Clinical characteristics.

Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, short stature, and subtle skeletal abnormalities. Most affected children exhibit delays in walking and speech and difficulty in managing oral secretions, followed by increased lower-limb spasticity and slow deterioration in both gait and speech. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. Emotional lability / difficulty in controlling emotions and affective disorders such as inappropriate euphoria and/or crying are frequently described. Life expectancy is normal.

Diagnosis/testing.

The diagnosis of Troyer syndrome is established in a proband with characteristic clinical findings and/or biallelic pathogenic variants in SPART identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy and nutritional support; developmental and educational support; antispasticity drugs; daily physical therapy; occupational therapy, assistive walking devices, and ankle-foot orthoses as needed; speech-language therapy to improve or maintain speech and swallowing; communication devices as needed; medication to reduce drooling as needed; antidepressant or mood stabilizer medication for individuals with emotional lability; treatment of skeletal manifestations per orthopedist; development of care plan for transition to adulthood; family and social work support.

Surveillance: At each visit assess growth, feeding, nutrition, developmental progress, educational needs, and family needs; cognitive testing as indicated; neurologic evaluation every six to 12 months or as needed; psychiatric/psychological assessment as indicated; annual assessment of orthopedic manifestations.

Agents/circumstances to avoid: Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.

Genetic counseling.

Troyer syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SPART pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SPART pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for Troyer syndrome are possible.

Suggestive Findings

Troyer syndrome should be suspected in probands with the following clinical and imaging findings and family history.

Clinical findings

• Developmental delay in early infancy / childhood: poor feeding, swallowing difficulties, delayed speech, delayed walking
• Childhood-onset spastic paraplegia
• Symmetric amyotrophy of the small muscles of hands and feet
• Progressive dysarthria and persistent drooling
• Learning difficulties
• Emotional lability
• Short stature

Additional clinical findings

• At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape
• Pyramidal signs: hyperreflexia, extensor plantar responses
• Extrapyramidal signs: mild choreoathetoid movements
• Cerebellar signs: dysdiadochokinesia, mild intention tremor, ataxia
• Skeletal abnormalities: pes cavus, pes planus, mild talipes equinovarus, kyphoscoliosis, pectus carinatum

Imaging findings on brain MRI. White matter abnormalities, particularly in the temporoparietal periventricular area, may be present.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of Troyer syndrome is established in a proband with characteristic clinical findings and/or biallelic pathogenic (or likely pathogenic) variants in SPART identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SPART variants of uncertain significance (or of one known SPART pathogenic variant and one SPART variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Troyer syndrome is characterized by both developmental and neurodegenerative processes. Symptoms are usually apparent in early childhood and progress slowly. The cardinal features of Troyer syndrome include global developmental delay, spastic paraparesis, distal amyotrophy, dysarthria, persistent drooling, learning difficulties, emotional lability, and skeletal manifestations including short stature [Liang et al 2020]. While Troyer syndrome was originally identified in the Old Order Amish population in Ohio, United States, with 21 individuals from this community comprising the largest clinical cohort thus reported [Proukakis et al 2004], it has since been reported in many other populations [Manzini et al 2010, Tawamie et al 2015, Butler et al 2016, Bizzari et al 2017, Dardour et al 2017, Spiegel et al 2017, Diquigiovanni et al 2019, Khoshaeen et al 2020, Liang et al 2020, Gürçay et al 2021, Bryson et al 2022, Alotaibi et al 2023].

Onset. There is limited information regarding prenatal presentation of Troyer syndrome; however, reduced third trimester fetal growth, shortening of the long bones, and relative macrocephaly has been described [Bryson et al 2022]. Clinical features that may be recognized from birth in affected Amish individuals, where the condition occurs at an increased frequency, include low birth weight, relative macrocephaly, triangular face shape, and poor feeding, reminiscent of Silver-Russell syndrome. Neurologic features become more apparent in early childhood and progress slowly. At early stages of the condition the predominant features may be restricted to poor growth and global developmental delay / intellectual disability [Diquigiovanni et al 2019, Liang et al 2020, Bryson et al 2022].

Delay in early developmental milestones. In the Old Order Amish, the presenting feature in most individuals is a delay in reaching early gross motor and speech-language milestones (walking and talking) [Proukakis et al 2004]. Twenty of the 21 individuals in this population were delayed in walking compared to their unaffected sibs (age range: 12-22 months; mean age: 16.1 months). The age at which they started talking ranged from seven to 36 months; mean age was 17.5 months. In those whose milestones were not noticeably delayed, the character of the gait and/or speech was the first abnormality reported.

