Mental Retardation, Autosomal Recessive 41

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-41 (MRT41) is caused by homozygous or compound heterozygous mutation in the KPTN gene (615620) on chromosome 19q13.

Clinical Features

Baple et al. (2014) reported 9 individuals from 4 nuclear Anabaptist Amish families from Ohio with autosomal recessive mental retardation. The patients had global developmental delay, mildly delayed walking, high levels of anxiety, stereotyped behavior, and repetitive speech. Dysmorphic features included macrocephaly (+3 to +5.4 SD) with frontal bossing, craniosynostosis, scaphocephaly, broad nasal bridge, hooded eyelids with small, downslanting palpebral fissures, and a prominent chin. Three patients had a seizure disorder, and 6 had childhood hypotonia. Less common features included fifth finger clinodactyly, recurrent pneumonia, and hepatosplenomegaly. Neuroimaging was unremarkable.

Pajusalu et al. (2015) reported 2 adult Estonian sibs with MRT41 apparent since early childhood. Both had normal early development, but presented with speech delay and intellectual disability at school age, resulting in special schooling. The brother had more severe behavioral abnormalities, including anxiety, autistic features, stereotypic movements, and some self-aggression. Both had macrocephaly (+4-4.5 SD), prominent forehead, high palate, and microretrognathia. The brother had a few isolated seizures in childhood, whereas the sister had no seizures. EEG in both patients showed generalized slowing of background activity. As adults, they lived in a special home for the intellectually disabled; they had basic self-care and communication skills.

Inheritance

The transmission pattern in the family with MRT41 reported by Baple et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 affected individuals from 2 consanguineous Amish families with autosomal recessive mental retardation and macrocephaly, Baple et al. (2014) identified a homozygous truncating mutation in the KPTN gene (S259X; 615620.0001). The mutation was found using a combination of homozygosity mapping and whole-exome sequencing. Five affected individuals from 2 additional consanguineous Amish families were compound heterozygous for S259X and an in-frame duplication in the KPTN gene (615620.0002). All 4 families were determined to be distantly related, consistent with 2 founder mutations in this community. Transfection of the mutations into COS-7 cells showed that the mutant proteins did not localize like wildtype proteins to F-actin-rich lamellipodia, but rather accumulated at irregular perinuclear sites, suggesting a loss of normal activity. The truncated protein showed a more pronounced tendency to form such accumulations compared to the duplication mutation. Baple et al. (2014) suggested that the mutations resulted in a loss of KPTN function, which could lead to impairment of the neuronal actin cytoskeleton that is required for dendritic arborization or spine formation during neurogenesis.

In 2 Estonian sibs with MRT41, Pajusalu et al. (2015) identified a homozygous 1-bp duplication (c.665dupA; 615620.0003) in the KPTN gene, predicted to result in a frameshift (Gln222fs). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The findings indicated that the disorder is not restricted to the Amish population.