Spastic Paraplegia 20, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-20, also known as Troyer syndrome, is caused by homozygous mutation in the SPG20 gene, encoding spartin (607111), on chromosome 13q13. SPG20 is a form of complicated SPG.

For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).

Clinical Features

In an Amish group in Ohio, Cross and McKusick (1967) observed 20 cases of spastic paraplegia with distal muscle wasting, and designated it Troyer syndrome for the surname of many of the affected persons. The disorder has its onset in early childhood with dysarthria, distal muscle wasting, and difficulty in learning to walk. Lower limb spasticity and contractures usually make walking impossible by the third or fourth decade. Drooling and mild cerebellar signs occur in some. All have weakness and atrophy of thenar, hypothenar, and dorsal interosseous muscles.

Bakowska et al. (2008) reported an Amish brother and sister from Ohio with Troyer syndrome. Both showed delayed motor and cognitive development and developed a progressive deterioration in gait and speech during childhood. Physical exam showed short stature, spastic dysarthria, mild pyramidal weakness in the lower extremities, distal amyotrophy, and hyperreflexia of the lower limbs. Skeletal examination in both sibs was notable for kyphoscoliosis, loss of teeth, pes cavus, small feet, and hyperextensible joints of the hands. The brother had severe pectus excavatum. Gait was wide-based and spastic; the brother ambulated with difficulty and required assistance, whereas the sister was wheelchair-bound. Both had occasional inappropriate euphoria or crying, consistent with emotional lability.

Manzini et al. (2010) reported a large Omani kindred with SPG20. All affected individuals presented with short stature and dysarthria, and showed delayed motor and cognitive development. The main features included spastic gait, hyperreflexia, and dysmetria of the upper limbs. Other findings included hypertelorism, overgrowth of the maxilla, brachydactyly, clinodactyly, camptodactyly, pes cavus, tightening of the heel cords, hammer toes, and ankle clonus. Brain MRI showed atrophy of the cerebellar vermis, mild white matter volume loss, and periventricular white matter changes suggestive of gliosis. Although the patients were young, there appeared to be progression of the disorder.

Tawamie et al. (2015) reported 2 sibs, born of consanguineous Turkish parents, with complicated spastic paraplegia. The patients were 26 and 17 years of age at the time of the report. The older sister had delayed psychomotor development in infancy. At age 5 years, she had overall growth retardation, generalized hypotonia, and joint hypermobility. As a teenager and young adult, she had muscle weakness and atrophy of the upper extremities, hoarse voice, high-arched feet, and hyperreflexia of the lower limbs. Skeletal abnormalities included low-set dysmorphic thumbs and clinodactyly with mild skeletal abnormalities of the hand. She developed psychiatric disturbances, including anxiety, panic attacks, hallucinations, psychosis, and suicidal ideation; her IQ was 46. Her brother had developmental delay, overall growth retardation, hypotonia with muscle atrophy, hyperextensible joints, ataxic gait, and slurred speech. Both patients had mild dysmorphic features, including prominent nose, raised nostrils, epicanthus, downslanting palpebral fissures, and low-set ears.

Butler et al. (2016) reported 2 sisters and an unrelated boy, all of Filipino descent, with SPG20. The patients had short stature, failure to thrive with poor overall growth and small head circumference, and mildly delayed development with variable learning difficulties and speech delay. All had an unsteady unbalanced gait, but only the sisters showed frank spasticity and inturned ankles. Additional features included mild proximal weakness, distal amyotrophy, dystonic posturing of the hands, and ankle contractures, as well as dysarthria and oromotor dysfunction. Dysmorphic features were mild, but included microcephaly, frontal bossing, flat midface, narrow mandible, upturned nostrils, and posterior rotation of the ears. All patients attended school; 2 were in special needs classes.

Inheritance

The transmission pattern of SPG20 in the families reported by Bakowska et al. (2008) was consistent with autosomal recessive inheritance.

Mapping

Patel et al. (2002) excluded 5 loci for autosomal recessive hereditary spastic paraplegia by linkage analysis and, using homozygosity mapping, mapped the Troyer syndrome gene to a 731-kb interval of chromosome 13q12.3. All affected individuals were homozygous for this segment. A maximum location score of 19.6 was obtained between markers D13S1841 and D13S1842.

Molecular Genetics

Patel et al. (2002) identified a frameshift mutation (1110delA; 607111.0001) in the SPG20 gene in individuals with Troyer syndrome from the Amish kindred in which the disorder was first described.

Bakowska et al. (2008) identified the 1110delA mutation in 2 Amish sibs with Troyer syndrome. Studies on patient fibroblasts and lymphoblasts showed spartin mRNA transcripts, but no translated protein, consistent with complete loss of function.

In affected members of a large Omani kindred with SPG20, Manzini et al. (2010) identified a homozygous truncating mutation in the SPG20 gene (364_365delAT; 607111.0002).

In 2 sibs, born of consanguineous Turkish parents, with SPG20, Tawamie et al. (2015) identified homozygosity for the same truncating mutation in the SPG20 gene (607111.0002) that had been identified in Omani patients by Manzini et al. (2010). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies and studies of patient cells were not performed. Haplotype analysis indicated that the mutation occurred independently from that in the Omani patients reported by Manzini et al. (2010).

In 3 patients of Filipino descent, including 2 sisters, Butler et al. (2016) also identified homozygosity for the previously reported c.364_365delAT frameshift mutation (607111.0002) in the SPG20 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed, but the occurrence of the same mutation in 3 families of different ethnicities confirmed the pathogenicity.

Associations Pending Confirmation

For discussion of a possible role of the GRID2 gene in the Troyer syndrome phenotype, see 602368.