Diseases Studied

Hereditary spastic paraplegia (HSP) refers to a group of rare, inherited neurological disorders that primarily affect the upper motor neurons in the brain and spinal cord. These neurons control movement by transmitting signals to lower motor neurons, which activate muscles. When upper motor neurons progressively degenerate, the result is spasticity (muscle stiffness), weakness, and increasing difficulty walking.

HSP is broadly classified into two types:

• Uncomplicated (Pure) HSP – Symptoms are confined to lower-limb weakness and spasticity.
• Complicated (Complex) HSP – In addition to spasticity and weakness, individuals may experience other neurological or systemic symptoms such as developmental delay, cognitive impairment, ataxia, peripheral neuropathy, epilepsy, swallowing or breathing difficulties, or vision and hearing loss.

Onset can occur at any age and varies greatly between individuals and families. HSP results from pathogenic variants in many different genes and may follow autosomal dominant, autosomal recessive, or X-linked inheritance patterns. Fewer than 50,000 people in the United States are affected.

Spastic paraplegia type 3A (SPG3A) is one of the most common early-onset forms of autosomal dominant hereditary spastic paraplegia, caused by pathogenic variants in the ATL1 gene. SPG3A typically presents as a “pure” form of HSP, characterized by progressive lower-limb spasticity and weakness beginning in early childhood.

Symptoms most often start before age 10, though onset can range from infancy to adolescence, and rarely adulthood. Affected children may develop toe-walking, gait disturbance, and hyperreflexia. Progression is generally slow, and some individuals may experience mild bladder symptoms or subtle sensory changes.

The ATL1 gene encodes atlastin-1, a protein essential for maintaining endoplasmic reticulum structure and axonal integrity. Dysfunction leads to degeneration of long corticospinal tract axons. SPG3A is inherited in an autosomal dominant manner with high penetrance, and family history is often evident, although symptom severity can vary.

Hereditary spastic paraplegia type 4 (SPG4) is the most common form of hereditary spastic paraplegia, caused by pathogenic variants in the SPAST gene and accounting for approximately 40–50% of all HSP cases. SPG4 typically presents as a “pure” form of HSP, characterized by progressive lower-limb spasticity and weakness leading to a stiff, scissoring gait. Other common features include hyperreflexia, urinary urgency or bladder dysfunction, and mild loss of vibration sense in the feet. Symptom onset is highly variable, ranging from infancy to late adulthood, even within the same family. The SPAST gene encodes spastin, a protein crucial for microtubule severing and axonal transport; dysfunction results in degeneration of long corticospinal tract fibers. SPG4 is inherited in an autosomal dominant manner, with age-dependent and variable penetrance—some carriers may experience mild symptoms or remain asymptomatic.

Spastic paraplegia type 47 (SPG47) is a childhood-onset, complex form of hereditary spastic paraplegia caused by biallelic pathogenic variants in AP4B1, one of the four genes encoding the adaptor protein complex 4 (AP-4). Related conditions include AP4M1 (SPG50), AP4E1 (SPG51), and AP4S1 (SPG52), together referred to as AP-4–associated HSP.

Symptoms typically begin before one year of age. Early signs include hypotonia, developmental delay, mild postnatal microcephaly, and often prolonged febrile seizures in early childhood. Over time, affected children develop progressive spastic paraparesis—seen in nearly all cases—along with moderate to severe intellectual disability and limited speech; many remain nonverbal. Behavioral features such as impulsivity, hyperactivity, and inattention are common.

While some children may walk independently for a short period, most experience progressive loss of mobility and eventually require wheelchairs or other assistive devices.

Spastic paraplegia type 49 (SPG49) is a complex, early-onset form of hereditary spastic paraplegia caused by biallelic pathogenic variants in TECPR2. The condition is also referred to as TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability (TECPR2-HSAN with ID), reflecting its broader neurological and systemic involvement.

Children typically present with global developmental delay progressing to intellectual disability and behavioral abnormalities. Early hypotonia evolves into spasticity and an ataxic gait, accompanied by sensory neuropathy and diminished or absent lower-limb reflexes. Autonomic dysfunction is prominent and may include central hypoventilation and apnea—major contributors to morbidity and mortality—as well as dysphagia, gastroesophageal reflux with aspiration risk, and gastrointestinal dysmotility.

SPG49 is inherited in an autosomal recessive manner and confirmed by identifying biallelic pathogenic or likely pathogenic variants in TECPR2 through molecular genetic testing.

Spastic paraplegia type 5A (SPG5A) is an autosomal recessive form of hereditary spastic paraplegia caused by biallelic pathogenic variants in CYP7B1. The condition displays wide clinical variability, ranging from a pure form with isolated lower-limb spasticity to a complex presentation that may include optic atrophy, cerebellar ataxia, bladder dysfunction, and distal sensory impairment.

Spastic paraplegia type 50 (SPG50) is a childhood-onset, complex form of hereditary spastic paraplegia caused by biallelic pathogenic variants in AP4M1, one of the four genes encoding the adaptor protein complex 4 (AP-4). Together with AP4B1 (SPG47), AP4E1 (SPG51), and AP4S1 (SPG52), it forms the group of AP-4–associated hereditary spastic paraplegias.

Symptoms typically begin before one year of age. Early signs include hypotonia, developmental delay, mild postnatal microcephaly, and sometimes prolonged febrile seizures in early childhood. Over time, affected children develop progressive spastic paraparesis, which is universal, along with moderate to severe intellectual disability and limited or absent speech. Behavioral symptoms such as impulsivity, hyperactivity, and inattention are common.

