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Mappings

MONDO

MONDO:0012476 hereditary spastic paraplegia 30 Not Yet Curated

MONDO:0012476 is a child of MONDO:0700055, the anchor of this entry, and its two children (SPG30A, SPG30B) are curated here as subtypes. The mapped class is narrower than the entry, so the predicate is skos:narrowMatch.

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Inheritance

2

Autosomal dominant inheritance HP:0000006

The more common mode. Most individuals with dominant KAND carry a de novo variant; some inherit it from an affected parent, and parental gonadal mosaicism gives an estimated 1% recurrence risk when the variant is absent from parental leukocyte DNA.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"Most individuals diagnosed with autosomal dominant KIF1A-NDD have the disorder as the result of a de novo pathogenic variant."

GeneReviews states that dominant disease is usually de novo.

PMID:33880452 SUPPORT Human Clinical

"Among our heterozygous individuals, the majority of KIF1A variants (64/115) were de novo, and 3 individuals were inherited from an affected parent."

Natural-history cohort quantifies de novo occurrence.

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"If the KIF1A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism."

Recurrence risk after an apparently de novo variant.

Autosomal recessive inheritance HP:0000007

Less common; biallelic variants cause SPG30B and HSAN2C. Heterozygous carriers of a single HSAN2C loss-of-function allele are asymptomatic.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"KIF1A-NDD can be inherited in an autosomal dominant or, less commonly, autosomal recessive manner."

GeneReviews states both modes of inheritance.

PMID:33880452 SUPPORT REVIEW SYNTHESIS Human Clinical

"In all families with recessive KIF1A-associated HSAN, individuals heterozygous for a single loss-of-function variant were asymptomatic."

Literature synthesis showing recessive transmission of HSAN2C.

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Subtypes

4

Intellectual disability, autosomal dominant 9 (NESCAV syndrome) MONDO:0013656

KIF1A hgnc:888

The classic and most frequent KAND presentation, caused by heterozygous, mostly de novo missense variants in the KIF1A motor domain. Features are developmental delay or intellectual disability with variable cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy and epilepsy. p.Thr99Met, in the P-loop ATP-binding site, was the first de novo variant reported in nonsyndromic intellectual disability and is recurrent.

Show evidence (2 references)

PMID:21376300 SUPPORT Human Clinical

"De novo missense mutations were identified in KIF1A (c.296C>T/p.Thr99Met), GRIN1 (c.1984G>A/p.Glu662Lys), EPB41L1 (c.2560C>T/p.Pro854Ser), and CACNG2 (c.427G>C/p.Val143Leu) (Table 2)."

Founding report of the de novo KIF1A p.Thr99Met variant in nonsyndromic intellectual disability.

PMID:25265257 SUPPORT Human Clinical

"Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy."

Defines the clinical picture of the de novo motor-domain subtype.

Spastic paraplegia 30A, autosomal dominant MONDO:0700307

KIF1A hgnc:888

Autosomal dominant (inherited or de novo) spastic paraplegia, slowly progressive and mostly pure, with onset from infancy to late adulthood. It is caused by motor-domain missense variants and, unlike the other KIF1A disorders, also by heterozygous loss-of-function variants outside the motor domain. KIF1A explained 6-7% of a Dutch clinical-exome cohort of mostly pure spastic paraplegia. Two families with motor-domain missense variants (p.Ser69Leu, p.Leu173Pro) also had learning difficulties, with borderline intellectual disability in one patient, placing SPG30A on a continuum with MRD9.

Show evidence (3 references)

PMID:31488895 SUPPORT Human Clinical

"In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years)."

Characterizes the autosomal dominant spastic paraplegia subtype.

PMID:31488895 SUPPORT Human Clinical

"Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families."

Establishes both de novo and inherited dominant transmission in this subtype.

PMID:31488895 SUPPORT Human Clinical

"The affected individuals from families P3 and P8 had learning difficulties, with an IQ varying from 68 to 80 points, where IQ below 70 is considered as borderline intellectual disability."

Mild cognitive involvement in two dominant spastic paraplegia families (both with motor-domain missense variants, Table 1).

Spastic paraplegia 30B, autosomal recessive MONDO:0971149

KIF1A hgnc:888

Autosomal recessive spastic paraplegia from biallelic KIF1A variants. The first family, an inbred Palestinian kindred, carried a homozygous p.Ala255Val motor-domain variant and had infantile-onset pure spastic gait; earlier-reported SPG30 patients had adolescent onset with distal wasting, sensory neuropathy and cerebellar ataxia.

Show evidence (2 references)

PMID:21487076 SUPPORT Human Clinical

"Our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that has not yet associated with HSP, which functions in anterograde axonal transportation."

First recessive KIF1A spastic paraplegia family.

PMID:21487076 SUPPORT Human Clinical

"Therefore, the only harmful variation according to our stringent analysis is Ala255Val in KIF1A."

Identifies the homozygous p.Ala255Val variant in the family.

Hereditary sensory neuropathy type 2C MONDO:0013634

KIF1A hgnc:888

Autosomal recessive ulcero-mutilating sensory and autonomic neuropathy from biallelic truncating KIF1A variants, almost all in an alternatively spliced exon. Curated as a subtype of the HSAN2 entry.

Show evidence (1 reference)

PMID:21820098 SUPPORT Human Clinical

"Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype."

Establishes KIF1A as an HSAN2 gene.

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Discussions and Knowledge Gaps

4

Does variant position or motility class predict severity in KAND, given that one cohort finds a strong association with P-loop and switch variants and another finds none?

KNOWLEDGE GAP OPEN kand_genotype_severity

Attached to

pathophysiology#KIF1A Motor Domain Missense Variants

Genotype-severity correlation matters for counseling and for selecting patients for allele-specific therapy. A 100-patient cohort links P-loop, switch I and switch II variants and rigor motility to severe disease, while a 28-patient Italian series found no correlation between mutation location and neurological or imaging presentation. Both are cross-sectional, and severity rises with age in a progressive disease.

Show evidence (2 references)

PMID:33880452 SUPPORT Human Clinical

"We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II."

Reports a genotype-severity association.

PMID:34487232 REFUTE Human Clinical

"Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations."

Finds no location-phenotype correlation.

Is a heterozygous KIF1A loss-of-function state benign enough that silencing the dominant-negative allele is a durable therapeutic goal?

KNOWLEDGE GAP OPEN kand_haploinsufficiency_tolerance

Attached to

pathophysiology#KIF1A Haploinsufficiency treatments#Allele-Specific Antisense Oligonucleotide (n-of-1)

Allele-specific knockdown converts a dominant-negative genotype into a haploinsufficient one. Loss-of-function carriers have a much milder, pure spastic paraplegia, but they do develop disease, sometimes from infancy, so the ceiling of benefit and the long-term outcome of knockdown are unknown.

Show evidence (2 references)

PMID:39122967 SUPPORT BACKGROUND Human Clinical

"Heterozygous variants leading to KIF1A haploinsufficiency are associated only with adult onset hereditary spastic paraplegia without seizures or cognitive impairment, a phenotype significantly milder than that associated with missense variants9 suggesting that gapmer ASO mediated therapy might..."

States the therapeutic rationale and its dependence on haploinsufficiency being mild.

PMID:31488895 SUPPORT Human Clinical

"However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families."

Loss-of-function heterozygosity is itself pathogenic.

Do recessive SPG30 alleles such as p.Ala255Val reduce KIF1A motor function or hyperactivate it?

KNOWLEDGE GAP OPEN kand_spg30b_direction_of_effect

Attached to

pathophysiology#Biallelic KIF1A Variants pathophysiology#KIF1A Motor Domain Missense Variants

The recessive SPG30B allele p.Ala255Val lies in the motor domain, yet worm studies have suggested that it and other familial alleles cause gain of function. The functional class of recessive alleles determines whether SPG30B shares the transport-loss mechanism of the dominant subtypes.

Show evidence (3 references)

PMID:35917346 SUPPORT BACKGROUND Model Organism

"On the other hand, we have suggested that KIF1A(V8M), KIF1A(A255V), and KIF1A(R350G) mutations (all of them are familial) result in a gain of function (25)."

Prior model data suggest hyperactivation for A255V.

PMID:31455732 SUPPORT In Vitro

"we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility."

SPG-associated variants hyperactivate purified KIF1A.

PMID:31455732 SUPPORT Model Organism

"Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs."

Increased, not decreased, SVP transport in worm knock-ins.

Can the slowly progressive human degeneration be studied in a model that carries a heterozygous KAND allele, given that the only cited mouse is a neonatal-lethal null?

HUMAN MODEL MISMATCH OPEN kand_mouse_model_genotype_mismatch

Attached to

pathophysiology#Progressive Neuronal Degeneration animal_models#Kif1a knockout mouse

Kif1a-null mice die within a day of birth, a genotype no patient has, while KAND knock-in worms reproduce the dominant-negative transport defect but lack the corticospinal, optic and cerebellar systems that degenerate in patients. Neither model can test which neurons degenerate first or whether reducing the mutant allele halts degeneration.

Show evidence (1 reference)

PMID:9548721 SUPPORT Model Organism

"KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances."

Null mice are neonatal lethal, unlike the heterozygous human disease.

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Pathophysiology

8

KIF1A Motor Domain Missense Variants

Mechanism confidence: Established

Heterozygous missense variants cluster in the KIF1A motor domain, altering conserved residues needed for ATP hydrolysis and microtubule binding (P-loop, switch I, switch II). All modeled variants impair transport, falling into three classes of motility defect: reduced microtubule binding, reduced velocity and processivity, and increased non-motile (rigor) microtubule binding. Rigor variants (for example p.Gly251Arg, p.Glu253Lys) track with the most severe disease and reduced microtubule binding with milder disease.

KIF1A hgnc:888

Genetic context KIF1A hgnc:888 allele_type: missense variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: DOMINANT_NEGATIVE

Mostly de novo heterozygous motor-domain missense variants; a minority of SPG30A families inherit them dominantly.

microtubule motor activity GO:0003777 ↓ DECREASED plus-end-directed microtubule motor activity GO:0008574 ↓ DECREASED microtubule binding GO:0008017 ⚠ ABNORMAL

Downstream

Dominant-Negative Inhibition of Wild-Type KIF1A Mutant subunits dimerize with wild-type KIF1A and impair the motility of the resulting heterodimers.

Show evidence (6 references)

PMID:25265257 SUPPORT Human Clinical

"All these de novo mutations are located in the motor domain (MD) of KIF1A."

De novo KAND variants localize to the motor domain.

PMID:21376300 SUPPORT Computational

"Thr99 lies in the highly conserved p loop consensus ATP-binding site of the KIF1A motor domain"

Places the founding MRD9 variant in the ATP-binding P-loop.

PMID:33880452 SUPPORT In Vitro

"We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding."

Defines the three motility defect classes from single-molecule and neurite-tip assays.

+ 3 more references

Dominant-Negative Inhibition of Wild-Type KIF1A

Mechanism confidence: Established

Activated KIF1A moves as a dimer, so in a heterozygous neuron about half of the motors are wild-type/mutant heterodimers. Mutant subunits suppress the motility of these heterodimers, and KAND knock-in worms heterozygous for the variant are more impaired than heterozygous null worms. Missense disease is clinically far more severe than loss-of-function disease, consistent with a dominant-negative rather than haploinsufficient mechanism; rigor motors may additionally act as roadblocks to other microtubule traffic.

Animal models

C. elegans unc-104 KAND knock-in models Caenorhabditis elegans recapitulates

Downstream

Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors Inhibited motors fail to deliver synaptic vesicle precursors along the axon.

Show evidence (3 references)

PMID:35917346 SUPPORT Model Organism

"Overall, the phenotypes of unc-104(R9Q)/+, unc-104(R251Q)/+, and unc-104(P298L)/+ were stronger than unc-104(null)/+, suggesting that the KAND mutations result in dominant-negative phenotypes for unc-104 transport in living animals."

In vivo dominant-negative effect of KAND alleles in C. elegans.

PMID:35917346 SUPPORT In Vitro

"We find that mutant KIF1A significantly impaired the motility of heterodimeric motors."

Single-molecule assays of wild-type/mutant heterodimers.

PMID:33880452 SUPPORT INDIRECT Human Clinical

"The clinical disease severity associated with missense variants in our study was much worse than any of the loss-of-function alleles, suggesting a dominant negative disease mechanism."

Clinical genotype comparison supports a dominant-negative mechanism by inference.

KIF1A Haploinsufficiency

Mechanism confidence: Provisional

Heterozygous loss-of-function variants outside the motor domain (nonsense, frameshift, deletion) cause autosomal dominant spastic paraplegia, most likely by halving KIF1A expression through nonsense-mediated decay or absent transcription rather than by producing a poisoning motor. Carriers reported in the literature have pure spastic paraplegia with normal cognition and no seizures or visual problems. The two SPG30A families in the same Dutch cohort that had learning difficulties or borderline intellectual disability carried motor-domain missense variants (p.Ser69Leu, p.Leu173Pro), not loss-of-function alleles.

KIF1A hgnc:888

Genetic context KIF1A hgnc:888 allele_type: loss-of-function (nonsense, frameshift, deletion) variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

microtubule motor activity GO:0003777 ↓ DECREASED

Downstream

Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors Reduced KIF1A dosage is presumed to lower anterograde transport capacity; transport has not been measured in patient neurons with loss-of-function alleles.

Show evidence (4 references)

PMID:31488895 SUPPORT Human Clinical

"However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families."

Loss-of-function variants cause dominant spastic paraplegia.

PMID:31488895 SUPPORT INDIRECT Human Clinical

"The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia."

Authors infer haploinsufficiency from the variant class.

PMID:31488895 SUPPORT INDIRECT Human Clinical

"In contrast to the variants in the motor domain, loss-of-function variants will not result in an impaired transport of KIF1A itself, but rather a reduced expression of KIF1A in neurons due to nonsense-mediated decay of the variant mRNA, or due to complete absence of transcription of the deleted allele."

Proposed molecular route from loss-of-function allele to reduced KIF1A dosage.

+ 1 more reference

Biallelic KIF1A Variants

Mechanism confidence: Provisional

Homozygous or compound heterozygous KIF1A variants cause recessive spastic paraplegia. The first family carried a homozygous motor-domain missense variant (p.Ala255Val); whether recessive SPG30 alleles reduce motor function or hyperactivate it is unresolved.

KIF1A hgnc:888

Genetic context KIF1A hgnc:888 allele_type: missense variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: UNKNOWN

microtubule motor activity GO:0003777 ⚠ ABNORMAL

Downstream

Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors Biallelic variants are presumed to disturb synaptic vesicle precursor transport, either by reducing it or by mislocalizing cargo through hyperactivation.

