Spinal muscular atrophies

Short description: Muscular degenerative disorders caused by dysfunction of spinal neurons

This page is about a group of rare diseases. For the most common disorder of the group, see Spinal muscular atrophy.

"SMAs" redirects here. For other uses, see SMA (disambiguation) and SMAS (disambiguation).

Spinal muscular atrophies

Location of neurons affected in spinal muscular atrophies
Specialty| 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.

## Contents

* 1 Classification
* 2 See also
* 3 References
* 4 Further reading
* 5 External links

## Classification

* 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.

Group  | Name
Alternative names | OMIM  | Gene | Locus | Mode of
inheritance | Characteristics

|
|
|
|
|
|

SMA | Spinal muscular atrophy (SMA)

* 5q spinal muscular atrophy
* Autosomal recessive proximal spinal muscular atrophy
* Werdnig–Hoffmann disease / Kugelberg–Welander disease

| Online Mendelian Inheritance in Man (OMIM) 253300
Online Mendelian Inheritance in Man (OMIM) 253550
Online Mendelian Inheritance in Man (OMIM) 253400
Online Mendelian Inheritance in Man (OMIM) 271150 | 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)

* Spinal and bulbar muscular atrophy (SBMA)
* Kennedy's disease (KD)

| Online Mendelian Inheritance in Man (OMIM) 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)

| Online Mendelian Inheritance in Man (OMIM) 301830 | 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)

* Distal spinal muscular atrophy – X-linked (DSMAX)

| Online Mendelian Inheritance in Man (OMIM) 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 neuronopathy type 6 (DHMN6)

| Online Mendelian Inheritance in Man (OMIM) 604320 | 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)

* Distal hereditary motor neuronopathy – Jerash type (DHMN-J)

| Online Mendelian Inheritance in Man (OMIM) 605726 | SIGMAR1 | 19p13.3 | Autosomal recessive | Slowly progressive
Distal spinal muscular atrophy type 3 (DSMA3)

* Distal hereditary motor neuronopathy types 3 & 4 (DHMN3/DHMN4)

| Online Mendelian Inheritance in Man (OMIM) 607088 | ?  | 11q13.3 | Autosomal recessive | Slowly progressive
Distal spinal muscular atrophy type 4 (DSMA4)  | Online Mendelian Inheritance in Man (OMIM) 611067 | PLEKHG5 | 1p36.31 | Autosomal recessive | Slowly progressive, described only in one family
Distal spinal muscular atrophy type 5 (DSMA5)  | Online Mendelian Inheritance in Man (OMIM) 614881 | DNAJB2 | 2q35 | Autosomal recessive | Young adult onset, slowly progressive
Distal spinal muscular atrophy type VA (DSMAVA)

* Distal hereditary motor neuronopathy type 5A (DHMN5A)

| Online Mendelian Inheritance in Man (OMIM) 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 VB (DSMAVB)

* Distal hereditary motor neuronopathy type 5B (DHMN5B)

| Online Mendelian Inheritance in Man (OMIM) 614751 | 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 (DHMN2D)

| Online Mendelian Inheritance in Man (OMIM) 615575 | 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 (DHMN7A)
* Harper–Young myopathy

| Online Mendelian Inheritance in Man (OMIM) 158580 | SLC5A7 | 2q12.3 | Autosomal dominant  | Adult-onset with vocal cord paralysis, very rare
Congenital distal spinal muscular atrophy

* Distal hereditary motor neuronopathy type 8 (DHMN8)

| Online Mendelian Inheritance in Man (OMIM) 600175 | 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)

* Scapuloperoneal neurogenic amyotrophy

| Online Mendelian Inheritance in Man (OMIM) 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
Autosomal dominant distal spinal muscular atrophy

* Distal hereditary motor neuronopathy type 2A (DHMN2A)

| Online Mendelian Inheritance in Man (OMIM) 158590 | HSPB8 | 12q24.23 | Autosomal dominant  | Adult-onset. Allelic with Charcot–Marie–Tooth disease type 2L (CMT2L)
Autosomal dominant juvenile distal spinal muscular atrophy

