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

Heterozygous mutation in the KIF1A gene can also cause spastic paraplegia-30 (SPG30; 610357), which shows some overlapping features.

NESCAV syndrome (NESCAVS) is a neurodegenerative disorder characterized by onset of features in infancy or early childhood. Affected individuals show global developmental delay with delayed walking or difficulty walking due to progressive spasticity mainly affecting the lower limbs and often leading to loss of independent ambulation. There is variably impaired intellectual development, speech delay, and learning disabilities and/or behavioral abnormalities. Additional features may include cortical visual impairment, often associated with optic atrophy, axonal peripheral neuropathy, seizures, dysautonomia, ataxia, and dystonia. Brain imaging often shows progressive cerebellar atrophy and thin corpus callosum. Some patients may show developmental regression, particularly of motor skills. The phenotype and presentation are highly variable (summary by Nemani et al., 2020).

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 diagnosed with NSID. They identified a single patient (patient 7) with a de novo mutation in the KIF1A gene (T99M; 601255.0004). The patient was a female, aged 3 years and 5 months, with severe mental retardation, axial hypotonia with peripheral spasticity, and mild atrophy of the vermian region of the cerebellum on brain MRI; she had no evidence of epilepsy.

Okamoto et al. (2014) reported an 8-year-old Japanese boy with NESCAVS due to a de novo heterozygous T99M mutation in the KIF1A gene. He had axial hypotonia, peripheral spasticity, and global developmental delay with severely impaired intellectual development and absent speech. He developed generalized seizures at age 4. Additional features included optic atrophy with poor visual evoked potentials, nystagmus, short stature associated with growth hormone deficiency, obstructive sleep apnea, and neurogenic bladder and constipation, suggesting autonomic involvement. The disorder was progressive, and he had poor overall growth. Brain imaging showed enlarged ventricles, hypoplasia of the corpus callosum, thin pituitary gland, and atrophic cerebellar vermis.

Lee et al. (2015) reported 14 patients, including a pair of monozygotic twins, with NESCAVS. The patients had mild to severe global developmental delay and impaired intellectual development. 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 NESCAVS. 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.

Ohba et al. (2015) reported 5 unrelated patients with NESCAVS who were ascertained from a large cohort of 68 patients with cerebellar atrophy. Three patients were children between 6 and 8 years of age, whereas 2 were 27 and 33 years old. Between 7 months and 5 years of age, they presented with developmental delay and/or unsteady ataxic gait associated with spasticity of the lower limbs and hyperreflexia. Upper limbs were mildly affected in some. The patients had variably impaired intellectual development (IQ range, 25-70). All patients had some type of ocular disturbance, including saccadic pursuit, nystagmus, optic atrophy, hypermetropic astigmatism, and oculomotor apraxia. Three patients, including the 2 adults, had peripheral sensorimotor axonal neuropathy associated with distal sensory impairment, distal muscle weakness and atrophy, and nerve conduction abnormalities. Two patients had seizures. Brain imaging in all patients showed progressive cerebellar atrophy, sometimes with nonspecific periventricular white matter abnormalities.

Hotchkiss et al. (2016) reported 2 unrelated boys, aged 15 and 6 years, with NESCAVS. They had early-onset axial hypotonia, global developmental delay with poor speech, and optic atrophy. Both had spasticity and hyperreflexia of the lower limbs; neither was able to stand or walk. The older patient developed generalized tonic-clonic seizures at age 15; seizures were not reported in the other patient. Other features in the patients included scoliosis, kyphosis, joint contractures, distal wasting, foot deformities, and electrophysiologic evidence of a peripheral sensorimotor polyneuropathy. Brain imaging showed progressive cerebellar atrophy and thin corpus callosum. Hotchkiss et al. (2016) concluded that NESCAVS is a neurodegenerative form of severe complicated spastic paraplegia with both central and peripheral nervous system involvement.

Langlois et al. (2016) reported a 15-year-old girl who presented at 2 months of age with infantile hypotonia and lack of visual fixation due to optic atrophy. She developed refractory seizures associated with hypsarrhythmia on EEG, and concurrently showed profound developmental delay. Brain imaging showed progressive loss of cerebellar tissue, marked atrophy of the corpus callosum, and enlarged ventricles. Dysmorphic features included bitemporal narrowing, retrognathia, downslanting palpebral fissures, short nose, and open mouth with curved upper lip. The authors noted that the patient had been diagnosed clinically with PEHO syndrome (260565) before whole-exome sequencing was performed, and suggested that some patients with NESCAVS may present with features of PEHO syndrome. Samanta and Gokden (2019) reported a 4-year-old girl with NESCAVS who presented clinically with features of PEHO syndrome as well as evidence suggestive of a mitochondrial disorder, including increased serum lactate and deficient mitochondrial respiratory complex IV activity in muscle biopsy. In infancy, she had hypotonia, poor visual fixation, and delayed motor development. At age 9 months, she developed refractory seizures associated with hypsarrhythmia on EEG; thereafter, she showed developmental regression and stagnation. Other features included hyperreflexia, progressive cerebral and cerebellar atrophy, thin corpus callosum, feeding difficulties requiring a feeding tube, and progressive restrictive lung disease, resulting in death at age 4.