Show evidence (4 references)

PMID:21487076 SUPPORT Human Clinical

"Therefore, the only harmful variation according to our stringent analysis is Ala255Val in KIF1A."

Homozygous p.Ala255Val is the causal recessive variant in the first family.

PMID:35917346 SUPPORT BACKGROUND Model Organism

"On the other hand, we have suggested that KIF1A(V8M), KIF1A(A255V), and KIF1A(R350G) mutations (all of them are familial) result in a gain of function (25)."

Prior worm work suggests the recessive A255V allele hyperactivates the motor, so the direction of effect is not settled.

PMID:31455732 SUPPORT In Vitro

"we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility."

Purified full-length motors carrying SPG-associated variants are hyperactive, arguing against simple loss of function for these alleles.

+ 1 more reference

Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors

Mechanism confidence: Established

KIF1A is the principal anterograde motor for synaptic vesicle precursors. Mutant motor domains fail to accumulate at neurite tips, KAND knock-in worms show reduced axonal RAB-3 and mislocalization of synaptic vesicles to dendrites, and Kif1a-null mice show a specific decrease in synaptic vesicle precursor transport.

neuron CL:0000540

anterograde axonal transport GO:0008089 ↓ DECREASED anterograde synaptic vesicle transport GO:0048490 ↓ DECREASED

Animal models

C. elegans unc-104 KAND knock-in models Caenorhabditis elegans recapitulates

Kif1a knockout mouse Mus musculus recapitulates

Downstream

Synaptic Vesicle Depletion and Synaptic Dysfunction Undelivered precursors leave presynaptic terminals depleted of synaptic vesicles.

Progressive Neuronal Degeneration Chronic transport failure leads to neuronal degeneration and death; the intervening steps (including loss of afferent trophic support) are not established in human neurons.

Show evidence (3 references)

PMID:21376300 SUPPORT In Vitro

"KIF1A-MD accumulated in distal regions of neurites, whereas both KIF1A-MD-T312M and KIF1A-MD-T99M showed greatly reduced distal localization and increased accumulation throughout the cell body and proximal neurites (Figure 1)."

The p.Thr99Met motor domain fails to move to distal neurites in cultured hippocampal neurons.

PMID:9548721 SUPPORT Model Organism

"In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease."

Kif1a loss in mice specifically reduces synaptic vesicle precursor transport.

PMID:35917346 SUPPORT Model Organism

"In KAND models, GFP::RAB-3 signals were reduced in the axon and strongly mislocalized within the dendrite"

Synaptic vesicle marker is depleted from axons in KAND worms.

Synaptic Vesicle Depletion and Synaptic Dysfunction

Mechanism confidence: Provisional

Reduced delivery of synaptic vesicle precursors lowers presynaptic vesicle density and causes synaptic deficits. This is shown in Kif1a-null mice and KAND knock-in worms; its contribution to developmental delay and seizures in patients is inferred.

neuron CL:0000540

Downstream

Global developmental delay Synaptic dysfunction is the presumed basis of the neurodevelopmental phenotype; the link is inferred from model data.

Show evidence (2 references)

PMID:35917346 SUPPORT Model Organism

"Both heterozygous and homozygous worms show synaptic deficiencies that are caused by defects in axonal transport."

Synaptic deficits follow transport failure in KAND worms.

PMID:9548721 SUPPORT Model Organism

"Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies."

Reduced synaptic vesicle density in Kif1a-null mice.

Progressive Neuronal Degeneration

Mechanism confidence: Provisional

KAND is neurodegenerative: spasticity and optic nerve atrophy progress with age and many severely affected individuals are wheelchair dependent by their twenties, while cognition largely does not regress. Long projection neurons (corticospinal, optic nerve, peripheral sensory and motor axons) are clinically affected; neuronal degeneration has been shown directly in Kif1a-null mice and in the cerebellum at autopsy.

neuron CL:0000540 upper motor neuron CL:0008048 retinal ganglion cell CL:0000740

corticospinal tract UBERON:0002707 optic nerve UBERON:0000941

Animal models

Kif1a knockout mouse Mus musculus partially recapitulates

Downstream

Progressive spastic paraplegia Degeneration of long corticospinal axons is the presumed basis of progressive lower-limb spasticity; corticospinal pathology has not been described at autopsy.

Lower limb muscle weakness Presumed consequence of corticospinal and peripheral motor axon degeneration.

Optic atrophy Retinal ganglion cell axon loss produces optic nerve atrophy, which progresses with age.

Peripheral neuropathy Presumed length-dependent degeneration of peripheral axons.

Loss of ambulation Progressive spasticity and weakness lead to loss of independent walking.

Cerebellar Purkinje and Granule Cell Loss The cerebellum is a prominent site of neuronal loss.

Show evidence (3 references)

PMID:33880452 SUPPORT Human Clinical

"By the time they reached their 20s, many individuals were largely wheelchair dependent."

Progressive motor decline in the natural-history cohort.

PMID:33880452 SUPPORT Human Clinical

"While the loss of vision and of motor skills limited an individual’s ability to participate in the activities of daily living over time, we largely did not see cognitive regression."

Degeneration affects motor and visual pathways more than cognition.

PMID:9548721 SUPPORT Model Organism

"Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons."

Neuronal degeneration follows KIF1A loss in mice.

Cerebellar Purkinje and Granule Cell Loss

Mechanism confidence: Established

Autopsies of two children with de novo p.Thr99Met showed severe cerebellar atrophy most prominent in the superior vermis, with a thin molecular layer, depletion of Purkinje and internal granule cells, Bergmann gliosis, white matter pallor and rare axonal spheroids, plus neuronal loss in the dentate and inferior olivary nuclei.

Purkinje cell CL:0000121 cerebellar granule cell CL:0001031

cerebellar vermis UBERON:0004720

Downstream

Cerebellar atrophy Loss of cerebellar neurons is seen as cerebellar atrophy on MRI.

Ataxia Cerebellar neuronal loss is the presumed basis of ataxia and cerebellar signs.

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Microscopic examination revealed severe cerebellar atrophy most prominent in the superior cerebellar vermis, including a thin molecular layer, a depletion of Purkinje and internal granule cells, Bergmann gliosis, and white matter pallor."

Neuropathology of p.Thr99Met KAND.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

36

Digestive 3

Gastroesophageal reflux FREQUENT HP:0002020

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Gastrointestinal issues were common, with 40% (40/100) reporting gastroesophageal reflux disease (GERD), constipation (39%, 39/100), and diarrhea (17%, 17/100)."

40% frequency.

Constipation FREQUENT HP:0002019

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Gastrointestinal issues were common, with 40% (40/100) reporting gastroesophageal reflux disease (GERD), constipation (39%, 39/100), and diarrhea (17%, 17/100)."

39% frequency.

Dysphagia OCCASIONAL HP:0002015

Show evidence (3 references)

PMID:33880452 SUPPORT Human Clinical

"Many affected individuals experienced excessive salivation (26%, 21/80) or problems swallowing (29%, 23/80)."

Problems swallowing in 29% (23/80).

PMID:33880452 SUPPORT Human Clinical

"Ten percent of the overall cohort (10/100) required enteric nutritional support, in many individuals due to the difficulty swallowing."

Dysphagia leads to enteral feeding in some individuals.

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"feeding therapy to manage dysphagia"

GeneReviews management addresses dysphagia.

Eye 3

Optic atrophy VERY_FREQUENT HP:0000648

Show evidence (2 references)

PMID:39009236 SUPPORT Human Clinical

"Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT)."

Prospective ophthalmic frequency.

PMID:33880452 SUPPORT Human Clinical

"Half of our cohort (50/100) had optic nerve atrophy or optic nerve hypoplasia, and there was a high prevalence of cortical visual impairment (20%, 20/100) and strabismus (26%, 26/100)."

Reported frequency in the natural-history cohort.

Strabismus FREQUENT HP:0000486

Show evidence (1 reference)

PMID:39009236 SUPPORT Human Clinical

"Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT). Almost 40% had strabismus."

Prospective frequency.

Cerebral visual impairment OCCASIONAL HP:0100704

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Half of our cohort (50/100) had optic nerve atrophy or optic nerve hypoplasia, and there was a high prevalence of cortical visual impairment (20%, 20/100) and strabismus (26%, 26/100)."

20% frequency.

Head and Neck 2

Microcephaly OCCASIONAL HP:0000252

Show evidence (2 references)

PMID:33880452 SUPPORT Human Clinical

"Individuals with earlier-onset disease were more likely to develop microcephaly, and individuals with later-onset disease more often underwent musculoskeletal surgeries."

Microcephaly occurs and associates with earlier onset.

PMID:33880452 SUPPORT Human Clinical

"Table 1Phenotypic summary of KAND individualsOur cohortLiterature cohortNeurologicalHypotonia84%(84/100)38%(17/45)Hypertonia81%(81/100)84%(38/45)Microcephaly18%(18/100)18%(8/45)Peripheral neuropathy27%(27/100)38%(17/45)"

Table 1 frequencies, microcephaly 18% in the cohort and literature; peripheral neuropathy 27% (cohort) and 38% (literature).

Drooling OCCASIONAL HP:0002307

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Many affected individuals experienced excessive salivation (26%, 21/80) or problems swallowing (29%, 23/80)."

Excessive salivation in 26% (21/80).

Limbs 1

Lower limb muscle weakness VERY_FREQUENT HP:0007340

Show evidence (1 reference)

PMID:42500835 SUPPORT Human Clinical

"Lower extremity weakness was nearly universal (88.2%) and inversely related with age"

Cohort frequency.

Metabolism 1

Abnormality of temperature regulation FREQUENT HP:0004370

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Just under half of individuals (46%, 37/80) experience difficulty with temperature regulation, including sporadic fevers unrelated to illness."

46% (37/80), including sporadic fevers unrelated to illness.

Musculoskeletal 4

Hypotonia FREQUENT HP:0001252

Show evidence (2 references)

PMID:42500835 SUPPORT Human Clinical

"A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%."

Cohort frequency of hypotonia.

PMID:33880452 SUPPORT Human Clinical

"The most frequently observed symptoms in our cohort were hypotonia (84%, 84/100) and hypertonia or spasticity (81%, 81/100)."

Second cohort frequency.

Progressive spastic paraplegia FREQUENT HP:0007020

Show evidence (1 reference)

PMID:42500835 SUPPORT Human Clinical

"Progressive spasticity occurred in 72.5%, predominantly affecting the lower extremities and correlated with age"

Cohort frequency of progressive spasticity.

Lower limb spasticity in hereditary spastic paraplegia subtypes HP:0002061

Show evidence (2 references)

PMID:31488895 SUPPORT Human Clinical

"In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years)."

SPG30A phenotype.

PMID:21487076 SUPPORT Human Clinical

"In our patients, the disease presented in infancy and has only involved spastic gait without additional abnormalities."

SPG30B phenotype in the first family.

Scoliosis OCCASIONAL HP:0002650

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain..."

14% frequency.

Nervous System 19

Global developmental delay VERY_FREQUENT HP:0001263

Show evidence (2 references)

PMID:42500835 SUPPORT Human Clinical

"A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%."

Cohort frequency of global developmental delay.

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic..."

GeneReviews lists developmental delay as a common feature.

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (2 references)

PMID:33880452 SUPPORT Human Clinical

"Nearly all individuals had some degree of developmental delay and/or intellectual disability (92%, 92/100)."

Cohort frequency.

PMID:25265257 SUPPORT Human Clinical

"Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy."

Cognitive impairment is the core feature of de novo disease.

Loss of ambulation HP:0002505

Show evidence (2 references)

PMID:42500835 SUPPORT Human Clinical

"Independent walking was achieved by 62.7% at a median age of 24 months, but only 31.4% retained independent ambulation at last evaluation."

Acquisition and loss of ambulation.

PMID:33880452 SUPPORT Human Clinical

"By the time they reached their 20s, many individuals were largely wheelchair dependent."

Wheelchair dependence in early adulthood.

Seizure FREQUENT HP:0001250

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Seizures were common in our cohort, with 42% (42/100) reporting a history of seizures."

Cohort frequency.

Absence seizures OCCASIONAL Generalized non-motor (absence) seizure HP:0002121

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Multiple seizure types were described, often in the same individual, with absence seizures as the most common in 29% (29/100) of the cohort overall and in 69% (29/42) of those with seizures."

29% of the cohort.

Cerebellar atrophy FREQUENT HP:0001272

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Among those who had neuroimaging, the majority (58%, 54/93) had abnormal findings, most commonly cerebellar atrophy (35%, 33/93), abnormalities in the corpus callosum (11%, 10/93), and cerebral atrophy (6%, 6/93)."

MRI frequency.

Abnormal corpus callosum morphology OCCASIONAL HP:0001273

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Among those who had neuroimaging, the majority (58%, 54/93) had abnormal findings, most commonly cerebellar atrophy (35%, 33/93), abnormalities in the corpus callosum (11%, 10/93), and cerebral atrophy (6%, 6/93)."

11% of imaged individuals.

Peripheral neuropathy OCCASIONAL HP:0009830

Show evidence (2 references)

PMID:25265257 SUPPORT Human Clinical

"Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy."

Peripheral neuropathy is part of the variable phenotype.

PMID:33880452 SUPPORT Human Clinical

"Table 1Phenotypic summary of KAND individualsOur cohortLiterature cohortNeurologicalHypotonia84%(84/100)38%(17/45)Hypertonia81%(81/100)84%(38/45)Microcephaly18%(18/100)18%(8/45)Peripheral neuropathy27%(27/100)38%(17/45)"

Table 1 frequencies, microcephaly 18% in the cohort and literature; peripheral neuropathy 27% (cohort) and 38% (literature).

Ataxia OCCASIONAL HP:0001251

Show evidence (2 references)

PMID:42500835 SUPPORT Human Clinical

"Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%)."

Cohort frequency.

PMID:32737135 SUPPORT Human Clinical

"Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype."

Congenital ataxic presentations of heterozygous KIF1A variants.

Motor stereotypy FREQUENT HP:0000733

Show evidence (1 reference)

PMID:42500835 SUPPORT Human Clinical

"Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%)."

43.1% frequency.

Action tremor OCCASIONAL HP:0002345

Show evidence (1 reference)

PMID:42500835 SUPPORT Human Clinical

"Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%)."

15.6% frequency.

Autism OCCASIONAL HP:0000717

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Frequently reported neurobehavioral diagnoses included autism (20%, 16/80), attention deficit hyperactivity disorder (24%, 19/80), anxiety (19%, 15/80), and obsessive-compulsive disorder (5%, 4/80)."

20% frequency.

Attention deficit hyperactivity disorder OCCASIONAL HP:0007018

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Frequently reported neurobehavioral diagnoses included autism (20%, 16/80), attention deficit hyperactivity disorder (24%, 19/80), anxiety (19%, 15/80), and obsessive-compulsive disorder (5%, 4/80)."