Neurologic features. Troyer syndrome leads to gait ataxia and progressive spastic paraparesis that typically develops during childhood. Lower-limb distal tendon reflexes are increased. Distal weakness, when present, is mild and disproportionate to the observed spasticity. Distal amyotrophy occurs in more than 90% of affected individuals [Liang et al 2020]. In the description of 21 Ohio Amish individuals with Troyer syndrome, most affected individuals had mild weakness of the abductor pollicis brevis, abductor digiti minimi, and palmar and dorsal interossei. More proximal upper-limb strength was preserved. The most severely affected individuals had choreoathetoid movements (i.e., an irregular, constant succession of slow, spasmodic writhing with involuntary flexion, extension, pronation, and supination) of the fingers and hands, and sometimes the toes and feet. Difficulty with walking increased with age; affected individuals generally became wheelchair bound during the sixth to seventh decade of life [Proukakis et al 2004].

Progressive spastic dysarthria has been reported with brisk jaw jerk, often accompanied by slow, spastic tongue movements. Excessive drooling is commonly observed in childhood and persists into adulthood in the most severely affected individuals [Liang et al 2020].

Microcephaly and macrocephaly have both been reported [Patel et al 2002, Proukakis et al 2004, Manzini et al 2010, Tawamie et al 2015, Butler et al 2016, Dardour et al 2017, Spiegel et al 2017].

Learning difficulties were reported in all but one affected individual of Amish descent [Proukakis et al 2004] and in 56/63 individuals reported up to 2019 [Liang et al 2020]. Most of the affected Amish individuals were able to complete eighth grade, the traditional end point of Amish education. In all but one individual, school performance was significantly worse than that of unaffected sibs. Most affected individuals had persistent cognitive deficits. Two individuals completed high school and worked for several years.

Emotional lability and affective disorders including inappropriate euphoria and/or crying are common [Proukakis et al 2004, Tawamie et al 2015, Liang et al 2020].

Skeletal abnormalities described in individuals with Troyer syndrome include the following:

• Short stature when compared to parents and/or sibs [Proukakis et al 2004]. In one fetus, short long bones and growth restriction were identified by prenatal ultrasound in the third trimester; earlier scans were reportedly normal [Bryson et al 2022].
• Overgrowth of the maxilla leading to overbite (5/6 individuals) [Manzini et al 2010]
• Small feet with pes cavus (17/21 individuals) [Proukakis et al 2004] or pes planus; mild talipes equinovarus
• "Hammer toes" in the most severely affected individuals [Proukakis et al 2004]
• Hyperextensible proximal interphalangeal joints of the fingers (8/21) [Proukakis et al 2004], hyperextensible knees [Gürçay et al 2021]
• Brachydactyly (5/6 individuals), clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges [Manzini et al 2010]
• Mild knee valgus (4/21) [Proukakis et al 2004]
• Mild kyphoscoliosis has been reported but radiographic correlation was not available [Proukakis et al 2004].
• Pectus carinatum [Liang et al 2020, Bryson et al 2022]
• Delayed bone age [Diquigiovanni et al 2019, Liang et al 2020]

Life expectancy is normal.

Neuroimaging. Although neuroimaging can be normal, white-matter hyperintensities, typically in posterior periventricular regions, have been identified on T₂-weighted images in 13 individuals [Proukakis et al 2004, Manzini et al 2010, Bizzari et al 2017, Dardour et al 2017, Liang et al 2020, Alotaibi et al 2023], with increased T₂/FLAIR signal within the ventrolateral thalami and posterior limb of the internal capsule reported in one individual [Butler et al 2016]. The white-matter abnormalities described are not specific to Troyer syndrome and can be present in other forms of hereditary spastic paraplegia.

Nerve conduction studies performed in two individuals who were not severely affected were normal in the right upper and lower limb. In one of these individuals, electromyography (EMG) was normal bilaterally except for a polyphasic potential in the medial head of the gastrocnemius on one side. In the other individual, EMG of the right upper and lower limb was normal [Proukakis et al 2004]. A further affected individual was reported to have a normal EMG [Gürçay et al 2021].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been observed.

Prevalence

A previous study documented 21 individuals with Troyer syndrome in a population of approximately 50,000 Old Order Amish in Ohio [Patel et al 2002]. To date, the c.1110delA variant has not been observed outside of the Old Order Amish population.

Troyer syndrome has now been reported in several additional individuals worldwide. A recurrent variant was identified in affected individuals from Omani, Turkish, and Filipino families (see Table 6) [Manzini et al 2010, Tawamie et al 2015, Butler et al 2016].

