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Proximal spinal muscular atrophy type 4
Proximal spinal muscular atrophy type 4 (SMA4) is the adult-onset 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.
ORPHA:83420Classification level: Subtype of disorder
- SMA type 4
- SMA type IV
- Spinal muscular atrophy, adult form
- Prevalence: 1-9 / 1 000 000
- Inheritance: Autosomal recessive
- Age of onset: Adult
- ICD-10: G12.1
- OMIM: 271150
- UMLS: C1838230
- MeSH: -
- GARD: -
- MedDRA: -
Prevalence is estimated at around 1/300,000.
SMA4 usually manifests in the second or third decade of life. The muscle weakness predominantly affects the legs and hip muscles and then progresses to the shoulders and arms. Waddling gait is common. Finger trembling, fasciculation and calf hypertrophy may occur. The clinical picture is similar to that seen in SMA3 (see this term) but the motor weakness is less severe in SMA4.
As for the other forms of SMA, SMA4 has been associated with 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) and some studies have shown that patients with the mild SMA4 form have multiple (four to six) SMN2 copies. However, no SMN1 gene mutations are found in some patients diagnosed with SMA4 and in these cases the genetic anomalies remain to be identified.
The diagnosis is based on clinical history and examination. In patients with SMN1 anomalies, the diagnosis may be confirmed by genetic testing. Electromyography and muscle biopsy may be necessary.
Differential diagnoses include the amyotrophic lateral sclerosis, primary lateral sclerosis, myasthenia gravis, and carbohydrate metabolism disorders (see these terms).
Prenatal diagnosis is possible for families in which the mutations in the SMN1 gene have been identified.
The SMN1 gene deletions are transmitted in an autosomal recessive manner. Genetic counseling should be provided.
Management and treatment
Management is symptomatic, involves a multidisciplinary approach, and aims to improve quality of life. Physiotherapy and occupational therapies are recommended. 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 SMA4 patients.
SMA4 is the mildest form of SMA and in general the disease course is benign with patients having a normal life expectancy.