OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: SPG20

SPG20 mutation

Hereditary spastic paraplegia
Motor neuron disease
Spasticity
Dysarthria

Troyer Syndrome

Clinical Characteristics

General description (for patients):

Troyer syndrome is an early onset and progressive form of lower limb stiffness.  Onset of walking is usually delayed for a year or two (average age 16 months), and from the start is characterized by clumsiness with frequent falls.  At the same time, speech is mildly delayed (average age 17 months) and slurred from the beginning. Drooling also begins in early childhood.  Mentation remains near normal and most are able to complete the eighth grade although school performance is often worse compared with siblings.  A few non-Amish (Mennonites) completed high school and were gainfully employed for short periods.  However, all symptoms progressively worsen and none have been married due to their physical disabilities.  Eventually, by the fifth and sixth decades, all are unable to walk unassisted due to severe stiffness in their legs.  Swallowing is not a severe problem in spite of the slurred speech and drooling.  Mild shortness of stature may be present.

Medical description:

This is an autosomal recessive form of spastic paraplegia that is relentlessly progressive. Developmental milestones such as walking and talking are always mildly delayed.  Drooling and slurred speech are always present from childhood.  Spasticity and hyperreflexia in the lower extremities (and variably in the upper extremities) are found in even the youngest individuals (the youngest examined include a two year old and two aged seven years).  Extensor plantar responses are uniformly noted and most have some cerebellar signs.  Mentation and memory seem grossly normal and there is little or no deterioration.  However, grade school performance is may be mildly subnormal.  There is often a distal amyotrophy most notable in the thenar and hypothenar eminences.  Shortness of stature has been reported and seems to be a common feature.  Sensory modalities are normal but mild cerebellar signs are usually present.   Emotional lability is frequently present. Electromyography in two middle-aged patients was normal.  Nerve conduction studies likewise have been normal.  Brain MRI scans in 5 patients revealed hyperintensity indicative of widespread white matter abnormalities with likely brainstem atrophy.  Lifespan is probably normal.

Genetics:

This is an autosomal recessive complicated form of early-onset, progressive spastic paraplegia. The mutation involves a frameshift mutation via a single bp deletion in the gene SPG20 located on chromosome 13 which encodes the spartin protein.  The intracellular function of spartin is as yet unknown.
Until recently, all known cases of Troyer syndrome have been found among the Amish and virtually all in the Holmes County, OH community.  Two families from a remote region of Oman have now been reported with the clinical features of Troyer syndrome and a novel mutation in the SPG20 gene.  Among 17 children in these two families, 4 males and 2 females with features characteristic of Troyer syndrome were homozygous for a 2bp deletion in SPG20.

Treatment:

There is no known treatment which prevents or delays the symptoms of Troyer syndrome.  Care consists of supportive and custodial measures.

Prognosis:

Troyer syndrome is relentlessly progressive.  Speech often becomes nearly unintelligible and locomotion impossible in the fourth to fifth decades of life.  There may be some dysphagia late in life but none have required percutaneous enterogastostomy.

Ancillary treatments and support:

No data regarding the benefits of physical and speech therapy have been collected but might be beneficial.  Generalized weakness resulting in poor ventilation seems to have been a cause of death in several cases suggesting that good pulmonary hygiene and prompt treatment for respiratory infections are indicated.

Specialists and specialty centers:

Most patients receive excellent care at home and are seldom seen by physicians outside their community.  The largest number has been evaluated by medical personnel in the Windows of Hope project.

References:

Cross, H.E., and McKusick, V.A.:  The Troyer syndrome.  Arch Neurol. 16: 473-485, 1967.  PubMed ID: 6022528

Patel, H., Cross, H., Proukakis, C., Hershberger, R., Bork, P., Ciccarelli, F.D., Patton, M.A., McKusick, V.A., and Crosby, A.H.:  SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.  Nat. Genet. 31: 347-348, 2002.   PubMed ID: 12134148

Proukakis, C., Cross, H., Patel, H., Patton, M.A., Valentine, A., and Crosby, A.H.:  Troyer syndrome revisited.  A clinical and radiological study of a complicated hereditary spastic paraplegia.  J. Neurol. 251: 1105-1110, 2004.  PubMed ID: 15372254

Manzini, M. C., Rajab, A, Maynard, T. M., Mochida, G. H., Tan, W.-H., Naxir, R., Hill, R. S., Gleason, D., Al Saffar, M., Partlow, J. N., Barry, B., J., Vernon, M., LaMantia, A.-S., and Walsh, C. A.  Developmental and degenerative features in a complicated spastic paraplegia.  Ann. Neurol. 67: 516-525, 2009.  PubMed ID: 20437587

Resources:

National Institute of Neurological Disease
Spastic Paraplegia Foundation