What is SMA?

Information for physicians

Spinal Muscular Atrophy (SMA) - the most common inherited lethal disorder of infants.

Spinal muscular atrophy (SMA) is a degenerative neuromuscular disease with an incidence of 1:10.000 (Orphanet). This rare condition is the most common inherited lethal disorder of infants (Arnold D et al). The autosomal recessive mutation usually affects the survival motor neuron (SMN) 1 gene on chromosome 5q13 (Melkie J et al). In only 5% of affected persons rare mutations are responsible and in further 2% a de novo mutation are present. Furthermore, there are also non-5q SMA cases (Lefebvre S et al).

Figure 1: Autosomal recessive inheritance of SMA

Parents who are carriers for the faulty SMN1 gene do not have clinical symptoms.
Green: faulty SMN1 gene, Grey: normal SMN1 gene

Frequencies of SMA carriers are about 1 in 37 to 1 in 125 depending on ethnic background (Hendrickson B et al). In case of both parents carrying one faulty SMN1 gene, 25% of their offspring will be healthy, 50% will be carriers and 25% of infants will be affected by SMA (Figure 1).

Consequences of faulty SMN1 genes

Faulty survival motor neuron (SMN) 1 genes leads to a lack of functional SMN proteins. These proteins are essential for normal motor neuron function. The outcome of missing SMN proteins is a deterioration of motor neurons in the spinal cord and brain resulting in a dysfunction of voluntary muscle movements and inevitably in progressive muscular weakness. In most cases, motor skills will not be obtained or motor skills already acquired are often lost.

SMN2 affect on SMA phenotype
The phenotype of 5q-SMA is modified by a second gene, the survival motor neuron 2 gene, The SMN2 gene is not able to produce functional SMN protein in adequate quantity however the number of SMN2 copies as well as the sequence of those copies influences the phenotype (Prior TW).

Classification of SMA
The clinical spectrum of SMA is categorized by the severity of symptoms and the age of clinical manifestation. The different SMA types are divided into the following categories (www.mda.org):

Early onset SMA:

  • Type I (acute infantile form)
  • Type II (chronic infantile or intermediate form)

Late onset SMA:

  • Type III  (juvenile form)
  • Type IV (adult form)

Most affected infants (approximately 70%) suffer from SMA type I (Werdnig-Hofmann disease) (Muralidharan et al). Characteristically, clinical manifestation of this type begins during the first months of life und is associated with severe disease course and death in early childhood. Approximately one third of affected persons suffer from milder forms like SMA type II and type III (Dubowitz and Kugelberg-Welander disease, respectively).

The clinical manifestation of SMA varies from reduced fetal movements before birth to severe muscular weakness, delayed or missing motor skills, feeding difficulties, breathing problems with risk of aspiration and recurrent infections of the lungs (Kindernetzwerk e.V.). In general, SMA affects all muscles however usually progressive muscular weakness begins in proximal muscles like the hip, thigh and shoulder. The life expectancy of affected patients varies from few months to normal life expectancy, depending on phenotype. For early onset SMA, clinical symptoms begin at two to 39 months of life on average. SMA diagnosis typically occurs from four to 44 months of life (Lin CW et al). At present, only a carrier screening is recommended (ACOG, Muralidharan K et al, Boardman FK et al). Experts suggest primary molecular genetic testing for faulty SMN1 genes in cases of suspected SMA (TREAT-NMD). An early diagnosis of affected newborns is important (Chien YH et al) because this enables an adequate drug or therapy intervention at an early stage, even before clinical manifestation (Finkel et al, Mendell et al). Today, efficient and specific diagnostic tests for SMA are available. These diagnostic tools offer the opportunity of a feasible prevention program like in newborn screening or with suspected cases like infants with muscular hypotonia or a rather floppy infant.

Clinical Indications for SMA Diagnosis:
I) Early onset (infantile) 5q-SMA:
Typical symptoms for early onset (infantile) SMA is symmetric, proximal impairment with muscular hypotonia and weakness, reduced or absent reflexes, legs are affected more than arms. Developmental milestones will not be reached or already acquired skills are disappearing. Diagnostics for SMA are recommended in the following scenarios (See also Table 1):

  • Family history of SMA
  • Reduced fetal movements during pregnancy; muscular hypotonia (proximal, symmetric) or muscular weakness of unknown origin.
  • During neonatal period (0-3 months)
    Floppy Infant Syndrome
  • During Infancy (3-10 months)
    Any occurrence of muscular hypotonia, chronic cough, feeding difficulties, reflux, recurrent vomiting and respiratory infections
    Motor milestones not reached:
    by 3 months of life – cannot hold the head up from the base
    by 5 months of life – no head control in upright position
    by 10 months of life – no sitting unassisted
  • During Early childhood (10+ months)
    Motor milestones not reached:
    by 17 months of life – no standing unassisted
    by 19 months of life – no walking unassisted

 

II) Late onset (adult) form:
Symptoms for late onset forms of SMA are similar to Early onset forms typically in milder presentations. Diagnostics for SMA are recommended with the following clinical manifestations.

  • Proximal, muscular hypotonia
  • Muscular weakness
  • Walking difficulties or tremors
  • Fibrillation of the tongue
  • Fasciculation of the muscle especially legs und upper arms
  • Muscular cramps and pains

Table 1: Indications for SMA diagnostics

Early onset (infantile) SMA suspected
Reduced fetal movements prenatally
Floppy infant syndrome
Muscular hypotonia
Feeding difficulties / reflux
Abnormal motor development:
3 months of life: cannot hold the head up from the base
5 months of life: no head control in upright position
10 months of life: no sitting unassisted
17 months of life: no standing unassisted
19 months of life: no walking unassisted
Chronic cough, recurrent respiratory infections with unknown origin
Late onset (adult) SMA suspected
Proximal, muscular hypotonia
Muscular weakness
Fibrillation of the tongue
Walking difficulties / tremor
Muscular fasciculation
Muscular cramps / pains

 

Novel promising treatment options

In Europe, a medicinal product Nusinersen, used to treat 5q-associated SMA in pediatric and adult affected persons, has been approved. Nusinersen is a new antisense oligonucleotide treatment for standard care. Repeated injections are applied intrathecally and leads to increased production of SMN proteins by the SMN2 genes (Finkel RS et al). Half of the affected individuals with early onset (infantile) SMA showed an improvement motor skills and increased survival rate without severe adverse reactions. Another pilot study including infants with SMA-type I presented neuromuscular improvements after single dose of an intravenous applied gene-replacement therapy (Mendell JR et al). In these therapies, the mutated SMN1 gene is replaced through an adeno-associated virus vector incorporating the SMN1 gene producing SMN proteins. Further innovative experimental treatment approaches are in development and new treatments are anticipated (Govoni A et al).

 

SMA-registry:
Germany, Austria: Friedrich-Baur-Institut, Medizinische Fakultät der Ludwig-Maximilians-Universität München, www.sma-register.de
Europe: TREAT-NMD Network
USA: www.cureSMA.org

 

References:

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