Van Beusichem et al. (2020) reported 2 new patients (patients 1 and 4) with NESCAVS, provided follow-up of 2 patients (patients 2 and 3) previously reported by Lee et al. (2015), and reviewed the phenotype of a large group of previously reported patients. Their 2 new patients, aged 18 and 15 years, presented in infancy with global developmental delay, delayed walking, and impaired intellectual development. They had frequent falls and unsteady gait due to spastic paraparesis. Patient 1 had seizures, microcephaly, and absent speech, and patient 4 did not have seizures or microcephaly and was able to attend a special needs school. Brain imaging showed cerebellar atrophy in patient 4 only. Neither patient had visual disturbance or optic atrophy. Patients 2 and 3, aged 10 and 14 years, respectively, presented with developmental delay, hypotonia, and progressive spastic paraplegia causing walking difficulties. One patient had ataxia and nystagmus, cerebellar atrophy, extensor plantar responses, and possible axonal neuropathy, as well as contractures of the large joints, resulting in a 'crouched' gait; she ultimately lost the ability to walk. The other patient had axial hypotonia and electrophysiologic evidence of a peripheral sensorimotor neuropathy, but no cerebellar atrophy. Neither had seizures or microcephaly; only 1 was confirmed to have optic atrophy. The authors emphasized the progressive nature of the disorder, with a particular emphasis on the loss of independent ambulation associated with contractures. The report also demonstrated the phenotypic variability of additional features associated with this disorder, which the authors classified as a type of complicated spastic paraplegia.

Nemani et al. (2020) identified 12 patients from 10 unrelated families with KIF1A-related disorders, confirmed by genetic testing, who were ascertained at a single tertiary center caring for patients with motor difficulties. The phenotype was highly variable. Two infants (patients 1 and 2) had a severe progressive encephalopathy with reduced fetal movements, arthrogryposis, spasticity, dystonia, axonal polyneuropathy, dysautonomia, seizures, optic atrophy, cerebellar atrophy, respiratory insufficiency, and almost no developmental progress. They died of respiratory insufficiency at 6 and 23 months of age; both carried the same heterozygous E253K mutation (601255.0007). At the least severe end of the phenotypic spectrum, 4 patients (6, 8A and 8B, and 9) had a clinical course more consistent with autosomal dominant SPG30. The remaining individuals had a phenotype on the spectrum of NESCAVS or complicated spastic paraplegia. These patients had onset of global developmental delay and progressive motor difficulties in the first year of life. Features included spasticity, hyperreflexia, extensor plantar responses, dystonia, and ataxia. Additional common features included optic atrophy, seizures, peripheral neuropathy, subtle autonomic features, and cerebellar atrophy with thin corpus callosum on brain imaging. Most patients also had learning disabilities and/or psychiatric problems, including autism spectrum disorder (ASD), attention deficit-hyperactivity disorder, and challenging behavior. Nemani et al. (2020) concluded that mutations in the KIF1A gene cause a wide phenotypic spectrum reflecting central and peripheral nervous system involvement.

The heterozygous mutations in the KIF1A gene that were identified in patients with NESCAV syndrome by Lee et al. (2015) and Esmaeeli Nieh et al. (2015) occurred de novo.

In a patient with NESCAV syndrome, Hamdan et al. (2011) identified a de novo heterozygous missense mutation in the KIF1A gene (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 NESCAVS, 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 NESCAVS, 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.

In 5 unrelated patients with NESCAVS, Ohba et al. (2015) identified 5 different de novo heterozygous missense mutations in the KIF1A gene (see, e.g., 601255.0011 and 601255.0012). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, all affected highly conserved residues in the motor domain. Functional studies of the variants and studies of patient cells were not performed, but molecular modeling predicted that they would destabilize the protein or affect protein function.

In 2 unrelated patients with NESCAVS, Hotchkiss et al. (2016) identified 2 de novo heterozygous missense mutations in the KIF1A gene (see, e.g., R307Q; 601255.0013). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in multiple public databases, including dbSNP, the Exome Variant Server, and ExAC. Functional studies of the variants and studies of patient cells were not performed, but both occurred in the motor domain and were predicted to interfere with microtubule binding, possibly with a dominant-negative effect.

In 2 unrelated patients with NESCAVS, Van Beusichem et al. (2020) identified de novo heterozygous missense variants in the KIF1A gene (R380W and R216C; 601255.0009). Functional studies of the variants and studies of patient cells were not performed. In a review of previously reported cases, the authors concluded that there is no apparent genotype/phenotype correlation.

In a 4-year-old girl with NESCAVS who presented with clinical features of PEHO and a mitochondrial disorder, Samanta and Gokden (2019) identified a de novo heterozygous E253K mutation in the KIF1A gene (601255.0007). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed.

In 8 patients with NESCAVS, Nemani et al. (2020) identified de novo heterozygous mutations in the KIF1A gene (see, e.g., R254W; 601255.0012 and R307P; 601255.0017). All except 1 were missense variants affecting the kinesin motor domain; 1 was a splice site mutation. Two patients with profound encephalopathy carried a heterozygous E253K mutation. Functional studies of the variants were not performed.