaarde CA, Stam M, et al. Muscle strength and motor function throughout life in a cross-sectional cohort of 180 patients with spinal muscular atrophy types 1c-4. Eur J Neurol. 2018;25(3):512-8. doi:10.1111/ene.1353419. Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002;25(3):445-7. doi:10.1002/mus.10050

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