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 an individual with characteristic clinical findings. Identification of biallelic pathogenic variants in SPART confirms the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Antispasticity drugs; daily physical therapy; occupational therapy, assistive walking devices, and ankle-foot orthotics as needed; antidepressant or mood stabilizer medication for individuals with emotional lability.

Surveillance: Neurologic and developmental/cognitive assessments; monitoring for dysphagia to reduce the risk of aspiration.

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. At conception, each sib of an affected individual has 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants have been identified in an affected family member.

Suggestive Findings

Troyer syndrome should be suspected in individuals with the following findings:

Clinical features

• Childhood-onset spastic paraplegia
• Dysarthria
• Persistent drooling
• Symmetric amyotrophy of the small muscles of hands and feet
• Short stature
• Emotional lability

Additional clinical features

• At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape, poor feeding
• Early infancy / childhood: delayed walking, delayed speech, swallowing difficulties
• Pyramidal signs: hyperreflexia, extensor plantar responses
• Extrapyramidal signs: mild choreoathetoid movements
• Cerebellar signs: dysdiadochokinesia, mild intention tremor
• Skeletal abnormalities: pes cavus, mild talipes equinovarus, kyphoscoliosis
• Mild to moderate intellectual disability

Imaging features on brain MRI. White matter abnormalities, particularly in the temporoparietal periventricular area (3/3 affected individuals)

Establishing the Diagnosis

The diagnosis of Troyer syndrome is established in a proband with childhood-onset spastic paraplegia, distal amyotrophy, short stature, and/or biallelic pathogenic variants in SPART identified by molecular genetic testing (see Table 1).

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) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Troyer syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Troyer syndrome has not been considered are more likely to be diagnosed using genomic testing (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 developmental delay, spastic paraparesis, dysarthria, distal amyotrophy, and short stature. To date, 36 individuals with Troyer syndrome have been reported, including 21 individuals from an Old Order Amish population in Ohio, USA [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].

Onset. Clinical features that may be recognized from birth in the Amish, where the condition occurs at an increased frequency, include low birth weight, relative macrocephaly, triangular face shape, and poor feeding. Neurologic features become more apparent in early childhood and progress slowly.

Early developmental milestones. In the Old Order Amish, Proukakis et al [2004] reported that the presenting feature in most individuals was a delay in reaching early gross motor and speech and language milestones (walking and talking) compared to unaffected sibs. Twenty of the 21 individuals were delayed in walking (age range 12-22 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.

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 was found in all individuals older than age 13 years and also in one child age seven years reported by Proukakis et al [2004]. 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 is 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.

Progressive spastic dysarthria is 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.

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. Most 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 [Proukakis et al 2004].

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

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

• Short stature when compared to parents and/or sibs [Proukakis et al 2004]
• 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]
• "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]
• 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]

Life expectancy is normal.

Neuroimaging. White-matter hyperintensities described include periventricular white-matter hyperintensity on T₂-weighted images reported in eight individuals [Proukakis et al 2004, Manzini et al 2010, Dardour et al 2017] and 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed.

Prevalence

The prevalence is unknown. A previous study documented 21 individuals with Troyer syndrome in a population of approximately 50,000 Amish [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.

Evaluations Following Initial Diagnosis

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

• Growth assessment including height, weight, and head circumference
• Consultation with a neurologist and examination to identify features of Troyer syndrome with attention to evidence of pyramidal and/or extrapyramidal movement disorders, distal amyotrophy, hyperreflexia, swallowing difficulties
• Developmental assessment with attention to gross motor and fine motor skills, as well as speech and language development, looking for possible dysarthria and tongue dyspraxia
• Psychological assessment, with attention to presence or absence of emotional lability
• Physical examination for skeletal abnormalities and x-ray examination for kyphoscoliosis as needed
• Consultation with a clinical geneticist and/or genetic counselor

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 and language therapist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms.

• Daily physical therapy regimen directed toward maintaining and improving cardiovascular health, muscle strength, and gait and reducing spasticity. 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 required
• Speech and language therapy to improve/maintain speech and swallowing, and communication devices as required
• Medication to reduce drooling may be helpful.
• Medications to reduce muscle spasticity (e.g., Lioresal^® [oral or intrathecal]). Dosages need to be individualized as some individuals have weakness with less spasticity (and thus do not benefit from large doses), while others have significant spasticity and require high doses. Tizanidine, dantrolene (see Agents/Circumstances to Avoid), and botulinum A and B toxin injections (Botox^®, Dysport^®, Xeomin^®, or Myobloc^®) have also been useful in reducing muscle spasticity.
• Medications to reduce urinary urgency (e.g., oxybutynin, solifenacin, mirabegron, intrabladder injections with Botox^®)
• Antidepressants or mood stabilizers to manage emotional lability

See also Hereditary Spastic Paraplegia Overview.

Surveillance

The following are appropriate:

• Evaluation with a neurologist every six to 12 months (or as required depending on age and severity) to review symptoms, assess need for multidisciplinary input, and update medications
• Monitor for dysphagia to reduce risk of aspiration
• Psychiatric/psychological assessment as indicated
• Developmental assessment / cognitive testing as indicated depending on age and severity
• 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.

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 information on clinical studies for a wide range of diseases and conditions.

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 obligate heterozygotes (i.e., carriers of one SPART pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, the sibs of an affected individual have 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. To date, individuals with Troyer syndrome are not known to reproduce [Patel & Crosby, personal observation].

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, clarification of carrier status, 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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the SPART pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The pathogenic basis of Troyer syndrome is currently unclear.

Gene structure. SPART (formerly SPG20) resides within 731 kb and comprises nine exons. Multiple alternatively spliced variants, encoding the same protein, have been identified; the longest transcript is NM_015087.5. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Four pathogenic SPART variants have been identified to date: c.1110delA in exon 4 in an extended Old Order Amish pedigree [Patel et al 2002], a recurrent homozygous 2-nucleotide deletion c.364_365delAT p.(Met122ValfsTer2) in Omani, Turkish, and Filipino families [Manzini et al 2010, Tawamie et al 2015, Butler et al 2016], a homozygous nonsense variant c.1369C>T (p.Arg457Ter) in a Moroccan family [Dardour et al 2017], and a homozygous 1-nucleotide substitution c.988A>G (p.Met330Val) in an Israeli-Arab child [Spiegel et al 2017].

Normal gene product. SPART (formerly 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].

Author History

Emma Baple, MBBS, MRCPCH, PhD (2019-present)
Andrew Crosby, PhD (2004-present)
Gaurav Harlalka, MRes; University of London (2011-2019)
Heema Patel, PhD; University of London (2004-2019)

Revision History

• 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

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