* Distal hereditary motor neuronopathy type 1 (DHMN1)

| Online Mendelian Inheritance in Man (OMIM) 182960 | ?  | 7q34–q36 | Autosomal dominant  | Juvenile-onset
| Juvenile segmental spinal muscular atrophy (JSSMA)  | Online Mendelian Inheritance in Man (OMIM) 183020 | ?  | 18q21.3 | ?  | Juvenile-onset, progressive with stabilisation after 2–4 years, affects primarily hands, very rare
Finkel type proximal spinal muscular atrophy (SMAFK)  | Online Mendelian Inheritance in Man (OMIM) 182980 | VAPB | 20q13.32 | Autosomal dominant  | Late-onset, affects proximal muscles in adults
James type infantile spinal muscular atrophy (SMAJI)  | Online Mendelian Inheritance in Man (OMIM) 619042 | 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)  | Online Mendelian Inheritance in Man (OMIM) 615048 | 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)  | Online Mendelian Inheritance in Man (OMIM) 158600 | DYNC1H1 | 14q32 | Autosomal dominant  | Affects proximal muscles in infants
Spinal muscular atrophy with lower extremity predominance 2A (SMALED2A)  | Online Mendelian Inheritance in Man (OMIM) 615290 | 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)  | Online Mendelian Inheritance in Man (OMIM) 618291 | 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)  | Online Mendelian Inheritance in Man (OMIM) 159950 | ASAH1 | 8p22 | Autosomal recessive |
Spinal muscular atrophy with congenital bone fractures 1 (SMABF1)  | Online Mendelian Inheritance in Man (OMIM) 616866 | 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)  | Online Mendelian Inheritance in Man (OMIM) 616867 | 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)

* Pontocerebellar hypoplasia type 1A (PCH1A)

| Online Mendelian Inheritance in Man (OMIM) 607596 | VRK1 | 14q32 | Autosomal dominant  | → see Pontocerebellar hypoplasia
MMA | Juvenile asymmetric segmental spinal muscular atrophy (JASSMA)

* Monomelic amyotrophy
* Hirayama disease
* Sobue disease

| Online Mendelian Inheritance in Man (OMIM) 602440 | ?  | ?  | ?  | → see Monomelic amyotrophy
PMA | Progressive spinal muscular atrophy

* Progressive muscular atrophy
* Duchenne-Aran 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).[citation needed]

## See also

* Distal hereditary motor neuropathies
* Motor neuron disease
* Polyneuropathy in dogs and cats

## References

1. ↑ "Spinal muscular atrophy". 2016-03-21. https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy/.
2. ↑ "Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures". American Journal of Human Genetics 98 (3): 473–489. March 2016. doi:10.1016/j.ajhg.2016.01.006. PMID 26924529.
3. ↑ "The new neuromuscular disease related with defects in the ASC-1 complex: report of a second case confirms ASCC1 involvement". Clinical Genetics 92 (4): 434–439. October 2017. doi:10.1111/cge.12997. PMID 28218388.
4. ↑ "A new case of SMABF2 diagnosed in stillbirth expands the prenatal presentation and mutational spectrum of ASCC1". American Journal of Medical Genetics. Part A 182 (3): 508–512. December 2019. doi:10.1002/ajmg.a.61431. PMID 31880396.

## Further reading

* "The spectrum of lower motor neuron syndromes". Journal of Neurology 250 (11): 1279–92. November 2003. doi:10.1007/s00415-003-0235-9. PMID 14648143.
* "Unusual clinical features in infantile Spinal Muscular Atrophies". Brain & Development 30 (3): 169–78. March 2008. doi:10.1016/j.braindev.2007.07.008. PMID 17804187.

