De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance

Abstract

Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.

Multigeneration family with dominant SPG30 hereditary spastic paraplegia

“…Intriguingly, most of these cases differ substantially from typical presentations of patients with heterozygous missense mutations in the motor domain, as these patients typically have a far more severe phenotype with prominent cognitive impairment and other associated neurologic findings 3, 4, 5, 16. Perhaps, the fact that Ser69 is not invariant and occurs within a small segment of the motor domain that appears relatively divergent (Fig.…”

“…Patients presenting with cognitive impairment often exhibit a relatively severe phenotype with a range of additional symptoms including optic atrophy, cerebellar ataxia, and neuropathy; they frequently carry heterozygous missense mutations in the motor domain, suggestive of a dominant‐negative pathogenic mode of action 3, 4, 5. Several different families presenting with neuropathy alone, characterized by common features of profound sensory loss and ulcero‐mutilation, have harbored recessive truncating mutations in the alternatively spliced exon 25b 6…”

The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation

“…Mutations in KIF1A have been associated with the motoneuron disease hereditary spastic paraplegia subtype 30 (SPG30; Erlich et al, 2011; Klebe et al, 2012; Citterio et al, 2015; Lee et al, 2015; Ylikallio et al, 2015), hereditary and sensory autonomic neuropathy type 2 (HSAN2; Rivière et al, 2011), and non-syndromic intellectual disability (ID; Hamdan et al, 2011). Autosomal recessive (Rivière et al, 2011) and autosomal dominant forms of inheritance (Citterio et al, 2015; Ylikallio et al, 2015) as well as heterozygous de novo mutations (Hamdan et al, 2011; Esmaeeli Nieh et al, 2015; Lee et al, 2015; Ohba et al, 2015; Hotchkiss et al, 2016) have been implicated in KIF1A -associated human diseases, suggesting loss-of-function, toxic gain-of-function or dominant negative modes of impairment.…”

The KIF1A homolog Unc-104 is important for spontaneous release, postsynaptic density maturation and perisynaptic scaffold organization

“…While truncation of KIF1A has been associated with another neurological disease HSAN2C14, various mutations of KIF1A have been associated with SPG30 as well as non-syndromic intellectual disability accompanied by variable additional symptoms including progressive encephalopathy and brain atrophy916175354. Recently, an amino acid exchange (S69L), proposed to be important for the ATP binding of KIF1A, has been shown to underlie SPG3010.…”

“…These diseases primarily affect nerve cells that have long axons and are thus most dependent on efficient cargo transport, consistent with kinesin-3’s important role for long-range intracellular trafficking. Apart from these symptoms in the peripheral nervous system, HSAN2C related mutations in KIF1A were also described to affect the central nervous system causing mental retardation and brain atrophy91617. While unc-104 ’s mammalian homolog KIF1A is important in facilitating synaptogenesis in an experience dependent manner18, Unc-104 has been proposed to be part of the molecular machinery that regulates activity-dependent feedback in Drosophila photoreceptors19.…”