Spinal muscular atrophies

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This article is about the whole group of disorders. For the specific form (SMA), see Spinal muscular atrophy.
Spinal muscular atrophies
Classification and external resources
Polio spinal diagram.PNG
Location of neurons affected in spinal muscular atrophies
ICD-10 G12
MeSH D009134

Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons (neuronal cells situated in the anterior horn of spinal cord) and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other types permit normal adult life with only mild weakness.

Classification[edit]

Based on the type of muscles affected, spinal muscular atrophies can be divided into:

When taking into account prevalence, spinal muscular atrophies are traditionally divided into::

  • Autosomal recessive proximal spinal muscular atrophy, responsible for 90-95% of cases and usually called simply spinal muscular atrophy (SMA) – a disorder associated with a genetic mutation on the SMN1 gene on chromosome 5q (locus 5q13), affecting people of any age but in its most severe form being the most common genetic cause of infant death;
  • Localised spinal muscular atrophies – much more rare conditions, in some instances described in but a few patients in the world, which are associated with mutations of genes other than SMN1 and for this reason sometimes termed simply non-5q spinal muscular atrophies.

A more detailed classification is based on the gene associated with the condition (where identified) and is presented in table below.

Group Name
Alternate names
OMIM Gene Locus Mode of
inheritance
Characteristics
SMA Spinal muscular atrophy (SMA)

Autosomal recessive proximal spinal muscular atrophy
Werdnig–Hoffmann / Dubowitz / Kugelberg–Welander disease

253300
253550
253400
271150
SMN1 5q13.2 Autosomal recessive Affects primarily proximal muscles in people of all ages, progressive, relatively common
XLSMA X-linked spinal muscular atrophy type 1 (SMAX1)

Spinal and bulbar muscular atrophy (SBMA)
Kennedy's disease (KD)

313200 NR3C4 Xq12 X-linked recessive Affects primarily bulbar muscles as well as sensory nerves mainly in adult men, progressive
X-linked spinal muscular atrophy type 2 (SMAX2)

Arthrogryposis multiplex congenita – X-linked type 1 (AMCX1)

301830 UBA1 Xp11.23 X-linked recessive Affects distal muscles mainly in newborn boys
X-linked spinal muscular atrophy type 3 (SMAX3)

Distal spinal muscular atrophy – X-linked (DSMAX)

300489 ATP7A Xq21.1 X-linked recessive Affects distal muscles of all extremities mainly in boys, slowly progressive
DSMA Distal spinal muscular atrophy type 1 (DSMA1)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1)
Distal hereditary motor neuropathy type 6 (HMN6)

604320 IGHMBP2 11q13.3 Autosomal recessive Affects mainly infant boys, progressive with diaphragmatic paralysis
Distal spinal muscular atrophy type 2 (DSMA2)

Distal hereditary motor neuropathy – Jerash type (HMN-J)

605726  ? 9p21.1–p12 Autosomal recessive Slowly progressive, described only in one family
Distal spinal muscular atrophy type 3 (DSMA3)

Distal hereditary motor neuropathy types 3 & 4 (HMN3, HMN4)

607088  ? 11q13.3 Autosomal recessive Slowly progressive
Distal spinal muscular atrophy type 4 (DSMA4) 611067 PLEKHG5 1p36.31 Autosomal recessive Slowly progressive, described only in one family
Distal spinal muscular atrophy type 5 (DSMA5) 614881 DNAJB2 2q35 Autosomal recessive Young adult onset, slowly progressive
Distal spinal muscular atrophy type VA (DSMAVA)

Distal hereditary motor neuropathy type 5A (HMN5A)

600794 GARS 7p14.3 Autosomal dominant With upper limb predominance; allelic and overlapping with CMT2D, phenotype overlapping with Silver syndrome
Distal spinal muscular atrophy type VB (DSMAVB)

Distal hereditary motor neuropathy type 5B (HMN5B)

614751 REEP1 2p11 Autosomal dominant With upper limb predominance; allelic and overlapping with HSP-31
Distal spinal muscular atrophy with calf predominance

Distal hereditary motor neuropathy type 2D (HMN2D)

615575 FBXO38 5q32 Autosomal dominant Juvenile- or adult-onset, slowly progressive, affects both proximal and distal muscles, initially manifests with calf weakness which progresses to hands
Distal spinal muscular atrophy with vocal cord paralysis

Distal hereditary motor neuropathy type 7A (HMN7A)
Harper–Young myopathy

158580 SLC5A7 2q12.3 Autosomal dominant Adult-onset with vocal cord paralysis, very rare
ADSMA Autosomal dominant distal spinal muscular atrophy

Distal hereditary motor neuropathy type 2A (HMN2A)

158590 HSPB8 12q24.23 Autosomal dominant Adult-onset. Allelic with Charcot–Marie–Tooth disease type 2L (CMT2L)
Autosomal dominant juvenile distal spinal muscular atrophy

Distal hereditary motor neuropathy type 1 (HMN1)

182960  ? 7q34–q36 Autosomal dominant Juvenile-onset
Congenital distal spinal muscular atrophy 600175 TRPV4 12q24.11 Autosomal dominant Affects primarily distal muscles of lower limbs, non-progressive, rare, allelic with SPSMA and CMT2C
Scapuloperoneal spinal muscular atrophy (SPSMA)

