DiagnosisClinical DiagnosisThe clinical features of Troyer syndrome include the following:Age at first symptoms: one to two years Early onset: delayed walking, delayed speech, dysarthria Pyramidal signs: spasticity (i.e., hypertonia in which resistance to externally imposed movement increases with increasing speed of stretch and varies with the direction of joint movement); hyperreflexia; extensor plantar responses Extrapyramidal signs: mild choreoathetoid movements Cortical signs: emotional lability Cerebellar signs: dysdiadochokinesia, mild intention tremor Amyotrophy: small muscles of hands and feet with symmetric involvement Skeletal abnormalities: pes cavus, mild talipes equinovarus, short stature, kyphoscoliosis Progression of disease: variable Brain MRI (performed in 3 affected individuals): white matter abnormalities, particularly in the temporoparietal periventricular area Life expectancy: normalMolecular Genetic TestingGene. SPG20, which encodes the protein spartin, is the only gene in which mutations are known to cause Troyer syndrome. Table 1. Summary of Molecular Genetic Testing Used in Troyer SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityAmish OmaniOther Populations SPG20Sequence analysisSequence variants 2, 3100% for c.1110delA 4100% for c.364_365delAT 5UnknownClinicalTargeted mutation analysisc.1110delA; c.364_365delATUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Includes the c.1110delA and c.364_365delAT mutation that may also be identified by targeted mutation analysis4. The causative mutation in an extended Old Order Amish pedigree [Patel et al 2002] 5. The causative mutation in two related Omani families [Manzini et al 2010] Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Testing Strategy To confirm/establish the diagnosis in a proband. In individuals with clinical findings consistent with Troyer syndrome and a family history consistent with autosomal recessive inheritance:1.Targeted mutation analysis for the SPG20 mutations:a.c.1110delA in individuals of Old Order Amish heritageb.c.364_365delAT in individuals of Omani heritage 2.If the mutations are not detected, sequence analysis of all SPG20 exons including intron-exon splice sites.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.}

Natural HistoryTroyer syndrome is characterized by both developmental and degenerative processes: findings apparent from infancy progress slowly. The cardinal features of Troyer syndrome include spastic paraparesis, dysarthria, distal amyotrophy, and short stature [Proukakis et al 2004]. Twenty-one individuals with Troyer syndrome in an Old Order Amish population in Ohio, USA including three from the original study by Cross & McKusick [1967] [Patel et al 2002] and six individuals in two related Omani families [Manzini et al 2010] have been reported. In the Old Order Amish, the presenting feature in most individuals was a delay in reaching early milestones (walking and talking) compared to unaffected sibs. Twenty of the 21 individuals were delayed in walking (age range 12 to 22 months; mean age 16.1 months). The age at which they started talking ranged from seven to 36 months, with a mean age of 17.5 months. In those whose milestones were not noticeably delayed, the character of the gait and/or speech was the first abnormality reported. Slow deterioration in both gait and speech was observed: spastic paraparesis with lower limb hyperreflexia and spastic dysarthria were present in all, severity being greater in older individuals compared to younger ones. Jaw jerk was brisk in the majority, often accompanied by slow, spastic tongue movements. Excessive drooling was observed in the most advanced cases. Distal amyotrophy was found in all individuals over age 13 years and also in one seven-year-old child. In the more severely affected, generally older, individuals, weakness of the small hand muscles was observed. Most individuals had mild weakness of the abductor pollicis brevis, abductor digiti minimi, and palmar and dorsal interossei. More proximal upper limb strength was preserved in all cases; lower limb weakness when present was mild and disproportionate to the observed spasticity. 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. Learning difficulties were reported in all but one person. Most were able to complete eighth grade, the traditional limit of Amish education. In all but one case, school performance was significantly worse than that of unaffected sibs. Two individuals completed high school and work for several years. Emotional lability and affective disorders including inappropriate euphoria and/or crying were common. Mild skeletal abnormalities included the following:Short stature in all individuals when compared to parents and/or sibs Small feet with pes cavus (17/21 individuals) “Hammer toes" in the most severely affected individuals Hyperextensible proximal interphalangeal joints of the fingers (8/21) Mild knee valgus (4/21)Mild kyphoscoliosis: present in some; radiographic correlation not available In the two related Omani families, all affected individuals had dysarthria and delays in motor and cognitive development. All had difficulties walking with a clumsy, mildly spastic gait, reported to worsen over time. The most common physical features were short stature; relative hypertelorism; overgrowth of the maxilla leading to overbite; and hand and foot anomalies including brachydactyly (5/6 individuals), hammer toes, and pes cavus. Additional nonspecific hand findings were clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges. Most affected individuals had persistent cognitive deficits and poor performance in school; emotional lability was not reported.The mean age of individuals in the Omani families (16.6 years) was younger than in the Old Order Amish individuals. To evaluate the natural history, the Amish cohort was divided into a younger set (Amish I) comparable in age to the Omani cohort (<27 years; mean age 15 years) and an older set (Amish II; >28 years; mean age, 43.5 years). The findings in the Omani cohort closely matched those of Amish I group. The Amish II group was more severely affected, consistent with the progressive nature of Troyer syndrome. Additional studies in the Old Order Amish families: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. White matter abnormalities have been noted on brain MRI imaging [Proukakis et al 2004].