24% frequency.

Reduced pain sensitivity FREQUENT Impaired pain sensation HP:0007328

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain..."

High pain tolerance in 65% (52/80).

Bruxism FREQUENT HP:0003763

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain..."

Bruxism in 35% (28/80).

Stereotypical hand wringing OCCASIONAL HP:0012171

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain..."

Stereotypic hand wringing or clasping in 21% (17/80).

Anxiety OCCASIONAL HP:0000739

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Frequently reported neurobehavioral diagnoses included autism (20%, 16/80), attention deficit hyperactivity disorder (24%, 19/80), anxiety (19%, 15/80), and obsessive-compulsive disorder (5%, 4/80)."

Anxiety in 19% (15/80).

Delayed speech and language development HP:0000750

Show evidence (2 references)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic..."

GeneReviews lists communication difficulties among common features.

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"speech-language therapy to improve communication"

Management targets communication.

Autonomic dysfunction Abnormal autonomic nervous system physiology HP:0012332

Show evidence (2 references)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic..."

GeneReviews lists autonomic neuropathy among common features.

PMID:33880452 SUPPORT Human Clinical

"While these symptoms may reflect autonomic dysfunction, there may be other underlying causative factors, and further direct assessment of autonomic function will be beneficial."

Temperature, gastrointestinal and swallowing symptoms may reflect autonomic dysfunction; not directly tested.

Constitutional 1

Extremities cold to touch FREQUENT HP:6000500

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain..."

Cold extremities in 60% (48/80).

Growth 2

Short stature OCCASIONAL HP:0004322

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Another feature not previously reported in KAND was short stature, which we observed in 11% (11/100) of our cohort."

11% frequency.

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic..."

GeneReviews lists poor weight gain among common features.

🧬

Genetic Associations

3

KIF1A de novo motor-domain missense variants (Causative)

Gene: KIF1A hgnc:888 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:25265257 SUPPORT Human Clinical

"Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases."

Recurrent de novo motor-domain alleles.

PMID:33880452 SUPPORT Human Clinical

"More than 30% of individuals with KAND have private variants, and there are likely many more variants that remain to be identified."

Allelic heterogeneity of KAND.

KIF1A dominant missense and loss-of-function variants (Causative)

Gene: KIF1A hgnc:888 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:31488895 SUPPORT Human Clinical

"Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia."

Identifies KIF1A variants in dominant spastic paraplegia.

KIF1A biallelic variants (Causative)

Gene: KIF1A hgnc:888 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:21487076 SUPPORT Human Clinical

"Therefore, the only harmful variation according to our stringent analysis is Ala255Val in KIF1A."

Causal recessive variant.

💊

Medical Actions

9

Allele-Specific Antisense Oligonucleotide (n-of-1)

Action: allele-specific antisense oligonucleotide therapy Ontology label: Antisense Therapy NCIT:C16236

Agent: nL-KIF1-001 (allele-specific antisense oligonucleotide) NCIT:C1291

Platform: Antisense oligonucleotide RNase H knockdown Delivery: Unformulated (free uptake) Targeting: Unconjugated Chemistry: 2′-MOE

RNA target: KIF1A hgnc:888 KIF1A mRNA from the p.Pro305Leu allele (allele-specific)

Experimental individualized therapy. A 9-year-old girl with severe KAND and a de novo p.Pro305Leu variant received intrathecal nL-KIF1-001, a 5-10-5 2'-MOE gapmer with mixed phosphorothioate/phosphodiester backbone designed to recruit RNase H1 to the transcript of the pathogenic allele, selected using a SNP in cis. Dosing escalated from 20 mg in 20 mg steps to 80 mg. Over 9 months it was safe apart from an epidural CSF collection after the first injection; spells of behavioral arrest, falls and quality of life improved, 6-minute walk distance changed little, and cognition was stable. The rationale is to remove the dominant-negative allele, leaving a haploinsufficient state that loss-of-function carriers suggest is much milder.

Mechanism Target:

INHIBITS Dominant-Negative Inhibition of Wild-Type KIF1A — Degrades the pathogenic-allele transcript to remove the dominant-negative subunit.

Show evidence (4 references)

PMID:39122967 SUPPORT Human Clinical

"Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the..."

Describes the n-of-1 allele-specific ASO treatment.

PMID:39122967 SUPPORT Human Clinical

"Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved."

Safety and outcome in the single treated patient.

PMID:39122967 SUPPORT In Vitro

"There was no significant reduction of the mRNA level from the wildtype allele at any concentration tested, highlighting the high selectivity of nL-KIF1-001 for the mRNA from the pathogenic allele over the wildtype allele (Figure 1B)"

Allele selectivity in patient iPSC-derived neurons.

+ 1 more reference

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy including stretching to reduce contractures and falls, as part of multidisciplinary supportive care.

Mechanism Target:

INHIBITS Progressive spastic paraplegia — Symptomatic management of spasticity and its complications.

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"physical therapy including stretching to help avoid contractures and falls"

GeneReviews management recommendation.

Speech-Language Therapy

Action: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech-language therapy to improve communication.

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"speech-language therapy to improve communication"

GeneReviews management recommendation.

Seizure and Neuropathic Pain Management

Action: Pharmacotherapy NCIT:C15986

Neurologist-directed management of seizures and of pain from peripheral neuropathy. Seizures in some individuals are refractory to multiple antiseizure medications.

Mechanism Target:

INHIBITS Seizure — Symptomatic seizure control.

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"management of seizures and pain associated with peripheral neuropathy by neurologist"

GeneReviews management recommendation.

Tendon Lengthening Surgery

Action: tendon lengthening Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Orthopedic surgery for progressive spasticity; 15% of a 100-patient cohort underwent tendon lengthening.

Show evidence (1 reference)

PMID:33880452 SUPPORT Human Clinical

"Spasticity was progressive, and a number of individuals required surgical intervention: 15% (15/100) received tendon lengthening procedures."

Frequency of tendon lengthening surgery.

Ubiquinol Supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: ubiquinol

Platform: Small molecule

Used in six patients with muscle-biopsy evidence of secondary oxidative metabolism impairment or low CoQ10, with subjective benefit only; no controlled data.

Show evidence (1 reference)

PMID:34487232 SUPPORT Human Clinical

"When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit."

Uncontrolled use with subjective benefit.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling on dominant (mostly de novo, about 1% sib recurrence from gonadal mosaicism) and recessive inheritance; prenatal and preimplantation testing once the familial variant is known.

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"Once the KIF1A pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."

GeneReviews genetic counseling guidance.

Feeding Therapy

Action: feeding therapy Ontology label: Swallowing Therapy NCIT:C156237

Platform: Behavioral / lifestyle

Feeding therapy to manage dysphagia.

Mechanism Target:

INHIBITS Dysphagia — Symptomatic management of swallowing difficulty.

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"feeding therapy to manage dysphagia"

GeneReviews management recommendation.

Refractive Error Management

Action: ophthalmologic management of refractive errors Ontology label: Supportive Care NCIT:C15747

Ophthalmologic treatment of refractive errors as part of supportive care.

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"treatment by ophthalmologist to manage refractive errors"

GeneReviews management recommendation.

🔬

Diagnosis

1

Molecular Genetic Testing

The diagnosis is established by finding a heterozygous, or less commonly biallelic, pathogenic KIF1A variant by molecular genetic testing (exome, genome or multigene panel) in a proband with suggestive findings; parental testing establishes de novo status.

molecular genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:41941559 SUPPORT REVIEW SYNTHESIS Human Clinical

"The diagnosis of KIF1A-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant or, less commonly, biallelic pathogenic variants in KIF1A identified by molecular genetic testing."

GeneReviews diagnostic criterion.

🐁

Animal Models

2

C. elegans unc-104 KAND knock-in models

CRISPR-Cas9 knock-ins of KAND motor-domain variants into the KIF1A ortholog unc-104. Heterozygotes and homozygotes have reduced axonal transport of synaptic vesicles, and heterozygotes are more impaired than heterozygous null worms. A suppressor screen recovered UNC-104(D177N), which restores motor activity.

Species

Caenorhabditis elegans

Genotype

unc-104(R9Q), unc-104(R251Q), unc-104(P298L) heterozygous and homozygous (human KIF1A R11Q, R254Q, P305L)

Publication

PMID:35917346

Pathograph links

Dominant-Negative Inhibition of Wild-Type KIF1A recapitulates fidelity: moderate observes: organism

Limitations: Worms lack the corticospinal tract, optic nerve and cerebellum, so the degenerative human phenotypes cannot be assessed.

Show evidence (1 reference)

PMID:35917346 SUPPORT Model Organism

"Overall, the phenotypes of unc-104(R9Q)/+, unc-104(R251Q)/+, and unc-104(P298L)/+ were stronger than unc-104(null)/+, suggesting that the KAND mutations result in dominant-negative phenotypes for unc-104 transport in living animals."

Heterozygous knock-ins show a dominant-negative effect in vivo.

Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors recapitulates fidelity: moderate observes: cellular

Show evidence (1 reference)

PMID:35917346 SUPPORT Model Organism

"In our C. elegans models, both heterozygotes and homozygotes exhibited reduced axonal transport."

Reduced axonal transport in KAND worms.

Show evidence (1 reference)

PMID:35917346 SUPPORT Model Organism

"Suppressor screening using the disease model identified a mutation that recovers the motor activity of mutated human KIF1A."

The worm model supports genetic suppressor screens.

Kif1a knockout mouse

Homozygous Kif1a disruption is mostly lethal within a day of birth, with motor and sensory disturbances, reduced synaptic vesicle precursor transport, reduced synaptic vesicle density and neuronal degeneration.

Species

Mus musculus

Genotype

Kif1a-/-

Publication

PMID:9548721

Pathograph links

Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors recapitulates fidelity: moderate observes: cellular

Limitations: Complete loss of function, a genotype not seen in patients, who are heterozygous for dominant-negative or loss-of-function alleles or carry partial-function recessive alleles.

Show evidence (1 reference)

PMID:9548721 SUPPORT Model Organism

"In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease."

Transport defect in knockout mice.

Progressive Neuronal Degeneration partially recapitulates fidelity: low observes: tissue

Limitations: Neonatal lethality prevents study of the slowly progressive degeneration seen in patients.

Show evidence (1 reference)

PMID:9548721 SUPPORT Model Organism

"Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons."

Neuronal degeneration in knockout mice.

Show evidence (1 reference)

PMID:9548721 SUPPORT Model Organism

"KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances."

Neonatal lethality of the knockout.

