Spinal muscular atrophies
Spinal muscular atrophies are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons and subsequent atrophy of various muscle groups in the body. 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:- Proximal spinal muscular atrophies, i.e., conditions that affect primarily proximal muscles;
- Distal spinal muscular atrophies where they affect primarily distal muscles.
- Autosomal recessive proximal spinal muscular atrophy, responsible for 90-95% of cases and usually called simply spinal muscular atrophy – a disorder associated with a genetic mutation on the SMN1 gene on chromosome 5q, 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.
| Group | Name Alternate names | OMIM | Gene | Locus | Mode of inheritance | Characteristics |
| SMA | Spinal muscular atrophy
| SMN1 | 5q13.2 | Autosomal recessive | Affects primarily proximal muscles in people of all ages, progressive, relatively common | |
| ' | X-linked spinal muscular atrophy type 1 | 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 | 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 | ATP7A | Xq21.1 | X-linked recessive | Affects distal muscles of all extremities mainly in boys, slowly progressive | |
| ' | Distal spinal muscular atrophy type 1 | IGHMBP2 | 11q13.3 | Autosomal recessive | Affects mainly infant boys, similar to SMA type 1 but with diaphragmatic paralysis | |
| ' | Distal spinal muscular atrophy type 2 | SIGMAR1 | 19p13.3 | Autosomal recessive | Slowly progressive | |
| ' | Distal spinal muscular atrophy type 3 | ? | 11q13.3 | Autosomal recessive | Slowly progressive | |
| ' | Distal spinal muscular atrophy type 4 | PLEKHG5 | 1p36.31 | Autosomal recessive | Slowly progressive, described only in one family | |
| ' | Distal spinal muscular atrophy type 5 | DNAJB2 | 2q35 | Autosomal recessive | Young adult onset, slowly progressive | |
| ' | Distal spinal muscular atrophy type VA | 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 | 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 | TRPV4 | 12q24.11 | Autosomal dominantor 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 | |
| ' | Autosomal dominant juvenile distal spinal muscular atrophy | ? | 7q34–q36 | Autosomal dominant | Juvenile-onset | |
| Juvenile segmental spinal muscular atrophy | ? | 18q21.3 | ? | Juvenile-onset, progressive with stabilisation after 2–4 years, affects primarily hands, very rare | ||
| Finkel-type proximal spinal muscular atrophy | VAPB | 20q13.32 | Autosomal dominant | Late-onset, affects proximal muscles in adults | ||
| Jokela-type spinal muscular atrophy | 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 | DYNC1H1 | 14q32 | Autosomal dominant | Affects proximal muscles in infants | ||
| Spinal muscular atrophy with lower extremity predominance 2 | BICD2 | 9q22.31 | Autosomal dominant | Congenital or early-onset, primarily affecting lower limbs, nonprogressive, very rare | ||
| Spinal muscular atrophy with progressive myoclonic epilepsy | ASAH1 | 8p22 | Autosomal recessive | |||
| Spinal muscular atrophy with congenital bone fractures | ASCC1 | 10q21 | Autosomal recessive | Characterised by severe muscle wasting as in SMA type I accompanied by congenital bone fractures | ||
| PCH | Spinal muscular atrophy with pontocerebellar hypoplasia | VRK1 | 14q32 | Autosomal dominant | → see Pontocerebellar hypoplasia | |
| MMA | Juvenile asymmetric segmental spinal muscular atrophy | ? | ? | ? | → see Monomelic amyotrophy | |
| PMA | Progressive spinal muscular atrophy | ? | ? | ? | ? | → see Progressive muscular atrophy |