## External links

Classification|

* ICD-10: G12
* MeSH: D009134

|

* v
* t
* e

Diseases of the nervous system, primarily CNS (G04–G47, 323–349)

Inflammation|

| Brain|

* Encephalitis
* Viral encephalitis
* Herpesviral encephalitis
* Limbic encephalitis
* Encephalitis lethargica
* Cavernous sinus thrombosis
* Brain abscess
* Amoebic

|

Spinal cord|

* Myelitis: Poliomyelitis
* Demyelinating disease
* Transverse myelitis
* Tropical spastic paraparesis
* Epidural abscess

Both/either|

* Encephalomyelitis
* Acute disseminated
* Myalgic
* Meningoencephalitis

Brain/
encephalopathy|

| Degenerative|

| Extrapyramidal and
movement disorders|

* Basal ganglia disease
* Parkinsonism
* PD
* Postencephalitic
* NMS
* PKAN
* Tauopathy
* PSP
* Striatonigral degeneration
* Hemiballismus
* HD
* OA

* Dyskinesia
* Dystonia
* Status dystonicus
* Spasmodic torticollis
* Meige's
* Blepharospasm
* Athetosis
* Chorea
* Choreoathetosis
* Myoclonus
* Myoclonic epilepsy
* Akathisia

* Tremor
* Essential tremor
* Intention tremor
* Restless legs
* Stiff-person

|

Dementia|

* Tauopathy
* Alzheimer's
* Early-onset
* Primary progressive aphasia
* Frontotemporal dementia/Frontotemporal lobar degeneration
* Pick's
* Dementia with Lewy bodies
* Posterior cortical atrophy

* Vascular dementia

Mitochondrial disease|

* Leigh syndrome

Demyelinating|

* autoimmune
* Multiple sclerosis
* Neuromyelitis optica
* Schilder's disease
* hereditary
* Adrenoleukodystrophy
* Alexander
* Canavan
* Krabbe
* ML
* PMD
* VWM
* MFC
* CAMFAK syndrome
* Central pontine myelinolysis
* Marchiafava–Bignami disease
* Alpers' disease

Episodic/
paroxysmal|

| Seizure/epilepsy|

* Focal
* Generalised
* Status epilepticus
* Myoclonic epilepsy

|

Headache|

* Migraine
* Familial hemiplegic
* Cluster
* Tension

Cerebrovascular|

* TIA
* Amaurosis fugax
* Transient global amnesia
* Acute aphasia

* Stroke
* MCA
* ACA
* PCA
* Foville's
* Millard–Gubler
* Lateral medullary
* Medial medullary
* Weber's
* Lacunar stroke

Sleep disorders|

* Insomnia
* Hypersomnia
* Sleep apnea
* Obstructive
* Congenital central hypoventilation syndrome
* Narcolepsy
* Cataplexy
* Kleine–Levin
* Circadian rhythm sleep disorder
* Advanced sleep phase disorder
* Delayed sleep phase disorder
* Non-24-hour sleep–wake disorder
* Jet lag

CSF|

* Intracranial hypertension
* Hydrocephalus/NPH
* Choroid plexus papilloma
* Idiopathic intracranial hypertension
* Cerebral edema
* Intracranial hypotension

Other|

* Brain herniation
* Reye's
* Hepatic encephalopathy
* Toxic encephalopathy
* Hashimoto's encephalopathy

Spinal cord/
myelopathy|

* Syringomyelia
* Syringobulbia
* Morvan's syndrome
* Vascular myelopathy
* Foix–Alajouanine syndrome
* Spinal cord compression

Both/either|

| Degenerative|

| SA|

* Friedreich's ataxia
* Ataxia–telangiectasia

|

MND|

* UMN only:
* Primary lateral sclerosis
* Pseudobulbar palsy
* Hereditary spastic paraplegia

* LMN only:
* Distal hereditary motor neuronopathies
* Spinal muscular atrophies
* SMA
* SMAX1
* SMAX2
* DSMA1
* Congenital DSMA
* SMA-PCH
* SMA-LED
* SMA-PME
* Progressive muscular atrophy
* Progressive bulbar palsy
* Fazio–Londe
* Infantile progressive bulbar palsy

* both:
* Amyotrophic lateral sclerosis

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*[XLSMA]: X-linked spinal muscular atrophies
*[DSMA]: Distal spinal muscular atrophies
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