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.

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 – 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.

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

Group	Name Alternative names	OMIM	Gene	Locus	Mode of inheritance	Characteristics
SMA	Spinal muscular atrophy 5q spinal muscular atrophy Autosomal recessive proximal spinal muscular atrophy Werdnig–Hoffmann disease / Kugelberg–Welander disease		SMN1	5q13.2	Autosomal recessive	Affects primarily proximal muscles in people of all ages, progressive, relatively common
'	X-linked spinal muscular atrophy type 1 Spinal and bulbar muscular atrophy Kennedy's disease		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 Arthrogryposis multiplex congenita – X-linked type 1		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 Distal spinal muscular atrophy – X-linked		ATP7A	Xq21.1	X-linked recessive	Affects distal muscles of all extremities mainly in boys, slowly progressive
'	Distal spinal muscular atrophy type 1 Spinal muscular atrophy with respiratory distress type 1 Distal hereditary motor neuronopathy type 6		IGHMBP2	11q13.3	Autosomal recessive	Affects mainly infant boys, similar to SMA type 1 but with diaphragmatic paralysis
'	Distal spinal muscular atrophy type 2 Distal hereditary motor neuronopathy – Jerash type		SIGMAR1	19p13.3	Autosomal recessive	Slowly progressive
'	Distal spinal muscular atrophy type 3 Distal hereditary motor neuronopathy types 3 and 4		?	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 Distal hereditary motor neuronopathy type 5A		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 Distal hereditary motor neuronopathy type 5B		REEP1	2p11	Autosomal dominant	With upper limb predominance; allelic and overlapping with HSP-31
'	Distal spinal muscular atrophy with calf predominance Distal hereditary motor neuronopathy type 2D		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 Distal hereditary motor neuronopathy type 7A Harper–Young myopathy		SLC5A7	2q12.3	Autosomal dominant	Adult-onset with vocal cord paralysis, very rare
'	Congenital distal spinal muscular atrophy Distal hereditary motor neuronopathy type 8		TRPV4	12q24.11	Autosomal dominant	Affects primarily distal muscles of lower limbs, non-progressive, rare, allelic with SPSMA and CMT2C
'	Scapuloperoneal spinal muscular atrophy Scapuloperoneal neurogenic amyotrophy		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 Distal hereditary motor neuronopathy type 2A		HSPB8	12q24.23	Autosomal dominant	Adult-onset. Allelic with Charcot–Marie–Tooth disease type 2L
'	Autosomal dominant juvenile distal spinal muscular atrophy Distal hereditary motor neuronopathy type 1		?	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
	James type infantile spinal muscular atrophy		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		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 2A		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		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		ASAH1	8p22	Autosomal recessive
	Spinal muscular atrophy with congenital bone fractures 1		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		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
PCH	Spinal muscular atrophy with pontocerebellar hypoplasia Pontocerebellar hypoplasia type 1A		VRK1	14q32	Autosomal dominant	→ see Pontocerebellar hypoplasia
MMA	Juvenile asymmetric segmental spinal muscular atrophy Monomelic amyotrophy Hirayama disease Sobue disease		?	?	?	→ see Monomelic amyotrophy
PMA	Progressive spinal muscular atrophy Progressive muscular atrophy Duchenne-Aran muscular atrophy	?	?	?	?	→ see Progressive muscular atrophy

In all forms of SMA, 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.