{ }

Source YAML

click to show

name: KIF1A-Related Neurological Disorder
creation_date: "2026-10-01T15:00:00Z"
category: Mendelian
description: >-
  KIF1A-related neurological disorder (KAND; KIF1A-related neurodevelopmental
  disorder, KIF1A-NDD) is the spectrum of developmental and degenerative
  neurological disease caused by pathogenic variants in KIF1A, the
  neuron-specific kinesin-3 motor that carries synaptic vesicle precursors
  anterogradely along axons. Heterozygous, usually de novo, motor-domain
  missense variants cause the most common and most severe presentation
  (intellectual disability, autosomal dominant 9): global developmental delay,
  hypotonia followed by progressive lower-limb spasticity and weakness, optic
  nerve atrophy, cerebellar atrophy, seizures, peripheral neuropathy and
  neurobehavioral features. Inherited heterozygous missense or loss-of-function
  variants cause a slowly progressive, mostly pure autosomal dominant spastic
  paraplegia (SPG30A); biallelic variants cause autosomal recessive spastic
  paraplegia (SPG30B) or hereditary sensory and autonomic neuropathy type 2C.
synonyms:
- KAND
- KIF1A-associated neurological disorder
- KIF1A-related neurodevelopmental disorder
- KIF1A-NDD
parents:
- hereditary disease
- nervous system disorder
disease_term:
  preferred_term: KIF1A related neurological disorder
  term:
    id: MONDO:0700055
    label: KIF1A related neurological disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0012476
      label: hereditary spastic paraplegia 30
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0012476 is a child of MONDO:0700055, the anchor of this entry, and
      its two children (SPG30A, SPG30B) are curated here as subtypes. The
      mapped class is narrower than the entry, so the predicate is
      skos:narrowMatch.
has_subtypes:
- name: MRD9
  display_name: Intellectual disability, autosomal dominant 9 (NESCAV syndrome)
  description: >-
    The classic and most frequent KAND presentation, caused by heterozygous,
    mostly de novo missense variants in the KIF1A motor domain. Features are
    developmental delay or intellectual disability with variable cerebellar
    atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy and
    epilepsy. p.Thr99Met, in the P-loop ATP-binding site, was the first de novo
    variant reported in nonsyndromic intellectual disability and is recurrent.
  subtype_term:
    preferred_term: intellectual disability, autosomal dominant 9
    term:
      id: MONDO:0013656
      label: intellectual disability, autosomal dominant 9
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  evidence:
  - reference: PMID:21376300
    reference_title: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo missense mutations were identified in KIF1A (c.296C>T/p.Thr99Met), GRIN1 (c.1984G>A/p.Glu662Lys), EPB41L1 (c.2560C>T/p.Pro854Ser), and CACNG2 (c.427G>C/p.Val143Leu) (Table 2)."
    explanation: Founding report of the de novo KIF1A p.Thr99Met variant in nonsyndromic intellectual disability.
  - reference: PMID:25265257
    reference_title: "De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy."
    explanation: Defines the clinical picture of the de novo motor-domain subtype.
- name: SPG30A
  display_name: Spastic paraplegia 30A, autosomal dominant
  description: >-
    Autosomal dominant (inherited or de novo) spastic paraplegia, slowly
    progressive and mostly pure, with onset from infancy to late adulthood. It is
    caused by motor-domain missense variants and, unlike the other KIF1A
    disorders, also by heterozygous loss-of-function variants outside the motor
    domain. KIF1A explained 6-7% of a Dutch clinical-exome cohort of mostly pure
    spastic paraplegia. Two families with motor-domain missense variants
    (p.Ser69Leu, p.Leu173Pro) also had learning difficulties, with borderline
    intellectual disability in one patient, placing SPG30A on a continuum with
    MRD9.
  subtype_term:
    preferred_term: spastic paraplegia 30A, autosomal dominant
    term:
      id: MONDO:0700307
      label: spastic paraplegia 30A, autosomal dominant
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  evidence:
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years)."
    explanation: Characterizes the autosomal dominant spastic paraplegia subtype.
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families."
    explanation: Establishes both de novo and inherited dominant transmission in this subtype.
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The affected individuals from families P3 and P8 had learning difficulties, with an IQ varying from 68 to 80 points, where IQ below 70 is considered as borderline intellectual disability."
    explanation: Mild cognitive involvement in two dominant spastic paraplegia families (both with motor-domain missense variants, Table 1).
- name: SPG30B
  display_name: Spastic paraplegia 30B, autosomal recessive
  description: >-
    Autosomal recessive spastic paraplegia from biallelic KIF1A variants. The
    first family, an inbred Palestinian kindred, carried a homozygous
    p.Ala255Val motor-domain variant and had infantile-onset pure spastic gait;
    earlier-reported SPG30 patients had adolescent onset with distal wasting,
    sensory neuropathy and cerebellar ataxia.
  subtype_term:
    preferred_term: spastic paraplegia 30B, autosomal recessive
    term:
      id: MONDO:0971149
      label: spastic paraplegia 30B, autosomal recessive
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  evidence:
  - reference: PMID:21487076
    reference_title: Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that has not yet associated with HSP, which functions in anterograde axonal transportation."
    explanation: First recessive KIF1A spastic paraplegia family.
  - reference: PMID:21487076
    reference_title: Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, the only harmful variation according to our stringent analysis is Ala255Val in KIF1A."
    explanation: Identifies the homozygous p.Ala255Val variant in the family.
- name: HSAN2C
  display_name: Hereditary sensory neuropathy type 2C
  curated_in: Hereditary_Sensory_and_Autonomic_Neuropathy_Type_2
  description: >-
    Autosomal recessive ulcero-mutilating sensory and autonomic neuropathy from
    biallelic truncating KIF1A variants, almost all in an alternatively spliced
    exon. Curated as a subtype of the HSAN2 entry.
  subtype_term:
    preferred_term: neuropathy, hereditary sensory, type 2C
    term:
      id: MONDO:0013634
      label: neuropathy, hereditary sensory, type 2C
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  evidence:
  - reference: PMID:21820098
    reference_title: "KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype."
    explanation: Establishes KIF1A as an HSAN2 gene.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The more common mode. Most individuals with dominant KAND carry a de novo
    variant; some inherit it from an affected parent, and parental gonadal
    mosaicism gives an estimated 1% recurrence risk when the variant is absent
    from parental leukocyte DNA.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most individuals diagnosed with autosomal dominant KIF1A-NDD have the disorder as the result of a de novo pathogenic variant."
    explanation: GeneReviews states that dominant disease is usually de novo.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among our heterozygous individuals, the majority of KIF1A variants (64/115) were de novo, and 3 individuals were inherited from an affected parent."
    explanation: Natural-history cohort quantifies de novo occurrence.
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "If the KIF1A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism."
    explanation: Recurrence risk after an apparently de novo variant.
- name: Autosomal recessive inheritance
  description: >-
    Less common; biallelic variants cause SPG30B and HSAN2C. Heterozygous
    carriers of a single HSAN2C loss-of-function allele are asymptomatic.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "KIF1A-NDD can be inherited in an autosomal dominant or, less commonly, autosomal recessive manner."
    explanation: GeneReviews states both modes of inheritance.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "In all families with recessive KIF1A-associated HSAN, individuals heterozygous for a single loss-of-function variant were asymptomatic."
    explanation: Literature synthesis showing recessive transmission of HSAN2C.
pathophysiology:
- name: KIF1A Motor Domain Missense Variants
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  subtypes:
  - MRD9
  - SPG30A
  description: >-
    Heterozygous missense variants cluster in the KIF1A motor domain, altering
    conserved residues needed for ATP hydrolysis and microtubule binding (P-loop,
    switch I, switch II). All modeled variants impair transport, falling into
    three classes of motility defect: reduced microtubule binding, reduced
    velocity and processivity, and increased non-motile (rigor) microtubule
    binding. Rigor variants (for example p.Gly251Arg, p.Glu253Lys) track with
    the most severe disease and reduced microtubule binding with milder disease.
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  genetic_context:
    gene:
      preferred_term: KIF1A
      term:
        id: hgnc:888
        label: KIF1A
    allele_type: missense
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: DOMINANT_NEGATIVE
    description: >-
      Mostly de novo heterozygous motor-domain missense variants; a minority of
      SPG30A families inherit them dominantly.
  molecular_functions:
  - preferred_term: microtubule motor activity
    term:
      id: GO:0003777
      label: microtubule motor activity
    modifier: DECREASED
  - preferred_term: plus-end-directed microtubule motor activity
    term:
      id: GO:0008574
      label: plus-end-directed microtubule motor activity
    modifier: DECREASED
  - preferred_term: microtubule binding
    term:
      id: GO:0008017
      label: microtubule binding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25265257
    reference_title: "De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All these de novo mutations are located in the motor domain (MD) of KIF1A."
    explanation: De novo KAND variants localize to the motor domain.
  - reference: PMID:21376300
    reference_title: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Thr99 lies in the highly conserved p loop consensus ATP-binding site of the KIF1A motor domain"
    explanation: Places the founding MRD9 variant in the ATP-binding P-loop.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding."
    explanation: Defines the three motility defect classes from single-molecule and neurite-tip assays.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II."
    explanation: Genotype-severity association in the natural-history cohort.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes."
    explanation: Links motility class to clinical severity.
  - reference: PMID:33496723
    reference_title: Pathogenic mutations in the kinesin-3 motor KIF1A diminish force generation and movement through allosteric mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although both mutations relieve autoinhibition of the full-length motor, the mutant motors display decreased velocities, run lengths, and landing rates and delayed cargo transport in cells."
    explanation: V8M and Y89D motor-domain variants reduce velocity, run length and landing rate.
  downstream:
  - target: Dominant-Negative Inhibition of Wild-Type KIF1A
    causal_link_type: DIRECT
    description: >-
      Mutant subunits dimerize with wild-type KIF1A and impair the motility of
      the resulting heterodimers.
    evidence:
    - reference: PMID:35917346
      reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We find that mutant KIF1A significantly impaired the motility of heterodimeric motors."
      explanation: Purified wild-type/mutant heterodimers show impaired motility.
- name: Dominant-Negative Inhibition of Wild-Type KIF1A
  role: mechanism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  subtypes:
  - MRD9
  - SPG30A
  description: >-
    Activated KIF1A moves as a dimer, so in a heterozygous neuron about half of
    the motors are wild-type/mutant heterodimers. Mutant subunits suppress the
    motility of these heterodimers, and KAND knock-in worms heterozygous for the
    variant are more impaired than heterozygous null worms. Missense disease is
    clinically far more severe than loss-of-function disease, consistent with a
    dominant-negative rather than haploinsufficient mechanism; rigor motors may
    additionally act as roadblocks to other microtubule traffic.
  evidence:
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, the phenotypes of unc-104(R9Q)/+, unc-104(R251Q)/+, and unc-104(P298L)/+ were stronger than unc-104(null)/+, suggesting that the KAND mutations result in dominant-negative phenotypes for unc-104 transport in living animals."
    explanation: In vivo dominant-negative effect of KAND alleles in C. elegans.
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We find that mutant KIF1A significantly impaired the motility of heterodimeric motors."
    explanation: Single-molecule assays of wild-type/mutant heterodimers.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The clinical disease severity associated with missense variants in our study was much worse than any of the loss-of-function alleles, suggesting a dominant negative disease mechanism."
    explanation: Clinical genotype comparison supports a dominant-negative mechanism by inference.
  downstream:
  - target: Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors
    causal_link_type: DIRECT
    description: >-
      Inhibited motors fail to deliver synaptic vesicle precursors along the
      axon.
    evidence:
    - reference: PMID:35917346
      reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In our C. elegans models, both heterozygotes and homozygotes exhibited reduced axonal transport."
      explanation: Heterozygous KAND worms have reduced axonal transport.
- name: KIF1A Haploinsufficiency
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  subtypes:
  - SPG30A
  description: >-
    Heterozygous loss-of-function variants outside the motor domain (nonsense,
    frameshift, deletion) cause autosomal dominant spastic paraplegia, most
    likely by halving KIF1A expression through nonsense-mediated decay or
    absent transcription rather than by producing a poisoning motor. Carriers
    reported in the literature have pure spastic paraplegia with normal
    cognition and no seizures or visual problems. The two SPG30A families in
    the same Dutch cohort that had learning difficulties or borderline
    intellectual disability carried motor-domain missense variants (p.Ser69Leu,
    p.Leu173Pro), not loss-of-function alleles.
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  genetic_context:
    gene:
      preferred_term: KIF1A
      term:
        id: hgnc:888
        label: KIF1A
    allele_type: loss-of-function (nonsense, frameshift, deletion)
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: microtubule motor activity
    term:
      id: GO:0003777
      label: microtubule motor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families."
    explanation: Loss-of-function variants cause dominant spastic paraplegia.
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia."
    explanation: Authors infer haploinsufficiency from the variant class.
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "In contrast to the variants in the motor domain, loss-of-function variants will not result in an impaired transport of KIF1A itself, but rather a reduced expression of KIF1A in neurons due to nonsense-mediated decay of the variant mRNA, or due to complete absence of transcription of the deleted allele."
    explanation: Proposed molecular route from loss-of-function allele to reduced KIF1A dosage.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "These individuals, some in their 60s at the time of report, all had normal cognition, normal MRIs, and no history of the visual problems or seizures common in our cohort."
    explanation: Literature loss-of-function carriers have a mild, pure phenotype.
  downstream:
  - target: Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced KIF1A dosage is presumed to lower anterograde transport capacity;
      transport has not been measured in patient neurons with loss-of-function
      alleles.
    evidence:
    - reference: PMID:31488895
      reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: "Finally, heterozygous KIF1A knockout mice develop neuropathy at older age, indicating that KIF1A haploinsufficiency leads to a neurological phenotype [28]."
      explanation: Heterozygous knockout mice show that reduced KIF1A dosage is pathogenic.
- name: Biallelic KIF1A Variants
  role: trigger
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  subtypes:
  - SPG30B
  description: >-
    Homozygous or compound heterozygous KIF1A variants cause recessive spastic
    paraplegia. The first family carried a homozygous motor-domain missense
    variant (p.Ala255Val); whether recessive SPG30 alleles reduce motor function
    or hyperactivate it is unresolved.
  genes:
  - preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  genetic_context:
    gene:
      preferred_term: KIF1A
      term:
        id: hgnc:888
        label: KIF1A
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: UNKNOWN
  molecular_functions:
  - preferred_term: microtubule motor activity
    term:
      id: GO:0003777
      label: microtubule motor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21487076
    reference_title: Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, the only harmful variation according to our stringent analysis is Ala255Val in KIF1A."
    explanation: Homozygous p.Ala255Val is the causal recessive variant in the first family.
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "On the other hand, we have suggested that KIF1A(V8M), KIF1A(A255V), and KIF1A(R350G) mutations (all of them are familial) result in a gain of function (25)."
    explanation: Prior worm work suggests the recessive A255V allele hyperactivates the motor, so the direction of effect is not settled.
  - reference: PMID:31455732
    reference_title: Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility."
    explanation: Purified full-length motors carrying SPG-associated variants are hyperactive, arguing against simple loss of function for these alleles.
  - reference: PMID:31455732
    reference_title: Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs."
    explanation: The same variants increase anterograde SVP transport in worms.
  downstream:
  - target: Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Biallelic variants are presumed to disturb synaptic vesicle precursor
      transport, either by reducing it or by mislocalizing cargo through
      hyperactivation.
    evidence:
    - reference: PMID:21487076
      reference_title: Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that has not yet associated with HSP, which functions in anterograde axonal transportation."
      explanation: Links the recessive variant to the anterograde transport function of KIF1A.
- name: Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors
  role: mechanism
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    KIF1A is the principal anterograde motor for synaptic vesicle precursors.
    Mutant motor domains fail to accumulate at neurite tips, KAND knock-in worms
    show reduced axonal RAB-3 and mislocalization of synaptic vesicles to
    dendrites, and Kif1a-null mice show a specific decrease in synaptic vesicle
    precursor transport.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: anterograde axonal transport
    term:
      id: GO:0008089
      label: anterograde axonal transport
    modifier: DECREASED
  - preferred_term: anterograde synaptic vesicle transport
    term:
      id: GO:0048490
      label: anterograde synaptic vesicle transport
    modifier: DECREASED
  evidence:
  - reference: PMID:21376300
    reference_title: Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "KIF1A-MD accumulated in distal regions of neurites, whereas both KIF1A-MD-T312M and KIF1A-MD-T99M showed greatly reduced distal localization and increased accumulation throughout the cell body and proximal neurites (Figure 1)."
    explanation: The p.Thr99Met motor domain fails to move to distal neurites in cultured hippocampal neurons.
  - reference: PMID:9548721
    reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease."
    explanation: Kif1a loss in mice specifically reduces synaptic vesicle precursor transport.
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In KAND models, GFP::RAB-3 signals were reduced in the axon and strongly mislocalized within the dendrite"
    explanation: Synaptic vesicle marker is depleted from axons in KAND worms.
  downstream:
  - target: Synaptic Vesicle Depletion and Synaptic Dysfunction
    causal_link_type: DIRECT
    description: >-
      Undelivered precursors leave presynaptic terminals depleted of synaptic
      vesicles.
    evidence:
    - reference: PMID:9548721
      reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies."
      explanation: Loss of transport reduces synaptic vesicle density in mice.
  - target: Progressive Neuronal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic transport failure leads to neuronal degeneration and death; the
      intervening steps (including loss of afferent trophic support) are not
      established in human neurons.
    evidence:
    - reference: PMID:9548721
      reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, our results demonstrate that KIF1A transports a synaptic vesicle precursor and that KIF1A-mediated axonal transport plays a critical role in viability, maintenance, and function of neurons, particularly mature neurons."
      explanation: KIF1A-mediated transport is required for neuronal survival in mice.
- name: Synaptic Vesicle Depletion and Synaptic Dysfunction
  role: mechanism
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Reduced delivery of synaptic vesicle precursors lowers presynaptic vesicle
    density and causes synaptic deficits. This is shown in Kif1a-null mice and
    KAND knock-in worms; its contribution to developmental delay and seizures in
    patients is inferred.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both heterozygous and homozygous worms show synaptic deficiencies that are caused by defects in axonal transport."
