Spastic Paraplegia 51, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-51 (SPG51) is caused by homozygous disruption in the AP4E1 gene (607244) on chromosome 15q21.

Description

Spastic paraplegia-51 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by Moreno-De-Luca et al., 2011).

Clinical Features

Moreno-De-Luca et al. (2011) reported a consanguineous Palestinian Jordanian family in which 2 sibs had spastic quadriplegia. Both sibs presented at birth with microcephaly and hypotonia, followed by delayed psychomotor development. The sister was more severely affected, developing spastic tetraplegia and hyperreflexia by the first year of life, and seizures at age 5. She never developed language or independent walking. At age 23 years, she was profoundly impaired and showed dysmorphic facial features. Brain MRI showed enlarged ventricles, cortical and cerebellar atrophy, and diffuse white matter loss. Her brother was similarly but less severely affected. He had delayed psychomotor development, learned a few words, could walk with support until age 9, and developed seizures at age 15. At age 22, he had spastic tetraplegia, nystagmus, and dysmorphic facial features.

Abou Jamra et al. (2011) reported a consanguineous Syrian family (MR071) in which 2 individuals had a phenotype consistent with SPG51. They presented with hypotonia in the neonatal period that later progressed to muscular hypertonia, especially of the lower limbs. Physical examination showed contractures, talipes equinovarus, decreased muscle mass of the shanks, short stature, and microcephaly. Both had severe mental retardation and absent speech, as well as dysmorphic prominent and bulbous nose, a wide mouth, and coarse features. One patient had seizures. Both had a shy, amicable, and calm character, and smiled or laughed for no obvious reason, but there were no bursts of laughter.

Molecular Genetics

In 2 sibs, born of consanguineous Palestinian Jordanian parents, with spastic quadriplegia, Moreno-De-Luca et al. (2011) identified a homozygous 192-kb deletion on chromosome 15q21.2 (chr15: 48,835,480-49,028,171, NCBI36) that included the 5-prime end of the AP4E1 gene (607244) and the 5-prime end of the SPPL2A gene (608238). Noting that mutation in the AP4M1 gene (602296), which forms a complex with AP4E1, causes a similar phenotype (SPG50; 612936), Moreno-De-Luca et al. (2011) concluded that disruption of the AP4E1 gene was responsible for the phenotype in their family, although they could not exclude a possible role for disruption of the SPPL2A gene. The authors proposed the designation 'AP4 deficiency syndrome' to refer to disorders caused by disruption of any of the 4 subunits of the AP4 complex.

By linkage analysis followed by candidate gene sequencing in a consanguineous Syrian family with mental retardation and spasticity, Abou Jamra et al. (2011) identified a homozygous truncating mutation in the AP4E1 gene (607244.0002). The authors concluded that AP4-complex-mediated vesicular trafficking plays a crucial role in brain development and function.

By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian; less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a frameshift mutation in the APE4E1 gene (607244.0003) in 3 affected members of a consanguineous family segregating SPG51.