Spinal muscular atrophies

Spinal muscular atrophies
Polio spinal diagram-en.svg
Location of neurons affected in spinal muscular atrophies
SpecialtyNeurology
SymptomsLoss of motor neurons resulting in muscle wasting

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 the spinal cord) and subsequent atrophy (wasting) of various muscle groups in the body.[1] While some SMAs lead to early infant death, other diseases of this group permit normal adult life with only mild weakness.

Classification

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), diagnosed predominantly in young children and in its most severe form being the most common genetic cause of infant death if left untreated;
  • 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; none has currently a causal treatment.

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

GroupName
Alternative names
OMIMGeneLocusMode of
inheritance
Characteristics
SMASpinal muscular atrophy (SMA)
  • 5q spinal muscular atrophy
  • Autosomal recessive proximal spinal muscular atrophy
  • Werdnig–Hoffmann disease / Kugelberg–Welander disease
253300
253550
253400
271150
SMN15q13.2Autosomal recessiveAffects primarily proximal muscles in people of all ages, progressive, relatively common
XLSMAX-linked spinal muscular atrophy type 1 (SMAX1)
  • Spinal and bulbar muscular atrophy (SBMA)
  • Kennedy's disease (KD)
313200NR3C4Xq12X-linked recessiveAffects 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)
301830UBA1Xp11.23X-linked recessiveCharacterised by bone fractures, affects mainly distal muscles in newborn boys, usually fatal in infancy
X-linked spinal muscular atrophy type 3 (SMAX3)
  • Distal spinal muscular atrophy – X-linked (DSMAX)
300489ATP7AXq21.1X-linked recessiveAffects distal muscles of all extremities mainly in boys, slowly progressive
DSMADistal spinal muscular atrophy type 1 (DSMA1)
  • Spinal muscular atrophy with respiratory distress type 1 (SMARD1)
  • Distal hereditary motor neuronopathy type 6 (DHMN6)
604320IGHMBP2 11q13.3Autosomal recessiveAffects mainly infant boys, similar to SMA type 1 but with diaphragmatic paralysis
Distal spinal muscular atrophy type 2 (DSMA2)
  • Distal hereditary motor neuronopathy – Jerash type (DHMN-J)
605726SIGMAR119p13.3Autosomal recessiveSlowly progressive
Distal spinal muscular atrophy type 3 (DSMA3)
  • Distal hereditary motor neuronopathy types 3 & 4 (DHMN3/DHMN4)
607088?11q13.3Autosomal recessiveSlowly progressive
Distal spinal muscular atrophy type 4 (DSMA4)611067PLEKHG51p36.31Autosomal recessiveSlowly progressive, described only in one family
Distal spinal muscular atrophy type 5 (DSMA5)614881DNAJB22q35Autosomal recessiveYoung adult onset, slowly progressive
Distal spinal muscular atrophy type VA (DSMAVA)
  • Distal hereditary motor neuronopathy type 5A (DHMN5A)
600794GARS7p14.3Autosomal dominantWith upper limb predominance; allelic and overlapping with CMT2D, phenotype overlapping with Silver syndrome
Distal spinal muscular atrophy type VB (DSMAVB)
  • Distal hereditary motor neuronopathy type 5B (DHMN5B)
614751REEP12p11Autosomal dominantWith upper limb predominance; allelic and overlapping with HSP-31
Distal spinal muscular atrophy with calf predominance
  • Distal hereditary motor neuronopathy type 2D (DHMN2D)
615575FBXO385q32Autosomal dominantJuvenile- 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 neuronopathy type 7A (DHMN7A)
  • Harper–Young myopathy
158580SLC5A72q12.3Autosomal dominantAdult-onset with vocal cord paralysis, very rare
Congenital distal spinal muscular atrophy
  • Distal hereditary motor neuronopathy type 8 (DHMN8)
600175TRPV412q24.11Autosomal dominantAffects primarily distal muscles of lower limbs, non-progressive, rare, allelic with SPSMA and CMT2C
Scapuloperoneal spinal muscular atrophy (SPSMA)
  • Scapuloperoneal neurogenic amyotrophy
181405TRPV412q24.11Autosomal dominant
or X-linked dominant
Affects muscles of lower limbs, non-progressive, rare, allelic with congenital distal spinal muscular atrophy and CMT2C
Autosomal dominant distal spinal muscular atrophy
  • Distal hereditary motor neuronopathy type 2A (DHMN2A)
158590HSPB812q24.23Autosomal dominantAdult-onset. Allelic with Charcot–Marie–Tooth disease type 2L (CMT2L)
Autosomal dominant juvenile distal spinal muscular atrophy
  • Distal hereditary motor neuronopathy type 1 (DHMN1)
182960?7q34–q36Autosomal dominantJuvenile-onset
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 (SMAFK)182980VAPB20q13.32Autosomal dominantLate-onset, affects proximal muscles in adults
James type infantile spinal muscular atrophy (SMAJI)619042GARS17p14.3Autosomal dominantInfantile-onset hypotonia, slowly progressive, resulting in delayed motor milestones and loss of previous motor skills. Children never walk. Milder disorders caused by GARS1 mutations are CMT2D and HMN5A.
Jokela type spinal muscular atrophy (SMAJ)615048CHCHD1022q11.2–q13.2Autosomal dominantLate-onset, slowly progressive, affects both proximal and distal muscles in adults
Spinal muscular atrophy with lower extremity predominance 1 (SMALED1)158600DYNC1H114q32Autosomal dominantAffects proximal muscles in infants
Spinal muscular atrophy with lower extremity predominance 2A (SMALED2A)615290BICD29q22.31Autosomal dominantEarly-onset, primarily affecting lower limbs, slowly progressive, non-life-limiting, very rare
Spinal muscular atrophy with lower extremity predominance 2B (SMALED2B)618291BICD29q22.31Autosomal dominantPresents with hypotonia, contractures and respiratory involvement at birth, frequently fatal in early childhood, very rare
Spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME)159950ASAH18p22Autosomal recessive
Spinal muscular atrophy with congenital bone fractures 1 (SMABF1)616866TRIP415q22.31Autosomal recessivePrenatal onset, characterised by severe muscle wasting, respiratory and feeding failure, and bone fractures at birth as in arthrogryposis multiplex congenita, usually fatal in infancy
Spinal muscular atrophy with congenital bone fractures 2 (SMABF2)616867ASCC110q22.1Autosomal recessivePrenatal onset, characterised by severe muscle wasting, respiratory and feeding failure, and bone fractures at birth as in arthrogryposis multiplex congenita, usually fatal in infancy[2][3][4]
PCHSpinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH)
  • Pontocerebellar hypoplasia type 1A (PCH1A)
607596VRK114q32Autosomal dominant→ see Pontocerebellar hypoplasia
MMAJuvenile asymmetric segmental spinal muscular atrophy (JASSMA)
  • Monomelic amyotrophy
  • Hirayama disease
  • Sobue disease
602440???→ see Monomelic amyotrophy
PMAProgressive spinal muscular atrophy
  • Progressive muscular atrophy
  • Duchenne-Aran muscular atrophy
????→ see Progressive muscular atrophy

