Mental Retardation, Autosomal Dominant 9

A number sign (#) is used with this entry because of evidence that this form of mental retardation is caused by heterozygous mutation in the KIF1A gene (601255) on chromosome 2q37.

Clinical Features

Hamdan et al. (2011) hypothesized that de novo mutations in synaptic genes explain an important fraction of sporadic nonsyndromic intellectual disability (NSID) cases. They sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. They identified a single patient with a de novo mutation in the KIF1A gene. The patient was a female 3 years and 5 months of age with severe mental retardation, no evidence of epilepsy, axial hypotonia with peripheral spasticity, and mild atrophy of the vermian region of the cerebellum on brain MRI.

Lee et al. (2015) reported 14 patients, including a pair of monozygotic twins, with MRD9. The patients had mild to severe global developmental delay and intellectual disability. Additional variable features included delayed language, optic nerve atrophy, microcephaly, seizures, progressive spastic paraparesis, peripheral neuropathy, and cerebral and/or cerebellar atrophy. There was a wide range in the severity of the disorder: 2 patients had severe hypotonia and died in early childhood, whereas others were able to walk independently and had mild speech delay in the teenage years.

Esmaeeli Nieh et al. (2015) reported 6 unrelated patients with MRD9. The patients had onset of severe developmental delay in the first months of life. Additional features included hypotonia, variable degrees of hyperreflexia and spasticity, microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, and movement disorders, such as athetoid movements. Two patients had seizures. The patients had a severe neurodegenerative encephalopathy with progressive cerebral and cerebellar atrophy, thus expanding the phenotype associated with de novo KIF1A mutations.

Molecular Genetics

In a patient with nonsyndromic intellectual disability, Hamdan et al. (2011) identified a de novo C-to-T transition at nucleotide 296 of the KIF1A gene resulting in a threonine-to-methionine substitution at codon 99 (T99M; 601255.0004). The mutation was not identified in 285 control samples. The threonine at position 99 lies in the highly conserved P loop consensus ATP-binding site of the KIF1A motor domain. Hamdan et al. (2011) transfected primary rat hippocampal neurons with different KIF1A MD-EGFP fusion constructs and showed that those carrying the T99M mutation showed greatly reduced distal localization and increased accumulation throughout the cell body and proximal neurites, as opposed to the wildtype accumulation in distal regions of neurites.

In 14 patients, including a pair of monozygotic twins, with MRD9, Lee et al. (2015) identified 11 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0004, 601255.0006-601255.0008). The mutations in 12 families were found by exome sequencing; the mutation in 1 family was found by targeted next-generation sequencing. All the mutations occurred at conserved residues in the motor domain. In vitro functional expression studies of 5 of the mutations in rat hippocampal cells showed that they resulted in greatly reduced distal localization in neurites compared to wildtype. Lee et al. (2015) hypothesized that, since KIF1A functions as an active dimer, heterozygous missense mutations may exert a dominant-negative effect, which may explain the severe phenotype.

In 6 unrelated patients with MRD9, Esmaeeli Nieh et al. (2015) identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0004, 601255.0007, 601255.0009-601255.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. All mutations occurred at conserved residues in the motor domain, and in vitro functional microtubule gliding assays of several of the mutations showed that they resulted in a loss of motility with evidence for a dominant-negative effect.