Although some children may achieve independent walking for a short period, most experience progressive motor decline and eventually require wheelchairs or other mobility aids.

Spastic paraplegia type 51 (SPG51) is a childhood-onset, complex form of hereditary spastic paraplegia caused by biallelic pathogenic variants in AP4E1, one of the four genes encoding the adaptor protein complex 4 (AP-4). Along with AP4B1 (SPG47), AP4M1 (SPG50), and AP4S1 (SPG52), it belongs to the group of AP-4–associated hereditary spastic paraplegias.

Symptoms usually begin before one year of age. Early signs include hypotonia, developmental delay, mild postnatal microcephaly, and occasionally prolonged febrile seizures in early childhood. Over time, affected children develop progressive spastic paraparesis, a universal feature, along with moderate to severe intellectual disability and limited or absent speech. Behavioral challenges such as impulsivity, hyperactivity, and inattention are frequently reported.

Some children may briefly achieve independent walking; however, most experience progressive motor decline and ultimately require wheelchairs or other mobility supports.

Spastic paraplegia type 52 (SPG52) is a childhood-onset, complex form of hereditary spastic paraplegia caused by biallelic pathogenic variants in AP4S1, one of the four genes encoding the adaptor protein complex 4 (AP-4). Together with AP4B1 (SPG47), AP4M1 (SPG50), and AP4E1 (SPG51), it belongs to the group of AP-4–associated hereditary spastic paraplegias.

Symptoms usually begin before one year of age. Early signs include hypotonia, developmental delay, mild postnatal microcephaly, and occasionally prolonged febrile seizures in early childhood. Over time, affected children develop progressive spastic paraparesis, a universal feature, along with moderate to severe intellectual disability and limited or absent speech. Behavioral challenges such as impulsivity, hyperactivity, and inattention are frequently reported.

Some children may briefly achieve independent walking; however, most experience progressive motor decline and ultimately require wheelchairs or other mobility supports.

Spastic paraplegia type 56 (SPG56) is a rare, autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in CYP2U1. It is characterized by early-onset progressive spasticity, most often affecting the lower limbs, with variable involvement of the upper limbs, cognition, and sensory pathways.

Onset typically occurs from birth to early childhood, most often before age three. Early motor signs include delayed walking, toe-walking, and gait instability, progressing to spastic paraparesis with hyperreflexia and extensor plantar responses. Many individuals also exhibit upper-limb spasticity or dystonia, cognitive impairment, and evidence of axonal neuropathy in the lower limbs. Ocular findings may include macular dystrophy or vision loss, which in some cases precedes motor symptoms.

Brain MRI may show periventricular white matter changes with a radial pattern, basal ganglia calcifications, and occasionally a thin corpus callosum or cerebellar atrophy. Disease severity varies widely, even within families. Progressive motor decline is common, and many affected individuals eventually require assistive mobility devices. Diagnosis is confirmed by identifying biallelic pathogenic variants in CYP2U1 through molecular genetic testing.

Spastic paraplegia type 83 (SPG83) is a juvenile-onset, autosomal recessive, predominantly pure form of hereditary spastic paraplegia caused by biallelic pathogenic variants in HPDL. Milder HPDL-associated disease manifests as SPG83, whereas more disruptive variants can lead to a severe neurodevelopmental disorder known as NEDSWMA (neurodevelopmental disorder with spasticity and white matter abnormalities).

Symptoms typically begin in late childhood to adolescence, most often around ages 14–15 (range: 8–17 years). The primary features include progressive lower-limb spasticity, gait instability, hyperreflexia, and extensor plantar responses. Many patients also report muscle cramps, myalgia, and reduced exercise tolerance. The disease course is usually slowly progressive, and loss of independent ambulation is uncommon.

Additional findings can include mild dysarthria, dysphagia, bladder urgency, or upper-limb pyramidal signs; rare cases show mild cognitive delay or subtle ocular movement abnormalities. Brain and spinal MRI are often normal, though nonspecific changes may occasionally be seen.

SPG83 is inherited in an autosomal recessive manner and caused by biallelic HPDL variants. Missense variants are typically associated with the milder SPG83 phenotype, while truncating variants lead to the more severe NEDSWMA. Certain founder variants, such as HPDL p.Gly50Asp (G50D), have been identified in specific populations.

GPT2-related neurodevelopmental disorder with spastic paraplegia and microcephaly (NEDSPM) is a rare, autosomal recessive neurologic condition caused by biallelic pathogenic variants in GPT2. It is characterized by global developmental delay, moderate to profound intellectual disability, markedly limited or absent speech, and progressive lower-limb spasticity leading to gait impairment.

Infants often present with hypotonia that evolves into spastic paraplegia or spastic diplegia over time. Additional common features include postnatal microcephaly, feeding difficulties, drooling, oromotor dysfunction, and poor overall growth. Some individuals also develop seizures. Brain MRI may be normal or reveal a thin corpus callosum, cortical or cerebellar atrophy, or other subtle structural changes. Mild dysmorphic features and behavioral abnormalities have been described.

To date, only a small number of affected individuals have been reported, most from consanguineous families. Diagnosis is confirmed by identifying biallelic pathogenic or likely pathogenic variants in GPT2 through molecular genetic testing.