Spastic Paraplegia And Psychomotor Retardation With Or Without Seizures

A number sign (#) is used with this entry because of evidence that spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is caused by homozygous or compound heterozygous mutation in the HACE1 gene (610876) on chromosome 6q16.3.

Description

Spastic paraplegia and psychomotor retardation with or without seizures is an autosomal recessive complex neurodevelopmental disorder with onset in infancy. Affected children show hypotonia followed by severely impaired global development and significant motor disability. Most develop seizures in childhood and have speech delay. Other features, such as ocular abnormalities, foot deformities, hypoplasia of the corpus callosum, and decreased white matter, are more variable (summary by Hollstein et al., 2015).

Clinical Features

Hollstein et al. (2015) reported 8 individuals from 2 unrelated families with a complex neurodevelopmental disorder. The patients ranged in age from 3 to 22 years. One family was consanguineous and from Pakistan, whereas the other was of German descent and contained 3 affected sibs. All patients showed hypotonia at birth followed by delayed psychomotor development and slowly progressive lower limb spasticity and/or ataxia resulting in significantly impaired mobility: 3 used a wheelchair or were bedridden, 2 were mobile over short distances, and the 3 German sibs had an unstable waddling gait. Five patients had seizures, most commonly myoclonic seizures. Other more variable features included ocular abnormalities, such as strabismus, myopia, and retinal dystrophy, dysarthria, and dystonic posturing. Three patients had sensorineural hearing loss. Brain imaging showed cerebral atrophy in 3 patients and hypoplastic corpus callosum in 2 others. Some patients had skeletal abnormalities, including kyphosis, scoliosis, hip dislocation, and foot deformities. Patients in the Pakistani family had a large head circumference at birth and hypoplastic genitalia in most males; in addition, the patients were overweight and doubly incontinent.

Akawi et al. (2015) reported 6 patients from 4 unrelated families with SPPRS. Three of the families were consanguineous. All patients had severely delayed psychomotor development with significant speech delay; only 1 patient was able to walk independently. The neuromuscular phenotype included truncal hypotonia and mixed spastic and dystonic tetraparesis. Brain imaging showed decreased white matter and delayed myelination in 2 patients, and hypoplasia of the corpus callosum in 2 other patients. Four patients had seizures, 4 were obese, 3 had short stature, and 2 had microcephaly. Mild facial dysmorphic features, such as hypertelorism, deep-set eyes, and downturned corners of the mouth, were observed in some patients, although there was no consistent pattern of abnormalities.

Inheritance

The transmission pattern of SPPRS in the families reported by Hollstein et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 2 unrelated families with SPPRS, Hollstein et al. (2015) identified biallelic truncating mutations in the HACE1 gene (610876.0001-610876.0003). The mutations, which were found either by autozygosity mapping and candidate gene analysis or by exome sequencing, segregated with the disorder in the families. The mutations were predicted to result in truncated proteins lacking part or all of the catalytic domain. Patient cells from 1 family showed no detectable HACE1 protein using antibodies, suggesting that the mutations resulted in a truncated protein or in nonsense-mediated mRNA decay. These findings were consistent with a loss of function.

In 6 patients from 4 unrelated families with SPPRS, Akawi et al. (2015) identified homozygous or compound heterozygous mutations in the HACE1 gene (610876.0004-610876.0008). The mutations, which were found by exome sequencing, segregated with the disorder in the families. One mutation resulted in the deletion of a conserved residue, and the others were predicted to result in a truncated protein. The patients were part of a very large study of 4,125 families with a variety of severe developmental disorders who underwent exome analysis.