Troyer syndrome, also known as spastic paraplegia type 3, is a rare genetic disorder characterized by progressive muscle stiffness (spasticity) and muscle weakness in the legs. The exact cause of Troyer syndrome is a mutation in the SPG20 gene.
What is Troyer syndrome?
Troyer syndrome belongs to a group of disorders called hereditary spastic paraplegias (HSPs). HSPs are a diverse group of genetic disorders that share the primary feature of progressive stiffness and contraction (spasticity) in the leg muscles. This leads to difficulties with walking due to stiffness, muscle weakness, and poor coordination.
In Troyer syndrome, symptoms begin in early childhood, usually between ages 1 and 4 years. The leg stiffness is progressive, meaning it worsens over time. Most people with Troyer syndrome will eventually require a wheelchair for mobility due to the severe leg spasticity.
In addition to leg spasticity, people with Troyer syndrome may experience:
- Muscle wasting (atrophy) in the lower legs
- Exaggerated reflexes in the legs
- Toe walking
- Scissoring gait (legs crossing over each other while walking due to spasticity)
- Speech difficulties (spastic-sounding speech)
A small subset of people with Troyer syndrome also develop mild intellectual disability and behavioral problems such as obsessive-compulsive tendencies. Seizures have also been reported in a few cases.
What causes Troyer syndrome?
Troyer syndrome is caused by mutations in the SPG20 gene. The SPG20 gene provides instructions for producing an enzyme called spartin. Spartin plays an important role in normal neuron (nerve cell) function and cellular trafficking processes.
Different mutations in the SPG20 gene can disrupt the production or function of spartin. When spartin is defective, neurons and other cells do not work properly, leading to the signs and symptoms of Troyer syndrome.
SPG20 gene
The SPG20 gene is located on the short arm of chromosome 13 (13q13.3). It contains 17 exons which code for the spartin protein.
At least 15 different mutations in SPG20 have been identified in people diagnosed with Troyer syndrome. These include:
- Nonsense mutations – Premature stop codons lead to a shortened, incomplete spartin protein
- Missense mutations – Single base pair substitutions alter the amino acid sequence of spartin
- Splice site mutations – Disruptions at splice junction sites lead to abnormally spliced spartin mRNA
- Frameshift mutations – Small deletions or insertions disrupt the spartin reading frame
All of these mutation types prevent cells from producing normal full-length spartin, leading to loss of protein function.
Spartin protein
The spartin protein encoded by SPG20 contains several important domains:
- MIT domain – Binds and interacts with lipid membranes
- Plant-related senescence domain – Unknown function but may regulate protein-protein interactions
- Microtubule interacting and trafficking (MIT) domain – Facilitates binding to microtubules and intracellular trafficking
- Src homology 3 (SH3) domain – Mediates protein-protein interactions
Research suggests spartin plays a role in several important cellular processes:
- Lipid droplet turnover
- Mitochondrial function and trafficking
- Microtubule dynamics and stability
- Membrane trafficking and protein sorting
- Autophagy
Through these critical functions, spartin helps maintain the normal health and function of neurons. When mutated, spartin can no longer perform these roles properly, leading to neuronal dysfunction.
Inheritance of Troyer syndrome
Troyer syndrome follows an autosomal recessive inheritance pattern. This means that a child must inherit two copies of the defective SPG20 gene to develop the disorder – one from each parent, who are known as carriers. The parents of an individual with Troyer syndrome each carry one copy of the mutated gene but do not show signs and symptoms themselves.
When two carrier parents have a child, the chance of the child inheriting two mutated genes and developing Troyer syndrome is 25% or 1 in 4. The chance of the child inheriting one faulty gene and becoming a carrier themselves is 50%. And the chance the child will inherit two normal genes is also 25%.
Autosomal recessive inheritance pattern:
| Normal gene | Mutated gene | |
|---|---|---|
| Parent 1 | X | X |
| Parent 2 | X | X |
| Child’s genotype | ||
| Unaffected | XX | 25% chance |
| Carrier | XX | 50% chance |
| Affected | XX | 25% chance |
Because Troyer syndrome is so rare, most cases arise when both parents are carriers of a SPG20 mutation. However, in populations where Troyer syndrome is more common, it can also occur when only one parent is a carrier.
Prevalence of Troyer syndrome
Troyer syndrome is considered very rare, though the exact prevalence is unknown. Since its initial description in 1967, approximately 50 cases have been reported worldwide.
