Congenital distal spinal muscular atrophy (cDSMA), also known as distal hereditary motor neuropathy (or neuronopathy) type VIII (dHMN8), is a hereditary medical 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), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...

), particularly of

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

muscles in legs and hands, and by early-onset

contracture In pathology, a contracture is a shortening of muscles, tendons, skin, and nearby soft tissues that causes the joints to shorten and become very stiff, preventing normal movement. A contracture is usually permanent, but less commonly can be temp ...

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 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 (anatomy), diaphragm and the sacrum. Naming and location The lumbar region is sometimes referred to as the lowe ...

and cervical 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 chann ...

'' 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 Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

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

Signs and symptoms

The presentation is as follows: * Neurogenic muscle weakness * Atrophy (of lower and upper limbs) *

Club foot Clubfoot is a congenital or acquired defect where one or both feet are supinated, rotated inward and plantar flexion, downward. Congenital clubfoot is the most common congenital malformation of the foot with an incidence of 1 per 1000 births. ...

Arthrogryposis Arthrogryposis (AMC) describes congenital joint contracture in two or more areas of the body. It derives its name from Greek, literally meaning 'curving of joints' (', 'joint'; ', late Latin form of late Greek ', 'hooking'). Children born with one ...

Scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...

* Platyspondyly * Pes cavus * Vocal cord paralysis

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 relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...

, 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 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

, 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 or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

and is permeable to Ca²⁺. Abnormal regulation of Ca²⁺ can lead to inefficient muscle contraction. ''TRPV4'' plays a major role in

mechanosensation Mechanosensation is the transduction of mechanical stimuli into neural signals. Mechanosensation provides the basis for the senses of light touch, hearing, proprioception, and pain. Mechanoreceptors found in the skin, called cutaneous mechanorecept ...

, as well as osmosensory functions in nerve endings, endothelia, and alveoli. The TRPV4 protein consists of 871

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s with its N- and C- terminals facing intracellularly. The protein also contains six

alpha helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

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 mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...

s 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 guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...

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 Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...

substitution * R315W, arginine to

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

substitution * R316C, arginine to

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

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 Denervation is any loss of nerve supply regardless of the cause. If the nerves lost to denervation are part of neural communication to an organ system or for a specific tissue function, alterations to or compromise of physiological functioning ca ...

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 electromyo ...

(EMG), also to detect denervation *

X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...

, to look for bone abnormalities *

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

(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 a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...

and

occupational therapy Occupational therapy (OT), also known as ergotherapy, is a healthcare profession. Ergotherapy is derived from the Greek wiktionary:ergon, ergon which is allied to work, to act and to be active. Occupational therapy is based on the assumption t ...

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