| Spinal muscular atrophies | |
| Field: | Neurology |
| Symptoms: | Loss 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.
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:
A more detailed classification is based on the gene associated with the condition (where identified) and is presented in table below.
| Group | Name Alternative names | OMIM | Gene | Locus | Mode of inheritance | Characteristics |
|---|---|---|---|---|---|---|
| SMA | Spinal muscular atrophy (SMA)
| SMN1 | 5q13.2 | Autosomal recessive | Affects primarily proximal muscles in people of all ages, progressive, relatively common | |
X-linked spinal muscular atrophy type 1 (SMAX1)
| 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)
| UBA1 | Xp11.23 | X-linked recessive | Characterised by bone fractures, affects mainly distal muscles in newborn boys, usually fatal in infancy | ||
X-linked spinal muscular atrophy type 3 (SMAX3)
| ATP7A | Xq21.1 | X-linked recessive | Affects distal muscles of all extremities mainly in boys, slowly progressive | ||
Distal spinal muscular atrophy type 1 (DSMA1)
| IGHMBP2 | 11q13.3 | Autosomal recessive | Affects mainly infant boys, similar to SMA type 1 but with diaphragmatic paralysis | ||
Distal spinal muscular atrophy type 2 (DSMA2)
| SIGMAR1 | 19p13.3 | Autosomal recessive | Slowly progressive | ||
Distal spinal muscular atrophy type 3 (DSMA3)
| ? | 11q13.3 | Autosomal recessive | Slowly progressive | ||
| Distal spinal muscular atrophy type 4 (DSMA4) | PLEKHG5 | 1p36.31 | Autosomal recessive | Slowly progressive, described only in one family | ||
| Distal spinal muscular atrophy type 5 (DSMA5) | DNAJB2 | 2q35 | Autosomal recessive | Young adult onset, slowly progressive | ||
Distal spinal muscular atrophy type VA (DSMAVA)
| 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)
| REEP1 | 2p11 | Autosomal dominant | With upper limb predominance; allelic and overlapping with HSP-31 | ||
Distal spinal muscular atrophy with calf predominance
| 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
| SLC5A7 | 2q12.3 | Autosomal dominant | Adult-onset with vocal cord paralysis, very rare | ||
Congenital distal spinal muscular atrophy
| 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)
| 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 | ||
Autosomal dominant distal spinal muscular atrophy
| HSPB8 | 12q24.23 | Autosomal dominant | Adult-onset. Allelic with Charcot–Marie–Tooth disease type 2L (CMT2L) | ||
Autosomal dominant juvenile distal spinal muscular atrophy
| ? | 7q34–q36 | Autosomal dominant | Juvenile-onset | ||
| Juvenile segmental spinal muscular atrophy (JSSMA) | ? | 18q21.3 | ? | Juvenile-onset, progressive with stabilisation after 2–4 years, affects primarily hands, very rare | ||
| Finkel type proximal spinal muscular atrophy (SMAFK) | VAPB | 20q13.32 | Autosomal dominant | Late-onset, affects proximal muscles in adults | ||
| James type infantile spinal muscular atrophy (SMAJI) | GARS1 | 7p14.3 | Autosomal dominant | Infantile-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) | CHCHD10 | 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) | DYNC1H1 | 14q32 | Autosomal dominant | Affects proximal muscles in infants | ||
| Spinal muscular atrophy with lower extremity predominance 2A (SMALED2A) | BICD2 | 9q22.31 | Autosomal dominant | Early-onset, primarily affecting lower limbs, slowly progressive, non-life-limiting, very rare | ||
| Spinal muscular atrophy with lower extremity predominance 2B (SMALED2B) | BICD2 | 9q22.31 | Autosomal dominant | Presents with hypotonia, contractures and respiratory involvement at birth, frequently fatal in early childhood, very rare | ||
| Spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME) | ASAH1 | 8p22 | Autosomal recessive | |||
| Spinal muscular atrophy with congenital bone fractures 1 (SMABF1) | TRIP4 | 15q22.31 | Autosomal recessive | Prenatal 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) | ASCC1 | 10q22.1 | Autosomal recessive | Prenatal 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] | ||
| PCH | Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH)
| VRK1 | 14q32 | Autosomal dominant | → see Pontocerebellar hypoplasia | |
| MMA | Juvenile asymmetric segmental spinal muscular atrophy (JASSMA)
| ? | ? | ? | → see Monomelic amyotrophy | |
| PMA | Progressive spinal 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).