Spinal muscular atrophies

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Spinal muscular atrophies

ICD-10	G12
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In atrophy, Spinal muscular atrophies are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by degeneration of lower motor neurons – that is, neuronal cells situated in the anterior horn of spinal cord – and subsequent atrophy (wasting) of various muscle groups in the body. The clinical spectrum of various spinal muscular atrophies ranges from early infant death to 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 (which significantly overlap with distal hereditary motor neuropathies) where they affect primarily distal muscles.

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	Inheritance	Characteristics
SMA	Spinal muscular atrophy (SMA) Autosomal recessive proximal spinal muscular atrophy Werdnig–Hoffman / Dubovitz / Kugelberg–Welander disease	(multiple)	SMN1	5q13	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	UBE1	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 5A (DSMA5A) 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 5B (DSMA5B) 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 vocal cord paralysis Distal hereditary motor neuropathy type 7A (HMN7A) Harper–Young myopathy	158580	?	2q14.2	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
	Autosomal dominant proximal spinal muscular atrophy	182980	VAPB	20q13.32	Autosomal dominant	Affects proximal muscles in adults
	Congenital distal spinal muscular atrophy	600175	TRPV4	12q24.11	Autosomal dominant	Affects primarily distal muscles of lower limbs, non-progressive, rare, allellic 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
	Segmental spinal muscular atrophy	183020	(multiple)	18q21.3	?	Affects primarily hands, non-progressive, rare
	Spinal muscular atrophy with lower extremity predominance (SMA-LED)	158600	DYNC1H1	14q32	Autosomal dominant	Affects proximal muscles in infants, 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 congenital bone fractures on top of typical muscle weakness; described only in a handful of infants
	Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) Pontocerebellar hypoplasia type 1A (PCH1A)	607596	VRK1	14q32	Autosomal dominant	→ see Pontocerebellar hypoplasia
	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

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

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

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

Main article: SMA Treatment Acceleration Act

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.

Further reading

• DOI:10.1007/s00415-003-0235-9
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• DOI:10.1016/j.braindev.2007.07.008
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See also

• Motor neuron disease
• Distal hereditary motor neuropathies
• Spinal muscular atrophy
• Polyneuropathy in dogs and cats

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