Adult-Onset Spinal Muscular Atrophy

1. ADULT-ONSET
SPINAL MUSCULAR ATROPHY
Ade Wijaya, MD – April 2020

2. Introduction
 A group of diverse genetic disorders that affect the spinal and bulbar lower motor
neurons.
 Several forms of Spinal Muscular Atrophy (SMA) have been described in association
with different gene mutations and significant phenotypic variability.
 The most frequent form of SMA is the autosomal-recessive proximal SMA, or SMN1-
linked SMA (neonatal/infantile onset)
 However, milder phenotype variants can be diagnosed in adulthood
 The second most common genetic disorder affecting lower motor neurons is
Kennedy disease (KD), or spinal and bulbar muscular atrophy (SBMA).
Morales RJ, Pageot N, Taieb G, Camu W. Adult-onset spinal muscular atrophy: An update. Revue neurologique. 2017 May 1;173(5):308-19.

3. SMA Secondary to SMN1 Gene Mutations
 Due to homozygous deletion or mutation of the survival motor neuron 1 (SMN1)
gene
 1/11,000 births
 The most common genetic cause of death in infants
 SMA type 1-4 (type 4: adult onset)
Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80:155–65.
Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve 2015;51:157–67.

4. Type 4 SMA
 An adult onset (> 18 years) and represents < 5% of cases. Patients remain
ambulant as adults and, in the majority of cases, have no need of respiratory
assistance.
 The differential diagnosis with limb-girdle muscle disease, especially Becker
dystrophinopathy, may be difficult based on clinical grounds due to their
overlapping clinical phenotypes
 Diagnosis: Electromyograpphy (EMG), muscle MRI, muscle biopsy
Morales RJ, Pageot N, Taieb G, Camu W. Adult-onset spinal muscular atrophy: An update. Revue neurologique. 2017 May 1;173(5):308-19.

5. Spinal and Bulbar Muscular Atrophy (SBMA)
 Kennedy Disease
 A rare late-onset, X-linked hereditary motor neuron disease is characterized by
slowly progressive bulbar and extremity muscle weakness, atrophy and
fasciculations. Its prevalence is estimated to be around 1–2/100,000 population
 SBMA is caused by an expanded trinucleotide cytosine– adenine–guanine (CAG)
repeat (> 38) encoding a polygluta-mine (polyQ) tract expansion in exon 1 of the
androgen receptor (AR) gene on chromosome X
 The age of disease onset varies between the second and seventh decade of life
Finsterer J. Bulbar and spinal muscular atrophy (Kennedy’s disease): a review. Eur J Neurol 2009;16:556–61.
La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9.
Echaniz-Laguna A, Rousso E, Anheim M, Cossee M, Tranchant C. A family with early-onset and rapidly progressive X-linked spinal and bulbar muscular atrophy. Neurology 2005;64:1458–60.

6. Spinal and Bulbar Muscular Atrophy (SBMA)
 The most frequent initial symptoms are lower-limb weakness, cramps and tremor.
 More rarely, upper-limb weakness, gynecomastia and myalgia are the initial
manifestations
 Clinical examination shows signs of motor neuron dysfunction associated with
androgen insensitivity, including gynecomastia and testicular atrophy.
 Widespread fasciculations, significant tongue atrophy despite near-normal tongue
strength, activity-related twitching of the perioral muscles
 The muscle weakness is usually more pronounced in the proximal lower limbs.
 Deep tendon reflexes are often reduced or absent, and reduced vibratory sensation
in the legs is found in the majority of patients.
 The evolution of the disease is slowly progressive, but many patients are
wheelchair-bound by the age of 60 years
Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, et al. Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 2009;65:140–50.

7. Morales RJ, Pageot N, Taieb G, Camu W. Adult-onset spinal muscular atrophy: An update. Revue neurologique. 2017 May 1;173(5):308-19.

8. Morales RJ, Pageot N, Taieb G, Camu W. Adult-onset spinal muscular atrophy: An update. Revue neurologique. 2017 May 1;173(5):308-19.

9. Summary
 A group of diverse genetic disorders that affect the spinal and bulbar lower motor
neurons
 Proximal lower motor neuron weakness with neurogenic EMG
 Several forms of Spinal Muscular Atrophy (SMA) have been described in association
with different gene mutations and significant phenotypic variability