Troyer syndrome appears to be most common in the Amish community. This founder effect originated from a shared mutation in an Amish couple several generations ago. Due to limited genetic variation in this closed community, the mutation was passed down through many descendants, leading to a higher prevalence of Troyer syndrome among the Amish.
Outside of the Amish population, Troyer syndrome cases are scattered around the world without any particular geographic concentration. It has been diagnosed in individuals of various ethnic backgrounds with no apparent links to one another.
Diagnosis of Troyer syndrome
Diagnosing Troyer syndrome involves clinical evaluation of symptoms along with genetic testing to identify a causative SPG20 mutation. The main specialties involved in diagnosis are neurology, medical genetics, and developmental pediatrics.
Clinical diagnosis is suspected based on the presentation of early-onset spastic paraplegia. The combination of lower limb spasticity, muscle weakness, brisk reflexes, and toe walking beginning in early childhood is highly suggestive of Troyer syndrome.
Other HSPs share overlapping symptoms, so genetic testing is necessary to confirm a diagnosis. This involves sequencing of the SPG20 gene to look for disease-causing mutations. Identification of two pathogenic SPG20 mutations confirms a diagnosis of Troyer syndrome.
Prenatal genetic testing and carrier testing for at-risk relatives are also possible for families with a known Troyer syndrome mutation.
Diagnostic criteria:
Both of the following:
- Early-onset lower limb spasticity and weakness
- Identification of two pathogenic mutations in SPG20
Plus two or more of the following:
- Toe walking
- Scissoring gait
- Exaggerated lower limb reflexes
- Lower limb muscle atrophy
- Speech and language deficits
- Cognitive impairment and/or behavior abnormalities (subset only)
Treatment and management of Troyer syndrome
There is currently no cure for Troyer syndrome. Treatment aims to manage symptoms and improve quality of life. The main therapies used include:
- Physical therapy – Stretching and exercises to improve mobility, prevent contractures, and retain muscle strength. Augmentative devices like ankle-foot orthoses can help.
- Occupational therapy – Adaptive techniques and tools to maximize independence in daily activities.
- Speech therapy – For those with speech/language deficits. Focuses on improving communication skills.
- Medications – Oral baclofen, diazepam, or other antispasmodic drugs to reduce spasticity. Botulinum toxin injections can also temporarily reduce muscle stiffness.
- Orthopedic surgery – Tendon lengthening, orthopedic procedures to correct bone/joint deformities caused by spasticity.
Supportive treatments also include assistive devices like walkers, braces, or wheelchairs for mobility. Care is coordinated by a neurologist and a multidisciplinary spasticity management team. Lifespan is normal, but progressive disability makes supportive care important.
Prognosis of Troyer syndrome
The long-term prognosis for individuals with Troyer syndrome relates closely to the degree of mobility impairment:
- Milder cases may walk with assistive devices throughout adulthood.
- Moderate cases often require a wheelchair for long distances by adolescence/early adulthood.
- Severe cases may rely on a wheelchair full-time by mid-childhood.
Life expectancy is normal, so the focus is optimizing comfort and independence. With supportive care, most individuals with Troyer syndrome have a good quality of life within the limitations of their mobility disability.
Ongoing research
Active research is underway to better understand Troyer syndrome and develop treatments. Key areas include:
- Animal models – Studying mice with a SPG20 mutation helps clarify spartin’s role in neuron function and HSP pathology.
- Neuroimaging – MRI and PET scans of those affected reveal patterns of neurodegeneration and spinal cord damage.
- Natural history studies – Collecting data on the progression of Troyer syndrome in larger groups over time.
- Gene therapy – Investigating techniques to replace or silence mutant SPG20 to restore spartin function.
- Drug therapies – Testing novel antispasmodic medications and other compounds that may improve mobility.
A better understanding of Troyer syndrome will pave the way for future treatments. Involved organizations like the Spastic Paraplegia Foundation and Troyer Syndrome Foundation support this important research.
Conclusion
Troyer syndrome is a rare HSP caused by mutations in the SPG20 gene, leading to defective spartin protein. Impaired neuron function produces progressive lower limb spasticity, muscle weakness, and mobility disability. While no cure exists, supportive therapies can improve quality of life. Ongoing research offers hope for those affected by this complex neurological disorder.