Congenital distal spinal muscular atrophy

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Congenital distal spinal muscular atrophy
Classification and external resources
OMIM 600175

Congenital distal spinal muscular atrophy (congenital dSMA) is a hereditary genetic condition characterized by muscle wasting (atrophy), particularly of distal muscles in legs and hands, and by early-onset contractures (permanent shortening of a muscle or joint) of the hip, knee, and ankle. Affected individuals often have shorter lower limbs relative to the trunk and upper limbs. The condition is a result of a loss of anterior horn cells localized to lumbar and cervical regions of the spinal cord early in infancy, which in turn is caused by a mutation of the TRPV4 gene. The disorder is inherited in an autosomal dominant manner.[1] Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.[2]

Radiograph showing dysplasia in lower limbs


There are five categories of SMA ranging in severity from 0-4. SMA 0 is characterized by very severe spinal muscular atrophy with respiratory distress at birth and is often linked to a short life expectancy. SMA 1 is characterized by the onset of the disease at an age younger than six months and the lack of sitting up without support; a life expectancy of two years is given to these patients. SMA 2 usually shows up between the ages of 6 and 18 months and these patients are usually able to sit up by themselves once put into a sitting position. SMA 3 shows symptoms after 18 months of age and the patients with this diagnosis are able to achieve the ability to walk without help. The final classification SMA 4 is classified with a normal life expectancy and onset of the disease is not until 10 years or older.[3]

Each of these five categories can be further divided into several subcategories defined by Dubowitz. There are both strong and weak sitters as well as strong and weak walkers. To clarify the differences Dubowitz suggested a system of 2.0, 2.5 and 2.9 to distinguish differences in weak and strong sitters and 3.0, 3.5, and 3.9 to distinguish differences in strong and weak walkers.[3]

A new classification, broken down into recessive and dominant forms of the disease, is based on DNA testing. The recessive form of the disease is linked to chromosome&nsbp;5 and is the most frequent type of SMA. The recessive form is subdivided into three main types according to both the age of onset and severity of the disease.[2] The dominant form affects the lower extremities of the body and has no link to chromosome 5. The dominant form of SMA is much less prominent in those diagnosed with spinal muscular atrophy.[2]

Signs and symptoms[edit]

Lack of muscle, high arch, and hammer toes are indicators of genetic disease


Congenital distal spinal muscular atrophy is caused by a mutation of the TRPV4 gene found on the 12q23-12q24.1.[4] The mutation causes an affected individual to have lower levels of TRPV4 expression. This deficiency can lead to abnormal osmotic regulation. Congenital dSMA is genetically heterogeneous, meaning a mutation on this gene can cause a plethora of other phenotypically related or phenotypically unrelated diseases depending on the region that is mutated.


The TRPV4 (transient receptor potential vanilloid 4) gene, located on chromosome 12, encodes for a protein that serves as an ion channel, typically found in the plasma membrane and is permeable to Ca2+. Abnormal regulation of Ca2+ can lead to inefficient muscle contraction.[5] TRPV4 plays a major role in mechanosensation, as well as osmosensory functions in nerve endings, endothoelia, and alveoli.[6] The TRPV4 protein consists of 871 amino acids with its N- and C- terminals facing intracellularly. The protein also contains six alpha helices that pass through the plasma membrane. Mutations in TRPV4 can result in the loss of its normal function, or a toxic gain of function. In the latter case, intracellular Ca2+ levels are increased, which results in abnormal regulation.[7]


The ankyrin repeat domain (ARD) is a region located near the intracellular N-terminal of the TRPV4 protein and consists of six ankyrin repeats. Four missense mutations have been identified at three specific positions all located within the ARD. All of these mutations are due to the swapping out of arginine with a different amino acid.[8] Arginine is highly polar and positively charged, while its replacements are less polar or nonpolar. Some of these identified amino acid substitutions are:[medical citation needed]

  • R296H, arginine to histidine substitution
  • R315W, arginine to tryptophan substitution
  • R316C, arginine to cysteine substitution
  • R594H, arginine to histidine substitution


