About SPG4
De Novo SPG4: At a Glance
Overview
Hereditary Spastic Paraplegia (HSP) is a group of genetic neurodegenerative disorders that cause progressive muscle stiffness (spasticity) and weakness in the legs. SPG4 is the most common form of HSP, typically inherited and often slow to progress.
But the children we represent face something far more urgent.
They carry a de novo mutation in the SPAST gene — a spontaneous change that occurs without any family history. One specific variant, p.Arg499His (c.1496G>A), has been identified in just ~22 children worldwide. This ultra-rare mutation leads to an especially severe, early-onset form of SPG4 that advances quickly and aggressively.
Unlike many adult-onset forms of HSP, this mutation can affect far more than walking. Children often lose mobility within their first decade of life and may also face weakening in the core and upper limbs, as well as impairments in speech, swallowing, and cognition.
Because it is so rare, childhood-onset de novo SPG4 is often misdiagnosed or misunderstood. Historically, it has received little to no dedicated research funding.
But that’s changing — thanks to families, scientists, and supporters like you.
With urgent investment and continued momentum, promising research is already moving forward — and with it, real hope for treatments or a cure.
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 22 cases of this devastating variant have been identified.
Why It’s Urgent
Most children with de novo SPG4 lose the ability to walk between ages 5 and 10.
Some will also face speech loss, swallowing difficulties, and cognitive decline.
Time is not on our side — but science, with your support, can change the outcome.
A Closer Look
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What is HSP?
Hereditary Spastic Paraplegia (HSP) refers to a group of over 80 rare genetic disorders that cause progressive spasticity (muscle stiffness and tightness) and weakness in the lower limbs. In HSP, mutations in certain genes lead to degeneration or dysfunction of the long nerve fibers in the spinal cord that control leg movement. Over time, individuals with HSP experience increasing difficulty walking and performing other motor tasks.
HSP can vary in severity and age of onset. Some people have mild symptoms later in life, while others – like the children we serve – develop severe symptoms in early childhood. Around 20,000 people are affected by some form of HSP. There is currently no cure for HSP, but understanding the genetic causes is the first step toward developing effective treatments.
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What is SPG4?
SPG4 is the most common subtype of HSP, accounting for a significant portion of HSP cases. Approximately 8,000 people have SPG4. This subtype is caused by mutations in the SPAST gene, which provides instructions for making a protein called spastin. Spastin is crucial for maintaining the health of nerve cells, particularly by regulating microtubules – the structural “rails” that transport important materials within cells.
SPG4 is usually inherited in an autosomal dominant pattern, meaning a mutation in just one copy of the SPAST gene can cause the disorder. However, in some cases (like those we focus on), an SPG4 mutation arises spontaneously (de novo) in a child whose parents do not carry the gene change. This spontaneous occurrence adds complexity to understanding and diagnosing SPG4, since it cannot be predicted by family history.
Not all SPG4 mutations are equal. Certain variants of the SPAST gene are exceptionally rare and particularly aggressive. For example, the p.Arg499His mutation in SPAST has been found in only 22 individuals. Children with this mutation typically have earlier onset and more severe symptoms than classic adult-onset SPG4. Their muscle stiffness may extend beyond the legs to affect the torso and arms; many also experience difficulties with speech and even cognition. These cases demonstrate how diverse SPG4 can be – and why research must address not just the “average” case, but the most severe manifestations as well.
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What is the Spastin Protein?
Spastin is the protein produced by the SPAST gene, and it plays a vital role in nerve cell maintenance. To understand spastin’s job, imagine each neuron (nerve cell) as a complex building, and microtubules as the steel beams and conveyor belts inside that keep the structure supported and materials moving. Spastin is like the maintenance worker for those beams – it helps assemble, regulate, and prune the microtubules to ensure the neuron’s internal framework stays healthy and functional.
In a healthy neuron, spastin makes sure that microtubules grow and branch properly, allowing nerve signals and nutrients to travel smoothly along the long fibers (axons) that connect the brain and spinal cord to muscles. When spastin is missing or not working correctly due to a SPAST mutation, the microtubule network can become tangled or broken down. As a result, neurons – especially the long spinal cord neurons that control leg movement – start to malfunction or degenerate. This leads to the hallmark symptoms of spastic paraplegia: muscles that progressively weaken and become spastic (overly tight), causing gait problems and, in severe cases, loss of independent mobility.
In short, without functional spastin, neurons lose their structural integrity and their ability to communicate effectively. Research into spastin function and microtubule regulation is one key avenue to understanding SPG4 and developing targeted treatments (for example, drugs that might stabilize microtubules or compensate for the loss of spastin).
Together We Can
Time is not on our side, but we hope you will be.