Congenital distal spinal muscular atrophy is a

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

condition characterized by muscle wasting (

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

), particularly of

distal Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position pro ...

muscles in legs and hands, and by early-onset

contracture In pathology, a contracture is a permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spasti ...

s (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 The anterior grey column (also called the anterior cornu, anterior horn of spinal cord, motor horn or ventral horn) is the front column of grey matter in the spinal cord. It is one of the three grey columns. The anterior grey column contains motor ...

localized to

lumbar In tetrapod anatomy, lumbar is an adjective that means ''of or pertaining to the abdominal segment of the torso, between the diaphragm and the sacrum.'' The lumbar region is sometimes referred to as the lower spine, or as an area of the back i ...

and

cervical In anatomy, cervical is an adjective that has two meanings: # of or pertaining to any neck. # of or pertaining to the female cervix: i.e., the ''neck'' of the uterus. *Commonly used medical phrases involving the neck are **cervical collar **cervic ...

regions of the spinal cord early in infancy, which in turn is caused by a mutation of the ''

TRPV4 Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the ''TRPV4'' gene. The ''TRPV4'' gene encodes TRPV4, initially named "vanilloid-receptor related osmotically activated channe ...

'' gene. The disorder is inherited in an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

manner. Arm muscle and function, as well as cardiac and respiratory functions are typically well preserved.

Signs and symptoms

The presentation is as follows: Charcot-marie-tooth foot

* Neurogenic muscle weakness * Atrophy (of lower and upper limbs) * Club foot * Arthrogryposis *

Scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

Platyspondyly Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condi ...

* Pes cavus *

Vocal cord paralysis Vocal cord paresis, also known as recurrent laryngeal nerve paralysis or vocal fold paralysis, is an injury to one or both recurrent laryngeal nerves (RLNs), which control all intrinsic muscles of the larynx except for the cricothyroid muscle. The ...

Causes

Congenital distal spinal muscular atrophy is caused by a mutation of the ''TRPV4'' gene found on the 12q23-12q24.1. 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 Homogeneity and heterogeneity are concepts often used in the sciences and statistics relating to the uniformity of a substance or organism. A material or image that is homogeneous is uniform in composition or character (i.e. color, shape, siz ...

, 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.

Pathophysiology

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 The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

and is permeable to Ca²⁺. Abnormal regulation of Ca²⁺ can lead to inefficient muscle contraction. ''TRPV4'' plays a major role in mechanosensation, as well as osmosensory functions in

nerve ending A free nerve ending (FNE) or bare nerve ending, is an unspecialized, afferent nerve fiber sending its signal to a sensory neuron. ''Afferent'' in this case means bringing information from the body's periphery toward the brain. They function as cut ...

s, endothoelia, and

alveoli Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit. Uses in anatomy and zoology * Pulmonary alveolus, an air sac in the lungs ** Alveolar cell or pneumocyte ** Alveolar duct ** Alveolar macrophage * ...

. 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.

Mechanism

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 Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...

with a different amino acid. Arginine is highly polar and positively charged, while its replacements are less polar or nonpolar. Some of these identified amino acid substitutions are: * R296H, arginine to histidine substitution * R315W, arginine to tryptophan substitution * R316C, arginine to

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

substitution * R594H, arginine to histidine substitution

Diagnosis

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. The following are useful in diagnosis: * Nerve conduction studies (NCS), to test for denervation *

Electromyography Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyog ...

(EMG), also to detect denervation * X-ray, to look for bone abnormalities *

Magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(MRI) * Skeletal muscle biopsy examination * Serum creatine kinase (CK) level in blood, usually elevated in affected individuals * Pulmonary function test

Management

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. Orthopaedic surgery can be an option for some patients with severely impaired movement.

Physical therapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...

and

occupational therapy Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field of ...

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.

References

External links

Connective Tissue Gene Tests (CTGT)
{{CNS diseases of the nervous system Systemic atrophies primarily affecting the central nervous system Autosomal dominant disorders Neurogenetic disorders