Denervation atrophy

Electrophysiological evidence of denervation with intact motor and sensory nerve conduction findings must be made by using nerve conduction studies, usually in conjunction with EMG. The presence of polyphasic potentials and fibrillation at rest are characteristic of congenital dSMA.[7] An x-ray of an individual will also show abnormal bone growth. Histologic evidence from muscle biopsy samples of denervation must also be present.[3] The following are useful in diagnosis:[medical citation needed]

After further study and progression in technology, it is now possible to map the classification of chromosome 5q13 and diagnose the disease using a DNA test.[3]


Congenital dSMA has a relatively stable disease course, with disability mainly attributed to increased contractures rather than loss of muscle strength. Individuals frequently use crutches, knee, ankle, and/or foot orthoses, or wheelchairs.[2] Orthopaedic surgery can be an option for some patients with severely impaired movement. Physical therapy and occupational therapy can help prevent further contractures from occurring, though they do not reverse the effects of preexisting ones. Some literature suggests the use of electrical stimulation or botulinum toxin to halt the progression of contractures.[9]


Prognosis is mainly dependent on maximum function achieved by an affected individual. Patients who can not sit alone typically have a life expectancy of less than four years. Patients who can sit, but could never walk, live for at least 20 to 30 years. And patients who have the ability to walk at some point in their lives have a lifespan that is indefinite. However, all patients lose function over time. SMA patients’ prognoses are related more to the level of function reached rather than the age of onset for the disease. Those with walking abilities were categorized into two groups: 1) those who could walk normally (meaning they could walk up and down stairs) and 2) those who could not walk normally (meaning they were never able to walk up and down stairs). Those who walked normally were able to walk longer - usually until 30 or 40 years of age - while those who were never able to walk normally were only able to walk until about age 15.[3]

See also[edit]


  1. ^ Oates EC, Reddel S, Rodriguez ML, et al. (June 2012). "Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells". Brain 135 (Pt 6): 1714–23. doi:10.1093/brain/aws108. PMID 22628388. 
  2. ^ a b c d Mercuri E, Messina S, Kinali M, et al. (February 2004). "Congenital form of spinal muscular atrophy predominantly affecting the lower limbs: a clinical and muscle MRI study". Neuromuscul. Disord. 14 (2): 125–9. doi:10.1016/j.nmd.2003.09.005. PMID 14733958. 
  3. ^ a b c d e Russman BS (August 2007). "Spinal muscular atrophy: clinical classification and disease heterogeneity". J. Child Neurol. (Review) 22 (8): 946–51. doi:10.1177/0883073807305673. PMID 17761648. 
  4. ^ Everaerts W, Nilius B, Owsianik G (September 2010). "The vanilloid transient receptor potential channel TRPV4: from structure to disease". Prog. Biophys. Mol. Biol. 103 (1): 2–17. doi:10.1016/j.pbiomolbio.2009.10.002. PMID 19835908. 
  5. ^ Menezes MP, North KN (June 2012). "Inherited neuromuscular disorders: pathway to diagnosis". J Paediatr Child Health 48 (6): 458–65. doi:10.1111/j.1440-1754.2011.02210.x. PMID 22050238. 
  6. ^ Auer-Grumbach M, Olschewski A, Papić L, et al. (February 2010). "Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C". Nat. Genet. 42 (2): 160–4. doi:10.1038/ng.508. PMC 3272392. PMID 20037588. 
  7. ^ a b Fiorillo C, Moro F, Brisca G, et al. (August 2012). "TRPV4 mutations in children with congenital distal spinal muscular atrophy". Neurogenetics 13 (3): 195–203. doi:10.1007/s10048-012-0328-7. PMID 22526352. 
  8. ^ Dai J, Cho TJ, Unger S, et al. (July 2010). "TRPV4-pathy, a novel channelopathy affecting diverse systems". J. Hum. Genet. 55 (7): 400–2. doi:10.1038/jhg.2010.37. PMID 20505684. 
  9. ^ Farmer SE, James M (September 2001). "Contractures in orthopaedic and neurological conditions: a review of causes and treatment". Disabil Rehabil 23 (13): 549–58. doi:10.1080/09638280010029930. PMID 11451189. 

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