Distal hereditary motor neuropathy, type V

Distal hereditary motor neuropathy, type V is a progressive genetic disorder that damages motor neurons in the spinal cord, primarily causing muscle weakness and wasting in the hands and feet.

Overview

Distal hereditary motor neuropathy, type V is a disorder that affects nerve cells in the spinal cord. This condition specifically affects motor neurons, which are specialized cells that control muscle movement. Damage to motor neurons results in muscle weakness that worsens over time. In people with this condition, the weakness primarily affects movement in the muscles that are furthest from the center of the body (distal muscles), such as the muscles in the hands and feet. Affected individuals typically have a normal life expectancy.

Symptoms

Signs and symptoms of distal hereditary motor neuropathy, type V usually begin during adolescence, but they can appear any time between infancy and the mid-30s. Key features include:

• Hand Cramps: Often the first symptom of the condition, typically brought on by exposure to cold temperatures.
• Muscle Weakness and Wasting: Characterized by weakness and wasting (atrophy) of the muscles of the hand, specifically on the side of the index finger near the thumb and in the palm of the hand at the base of the thumb.
• Lower Limb Weakness: About half of affected individuals develop muscle weakness in the feet and lower legs. This can lead to walking problems (gait disturbance), difficulty lifting the front part of the foot (foot drop), and a high foot arch.
• Reflex and Sensory Disturbances: Some people experience exaggerated reflexes (hyperreflexia) or disturbances in the nerves used to detect sensations (sensory neuropathy). Although sensory neuropathy is uncommon in this condition, it is a typical feature of a related disorder called Charcot-Marie-Tooth disease, which shares overlapping features and genetic causes.

Frequency

The prevalence of all types of distal hereditary motor neuropathy is estimated to be about 2 in 100,000 individuals. The specific prevalence of distal hereditary motor neuropathy, type V is unknown.

Causes

Variants (also called mutations) in multiple genes can cause distal hereditary motor neuropathy, type V. Most commonly, variants in the BSCL2 and GARS1 genes cause this condition.

• BSCL2 Gene: This gene provides instructions for making a protein called seipin, which is located in the membrane of the endoplasmic reticulum (a cell structure involved in protein processing and transport). Variants in this gene likely alter the structure of seipin, causing the proteins to build up in the endoplasmic reticulum. This accumulation likely damages motor neurons, leading to muscle weakness.
• GARS1 Gene: This gene provides instructions for making the enzyme glycine—tRNA ligase, which is involved in protein production. Variants in this gene reduce the enzyme's activity, which researchers believe may impair the transmission of nerve impulses and cause motor neurons to slowly lose the ability to communicate with muscles.

In rare instances, variants in other genes, such as REEP1, can also cause the condition.

Associated Genes

• BSCL2
• GARS1
• REEP1

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, some people who inherit the altered gene never develop the condition, a situation known as reduced penetrance.

Other Names for This Condition

• DHMN5
• DHMNV
• Distal hereditary motor neuronopathy type 5
• Distal hereditary motor neuronopathy, type V
• Distal spinal muscular atrophy, type V
• DSMAV
• HMN V
• Spinal muscular atrophy, distal type V
• Spinal muscular atrophy, distal, with upper limb predominance