    explanation: Synaptic deficits follow transport failure in KAND worms.
  - reference: PMID:9548721
    reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consequently, synaptic vesicle density decreased dramatically, and clusters of clear small vesicles accumulated in the cell bodies."
    explanation: Reduced synaptic vesicle density in Kif1a-null mice.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Synaptic dysfunction is the presumed basis of the neurodevelopmental
      phenotype; the link is inferred from model data.
    evidence:
    - reference: PMID:25265257
      reference_title: "De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons."
      explanation: Variants found in cognitively impaired individuals impair axonal transport of the motor domain.
- name: Progressive Neuronal Degeneration
  role: mechanism
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    KAND is neurodegenerative: spasticity and optic nerve atrophy progress with
    age and many severely affected individuals are wheelchair dependent by their
    twenties, while cognition largely does not regress. Long projection neurons
    (corticospinal, optic nerve, peripheral sensory and motor axons) are
    clinically affected; neuronal degeneration has been shown directly in
    Kif1a-null mice and in the cerebellum at autopsy.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  - preferred_term: retinal ganglion cell
    term:
      id: CL:0000740
      label: retinal ganglion cell
  locations:
  - preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  - preferred_term: optic nerve
    term:
      id: UBERON:0000941
      label: cranial nerve II
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By the time they reached their 20s, many individuals were largely wheelchair dependent."
    explanation: Progressive motor decline in the natural-history cohort.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the loss of vision and of motor skills limited an individual’s ability to participate in the activities of daily living over time, we largely did not see cognitive regression."
    explanation: Degeneration affects motor and visual pathways more than cognition.
  - reference: PMID:9548721
    reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons."
    explanation: Neuronal degeneration follows KIF1A loss in mice.
  downstream:
  - target: Progressive spastic paraplegia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Degeneration of long corticospinal axons is the presumed basis of
      progressive lower-limb spasticity; corticospinal pathology has not been
      described at autopsy.
    evidence:
    - reference: PMID:33880452
      reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Spasticity was progressive, and a number of individuals required surgical intervention: 15% (15/100) received tendon lengthening procedures."
      explanation: Spasticity progresses over time, consistent with ongoing degeneration.
  - target: Lower limb muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Presumed consequence of corticospinal and peripheral motor axon degeneration.
  - target: Optic atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Retinal ganglion cell axon loss produces optic nerve atrophy, which
      progresses with age.
    evidence:
    - reference: PMID:33880452
      reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "When present, optic nerve atrophy also appeared to be progressive in most individuals."
      explanation: Optic nerve atrophy is progressive.
  - target: Peripheral neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Presumed length-dependent degeneration of peripheral axons.
  - target: Loss of ambulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Progressive spasticity and weakness lead to loss of independent walking.
    evidence:
    - reference: PMID:42500835
      reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Independent walking was achieved by 62.7% at a median age of 24 months, but only 31.4% retained independent ambulation at last evaluation."
      explanation: Ambulation is acquired and then lost in many individuals.
  - target: Cerebellar Purkinje and Granule Cell Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The cerebellum is a prominent site of neuronal loss.
    evidence:
    - reference: PMID:33880452
      reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Microscopic examination revealed severe cerebellar atrophy most prominent in the superior cerebellar vermis, including a thin molecular layer, a depletion of Purkinje and internal granule cells, Bergmann gliosis, and white matter pallor."
      explanation: Autopsy shows neuronal loss in the cerebellum.
- name: Cerebellar Purkinje and Granule Cell Loss
  role: consequence
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  subtypes:
  - MRD9
  description: >-
    Autopsies of two children with de novo p.Thr99Met showed severe cerebellar
    atrophy most prominent in the superior vermis, with a thin molecular layer,
    depletion of Purkinje and internal granule cells, Bergmann gliosis, white
    matter pallor and rare axonal spheroids, plus neuronal loss in the dentate
    and inferior olivary nuclei.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  locations:
  - preferred_term: cerebellar vermis
    term:
      id: UBERON:0004720
      label: cerebellar vermis
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microscopic examination revealed severe cerebellar atrophy most prominent in the superior cerebellar vermis, including a thin molecular layer, a depletion of Purkinje and internal granule cells, Bergmann gliosis, and white matter pallor."
    explanation: Neuropathology of p.Thr99Met KAND.
  downstream:
  - target: Cerebellar atrophy
    causal_link_type: DIRECT
    description: Loss of cerebellar neurons is seen as cerebellar atrophy on MRI.
    evidence:
    - reference: PMID:33880452
      reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Microscopic examination revealed severe cerebellar atrophy most prominent in the superior cerebellar vermis, including a thin molecular layer, a depletion of Purkinje and internal granule cells, Bergmann gliosis, and white matter pallor."
      explanation: The atrophy is accounted for by Purkinje and granule cell depletion.
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar neuronal loss is the presumed basis of ataxia and cerebellar signs.
genetic:
- name: KIF1A de novo motor-domain missense variants
  gene_term:
    preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  subtype: MRD9
  features: >-
    Heterozygous, usually de novo missense variants in the motor domain;
    recurrent alleles include p.Thr99Met and p.Glu253Lys. More than 30% of
    individuals carry private variants.
  evidence:
  - reference: PMID:25265257
    reference_title: "De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases."
    explanation: Recurrent de novo motor-domain alleles.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than 30% of individuals with KAND have private variants, and there are likely many more variants that remain to be identified."
    explanation: Allelic heterogeneity of KAND.
- name: KIF1A dominant missense and loss-of-function variants
  gene_term:
    preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: SPG30A
  features: >-
    Motor-domain missense variants and loss-of-function variants outside the
    motor domain, inherited dominantly or arising de novo.
  case_fractions:
  - population: Dutch clinical exome cohort of mostly pure spastic paraplegia
    case_fraction_low: 6.0
    case_fraction_high: 7.0
    cohort_size: 347
    notes: KIF1A variants in 24 of 347 individuals.
    evidence:
    - reference: PMID:31488895
      reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%)."
      explanation: Share of spastic paraplegia explained by KIF1A in this cohort.
  evidence:
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia."
    explanation: Identifies KIF1A variants in dominant spastic paraplegia.
- name: KIF1A biallelic variants
  gene_term:
    preferred_term: KIF1A
    term:
      id: hgnc:888
      label: KIF1A
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: SPG30B
  features: >-
    Homozygous motor-domain missense variant (p.Ala255Val) in the first family,
    an inbred Palestinian kindred whose parents denied consanguinity but came
    from the same village.
  evidence:
  - reference: PMID:21487076
    reference_title: Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, the only harmful variation according to our stringent analysis is Ala255Val in KIF1A."
    explanation: Causal recessive variant.
phenotypes:
- category: Neurological
  name: Global developmental delay
  frequency: VERY_FREQUENT
  subtype: MRD9
  description: >-
    Developmental delay is present in nearly all individuals with the
    neurodevelopmental presentation (96.1% of a 51-patient cohort; 92% with
    developmental delay or intellectual disability in a 100-patient cohort).
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%."
    explanation: Cohort frequency of global developmental delay.
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic neuropathy, poor weight gain, and neurobehavioral issues including autism spectrum disorder."
    explanation: GeneReviews lists developmental delay as a common feature.
- category: Neurological
  name: Intellectual disability
  frequency: VERY_FREQUENT
  subtype: MRD9
  description: >-
    Cognitive impairment of variable degree; cognition generally does not
    regress.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly all individuals had some degree of developmental delay and/or intellectual disability (92%, 92/100)."
    explanation: Cohort frequency.
  - reference: PMID:25265257
    reference_title: "De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy."
    explanation: Cognitive impairment is the core feature of de novo disease.
- category: Neurological
  name: Hypotonia
  frequency: FREQUENT
  description: >-
    Neonatal or infantile hypotonia, typically followed by spasticity (62.7% in
    one cohort; 84% current or resolved hypotonia in another).
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%."
    explanation: Cohort frequency of hypotonia.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequently observed symptoms in our cohort were hypotonia (84%, 84/100) and hypertonia or spasticity (81%, 81/100)."
    explanation: Second cohort frequency.
- category: Neurological
  name: Progressive spastic paraplegia
  frequency: FREQUENT
  description: >-
    Progressive, lower-limb predominant spasticity that correlates with age
    (72.5% in a 51-patient cohort; hypertonia or spasticity in 81% of a
    100-patient cohort). It is the defining feature of SPG30A and SPG30B.
  phenotype_term:
    preferred_term: Progressive spastic paraplegia
    term:
      id: HP:0007020
      label: Progressive spastic paraplegia
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive spasticity occurred in 72.5%, predominantly affecting the lower extremities and correlated with age"
    explanation: Cohort frequency of progressive spasticity.
- category: Neurological
  name: Lower limb spasticity in hereditary spastic paraplegia subtypes
  subtypes:
  - SPG30A
  - SPG30B
  description: >-
    In SPG30A the spastic paraplegia is slowly progressive and mostly pure with
    onset from 0 to 57 years; in the first SPG30B family it began in infancy and
    involved only spastic gait.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years)."
    explanation: SPG30A phenotype.
  - reference: PMID:21487076
    reference_title: Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our patients, the disease presented in infancy and has only involved spastic gait without additional abnormalities."
    explanation: SPG30B phenotype in the first family.
- category: Neurological
  name: Lower limb muscle weakness
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower extremity weakness was nearly universal (88.2%) and inversely related with age"
    explanation: Cohort frequency.
- category: Neurological
  name: Loss of ambulation
  description: >-
    62.7% achieve independent walking (median 24 months) but only 31.4% retain
    it at last evaluation; many severely affected individuals are wheelchair
    dependent by their twenties.
  phenotype_term:
    preferred_term: Loss of ambulation
    term:
      id: HP:0002505
      label: Loss of ambulation
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Independent walking was achieved by 62.7% at a median age of 24 months, but only 31.4% retained independent ambulation at last evaluation."
    explanation: Acquisition and loss of ambulation.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By the time they reached their 20s, many individuals were largely wheelchair dependent."
    explanation: Wheelchair dependence in early adulthood.
- category: Ophthalmological
  name: Optic atrophy
  frequency: VERY_FREQUENT
  subtype: MRD9
  description: >-
    Optic nerve atrophy is the primary ocular finding: 95% of a prospectively
    examined cohort on examination and/or OCT, against 50% by caregiver report
    in a larger cohort. It appears progressive, and adults have worse acuity
    than children.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:39009236
    reference_title: Ophthalmic Findings in the KIF1A-Associated Neurologic Disorder (KAND).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT)."
    explanation: Prospective ophthalmic frequency.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of our cohort (50/100) had optic nerve atrophy or optic nerve hypoplasia, and there was a high prevalence of cortical visual impairment (20%, 20/100) and strabismus (26%, 26/100)."
    explanation: Reported frequency in the natural-history cohort.
- category: Ophthalmological
  name: Strabismus
  frequency: FREQUENT
  subtype: MRD9
  description: Almost 40% on prospective examination; 26% by report.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:39009236
    reference_title: Ophthalmic Findings in the KIF1A-Associated Neurologic Disorder (KAND).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT). Almost 40% had strabismus."
    explanation: Prospective frequency.
- category: Ophthalmological
  name: Cerebral visual impairment
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Cortical visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of our cohort (50/100) had optic nerve atrophy or optic nerve hypoplasia, and there was a high prevalence of cortical visual impairment (20%, 20/100) and strabismus (26%, 26/100)."
    explanation: 20% frequency.
- category: Neurological
  name: Seizure
  frequency: FREQUENT
  subtype: MRD9
  description: >-
    42% report seizures, often of several types; absence seizures are the most
    common. Seizures can be refractory.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures were common in our cohort, with 42% (42/100) reporting a history of seizures."
    explanation: Cohort frequency.
- category: Neurological
  name: Absence seizures
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Absence seizure
    term:
      id: HP:0002121
      label: Generalized non-motor (absence) seizure
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple seizure types were described, often in the same individual, with absence seizures as the most common in 29% (29/100) of the cohort overall and in 69% (29/42) of those with seizures."
    explanation: 29% of the cohort.
- category: Neurological
  name: Cerebellar atrophy
  frequency: FREQUENT
  subtype: MRD9
  description: >-
    The most common MRI abnormality (35% of imaged individuals in one cohort,
    65% in the literature cohort); progressive and vermis-predominant.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among those who had neuroimaging, the majority (58%, 54/93) had abnormal findings, most commonly cerebellar atrophy (35%, 33/93), abnormalities in the corpus callosum (11%, 10/93), and cerebral atrophy (6%, 6/93)."
    explanation: MRI frequency.
- category: Neurological
  name: Abnormal corpus callosum morphology
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Corpus callosum atrophy or hypoplasia
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among those who had neuroimaging, the majority (58%, 54/93) had abnormal findings, most commonly cerebellar atrophy (35%, 33/93), abnormalities in the corpus callosum (11%, 10/93), and cerebral atrophy (6%, 6/93)."
    explanation: 11% of imaged individuals.
- category: Neurological
  name: Microcephaly
  frequency: OCCASIONAL
  subtype: MRD9
  description: >-
    Reported in 18% of a 100-patient cohort; more likely with earlier disease
    onset.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with earlier-onset disease were more likely to develop microcephaly, and individuals with later-onset disease more often underwent musculoskeletal surgeries."
    explanation: Microcephaly occurs and associates with earlier onset.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Table 1Phenotypic summary of KAND individualsOur cohortLiterature cohortNeurologicalHypotonia84%(84/100)38%(17/45)Hypertonia81%(81/100)84%(38/45)Microcephaly18%(18/100)18%(8/45)Peripheral neuropathy27%(27/100)38%(17/45)"
    explanation: Table 1 frequencies, microcephaly 18% in the cohort and literature; peripheral neuropathy 27% (cohort) and 38% (literature).
- category: Neurological
  name: Peripheral neuropathy
  frequency: OCCASIONAL
  description: >-
    Axonal sensorimotor neuropathy in 27% of a 100-patient cohort and 38% of the
    literature cohort; prominent in HSAN2C.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:25265257
    reference_title: "De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy."
    explanation: Peripheral neuropathy is part of the variable phenotype.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Table 1Phenotypic summary of KAND individualsOur cohortLiterature cohortNeurologicalHypotonia84%(84/100)38%(17/45)Hypertonia81%(81/100)84%(38/45)Microcephaly18%(18/100)18%(8/45)Peripheral neuropathy27%(27/100)38%(17/45)"
    explanation: Table 1 frequencies, microcephaly 18% in the cohort and literature; peripheral neuropathy 27% (cohort) and 38% (literature).
- category: Neurological
  name: Ataxia
  frequency: OCCASIONAL
  description: >-
    Ataxia in 19.6% and cerebellar signs in 37.2% of a 51-patient cohort; a
    subset presents with early-onset or congenital ataxia.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%)."
    explanation: Cohort frequency.
  - reference: PMID:32737135
    reference_title: Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype."
    explanation: Congenital ataxic presentations of heterozygous KIF1A variants.
- category: Neurological
  name: Motor stereotypy
  frequency: FREQUENT
  subtype: MRD9
  phenotype_term:
    preferred_term: Motor stereotypy
    term:
      id: HP:0000733
      label: Motor stereotypy
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%)."
    explanation: 43.1% frequency.
- category: Neurological
  name: Action tremor
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Action tremor
    term:
      id: HP:0002345
      label: Action tremor
  evidence:
  - reference: PMID:42500835
    reference_title: "KIF1A-Associated Neurological Disorder (KAND): Spectrum of Movement and Motor Disorders in a Cohort of 51 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Movement disorders included motor stereotypies (43.1%), ataxia (19.6%), action tremor (15.6%), and dystonia (3.9%)."
    explanation: 15.6% frequency.
- category: Behavioral
  name: Autism
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frequently reported neurobehavioral diagnoses included autism (20%, 16/80), attention deficit hyperactivity disorder (24%, 19/80), anxiety (19%, 15/80), and obsessive-compulsive disorder (5%, 4/80)."
    explanation: 20% frequency.
- category: Behavioral
  name: Attention deficit hyperactivity disorder
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frequently reported neurobehavioral diagnoses included autism (20%, 16/80), attention deficit hyperactivity disorder (24%, 19/80), anxiety (19%, 15/80), and obsessive-compulsive disorder (5%, 4/80)."
    explanation: 24% frequency.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal issues were common, with 40% (40/100) reporting gastroesophageal reflux disease (GERD), constipation (39%, 39/100), and diarrhea (17%, 17/100)."
    explanation: 40% frequency.
- category: Gastrointestinal
  name: Constipation
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gastrointestinal issues were common, with 40% (40/100) reporting gastroesophageal reflux disease (GERD), constipation (39%, 39/100), and diarrhea (17%, 17/100)."
    explanation: 39% frequency.
- category: Growth
  name: Short stature
  frequency: OCCASIONAL
  description: Short stature in 11%, with complete growth hormone deficiency in three individuals.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Another feature not previously reported in KAND was short stature, which we observed in 11% (11/100) of our cohort."
    explanation: 11% frequency.
- category: Musculoskeletal
  name: Scoliosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain tolerance (65%, 52/80)."
    explanation: 14% frequency.
- category: Autonomic
  name: Abnormality of temperature regulation
  frequency: FREQUENT
  subtype: MRD9
  description: >-
    Reported in 46%, including sporadic fevers unrelated to illness; possibly a feature of dysautonomia.
  phenotype_term:
    preferred_term: Difficulty with temperature regulation
    term:
      id: HP:0004370
      label: Abnormality of temperature regulation
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Just under half of individuals (46%, 37/80) experience difficulty with temperature regulation, including sporadic fevers unrelated to illness."
    explanation: 46% (37/80), including sporadic fevers unrelated to illness.
- category: Autonomic
  name: Extremities cold to touch
  frequency: FREQUENT
  subtype: MRD9
  phenotype_term:
    preferred_term: Cold extremities
    term:
      id: HP:6000500
      label: Extremities cold to touch
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain tolerance (65%, 52/80)."
    explanation: Cold extremities in 60% (48/80).
- category: Neurological
  name: Reduced pain sensitivity
  frequency: FREQUENT
  subtype: MRD9
  description: >-
    Caregiver-reported high pain tolerance (65%); bound to the broader impaired pain sensation rather than pain insensitivity.
  phenotype_term:
    preferred_term: High pain tolerance
    term:
      id: HP:0007328
      label: Impaired pain sensation
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain tolerance (65%, 52/80)."
    explanation: High pain tolerance in 65% (52/80).
- category: Neurological
  name: Bruxism
  frequency: FREQUENT
  subtype: MRD9
  phenotype_term:
    preferred_term: Bruxism
    term:
      id: HP:0003763
      label: Bruxism
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain tolerance (65%, 52/80)."
    explanation: Bruxism in 35% (28/80).
- category: Neurological
  name: Stereotypical hand wringing
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Stereotypic hand wringing or clasping
    term:
      id: HP:0012171
      label: Stereotypical hand wringing
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also saw some features commonly seen in Rett syndrome, including stereotypic hand movements like wringing or clasping (21%, 17/80), small extremities (34% 27/90), cold extremities (60%, 48/80), bruxism (35%, 28/80), abnormal laughing spells (15%, 11/80), scoliosis (14%, 14/100), and high pain tolerance (65%, 52/80)."
    explanation: Stereotypic hand wringing or clasping in 21% (17/80).
- category: Behavioral
  name: Anxiety
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Frequently reported neurobehavioral diagnoses included autism (20%, 16/80), attention deficit hyperactivity disorder (24%, 19/80), anxiety (19%, 15/80), and obsessive-compulsive disorder (5%, 4/80)."
    explanation: Anxiety in 19% (15/80).
- category: Gastrointestinal
  name: Drooling
  frequency: OCCASIONAL
  subtype: MRD9
  phenotype_term:
    preferred_term: Excessive salivation
    term:
      id: HP:0002307
      label: Drooling
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many affected individuals experienced excessive salivation (26%, 21/80) or problems swallowing (29%, 23/80)."
    explanation: Excessive salivation in 26% (21/80).
- category: Gastrointestinal
  name: Dysphagia
  frequency: OCCASIONAL
  description: >-
    Swallowing problems in 29%; 10% of a 100-patient cohort needed enteral nutritional support, often because of dysphagia.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many affected individuals experienced excessive salivation (26%, 21/80) or problems swallowing (29%, 23/80)."
    explanation: Problems swallowing in 29% (23/80).
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten percent of the overall cohort (10/100) required enteric nutritional support, in many individuals due to the difficulty swallowing."
    explanation: Dysphagia leads to enteral feeding in some individuals.
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "feeding therapy to manage dysphagia"
    explanation: GeneReviews management addresses dysphagia.
- category: Neurological
  name: Delayed speech and language development
  description: >-
    GeneReviews lists communication difficulties as common; no cohort frequency is available in the cached sources.
  phenotype_term:
    preferred_term: Communication difficulties
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic neuropathy, poor weight gain, and neurobehavioral issues including autism spectrum disorder."
    explanation: GeneReviews lists communication difficulties among common features.
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "speech-language therapy to improve communication"
    explanation: Management targets communication.
- category: Growth
  name: Failure to thrive
  phenotype_term:
    preferred_term: Poor weight gain
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic neuropathy, poor weight gain, and neurobehavioral issues including autism spectrum disorder."
    explanation: GeneReviews lists poor weight gain among common features.
- category: Autonomic
  name: Autonomic dysfunction
  description: >-
    GeneReviews lists autonomic neuropathy; cohort temperature, gastrointestinal and salivary symptoms may reflect dysautonomia but autonomic function has not been tested directly.
  phenotype_term:
    preferred_term: Autonomic neuropathy
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "KIF1A-related neurodevelopmental disorder (KIF1A-NDD) is both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic neuropathy, poor weight gain, and neurobehavioral issues including autism spectrum disorder."
    explanation: GeneReviews lists autonomic neuropathy among common features.
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While these symptoms may reflect autonomic dysfunction, there may be other underlying causative factors, and further direct assessment of autonomic function will be beneficial."
    explanation: Temperature, gastrointestinal and swallowing symptoms may reflect autonomic dysfunction; not directly tested.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    The diagnosis is established by finding a heterozygous, or less commonly
    biallelic, pathogenic KIF1A variant by molecular genetic testing (exome,
    genome or multigene panel) in a proband with suggestive findings; parental
    testing establishes de novo status.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The diagnosis of KIF1A-NDD is established in a proband with suggestive findings and a heterozygous pathogenic variant or, less commonly, biallelic pathogenic variants in KIF1A identified by molecular genetic testing."
    explanation: GeneReviews diagnostic criterion.
treatments:
- name: Allele-Specific Antisense Oligonucleotide (n-of-1)
  description: >-
    Experimental individualized therapy. A 9-year-old girl with severe KAND and
    a de novo p.Pro305Leu variant received intrathecal nL-KIF1-001, a 5-10-5
    2'-MOE gapmer with mixed phosphorothioate/phosphodiester backbone designed
    to recruit RNase H1 to the transcript of the pathogenic allele, selected
    using a SNP in cis. Dosing escalated from 20 mg in 20 mg steps to 80 mg.
    Over 9 months it was safe apart from an epidural CSF collection after the
    first injection; spells of behavioral arrest, falls and quality of life
    improved, 6-minute walk distance changed little, and cognition was stable.
    The rationale is to remove the dominant-negative allele, leaving a
    haploinsufficient state that loss-of-function carriers suggest is much
    milder.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  oligonucleotide_details:
    oligonucleotide_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: KIF1A
      term:
        id: hgnc:888
        label: KIF1A
    target_transcript: KIF1A mRNA from the p.Pro305Leu allele (allele-specific)
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
  delivery_system:
    delivery_platform: UNFORMULATED
    targeting_ligand: UNCONJUGATED
  treatment_term:
    preferred_term: allele-specific antisense oligonucleotide therapy
    term:
      id: NCIT:C16236
      label: Antisense Therapy
    therapeutic_agent:
    - preferred_term: nL-KIF1-001 (allele-specific antisense oligonucleotide)
      term:
        id: NCIT:C1291
        label: Antisense Oligonucleotides
  target_mechanisms:
  - target: Dominant-Negative Inhibition of Wild-Type KIF1A
    treatment_effect: INHIBITS
    description: Degrades the pathogenic-allele transcript to remove the dominant-negative subunit.
  evidence:
  - reference: PMID:39122967
    reference_title: Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele."
    explanation: Describes the n-of-1 allele-specific ASO treatment.
  - reference: PMID:39122967
    reference_title: Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved."
    explanation: Safety and outcome in the single treated patient.
  - reference: PMID:39122967
    reference_title: Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "There was no significant reduction of the mRNA level from the wildtype allele at any concentration tested, highlighting the high selectivity of nL-KIF1-001 for the mRNA from the pathogenic allele over the wildtype allele (Figure 1B)"
    explanation: Allele selectivity in patient iPSC-derived neurons.
  - reference: PMID:39122967
    reference_title: Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The oligonucleotide general structure is a 5-10-5 2′methoxyethyl (MOE) gapmer and comprises five nucleotides at the 5′ end and five nucleotides at the 3′ end that are modified at the 2′-O of ribose with a MOE group."
    explanation: Oligonucleotide chemistry.
- name: Physical Therapy
  description: >-
    Physical therapy including stretching to reduce contractures and falls, as
    part of multidisciplinary supportive care.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Progressive spastic paraplegia
    treatment_effect: INHIBITS
    description: Symptomatic management of spasticity and its complications.
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "physical therapy including stretching to help avoid contractures and falls"
    explanation: GeneReviews management recommendation.
- name: Speech-Language Therapy
  description: Speech-language therapy to improve communication.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "speech-language therapy to improve communication"
    explanation: GeneReviews management recommendation.
- name: Seizure and Neuropathic Pain Management
  description: >-
    Neurologist-directed management of seizures and of pain from peripheral
    neuropathy. Seizures in some individuals are refractory to multiple
    antiseizure medications.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Seizure
    treatment_effect: INHIBITS
    description: Symptomatic seizure control.
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "management of seizures and pain associated with peripheral neuropathy by neurologist"
    explanation: GeneReviews management recommendation.
- name: Tendon Lengthening Surgery
  description: >-
    Orthopedic surgery for progressive spasticity; 15% of a 100-patient cohort
    underwent tendon lengthening.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: tendon lengthening
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spasticity was progressive, and a number of individuals required surgical intervention: 15% (15/100) received tendon lengthening procedures."
    explanation: Frequency of tendon lengthening surgery.
- name: Ubiquinol Supplementation
  description: >-
    Used in six patients with muscle-biopsy evidence of secondary oxidative
    metabolism impairment or low CoQ10, with subjective benefit only; no
    controlled data.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ubiquinol
  evidence:
  - reference: PMID:34487232
    reference_title: "Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit."
    explanation: Uncontrolled use with subjective benefit.
- name: Genetic Counseling
  description: >-
    Counseling on dominant (mostly de novo, about 1% sib recurrence from
    gonadal mosaicism) and recessive inheritance; prenatal and preimplantation
    testing once the familial variant is known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Once the KIF1A pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: GeneReviews genetic counseling guidance.
- name: Feeding Therapy
  description: Feeding therapy to manage dysphagia.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: feeding therapy
    term:
      id: NCIT:C156237
      label: Swallowing Therapy
  target_mechanisms:
  - target: Dysphagia
    treatment_effect: INHIBITS
    description: Symptomatic management of swallowing difficulty.
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "feeding therapy to manage dysphagia"
    explanation: GeneReviews management recommendation.
- name: Refractive Error Management
  description: Ophthalmologic treatment of refractive errors as part of supportive care.
  treatment_term:
    preferred_term: ophthalmologic management of refractive errors
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41941559
    reference_title: KIF1A-Related Neurodevelopmental Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "treatment by ophthalmologist to manage refractive errors"
    explanation: GeneReviews management recommendation.
animal_models:
- name: C. elegans unc-104 KAND knock-in models
  species: Caenorhabditis elegans
  genotype: unc-104(R9Q), unc-104(R251Q), unc-104(P298L) heterozygous and homozygous (human KIF1A R11Q, R254Q, P305L)
  description: >-
    CRISPR-Cas9 knock-ins of KAND motor-domain variants into the KIF1A ortholog
    unc-104. Heterozygotes and homozygotes have reduced axonal transport of
    synaptic vesicles, and heterozygotes are more impaired than heterozygous
    null worms. A suppressor screen recovered UNC-104(D177N), which restores
    motor activity.
  publication: PMID:35917346
  modeled_mechanisms:
  - target: Dominant-Negative Inhibition of Wild-Type KIF1A
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      Worms lack the corticospinal tract, optic nerve and cerebellum, so the
      degenerative human phenotypes cannot be assessed.
    evidence:
    - reference: PMID:35917346
      reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overall, the phenotypes of unc-104(R9Q)/+, unc-104(R251Q)/+, and unc-104(P298L)/+ were stronger than unc-104(null)/+, suggesting that the KAND mutations result in dominant-negative phenotypes for unc-104 transport in living animals."
      explanation: Heterozygous knock-ins show a dominant-negative effect in vivo.
  - target: Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    evidence:
    - reference: PMID:35917346
      reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In our C. elegans models, both heterozygotes and homozygotes exhibited reduced axonal transport."
      explanation: Reduced axonal transport in KAND worms.
  evidence:
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Suppressor screening using the disease model identified a mutation that recovers the motor activity of mutated human KIF1A."
    explanation: The worm model supports genetic suppressor screens.
- name: Kif1a knockout mouse
  species: Mus musculus
  genotype: Kif1a-/-
  description: >-
    Homozygous Kif1a disruption is mostly lethal within a day of birth, with
    motor and sensory disturbances, reduced synaptic vesicle precursor
    transport, reduced synaptic vesicle density and neuronal degeneration.
  publication: PMID:9548721
  modeled_mechanisms:
  - target: Impaired Anterograde Axonal Transport of Synaptic Vesicle Precursors
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      Complete loss of function, a genotype not seen in patients, who are
      heterozygous for dominant-negative or loss-of-function alleles or carry
      partial-function recessive alleles.
    evidence:
    - reference: PMID:9548721
      reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the nervous systems of these mutants, the transport of synaptic vesicle precursors showed a specific and significant decrease."
      explanation: Transport defect in knockout mice.
  - target: Progressive Neuronal Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    limitations: >-
      Neonatal lethality prevents study of the slowly progressive degeneration
      seen in patients.
    evidence:
    - reference: PMID:9548721
      reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, marked neuronal degeneration and death occurred both in KIF1A mutant mice and in cultures of mutant neurons."
      explanation: Neuronal degeneration in knockout mice.
  evidence:
  - reference: PMID:9548721
    reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances."
    explanation: Neonatal lethality of the knockout.
discussions:
- discussion_id: kand_genotype_severity
  prompt: >-
    Does variant position or motility class predict severity in KAND, given
    that one cohort finds a strong association with P-loop and switch variants
    and another finds none?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#KIF1A Motor Domain Missense Variants
  rationale: >-
    Genotype-severity correlation matters for counseling and for selecting
    patients for allele-specific therapy. A 100-patient cohort links P-loop,
    switch I and switch II variants and rigor motility to severe disease, while
    a 28-patient Italian series found no correlation between mutation location
    and neurological or imaging presentation. Both are cross-sectional, and
    severity rises with age in a progressive disease.
  evidence:
  - reference: PMID:33880452
    reference_title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II."
    explanation: Reports a genotype-severity association.
  - reference: PMID:34487232
    reference_title: "Monoallelic KIF1A-related disorders: a multicenter cross sectional study and systematic literature review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations."
    explanation: Finds no location-phenotype correlation.
- discussion_id: kand_haploinsufficiency_tolerance
  prompt: >-
    Is a heterozygous KIF1A loss-of-function state benign enough that
    silencing the dominant-negative allele is a durable therapeutic goal?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#KIF1A Haploinsufficiency
  - treatments#Allele-Specific Antisense Oligonucleotide (n-of-1)
  rationale: >-
    Allele-specific knockdown converts a dominant-negative genotype into a
    haploinsufficient one. Loss-of-function carriers have a much milder, pure
    spastic paraplegia, but they do develop disease, sometimes from infancy, so
    the ceiling of benefit and the long-term outcome of knockdown are unknown.
  evidence:
  - reference: PMID:39122967
    reference_title: Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Heterozygous variants leading to KIF1A haploinsufficiency are associated only with adult onset hereditary spastic paraplegia without seizures or cognitive impairment, a phenotype significantly milder than that associated with missense variants9 suggesting that gapmer ASO mediated therapy might provide a bridging therapeutic approach for dominant negative missense variants in KIF1A until other treatment options are available."
    explanation: States the therapeutic rationale and its dependence on haploinsufficiency being mild.
  - reference: PMID:31488895
    reference_title: KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families."
    explanation: Loss-of-function heterozygosity is itself pathogenic.
- discussion_id: kand_spg30b_direction_of_effect
  prompt: >-
    Do recessive SPG30 alleles such as p.Ala255Val reduce KIF1A motor function
    or hyperactivate it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Biallelic KIF1A Variants
  - pathophysiology#KIF1A Motor Domain Missense Variants
  rationale: >-
    The recessive SPG30B allele p.Ala255Val lies in the motor domain, yet worm
    studies have suggested that it and other familial alleles cause gain of
    function. The functional class of recessive alleles determines whether
    SPG30B shares the transport-loss mechanism of the dominant subtypes.
  evidence:
  - reference: PMID:35917346
    reference_title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "On the other hand, we have suggested that KIF1A(V8M), KIF1A(A255V), and KIF1A(R350G) mutations (all of them are familial) result in a gain of function (25)."
    explanation: Prior model data suggest hyperactivation for A255V.
  - reference: PMID:31455732
    reference_title: Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we established in vitro motility assays with purified full-length human KIF1A and found that KIF1A mutations associated with the hereditary SPG lead to hyperactivation of KIF1A motility."
    explanation: SPG-associated variants hyperactivate purified KIF1A.
  - reference: PMID:31455732
    reference_title: Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Introduction of the corresponding mutations into the Caenorhabditis elegans KIF1A homolog unc-104 revealed abnormal accumulation of SVPs at the tips of axons and increased anterograde axonal transport of SVPs."
    explanation: Increased, not decreased, SVP transport in worm knock-ins.
- discussion_id: kand_mouse_model_genotype_mismatch
  prompt: >-
    Can the slowly progressive human degeneration be studied in a model that
    carries a heterozygous KAND allele, given that the only cited mouse is a
    neonatal-lethal null?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Neuronal Degeneration
  - animal_models#Kif1a knockout mouse
  rationale: >-
    Kif1a-null mice die within a day of birth, a genotype no patient has, while
    KAND knock-in worms reproduce the dominant-negative transport defect but
    lack the corticospinal, optic and cerebellar systems that degenerate in
    patients. Neither model can test which neurons degenerate first or whether
    reducing the mutant allele halts degeneration.
  evidence:
  - reference: PMID:9548721
    reference_title: Defect in synaptic vesicle precursor transport and neuronal cell death in KIF1A motor protein-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "KIF1A mutants died mostly within a day after birth showing motor and sensory disturbances."
    explanation: Null mice are neonatal lethal, unlike the heterozygous human disease.
notes: >-
  MONDO places hereditary spastic paraplegia 30 (MONDO:0012476) under both
  hereditary spastic paraplegia and this disorder; its two children, SPG30A
  (MONDO:0700307) and SPG30B (MONDO:0971149), are curated here as subtypes, as
  the Hereditary_Spastic_Paraplegia entry defers SPG30 to this record. HSAN2C
  (MONDO:0013634) is a pointer subtype curated on
  Hereditary_Sensory_and_Autonomic_Neuropathy_Type_2. Phenotype frequencies come
  mainly from KAND cohorts dominated by de novo motor-domain variants (MRD9), so
  features absent from loss-of-function SPG30A carriers (developmental delay,
  seizures, visual involvement) are scoped to MRD9. The 50% optic atrophy
  figure of PMID:33880452 is caregiver-reported, against 95% on prospective
  examination with OCT in PMID:39009236. ClinGen curates KIF1A against
  syndromic intellectual disability rather than against these MONDO subtypes,
  so no gene-disease validity tier is recorded.
references:
- reference: PMID:41941559
  title: KIF1A-Related Neurodevelopmental Disorder.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:33880452
  title: Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.
  found_in:
  - KIF1A_Related_Neurological_Disorder-deep-research-claude_code.md
  findings: []
- reference: PMID:35917346
  title: De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.
  found_in:
  - KIF1A_Related_Neurological_Disorder-deep-research-claude_code.md
  findings: []
- reference: PMID:39122967
  title: Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.
  found_in:
  - KIF1A_Related_Neurological_Disorder-deep-research-claude_code.md
  findings: []