The estimated worldwide prevalence is less than one in 10,000,000 [Liang et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with Troyer syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No specific treatment to prevent or reverse the neurologic degeneration in Troyer syndrome currently exists. Treatments are directed at reducing symptoms, maintaining mobility, and improving balance, strength, and agility. Individuals should be evaluated periodically (annually or as needed) by a neurologist, physiatrist, occupational therapist, and speech-language therapist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms. See also Uncomplicated Hereditary Spastic Paraplegia Overview.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Troyer syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a SPART pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a SPART pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a SPART pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with Troyer syndrome are obligate heterozygotes (carriers) for a pathogenic variant in SPART.

Other family members. Each sib of the proband's parents is at 50% risk of being a carrier of a SPART pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SPART pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of affected individuals and established carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in the Amish and Mennonite population with Ohio ancestry; a recurrent variant has been identified in Omani, Turkish, and Filipino families (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Once the SPART pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for Troyer syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SPART is widely expressed in adult and fetal human tissues. It encodes a 666-amino acid protein named spartin (spastic paraplegia autosomal recessive Troyer syndrome). Spartin possesses an MIT domain (contained within microtubule-interacting and trafficking molecules) [Ciccarelli et al 2003], as does spastin, which is encoded by SPAST, the most commonly mutated gene in hereditary spastic paraplegia (HSP), accounting for approximately 40% of autosomal dominant HSP [Hazan et al 1999] (see Spastic Paraplegia Type 4). The identification of the same domain in spastin and spartin suggests related functionality of these proteins.

Spartin has been shown to localize to endosomes and lipid droplets, with recent studies confirming it has a critical role in the turnover of both lipid droplets (lipophagy) and damaged lysosomes (lisophagy) [Chung et al 2023, Gahlot et al 2024].

Mechanism of disease causation. The pathogenic basis of Troyer syndrome is currently unclear. Troyer syndrome is most likely caused by loss of function of spartin.

Author Notes

Further information on our work with the Amish and Mennonite communities can be found at Windows of Hope Project.

Prof Andrew Crosby, Prof Emma Baple, and Dr Jacob Day are actively involved in clinical research regarding individuals with hereditary spastic paraplegia (HSP). They would be happy to communicate with persons who have any questions regarding diagnosis of HSP, Troyer syndrome, or other considerations.

Prof Andrew Crosby, Prof Emma Baple, and Dr Jacob Day are also interested in hearing from clinicians treating families affected by HSP in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Acknowledgments

The authors would like to thank the patients and their families as well as the collaborators who have been involved in describing Troyer syndrome. We would also like to thank Dr Olivia Wenger, Dr Ethan Scott, staff at the New Leaf Center Clinic for Special Children, Mount Eaton, staff at the Centre for Special Children, La Farge, and the Amish and Mennonite communities for their support of our work on this condition.

Author History

Emma Baple, MBBS, MRCPCH, PhD (2019-present)
Andrew Crosby, PhD (2004-present)
Jacob Day, MRCP, BM BCh, BA (2025-present)
Gaurav Harlalka, MRes; University of London (2011-2019)
Allison Newman, MSci (2025-present)
Heema Patel, PhD; University of London (2004-2019)

Revision History

• 14 August 2025 (sw) Comprehensive update posted live
• 6 June 2019 (sw) Comprehensive update posted live
• 4 August 2011 (me) Comprehensive update posted live
• 16 November 2004 (me) Review posted live
• 11 August 2004 (ac) Original submission

