Background

The spinal muscular atrophies (SMAs) comprise a group of autosomal-recessive disorders characterized by progressive weakness of the lower motor neurons.

In the early 1980s, Werdnig and Hoffman described a disorder of progressive muscular weakness beginning in infancy that resulted in early death, though the age of death was variable. In pathologic terms, the disease was characterized by loss of anterior horn cells. The central role of lower motor neuron degeneration was confirmed in subsequent pathologic studies demonstrating a loss of anterior horn cells in the spinal cord and cranial nerve nuclei.^[1]

Since then, several types of spinal muscular atrophies have been described based on age when accompanying clinical features appear. The most common types are acute infantile (SMA type I, or Werdnig-Hoffman disease), chronic infantile (SMA type II), chronic juvenile (SMA type III or Kugelberg-Welander disease), and adult onset (SMA type IV) forms.

The genetic defects associated with SMA types I-III are localized on chromosome 5q11.2-13.3.^{[2, 3, 4, 5]}

Many classification systems have been proposed and include variants based on inheritance, clinical, and genetic criteria. Among these are the Emery^[6] , Pearn^[7] , and International SMA Consortium system^[8] . The ISMAC system is most widely accepted and is used in this review.

Next

Pathophysiology

In 1995, the spinal muscular atrophy disease-causing gene, termed the survival motor neuron (SMN), was discovered.^[9] Each individual has 2 SMN genes, SMN1 and SMN2. More than 95% of patients with spinal muscular atrophy have a homozygous disruption in the SMN1 gene on chromosome 5q, caused by mutation, deletion, or rearrangement. However, all patients with spinal muscular atrophy retain at least 1 copy of SMN2, which generates only 10% of the amount of full-length SMN protein versus SMN1. This genomic organization provides a therapeutic pathway to promote SMN2, existing in all patients, to function like the missing SMN1 gene.^[10]

Epidemiology

Frequency

United States

The spinal muscular atrophies are the second most common autosomal-recessive inherited disorders after cystic fibrosis. The acute infantile-onset SMA (type I) affects approximately 1 per 10,000 live births; the chronic forms (types II and III) affect 1 per 24,000 births. SMA types I and III each account for about one fourth of cases, whereas SMA type II is the largest group and accounts for one half of all cases.^[11]

International

The incidence of spinal muscular atrophy is about 1 in 10,000 live births with a carrier frequency of approximately 1 in 50.^{[7, 12, 13]}

Mortality/Morbidity

The mortality and/or morbidity rates of spinal muscular atrophy are inversely correlated with the age at onset. High death rates are associated with early onset disease. In patients with SMA type I, the median survival is 7 months, with a mortality rate of 95% by age 18 months.

• Respiratory infections account for most deaths.
• In type II SMA, the age of death varies, but death is most often due to respiratory complications.
• See Prognosis for more information.

Sex

Male individuals are most frequently affected, especially with the early-onset forms of spinal muscular atrophy, ie, types I and II.^[14]

Age

The ISMAC classification system is based on the age of onset.^[8] See Background, History, and Physical for a review of the existing classification systems and a brief discussion of their relevancy to the role of age in spinal muscular atrophies.

According to the ISMAC system, the age of onset for spinal muscular atrophies is as follows:

• SMA type I (acute infantile or Werdnig Hoffman): Onset is from birth to 6 months.
• SMA type II (chronic infantile): Onset is between 6 and 18 months.
• SMA type III (chronic juvenile): Onset is after 18 months.
• SMA type IV (adult onset): Onset is in adulthood (mean onset, mid 30s).

Clinical Presentation