Spastic Paraplegia 54, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-54 (SPG54) is caused by homozygous or compound heterozygous mutation in the DDHD2 gene (615003) on chromosome 8p11.

Description

Spastic paraplegia-54 is a complicated form of spastic paraplegia, a neurodegenerative disorder affecting fibers of the corticospinal tract. Affected individuals have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions. Brain magnetic resonance spectroscopy shows an abnormal lipid peak (summary by Schuurs-Hoeijmakers et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.

Clinical Features

Schuurs-Hoeijmakers et al. (2012) reported 2 unrelated families in which 2 sibs in each family had early-onset spastic paraplegia and intellectual disability. Subsequently, a large Omani family and an unrelated Iranian patient with a similar disorder were ascertained. The phenotype among all 4 families was relatively homogeneous. Affected individuals showed delayed psychomotor development that evolved into mental retardation, and early onset of progressive spasticity before age 2 years. Other features included foot contractures, dysarthria, dysphagia, and strabismus. Three of 5 patients examined had optic hypoplasia. Brain imaging showed thin corpus callosum and subtle periventricular white matter hyperintensities. Five individuals from 3 families showed an abnormal lipid peak on magnetic resonance spectroscopy (MRS) of cerebral tissue, with the highest intensity around the basal ganglia and thalamus. This peak was similar to that observed in Sjogren-Larssen syndrome (SLS; 270200) and is indicative of abnormal brain lipid accumulation. Two unrelated males had a syrinx on spinal MRI.

Gonzalez et al. (2013) identified 2 unrelated families with SPG54 among a cohort of 79 probands with autosomal recessive SPG who underwent exome sequencing. The first family contained 2 affected sibs, born of consanguineous Iranian parents. Both sibs developed a spastic gait disorder in early childhood, but were still able to walk unsupported at ages 19 and 25 years. Both had mental retardation requiring special schooling, as well as short stature, high-arched palate, and dysgenesis of the corpus callosum on brain imaging. The second family was of Indian origin with no known consanguinity, but the parents originated from the same village and were part of the Muslim community. These brothers developed spasticity of the lower limbs in the first year of life. They also had mental retardation, short stature, and thin corpus callosum. One had dysmorphic features, with telecanthus and slanted palpebral fissures. The phenotype in these patients was similar to that reported by Schuurs-Hoeijmakers et al. (2012).

Novarino et al. (2014) identified 2 additional, consanguineous families with SPG54. In 1 family (family 1314), 4 individuals presented with tiptoe walking between 15 and 18 months of age. All developed spasticity and dysarthria, and all had mild to moderate intellectual disability. When last examined, the oldest patient (23 years of age) was nonambulatory, whereas the other 3 (aged 2 to 20 years) could walk unsupported. In the other family (family 1675), 3 sibs presented in early infancy. When last examined, all 3 (aged 7 to 10 years) displayed spasticity, dysarthria, abnormal gait, strabismus, periventricular leukomalacia, high lipid peak on brain MRI, and moderate intellectual disability. All could walk unsupported with abnormal gait.

Inheritance

The transmission pattern of SPG54 in the families reported by Schuurs-Hoeijmakers et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By exome sequencing in 2 unrelated families with a complex form of autosomal recessive spastic paraplegia, Schuurs-Hoeijmakers et al. (2012) identified biallelic mutations in the DDHD2 gene (615003.0001-615003.0004). The mutations segregated with the phenotype in both families. Different homozygous mutations in the DDHD2 gene were found in affected individuals from a large Omani family with a similar disorder, originally reported as family A by Al-Yahyaee et al. (2006), an in an unrelated Iranian patient (see 615003.0005 and 615003.0006). Knockdown of the Drosophila ortholog resulted in a reduction of the number of active zones at the synaptic terminal, suggesting that the DDHD2 gene plays a role in synaptic function. The DDHD2 gene was found to be highly expressed in various human brain regions.

In affected members of 2 unrelated families with SPG54, Gonzalez et al. (2013) identified homozygous truncating mutations in the DDHD2 gene (615003.0006 and 615003.0007). The 2 families were identified from a larger cohort of 79 probands with autosomal recessive SPG who underwent exome sequencing.

In affected members of 2 consanguineous families with SPG54, Novarino et al. (2014) identified homozygous mutations in the DDHD2 gene: a previously identified nonsense mutation (615003.0006) and a splice site mutation (615003.0008).