Arthrogryposis, Mental Retardation, And Seizures

A number sign (#) is used with this entry because of evidence that arthrogryposis, mental retardation, and seizures (AMRS) is caused by compound heterozygous mutation in the SLC35A3 gene (605632) on chromosome 1p21. One such family has been reported.

Clinical Features

Edvardson et al. (2013) reported a large kindred of Ashkenazi Jewish descent in which 8 individuals had arthrogryposis, mental retardation, autism spectrum disorder, and epilepsy. Limb malformations were detected in utero at midgestation, but all 8 were born at term. At birth, knee and hip dislocation with dysplasia of the acetabuli and flexion contractures of the fingers were seen. Although involvement of the large joints varied, all patients had distal joint involvement, with mild flexion contractures of the fingers, deviation of the distal phalanges, and swan-neck deformity. The severity of the contractures did not change over time, and no bone dysplasia was observed on radiographs. Other common features included microcephaly, retromicrognathia, and general muscle hypotonia. The patients had delayed psychomotor development followed by mild to moderate mental retardation and autistic features. Six patients developed localization-related or atypical absence seizures between 3 and 11 years of age. Brain MRI in 2 patients was normal. Studies of the serum N-glycome were similar to controls, but the cellular N-glycome of cultured fibroblasts showed a severe reduction of tetraantennary N-glycans in patient cells with an increase in bi- and triantennary N-glycans that were not present in control cells. The product of the MGAT5 gene (601774) was missing. These features indicated a marked shortage of UDP-GlCNAc in the Golgi of patient cells.

Inheritance

The transmission pattern of AMRS in the family reported by Edvardson et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 individuals from an Ashkenazi Jewish family with arthrogryposis, mental retardation, and seizures, Edvardson et al. (2013) identified compound heterozygous mutations in the SLC35A3 gene (605632.0001-605632.0002). The mutations were found by linkage analysis combined with whole-exome sequencing and segregated with the disorder in the family. Patient cells showed no normal transcript, indicating that they had no functional SLC35A3 protein. Golgi vesicles derived from patient fibroblasts showed significantly reduced transport of UDP-GlCNAc compared to controls. Edvardson et al. (2013) noted that some of the skeletal features in these patients resembled the complex vertebral malformation (CVM) manifest in cattle with Slc35a3 mutations.