Spinal muscular atrophies
|Spinal muscular atrophies|
|Location of neurons affected in spinal muscular atrophies|
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. 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:
- Proximal spinal muscular atrophies, i.e., conditions that affect primarily proximal muscles;
- Distal spinal muscular atrophies (which significantly overlap with distal hereditary motor neuronopathies) 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 (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.
|SMA||Spinal muscular atrophy (SMA)
||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)
||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|
|DSMA||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)
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
|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 (SMA-FK)||VAPB||20q13.32||Autosomal dominant||Late-onset, affects proximal muscles in adults|
|Jokela-type spinal muscular atrophy (SMA-J)||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 2 (SMALED2)||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)||ASAH1||8p22||Autosomal recessive|
|Spinal muscular atrophy with congenital bone fractures||?||?||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)
||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).
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.
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.
Since December 2016, autosomal recessive proximal spinal muscular atrophy can be treated with nusinersen. No cure is known to any of the remaining disorders of the spinal muscular atrophies group. The main objective there is to improve quality of life which can be measured using specific questionnaires. 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.In May 2019, the FDA approved the use of Zolgensma(a gene therapy, biological drug) for treatment of Type 1 SMA after successful clinical trials. This drug is extremely expensive(over $2 million).it is not yet available in Europe.
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