📚

References & Deep Research

References

4

PMID:41941559

KIF1A-Related Neurodevelopmental Disorder.

No top-level findings curated for this source.

PMID:33880452

Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder.

No top-level findings curated for this source.

PMID:35917346

De novo mutations in KIF1A-associated neuronal disorder (KAND) dominant-negatively inhibit motor activity and axonal transport of synaptic vesicle precursors.

No top-level findings curated for this source.

PMID:39122967

Antisense oligonucleotide therapy in an individual with KIF1A-associated neurological disorder.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: KIF1A_Related_Neurological_Disorder · 2026-10-01T15:08:51Z · View source

Created the KIF1A-related neurological disorder (KAND, MONDO:0700055, KIF1A hgnc:888) entry as a Disease with four has_subtypes rows: MRD9 (MONDO:0013656, de novo motor-domain missense; PMID:21376300 p.Thr99Met), SPG30A (MONDO:0700307, dominant missense plus loss-of-function outside the motor domain; PMID:31488895, case fraction 6-7%), SPG30B (MONDO:0971149, biallelic; PMID:21487076 homozygous p.Ala255Val) and HSAN2C (MONDO:0013634) as a pointer subtype with curated_in: Hereditary_Sensory_and_Autonomic_Neuropathy_Type_2. All MONDO IDs/labels checked with runoak ols:mondo. Pathophysiology: 8 nodes; the three KIF1A trigger nodes (motor-domain missense / dominant-negative; haploinsufficiency; biallelic) carry GO microtubule motor activity (GO:0003777) and plus-end-directed microtubule motor activity (GO:0008574) to satisfy the gene-activity grounding gate, scoped with the subtypes list slot; downstream: dominant-negative heterodimer inhibition (PMID:35917346), impaired anterograde SVP transport, synaptic vesicle depletion, progressive neuronal degeneration, cerebellar Purkinje/granule cell loss (autopsy, PMID:33880452). 25 phenotypes with cohort frequencies (PMID:42500835, 33880452, 39009236); neurodevelopmental, seizure and visual features scoped to MRD9 because loss-of-function SPG30A carriers lack them. Treatments: n-of-1 allele-specific 2'-MOE gapmer ASO (PMID:39122967) with oligonucleotide_details, plus GeneReviews-sourced supportive care, tendon lengthening, ubiquinol (uncontrolled, PMID:34487232) and genetic counseling. Animal models: C. elegans unc-104 KAND knock-ins and Kif1a-null mouse. Discussions: genotype-severity conflict (PMID:33880452 vs 34487232), haploinsufficiency tolerance for ASO strategy, SPG30B direction of effect (A255V suggested gain of function), and a HUMAN_MODEL_MISMATCH for the neonatal-lethal null mouse. GeneReviews PMID:41941559 tagged in references and confirmed TAGGED by just check-genereviews --online. Deep research: requested falcon was not configured (ProviderNotConfiguredError) and the run fell back to claude_code; 17/17 references resolved. just preflight-dr returned SKIP because MONDO records no causal gene at the umbrella class; manual check found KIF1A is the sole gene discussed (46 mentions). Stubs retired: KIF1A_Related_Neurological_Disorder, Intellectual_Disability_Autosomal_Dominant_9, Hereditary_Spastic_Paraplegia_30. Validation: just validate 0 issues (105/105 snippets verified); check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, gene-activity grounding (against origin/main), check-snippet-grading, check-title-snippets, check-snippet-length, check-coarse-phenotypes, check-term-cache-integrity and check-cache-order all OK.

Claude Code ▸

KIF1A-Related Neurological Disorder (KAND; MONDO:0700055): research report

claude-haiku-4-5-20251001, claude-opus-5-5 15 citations 2026-10-01T10:35:25.450484

Found the core identifiers, mechanism papers, and treatment reports. Next I'm pulling phenotype frequencies from the full texts already cached locally, then I'll write the report.

KIF1A-Related Neurological Disorder (KAND; MONDO:0700055): research report

Prepared: 2026-10-01. Scope: a source dossier for curating kb/disorders/KIF1A_Related_Neurological_Disorder.yaml.

How to read this report - Cached quotes. Quotes marked ✅ come word-for-word from references_cache/PMID_*.md files already in this worktree, so they can be used directly as snippet: values. - Uncached sources. Other PMIDs or sources are leads. Fetch them with just fetch-reference and confirm the wording before quoting. - Ontology IDs. All ontology CURIEs below are candidates I recalled from memory. CLAUDE.md requires every one to be looked up with runoak or the term cache before it is written into the entry.

1. Disease information

Overview. KAND is a spectrum of rare neurodevelopmental and neurodegenerative conditions. They are caused by pathogenic variants in KIF1A, which encodes a neuron-specific kinesin-3 motor that carries synaptic vesicle precursors (SVPs) and dense-core vesicles forward along axons. - ✅ PMID:33880452 (Boyle et al. 2021, HGG Adv): "KIF1A-associated neurological disorder (KAND) encompasses a group of rare neurodegenerative conditions caused by variants in KIF1A,a gene that encodes an anterograde neuronal microtubule (MT) motor protein." - The GeneReviews chapter "KIF1A-Related Neurodevelopmental Disorder" (NBK621569; Chung lab authorship) describes it as "both a developmental and degenerative condition with a broad phenotypic spectrum commonly including developmental delay, communication difficulties, optic nerve atrophy, seizures, progressive spastic paraplegia, peripheral and autonomic neuropathy, poor weight gain, and neurobehavioral issues including autism spectrum disorder" (NCBI Bookshelf). - I could not fetch the page (it is behind a reCAPTCHA). The quote comes from search-result text. - Run just check-genereviews and fetch the chapter's PMID before citing it. Per review item 15, GeneReviews is the required phenotype baseline for a Mendelian entry.

Identifiers

System	ID	Notes
MONDO	MONDO:0700055	"KIF1A-related neurological disorder" (SAIL concept library)
OMIM gene	601255	KIF1A, 2q37.3
OMIM phenotype: NESCAV syndrome (AD)	614255	Formerly "mental retardation, AD 9" (MRD9)
OMIM phenotype: SPG30A (AD)	610357
OMIM phenotype: SPG30B (AR)	620607	Recessive SPG30 now has its own entry (OMIM mirror)
OMIM phenotype: HSN2C (AR)	614213	Hereditary sensory neuropathy IIC
Orphanet	ORPHA:178469 (?)	Reported by one search snippet only. Unverified; confirm before use.
HGNC	hgnc:888 (KIF1A)	Verify against `cache/hgnc/terms.csv`
MeSH	none disease-specific	Use "Kinesins/genetics" or "Spastic Paraplegia, Hereditary"

Synonyms: KIF1A-associated neurological disorder; KIF1A-associated neuronal disorder; KIF1A-related neurodevelopmental disorder (KIF1A-NDD, the GeneReviews name); NESCAV syndrome (neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment); MRD9; SPG30.

Source of data: all disease-level knowledge comes from aggregated cohorts and case series, not EHR data. The main sources are: - the KIF1A.ORG–Columbia natural-history cohort (n = 117); - the Dutch HSP exome cohort (n = 347); - Italian multicentre series; - the KOALA prospective study.

Lump/split note for curation. MONDO:0700055 is the umbrella term. NESCAV, SPG30A, SPG30B and HSN2C are natural has_subtypes rows, with MONDO-bound terms if they exist. The case for lumping: severity runs on a continuous spectrum across the subtypes (PMID:32737135, PMID:34487232, PMID:33880452).

2. Etiology

Cause. The disorder is monogenic and caused by KIF1A variants. - Most cases are heterozygous de novo missense variants in the motor domain. - Rarer forms: - biallelic variants (recessive SPG30B and HSN2C); - inherited dominant variants (SPG30A); - heterozygous loss-of-function variants outside the motor domain (dominant HSP). - ✅ PMID:25265257 (Lee et al. 2015): "Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins." and "All these de novo mutations are located in the motor domain (MD) of KIF1A." - ✅ PMID:21487076 (Erlich 2011, the first recessive HSP family): "Our analysis implicated the causative mutation in the motor domain of KIF1A, a gene that has not yet associated with HSP, which functions in anterograde axonal transportation." - ✅ PMID:21820098 (Rivière 2011, HSAN2): "Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotyp…" Read the full sentence in the cache before quoting it.