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).

See also

References

  1. ^ "Spinal muscular atrophy". Genetics Home Reference. 2016-03-21. Retrieved 2016-03-26.
  2. ^ Knierim E, Hirata H, Wolf NI, Morales-Gonzalez S, Schottmann G, Tanaka Y, et al. (March 2016). "Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures". American Journal of Human Genetics. 98 (3): 473–489. doi:10.1016/j.ajhg.2016.01.006. PMC 4800037. PMID 26924529.
  3. ^ Oliveira J, Martins M, Pinto Leite R, Sousa M, Santos R (October 2017). "The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement". Clinical Genetics. 92 (4): 434–439. doi:10.1111/cge.12997. PMID 28218388. S2CID 28768062.
  4. ^ Giuffrida MG, Mastromoro G, Guida V, Truglio M, Fabbretti M, Torres B, et al. (December 2019). "A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1". American Journal of Medical Genetics. Part A. 182 (3): 508–512. doi:10.1002/ajmg.a.61431. PMID 31880396. S2CID 209490732.

Further reading

External links

Classification

Media files used on this page

Polio spinal diagram-en.svg
Author/Creator: , Licence: CC BY-SA 4.0
The poliovirus affects the motor neurons of the anterior horn cells, or the ventral (front) grey matter section in the spinal column, which control movement of the trunk and limb muscles including the intercostal muscles.