Genotype-Phenotype CorrelationsNo phenotype genotype phenotype correlations have been observed.

Differential DiagnosisSee Hereditary Spastic Paraplegia Overview for a review. Troyer syndrome shares some features with ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay); however, nystagmus, abnormalities of ocular movement, and mitral valve prolapse are not features of Troyer syndrome.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Troyer syndrome, the following evaluations are recommended:Height Occipitofrontal circumference (OFC)Speech and language development with attention to possible dysarthria and tongue dyspraxia Gross motor and fine motor skills Neurologic examination with attention to evidence of pyramidal and/or extrapyramidal movement disorders, distal amyotrophy, hyperreflexia School performance Emotional status, including presence or absence of emotional lability Skeletal abnormalities and skeletal x-rays as needed Brain MRI EMG Treatment of ManifestationsTreatment for spasticity is presently limited to reducing muscle spasticity through exercise and medication, especially Lioresal^®, which is given either orally or via intrathecal pump. Dosages need to be individualized as some patients have mainly weakness with less spasticity (and thus do not benefit from large doses), while others have significant spasticity and require high doses. Tizanidine, dantrolene (see, however, Agents/Circumstances to Avoid), and Botox^® have also been useful in reducing muscle spasticity.It is recommended that affected individuals participate in daily physical therapy designed to:Maintain and improve muscle flexibility and range of motion (stretching exercises); Improve muscle strength (through resistance exercise); Maintain walking reflexes (walking on a slowly moving treadmill with arm supports or walking in a swimming pool); andImprove cardiovascular fitness. These recommendations are based on the experience of approximately 200 persons with hereditary spastic paraplegia, who nearly unanimously reported benefit from daily physical exercise [Fink 2003].Occupational therapy, assistive walking devices, and ankle-foot orthotics as needed are appropriate.Oxybutynin is helpful in reducing urinary urgency.Antidepressants or mood stabilizers can be prescribed to manage emotional lability.See also Hereditary Spastic Paraplegia Overview. Prevention of Secondary ComplicationsProvide good nursing care and physiotherapy during disease progression; monitor for dysphagia to reduce risk of aspiration.SurveillanceThe following are appropriate:Specialized outpatient evaluations every six months to update medications and physical rehabilitationCognitive testingRepeat skeletal surveyAgents/Circumstances to AvoidDantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Troyer Syndrome: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSPG20SPG2013q13​.3SpartinHSP mutation database
SPG20 homepage - Mendelian genesSPG20Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Troyer Syndrome (View All in OMIM) View in own window 275900SPASTIC PARAPLEGIA 20, AUTOSOMAL RECESSIVE; SPG20 607111SPG20 GENE; SPG20Molecular Genetic PathogenesisThe pathogenic basis of Troyer syndrome is currently unclear.Normal allelic variants. SPG20 resides within 731 kb and comprises nine exons. Multiple alternatively spliced variants, encoding the same protein, have been identified. Two normal benign variants have been identified (Table 2): c.1629A>G in a family of European descent and c.1130A>T in a non-Amish control of European descent. Pathologic allelic variants. Only two pathogenic SPG20 mutations have been identified to date: c.1110delA in exon 4 in an extended Old Order Amish pedigree [Patel et al 2002] and c.364_365delAT in exon 1 in two related Omani families [Manzini et al 2010].Table 2. Selected SPG20 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias ¹)Reference SequencesNormal c.1629A>Gp.AlaA543AlaNM_015087​.4
NP_055902​.1 c.1130A>Tp.Lys377MetPathologicc.1110delAp.Lys370Asnfs*30
(fs369-398X399)c.364_365delATp.Met122Valfs*2 (M122V_C123X)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. SPG20 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 a 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, accounting for approximately 40% of autosomal dominant cases [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, a cytosolic and membrane-associated protein that interacts with EPS15, an endocytic and trafficking protein, may have a number of roles, including functioning at endosomes and in droplet formation [Bakowska et al 2005]. SPG20 associates with the surface of lipid droplets (LDs), regulating their size and number. SPG20 binds to another LD protein, TIP47; both proteins compete with an additional LD protein, adipophilin/adipocyte differentiation-related protein. Spartin may also be involved in endocytosis and vesicle trafficking [Bakowska et al 2005].Abnormal gene product. Troyer syndrome is most likely caused by loss of function of spartin, as would be expected with an autosomal recessive disorder. A full explanation for the disease will require an understanding of the normal functions of spartin and the relevance of each function to axonal biology [Edwards et al 2009].