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Proximal spinal muscular atrophy type 3

ORPHA83419
Synonym(s) Juvenile spinal muscular atrophy
Kugelberg-Welander disease
SMA type 3
SMA-III
SMA3
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Childhood
ICD-10
  • G12.1
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Proximal spinal muscular atrophy type 3 (SMA3) is a relatively mild form of proximal spinal muscular atrophy (see this term) characterized by muscle weakness and hypotonia resulting from the degeneration and loss of the lower motor neurons in the spinal cord and the brain stem nuclei.

Prevalence is estimated at around 1/375,000.

The disease manifests after 12 months of age (usually between childhood and adolescence), after ambulation has been acquired. Two subtypes (SMA3a and SMA3b) have been distinguished by some authors: SMA3a defines patients with onset before the age of 3 years, whereas SMA3b defines patients with onset after 3 years. Difficulties walking, running, and going up and down stairs are common. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Legs are always more severely affected than arms. Weak finger trembling and scoliosis are frequent and the patellar reflex is absent.

As for other forms of SMA, SMA3 is primarily caused by deletions in the SMN1 gene (5q12.2-q13.3) encoding the SMN (survival motor neuron) protein. Although there is some variation, disease severity in SMA is inversely correlated with the number of copies of the second SMN gene (SMN2; 5q13.2), with patients with MSA3 having three (SMA3a) or four (SMA3b) SMN2copies. Deletions of the NAIP (5q13.1) gene, which may play a role in modifying disease severity, have also been identified in SMA3 patients but are less frequent than in individuals with SMA1 and 2.

Diagnosis is based on clinical history and examination but is confirmed by genetic testing. Electromyography and muscle biopsy may be necessary.

Differential diagnoses include amyotrophic lateral sclerosis, congenital muscular dystrophies, congenital myopathies, primary lateral sclerosis, myasthenia gravis, and carbohydrate metabolism disorders (see these terms).

Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples.

Transmission is autosomal recessive but around 2% of cases are caused by de novo mutations. Genetic counseling should be offered to patients and their families.

Clinical trials to identify specific drug treatments for SMA are ongoing, and preliminary studies have indicated that valproic acid (as a histone deacetylase inhibitor) may improve quantitative muscle strength and subjective motor function in SMA3 patients. However, at present, management is symptomatic, involving a multidisciplinary approach aiming to improve quality of life. Physiotherapy and occupational therapies are recommended.

A wheelchair may be required during childhood for some patients (more commonly those with SMA3a), whilst others retain the ability to walk into adulthood (more commonly those with SMA3b). SMA3 progresses slowly and life expectancy is usually normal. However, deformities of the vertebral column are frequent and complications may lead to respiratory restriction.

Expert reviewer(s)

  • Dr Haluk TOPALOGLU

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Detailed information

Review article
  • EN (2011)
Guidance for genetic testing
  • EN (2012,pdf)
Article for general public
  • FR (2007,pdf)
Clinical genetics review
  • EN (2011)
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