Kruer et al. (2013) reported 4 sibs, born of consanguineous Jordanian parents, with a neurodevelopmental disorder characterized by variable spasticity and cognit...
Kruer et al. (2013) reported 4 sibs, born of consanguineous Jordanian parents, with a neurodevelopmental disorder characterized by variable spasticity and cognitive impairment. Three patients developed severe spastic quadriplegia in the first months or years of life. All had cognitive impairment and poor speech. One patient developed seizures by age 2 that responded to medication. One patient was slightly less severely affected, with spastic diplegia and borderline intellectual function at age 7 years. All 4 patients had borderline microcephaly. More variable features included pyramidal signs, dysarthria, dysphagia, exotropia, supranuclear gaze palsy, strabismus, and nystagmus. One of the patients was dependent for all activities of daily living at age 16 years. Brain imaging was abnormal in all 4 patients: all had some T2-weighted hyperintensities, and the patient with seizures also had gray matter heterotopia. Three patients also had transient conjugated hyperbilirubinemia during illness, which was attributed to a homozygous S1342Y mutation in the ABCC2 gene (601107), resulting in Dubin-Johnson syndrome (DJS; 237500).
The transmission pattern of CPSQ3 in the family reported by Kruer et al. (2013) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 4 sibs, born of consanguineous Jordanian parents, with CPSQ3, Kruer et al. (2013) identified a homozygous missense mutation in the ADD3 gene (G367D; 601568.0001) that was responsible for the neurologic phenotype. 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. Lysates from patient fibroblasts showed a significant increase in actin polymerization compared to controls, consistent with impaired actin capping activity and a loss of function. Compared to controls, mutant fibroblast showed a lack of neurite-like processes and increased proliferation and migration. The mutation also impaired the ability of mutant ADD3 to associate with the ADD1 (102680) subunit. Overall, the biologic studies implicated abnormalities of components of the dynamic cytoskeleton and process outgrowth in neuromotor dysfunction.
▼ Animal Model
Kruer et al. (2013) found that knockdown of the Add3 homolog in Drosophila resulted in lesions in the brain lamina and medulla, as well as impaired locomotion, consistent with a role in normal neuromotor function.