About SPG4

Overview

Hereditary spastic paraplegia (HSP) SPG4 is a neurodegenerative disease caused by a mutation in the SPAST gene. The disease is characterized by progressive muscle stiffness in the legs and potential paralysis. ‘De novo’ refers to a random genetic mutation that is not inherited, despite this traditionally being an inherited disease. The variant SPAST c.1496G>A, p.Arg499His has been identified in just 19 individuals and is associated with a nano-rare, early-onset and complex diagnosis. This means that in addition to potential leg paralysis, their upper limbs, speech and cognitive abilities can be drastically compromised - often within the first decade of life.

Childhood-onset spastic paraplegia is often overlooked due to its rarity, which limits awareness and funding. However, there is progress toward understanding the disease and a treatment or cure is possible. Your donation drives crucial research along the path to clinical trial and gives hope to the children and families impacted by this devastating disease.

By the Numbers

Rare Diseases: <10%

1 in 10 people in the United States have a rare disease.

Spastic Paraplegia: 0.0060%

Just 20,000 people have spastic paraplegia.

SPG4: 0.0024%

8,000 people have subtype SPG4.

Early-Onset: 0.00060%

2,000 people have early-onset.

De Novo: 0.00030%

1,000 cases are de novo.

(SPAST c.1496G>A, p.Arg499His) Variant: 0.000005%

Just 19 cases of this devastating variant have been identified.

A Closer Look

What is HSP?

Hereditary Spastic Paraplegia (HSP) refers to a group of rare genetic disorders that cause progressive stiffness (spasticity) and weakness in the muscles of the lower limbs. These conditions result from changes in genes that affect nerve cells responsible for controlling movement, leading to difficulties in walking and performing daily activities. In the United States, around 20,000 people are affected by various forms of HSP.
What is SPG4?

SPG4, a subtype of HSP found in just 8,000 people, is caused by mutations in the SPAST gene. This gene provides instructions for producing the spastin protein that is essential for maintaining the structure of nerve cells by regulating microtubule dynamics, crucial for cellular support.
SPG4 is inherited in an autosomal dominant manner, meaning a mutation in just one copy of the SPAST gene is enough to cause the disorder. In some cases, SPG4 can arise spontaneously (de novo) in an individual with no family history of the condition. This spontaneous occurrence complicates the understanding of SPG4's genetic basis and adds challenges to its diagnosis and management.
Some specific variants of SPG4 have been identified in very few individuals. The SPAST c.1496G>A, p.Arg499His mutation is found in only 19 people, highlighting the unique and complex nature of their condition. These variants may lead to more severe symptoms, affecting not only the legs but potentially extending to the core, arms, speech, and cognitive functions, particularly when the condition begins in childhood.
What is the Spastin Protein?

Nerve cells (neurons) in our bodies have a structure that helps them function properly. Think of neurons like wires that transmit signals throughout our body. These "wires" are supported by tiny structures called microtubules, which act like the framework or scaffolding that keeps everything in place.
Spastin is a protein that plays a vital role in keeping these microtubules working correctly. It helps regulate how these structures grow, change, and maintain their shape over time. This is important because stable microtubules ensure that nerve cells can send signals effectively and stay healthy.
When there's a problem with spastin due to genetic mutations, like in SPG4, it can lead to issues in how nerve cells are structured and supported. This can ultimately result in the stiffness and weakness in muscles characteristic of spastic paraplegia.