What are the variants of spinal muscular atrophy (SMA)?

Updated: May 29, 2019
  • Author: Jeffrey Rosenfeld, MD, PhD, FAAN; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP  more...
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Answer

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]


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