Troyer Syndrome

Clinical Diagnosis

The clinical features of Troyer syndrome:

• Age at first symptoms: 1-2 years

• Early symptoms: Delayed walking, delayed speech, dysarthria

• Pyramidal signs: Spasticity, 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 both sides equally affected

• Skeletal abnormalities: Pes cavus, mild talipes equinovarus, short stature, kyphoscoliosis

• Progression of disease: Variable

• Brain MRIs (performed in three affected individuals): White matter abnormalities, particularly in the temporoparietal periventricular area

• Life expectancy: Slightly reduced

Molecular Genetic Testing

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Gene. SPG20, which encodes the protein spartin, is the only gene known to be associated with Troyer syndrome.

Molecular genetic testing: Clinical uses

• Diagnostic testing

• Predictive testing

Molecular genetic testing: Clinical method

• Mutations are detected by direct sequencing of exons. Only one pathogenic mutation has been identified to date. The 1110delA mutation in exon 4 of the SPG20 gene was identified as the causative mutation in an extended Old Order Amish pedigree [Patel et al 2002].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Troyer Syndrome

Test Method	Mutations Detected	Mutation Detection Rate		Test Availability
		Amish	Other Populations
Direct sequencing	1110delA	100%	Unknown	Clinical
	Other sequence variations in SPG20

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related Disorders

No other phenotypes are known to be associated with mutations in SPG20.

Natural History

Troyer syndrome appears to involve both developmental and degenerative processes, as symptoms are apparent from infancy and the disorder displays very slow progression. 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, have been examined, including three from the original study by Cross and McKusick (1967).

The presenting feature in most individuals studied was a delay in reaching early milestones (walking and talking) compared to unaffected sibs. Twenty out of the 21 individuals studied (95%) were delayed in walking (range 12 to 22 months; mean 16.1 months). The age at which they started talking ranged from seven to 36 months, with a mean of 17.5 months. In those whose milestones were not noticeably delayed, the character of the walking 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. Jaw jerk was brisk in over half, often accompanied by slow, spastic tongue movements. 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. Individuals were mobile and able to walk, although with more difficulty as age increased. Affected individuals generally become wheelchair-bound during their 6th-7th decade of life.

Excessive drooling was observed in the most advanced cases. Mild cerebellar signs were common. The most severely affected individuals had choreoathetoid movements (i.e., an irregular, constant succession of slow, spasmodic, writhing, involuntary flexion, extension, pronation, and supination of the fingers and hands, and sometimes the toes and feet).

Learning difficulties were reported in all but one person. Most were able to complete 8th grade, which is the traditional limit of Amish education. In all but one case, school performance was significantly worse than that of unaffected sibs. Two individuals managed to finish high school and work for several years.

Emotional lability and affective disorders such as inappropriate euphoria and/or crying were common.

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.

In addition to the neurological features, mild skeletal abnormalities were present in all individuals. Short stature in all individuals was apparent relative to parents and/or sibs. Other features included small feet with pes cavus (17/21 individuals) and "hammer toes" in the most severely affected individuals, hyperextensible proximal interphalangeal joints of the fingers (8/21), and mild knee valgus (4/21). Mild kyphoscoliosis was present in some; radiographic correlation was not available.

Genotype-Phenotype Correlations

Since the same mutation occurs in all affected individuals in the Old Order Amish population reported to date, genotype-phenotype correlations are not possible.

Penetrance

Penetrance is complete.

Prevalence

Twenty-one individuals with Troyer syndrome have been identified in a population of approximately 9,000 Amish [Patel et al 2002]. Carrier frequency is about 7.5% in this community [Cross & McKusick 1967]. Several similar cases have been reported around the world; however, some clinical features differ from those in the original description of Troyer syndrome [Neuhauser et al 1976, Farag et al 1994, Malandrini et al 1996, Farah et al 1997, Bertini et al 1998, Auer-Grumbach et al 1999]. To date no SPG20 mutations have been reported outside the Amish population.

Treatment of Manifestations

• Antispasticity drugs. See Hereditary Spastic Paraplegia Overview.

• Antidepressent medication for individuals with emotional lability

Prevention of Secondary Complications

• Good nursing care and physiotherapy during disease progression and monitoring for dysphagia to reduce risk of aspiration

Therapies Under Investigation

Search ClinicalTrials.gov for access to 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 and therefore carry one mutant allele.

• Heterozygotes (carriers) are unaffected.

Sibs of a proband

• At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are unaffected.

Offspring of a proband. While the effect of homozygous SPG20 mutations on fertility is not known, no individual with Troyer syndrome is known to have had children [Patel and Crosby, personal observation].

Other family members of a proband. Sibs of the proband's parents are at 50% risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is available once the mutations have been identified in the proband.

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 testing is before pregnancy.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation* or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

* Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Molecular Genetic Pathogenesis

The pathogenic basis of Troyer syndrome is currently unclear.

Normal allelic variants: SPG20 resides within 731kb and is composed of nine exons. Two polymorphisms have been identified: A543A in a family of European descent and K377M in a non-Amish Caucasian control sample.

Pathologic allelic variants: Only one pathogenic mutation has been identified to date. The 1110delA mutation in exon 4 of the SPG20 gene was identified as the causative mutation in an extended Old Order Amish pedigree [Patel et al 2002].

Normal 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 the most commonly mutated gene in hereditary spastic paraplegia, accounting for approximately 40% of autosomal dominant cases [Hazan et al 1999] (see Hereditary Spastic Paraplegia, Spastic Type). The identification of the same domain in spastin and spartin suggests that the functionality of these proteins is related.

Abnormal gene product: The disease appears to be fully penetrant and is most likely caused by a loss of function of spartin, as would be expected with a recessive disorder.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.