Scapuloperoneal neurogenic amyotrophy

181405 TRPV4 12q24.11 Autosomal dominant
or X-linked dominant
Affects muscles of lower limbs, non-progressive, rare, allelic with congenital distal spinal muscular atrophy and CMT2C
Juvenile segmental spinal muscular atrophy (JSSMA) 183020  ? 18q21.3  ? Juvenile-onset, progressive with stabilisation after 2–4 years, affects primarily hands, very rare
Finkel-type proximal spinal muscular atrophy (SMA-FK) 182980 VAPB 20q13.32 Autosomal dominant Late-onset, affects proximal muscles in adults
Jokela-type spinal muscular atrophy (SMA-J) 615048  ? 22q11.2–q13.2 Autosomal dominant Late-onset, slowly progressive, affects both proximal and distal muscles in adults
Spinal muscular atrophy with lower extremity predominance 1 (SMALED1) 158600 DYNC1H1 14q32 Autosomal dominant Affects proximal muscles in infants
Spinal muscular atrophy with lower extremity predominance 2 (SMALED2) 615290 BICD2 9q22.31 Autosomal dominant Congenital or early-onset, primarily affecting lower limbs, nonprogressive, very rare
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) 159950 ASAH1 8p22 Autosomal recessive
Spinal muscular atrophy with congenital bone fractures (SMA-CBF) 271225  ?  ? Autosomal recessive (?) Characterised by severe muscle wasting as in SMA type I accompanied by congenital bone fractures
PCH Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH)

Pontocerebellar hypoplasia type 1A (PCH1A)

607596 VRK1 14q32 Autosomal dominant → see Pontocerebellar hypoplasia
MMA Juvenile asymmetric segmental spinal muscular atrophy (JASSMA)

Monomelic amyotrophy; Hirayama disease; Sobue disease

602440  ?  ?  ? → see Monomelic amyotrophy

In all forms of SMA (with an exception of X-linked spinal muscular atrophy type 1), only motor neurons, located at the anterior horn of spinal cord, are affected; sensory neurons, which are located at the posterior horn of spinal cord, are not affected. By contrast, hereditary disorders that cause both weakness due to motor denervation along with sensory impairment due to sensory denervation are known as hereditary motor and sensory neuropathies (HMSN).

Symptoms[edit]

In all spinal muscular atrophies, the primary feature is muscle weakness accompanied by atrophy of muscle. This is the result of denervation, or loss of the signal to contract that is transmitted by the motor neurons in the spinal cord. The signal is normally transmitted from the spinal cord to muscle via the motor neuron's axon, but in spinal muscular atrophies either the entire motor neuron or the motor neuron's axon loses the ability to transmit signals to muscles.

The symptoms are strongly related to the exact disease (see above) and, sometimes, to the age of onset. Certain conditions (e.g., spinal muscular atrophy or spinal and bulbar muscular atrophy) have a wide range, from infancy to adult, fatal to trivial, with different affected individuals manifesting every shade of impairment between these two extremes. Other muscular atrophies have a different and often very severe course. Some of them are extremely rare and described only in a handful of individuals. However, in all cases the majority of symptoms are a consequence of muscle weakness.

Diagnosis[edit]

While the presence of several symptoms may point towards a particular genetic disorder of the spinal muscular atrophy group, the actual disease can be established with full certainty only by genetic testing which detects the underlying genetic mutation.

Treatment[edit]

As with many genetic disorders, there is no known cure to any disorder of the spinal muscular atrophies group. Supportive therapies are widely employed for patients who often also require comprehensive medical care involving multiple disciplines, including pulmonology, neurology, orthopedic surgery, critical care, and clinical nutrition. Various forms of physiotherapy and occupational therapy are frequently able to slow down the pace of nerve degeneration and muscle wasting. Patients also benefit greatly from the use of assistive technology.

For more detailed therapeutic pathways, see articles on individual diseases.

SMA Treatment Acceleration Act[edit]

In 2007, an act of law called SMA Treatment Acceleration Act was introduced in the United States Congress in order to "authorize the Secretary of Health and Human Services to conduct activities to rapidly advance treatments for spinal muscular atrophy, neuromuscular disease, and other pediatric diseases, and for other purposes." As of 2012, it remains in a committee in the 111th Congress.

References[edit]


Further reading[edit]

  • Van Den Berg-Vos, R. M.; Van Den Berg, L. H.; Visser, J.; De Visser, M.; Franssen, H.; Wokke, J. H. J. (2003). "The spectrum of lower motor neuron syndromes". Journal of Neurology 250 (11): 1279–1292. doi:10.1007/s00415-003-0235-9. PMID 14648143.  edit
  • Guillot, N.; Cuisset, J. M.; Cuvellier, J. C.; Hurtevent, J. F. O.; Joriot, S.; Vallee, L. (2008). "Unusual clinical features in infantile Spinal Muscular Atrophies". Brain and Development 30 (3): 169–178. doi:10.1016/j.braindev.2007.07.008. PMID 17804187.  edit

See also[edit]