Literature Cited

• Alotaibi MA, Almutairi HA, Alsharkawy AA. A SPART missense mutation causes Troyer syndrome in two siblings. MGM J Med Sci. 2023;10:352-4.
• Bizzari S, Hamzeh AR, Nair P, Mohamed M, Saif F, Aithala G, Al-Ali MT, Bastaki F. Novel SPG20 mutation in an extended family with Troyer syndrome. Metab Brain Dis. 2017;32:2155-9. [PubMed: 28875386]
• Bryson L, Anderson L, Pagan J, Hamzollari R, Hamilton MJ. The perinatal phenotype of Troyer syndrome: case report and literature review. Am J Med Genet A. 2022;188:3558-62. [PubMed: 36135318]
• Butler S, Helbig KL, Alcaraz W, Seaver LH, Hsieh DT, Rohena L. Three cases of Troyer syndrome in two families of Filipino descent. Am J Med Genet A. 2016;170:1780–5. [PubMed: 27112432]
• Chung J, Park J, Lai ZW, Lambert TJ, Richards RC, Zhang J, Walther TC, Farese RV Jr. The Troyer syndrome protein spartin mediates selective autophagy of lipid droplets. Nat Cell Biol. 2023;25:1101-10. [PMC free article: PMC10415183] [PubMed: 37443287]
• Ciccarelli FD, Proukakis C, Patel H, Cross H, Azam S, Patton MA, Bork P, Crosby AH. The identification of a conserved domain in both spartin and spastin, mutated in hereditary spastic paraplegia. Genomics. 2003;81:437–41. [PubMed: 12676568]
• Dardour L, Roelens F, Race V, Souche E, Holvoet M, Devriendt K. SPG20 mutation in three siblings with familial hereditary spastic paraplegia. Cold Spring Harb Mol Case Stud. 2017;3. [PMC free article: PMC5495031] [PubMed: 28679690]
• Diquigiovanni C, Bergamini C, Diaz R, Liparulo I, Bianco F, Masin L, Baldassarro VA, Rizzardi N, Tranchina A, Buscherini F, Wischmeijer A, Pippucci T, Scarano E, Cordelli DM, Fato R, Seri M, Paracchini S, Bonora E. A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism. FASEB J. 2019;33:11284-302. [PubMed: 31314595]
• Fink JK. Advances in hereditary spastic paraplegias. Exp Neurol. 2003;184:S106–10. [PubMed: 14597333]
• Gahlot P, Kravic B, Rota G, van den Boom J, Levantovsky S, Schulze N, Maspero E, Polo S, Behrends C, Meyer H. Lysosomal damage sensing and lysophagy initiation by SPG20-ITCH. Mol Cell. 2024;84:1556-69.e10. [PubMed: 38503285]
• Gürçay E, Ayçiçek HB, Karaahmet ÖZ, Korkmaz N, Yaşar E. An unusual case with genetic transition in a rehabilitation clinic: Troyer syndrome. Turk J Phys Med Rehabil. 2021;67:264-5. [PMC free article: PMC8343149] [PubMed: 34396080]
• Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Durr A, Wincker P, Brottier P, Cattolico L, Barbe V, Burgunder JM, Prud'homme JF, Brice A, Fontaine B, Heilig B, Weissenbach J. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet. 1999;23:296–303. [PubMed: 10610178]
• Khoshaeen A, Najafi M, Mahdavi MR, Jalali H, Mahdavi M. A novel missense mutation (c.1006C>T) of SPG20 gene associated with Troyer syndrome. J Genet. 2020;99:55. [PubMed: 32661208]
• Liang H, Miao H, Yang H, Gong F, Chen S, Wang L, Zhu H, Pan H. Dwarfism in Troyer syndrome: a family with SPG20 compound heterozygous mutations and a literature review. Ann N Y Acad Sci. 2020;1462:118-27. [PubMed: 31535723]
• Manzini MC, Rajab A, Maynard TM, Mochida GH, Tan W, Nasir R, Hill RS, Gleason D, Al Saffar M, Partlow JN, Barry BJ, Vernon M, LaMantia A, Walsh CA. Developmental and degenerative features in a complicated spastic paraplegia. Ann Neurol. 2010;67:516–25. [PMC free article: PMC3027847] [PubMed: 20437587]
• Murala S, Nagarajan E, Bollu PC. Hereditary spastic paraplegia. Neurol Sci. 2021;42:883-894. [PubMed: 33439395]
• Patel H, Cross H, Proukakis C, Hershberger R, Bork P, Ciccarelli FD, Patton MA, McKusick VA, Crosby AH. SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia. Nat Genet. 2002;31:347–8. [PubMed: 12134148]
• Proukakis C, Cross H, Patel H, Patton MA, Valentine A, Crosby AH. Troyer syndrome revisited. A clinical and radiological study of a complicated hereditary spastic paraplegia. J Neurol. 2004;251:1105–10. [PubMed: 15372254]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Spiegel R, Soiferman D, Shaag A, Shalev S, Elpeleg O, Saada A. Novel homozygous missense mutation in SPG20 gene results in Troyer syndrome associated with mitochondrial cytochrome c oxidase deficiency. JIMD Rep. 2017;33:55–60. [PMC free article: PMC5413448] [PubMed: 27539578]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Tawamie H, Wohlleber E, Uebe S, Schmäl C, Nöthen MM, Abou Jamra R. Recurrent null mutation in SPG20 leads to Troyer syndrome. Mol Cell Probes. 2015;29:315–8. [PubMed: 26003402]