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HEREDITARY MONOGENIC DISEASES

           

Spinal muscular atrophy

The spinal muscular atrophies are a group of muscle disorders characterized by progressive muscle weakness as a result of degeneration and loss of lower motor neurons in the spinal cord and brainstem nuclei. A prevalence of 1 / 30,000 individuals is estimated approximately.

They defined 3 subtypes depending on the age of onset and the severity of the disease:

  • Type I SMA (ONIM entry 253300) is characterized by severe muscle weakness and hypotonia in the first few months of life and the inability to sit or walk, fatal respiratory failure occurs before the age of 2 years.
  • Type II SMA (ONIM entry 253550) is characterized by the onset of muscle weakness before the 18 months of age. SMA type II patients have the ability to sit but not to walk and survival beyond 4 years of age.
  • Type III SMA (ONIM entry 253400) is characterized by the onset of muscle weakness after the 2 years and the ability to walk and survival into adulthood.

All these subtypes are characterized by muscle weakness and atrophy of varying severity, affecting mainly the lower limbs and respiratory muscles. The weakness is almost always symmetrical and progressive. They can produce muscle contractures, scoliosis and joint contractures. Also, in most children, digestive problems such as constipation and gastroesophageal reflux can occur, making nutritional management difficult.

About 95% of cases are caused by SMA homozygous deletions of exon 7 or exons 7 and 8 in the SMN1 gene (5q12.2-q13.3) encoding the SMN protein (motor neuron survivor). It has identified a second SMN gene called SMN2 (5q13.2) contributing to the production of only 10% of the entire SMN protein. However, although there is some variation, the disease severity in SMA is inversely correlated with the number of copies of SMN2 gene; patients with 3 or 4 copies manifest the SMA3 or SMA4 most frequently than SMA1. Deletions have been identified in the NAIP gene (5q13.1) that may play an important role changing the severity of the disease. The transmission of deletions in SMN1 is autosomal recessive. About 2% of cases are caused by de novo mutations.

The diagnosis is based on clinical examination and history. It can be confirmed by genetic testing. Sometimes, to complement the study electromyography and muscle biopsy can be performed. The differential diagnosis should include amyotrophic lateral sclerosis, congenital muscular dystrophies, congenital myopathies, primary lateral sclerosis, myasthenia gravis and carbohydrate metabolism disorders.

Prenatal diagnosis is possible through molecular analysis of chorionic villus sampling or amniocytes. It should always be offered genetic counseling to affected families.

Clinical trials are ongoing to identify potential treatments for SMA, especially aimed at increasing levels of SMN protein in its entirety. However, at present, the management of the affected individual is still only symptomatic, involving a multidisciplinary approach aimed at increasing the quality of life. Respiratory physiotherapy and occupational therapies are needed.

The prognosis depends on the severity of the disease, which is usually associated with the age of onset: early-onset forms usually have a worse prognosis, while life expectancy may be normal in late onset forms. Death usually occurs due to respiratory failure and associated infections.

GENE OR REGION STUDIED


  • SMN1