Risk factors: - The main risk factor is a de novo germline mutation. - Parental germline or somatic mosaicism explains rare recurrence. One mosaic proband appears in Boyle 2021. - Consanguinity matters for the recessive SPG30B and HSN2C forms (Palestinian and Afghan families: PMID:21487076, PMID:21820098).

Environmental, protective, and gene–environment factors: none are documented, and the disease is not known to be modifiable by exposure. Fever and intercurrent illness are anecdotally reported to lower the seizure threshold, but I found no primary citation for this. Do not curate an environmental: entry without one.

Genetic modifiers: none have been established in humans. In C. elegans, an intragenic suppressor restores the motility of mutant KIF1A (PMID:35917346; see section 15).

3. Phenotypes

The main frequency source is Boyle 2021 Table 1 (✅ cached full text, n = 100), supplemented by Bernardi 2026 (✅ PMID:42500835, n = 51) and Abdelhakim 2024 (✅ PMID:39009236, n = 24).

Phenotype	Frequency (source)	Candidate HPO (verify)	Notes
Developmental delay / intellectual disability	92% (92/100) [Boyle]; global developmental delay 96.1% [Bernardi]	HP:0001263 Global developmental delay; HP:0001249 Intellectual disability	Onset in infancy. Cognitive regression is largely absent.
Hypotonia (neonatal/infantile)	84% [Boyle]; 62.7% [Bernardi]	HP:0001252 Hypotonia	Early sign, typically followed later by spasticity
Hypertonia/spasticity, progressive, lower-limb predominant	81% [Boyle]; 72.5% progressive [Bernardi]	HP:0001257 Spasticity; HP:0002061 Lower limb spasticity	Correlates with age (OR 1.56)
Lower-extremity weakness	88.2% [Bernardi]	HP:0007340 Lower limb muscle weakness
Loss of independent ambulation	62.7% achieve walking; 31.4% retain it [Bernardi]	HP:0002540 Inability to walk	"By the time they reached their 20s, many individuals were largely wheelchair dependent" ✅ Boyle
Optic nerve atrophy/hypoplasia	50% [Boyle]; 95% on exam/OCT [Abdelhakim]	HP:0000648 Optic atrophy	Progressive; prevalence underestimated without OCT
Cortical visual impairment	20% [Boyle]	HP:0100704 Cortical visual impairment
Strabismus	26% [Boyle]; ~40% [Abdelhakim]	HP:0000486 Strabismus
Seizures (overall)	42% [Boyle]	HP:0001250 Seizure	Absence most common: 29% of the cohort, 69% of those with seizures
Absence / generalized tonic-clonic / atonic / infantile spasms	29% / 17% / 9% / 4%	HP:0002121; HP:0002069; HP:0010819; HP:0012469
Abnormal brain MRI	58% (54/93)	HP:0012443 Abnormality of brain morphology
Cerebellar atrophy	35% [Boyle]; 65% [literature]	HP:0001272 Cerebellar atrophy	Progressive; vermis-predominant at autopsy
Corpus callosum hypoplasia/atrophy	11%	HP:0002079 Hypoplasia of the corpus callosum
Cerebral atrophy	6%	HP:0002059 Cerebral atrophy
Microcephaly	18%	HP:0000252 Microcephaly	Associated with earlier onset
Peripheral neuropathy (axonal, sensorimotor)	27% [Boyle]; 38% [literature]	HP:0009830 Peripheral neuropathy; HP:0003477 Peripheral axonal neuropathy	Prominent in HSN2C, with acral ulceration and mutilation
Ataxia / cerebellar signs	19.6% ataxia; 37.2% cerebellar signs [Bernardi]	HP:0001251 Ataxia	Congenital ataxia group (PMID:32737135)
Motor stereotypies; tremor; dystonia	43.1%; 15.6%; 3.9% [Bernardi]	HP:0000733 Stereotypy; HP:0002345 Action tremor; HP:0001332 Dystonia
Autism / ADHD / anxiety / OCD	20% / 24% / 19% / 5% (n = 80)	HP:0000729; HP:0007018; HP:0000739; HP:0000722
Rett-like features	Hand stereotypies 21%, bruxism 35%, high pain tolerance 65%	HP:0012171 Stereotypical hand wringing; HP:0003763 Bruxism	Some patients were clinically diagnosed with Rett syndrome
Dysautonomia-like features	Temperature dysregulation 46%, sialorrhea 26%, dysphagia 29%	HP:0004370 Abnormality of temperature regulation; HP:0002307 Drooling; HP:0002015 Dysphagia
GERD / constipation / diarrhea	40% / 39% / 17%	HP:0002020; HP:0002019; HP:0002014	10% need enteral feeding
Short stature; growth hormone deficiency	13%; 3%	HP:0004322; HP:0000824
Scoliosis	14%	HP:0002650 Scoliosis
Small penis/scrotum	17% of males (9/53)	HP:0008736 Hypoplasia of penis	Newly described

Key ✅ quotes - PMID:42500835: "A history of global developmental delay was present in 96.1% and neonatal or infantile hypotonia in 62.7%. Progressive spasticity occurred in 72.5%, predominantly affecting the lower extremities and correlated with age" - PMID:42500835: "Independent walking was achieved by 62.7% at a median age of 24 months, but only 31.4% retained independent ambulation at last evaluation." - PMID:39009236: "Ninety-five percent of participants examined had some degree of optic nerve atrophy detected by clinical examination and/or optical coherence tomography (OCT). Almost 40% had strabismus." - PMID:25265257: "Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy." - PMID:31488895 (pure HSP): "In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years)."

Quality of life. - Mean VABS-3 Adaptive Behavior Composite is 60.6, a low level of adaptive functioning (Boyle). - Loss of ambulation and progressive visual loss limit activities of daily living. - No EQ-5D or SF-36 data were found.

4. Genetic and molecular information

Gene and protein - Gene: KIF1A (hgnc:888; NCBI Gene 547; 2q37.3). Reference transcript in the main cohort study: NM_001244008.2. - Protein: kinesin-3 family. Domains, from N- to C-terminus: - motor domain (about aa 1–361), containing the P-loop, switch I, switch II and K-loop; - neck linker; - CC1, the autoinhibitory coiled coil; - FHA domain; - CC2 and CC3; - the C-terminal PH domain, which binds cargo lipids.

Variant spectrum - More than 110 variants are reported. Most are missense variants in the motor domain. - Recurrent variants include p.Thr99Met, p.Glu253Lys, p.Arg254Trp/Gln, p.Arg307Gln, p.Arg316Trp, p.Ala255Val, p.Pro305Leu and p.Arg350Gly. - ✅ PMID:33880452: "More than 30% of individuals with KAND have private variants". - ✅ PMID:33880452: "the majority of KIF1A variants (64/115) were de novo".

Variant types - Missense: predominant in all forms. - Truncating or loss-of-function: in HSN2C and in dominant HSP. ✅ PMID:31488895: "unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families." - Copy-number variants: one CNV encompassing KIF1A (PMID:34487232).

Classification and population frequency. - Pathogenic variants are absent from gnomAD. - The gene is highly constrained, so missense variants in the motor domain receive ACMG PM1 and PM2 support. - Check ClinGen gene-disease validity with just list-gene-validity. Recording a validity tier requires the CGGV: record, and none is cached yet.

Functional consequences: three molecular classes plus hyperactivation - ✅ PMID:33880452: "we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes." - ✅ PMID:35917346: "In our C. elegans models, both heterozygotes and homozygotes exhibited reduced axonal transport." and "We find that mutant KIF1A significantly impaired the motility of heterodimeric motors." These are dominant-negative effects. - Budaitis et al. 2021, eLife (PMC7844421; PMID not yet confirmed): KAND motor-domain mutants relieve autoinhibition but "display decreased velocities, run lengths, and landing rates", reduce force generation, and behave in a dominant-negative way (PMC). - Chiba et al. 2019, PNAS (PMC6744892): some SPG30 variants (e.g. V8M, R350G, A255V) hyperactivate motility, with SVP accumulation at axon tips. "Hyperactivation of kinesin motor activity, rather than its loss of function, is a cause of motor neuron disease" (PMC). - Haploinsufficiency is a mechanism in a subset of dominant HSP. ✅ PMID:31488895: "The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic…" (the sentence is truncated in this excerpt).

Recommended functional_impact_category values: - DOMINANT_NEGATIVE for de novo motor-domain missense variants; - LOSS_OF_FUNCTION for truncating variants (HSN2C, dominant HSP); - HYPERMORPHIC for a subset of SPG30 variants (Chiba 2019).

Genotype–severity correlation - ✅ PMID:33880452: "We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II." - ✅ PMID:42500835: "The p.Glu253Lys variant was associated with the most severe phenotype." - Conflicting evidence: ✅ PMID:34487232 found that "location of mutation did not correlate with neurological and imaging presentations."

Epigenetic and chromosomal findings. No epigenetic signature has been reported. The only structural variant is a rare CNV at 2q37.3; 2q37 deletion syndrome includes KIF1A but is a separate entity.

5. Environmental information

No environmental, lifestyle, or infectious causes are known. This section is not applicable.

6. Mechanism and pathophysiology

Ordered causal chain

Germline KIF1A variant. Usually a heterozygous de novo missense change in the motor domain; rarer forms are biallelic or truncating.
The variant alters ATP hydrolysis or microtubule binding in the motor domain (P-loop, switch I/II, K-loop/L12). This leads to one of four motor defects:
(a) reduced microtubule binding;
(b) reduced velocity and processivity, with reduced force;
(c) non-motile rigor binding;
(d) branch: loss of CC1 autoinhibition, causing hyperactive motility (some SPG30 alleles).
Sources: PMID:33880452, Budaitis 2021, Chiba 2019. The steps are demonstrated in vitro and in C. elegans.
The mutant subunit forms heterodimers with wild-type KIF1A. This results in dominant-negative suppression of total motor output. The step is demonstrated in vitro and in worms (PMID:35917346). In the truncating-allele branch, haploinsufficiency is inferred (PMID:31488895).
Anterograde axonal transport of SVPs (synaptophysin, synaptotagmin, RAB3) and dense-core vesicles (BDNF/TrkA) is impaired or, for hypermorphs, mislocalized. This leads to reduced cargo delivery to presynaptic sites, or cargo piling up at axon tips. Demonstrated in rodent neurons and worms (Guedes-Dias 2019, PMC6342647; Yonekawa 1998).
Synaptogenesis and synaptic vesicle release are impaired. This results in neurodevelopmental dysfunction (developmental delay/ID, autism, seizures, hypotonia). The link to seizures is inferred.
Neurons with the longest axons are the most vulnerable to chronic transport insufficiency, which leads to length-dependent axonal degeneration:
corticospinal tract → progressive spastic paraplegia;
optic nerve (retinal ganglion cells) → optic atrophy;
peripheral sensory and autonomic neurons → neuropathy and dysautonomia features;
cerebellar Purkinje and granule cells and olivary neurons → cerebellar atrophy and ataxia.
Supporting evidence: the Kif1a-knockout mouse shows neuronal death (Yonekawa 1998, PMID:9548721). The Kif1a^Lgdg mouse shows cerebellar axonal torpedoes. Autopsy findings are described next.
Neuropathology: two p.Thr99Met autopsies. ✅ PMID:33880452: "Microscopic examination revealed severe cerebellar atrophy most prominent in the superior cerebellar vermis, including a thin molecular layer, a depletion of Purkinje and internal granule cells, Bergmann gliosis, and white matter pallor. Rare axonal spheroids were observed."
These changes produce the clinical course: early developmental phenotype, then progressive motor, visual and cerebellar decline. ✅ PMID:33880452: "Spasticity was progressive … we largely did not see cognitive regression."

Two additional nodes: - Mitochondrial node (Vecchia 2022). Muscle biopsy shows "oxidative metabolism alteratio[ns]" (✅ PMID:34487232; the snippet is truncated). This is probably secondary; the mechanism is uncertain. - TrkA/BDNF dense-core vesicle node. Loss of KIF1A-dependent TrkA transport causes sensory neuron loss in mice (Tanaka et al. 2016, Cell Rep; PMID to confirm). This supports the HSN2C branch.

Suggested ontology bindings (verify all)

Category	Candidate terms
GO biological process	GO:0008089 anterograde axonal transport; GO:0048490 anterograde synaptic vesicle transport; GO:0047496 vesicle transport along microtubule; GO:0007416 synapse assembly; GO:0016079 synaptic vesicle exocytosis
GO molecular function	GO:0003777 microtubule motor activity; GO:0008017 microtubule binding; GO:0016887 ATP hydrolysis activity
GO cellular component	GO:0030424 axon; GO:0008021 synaptic vesicle; GO:0031045 dense core granule
Cell Ontology	CL:0000540 neuron; CL:0011113 spinal cord motor neuron / corticospinal (upper motor) neuron (check which label CL provides); CL:0000121 Purkinje cell; CL:0000740 retinal ganglion cell; CL:0000101 sensory neuron; CL:0001031 cerebellar granule cell

Molecular profiling. No patient transcriptomic, proteomic or metabolomic datasets were found. iPSC-derived motor-neuron models are reported in KIF1A.ORG-funded projects but are largely unpublished. Run just discover-datasets before curating datasets:.

7. Anatomical structures affected

Primary site: the nervous system, central and peripheral. Candidate UBERON terms (verify):
corticospinal tract (UBERON:0002707);
cerebellum, especially the vermis (UBERON:0002037 / UBERON:0004720);
optic nerve (UBERON:0000941);
inferior olivary complex (UBERON:0002127);
dentate nucleus (UBERON:0002132);
corpus callosum (UBERON:0002336);
peripheral nerve (UBERON:0001021).
Secondary involvement:
gastrointestinal (GERD, dysmotility);
musculoskeletal (contractures, scoliosis, tendon-lengthening surgery in 15%);
endocrine (growth hormone deficiency);
genitourinary (rare).
Subcellular level: axon; synaptic vesicle; presynaptic active zone; microtubules.
Laterality: bilateral and symmetric (spasticity, optic atrophy).

8. Temporal development

Onset: birth to 9 years in the severe cohort (median 6 months, mean 11 months; ✅ Boyle). Pure HSP can start anywhere from 0 to 57 years (✅ PMID:31488895).
Pattern: a congenital or infantile developmental phenotype followed by slow neurodegeneration.
Progression:
spasticity worsens with age;
ambulation is lost (62.7% → 31.4%);
optic atrophy progresses, and adults have worse acuity than children (20/119 vs 20/43; ✅ PMID:39009236);
cerebellar atrophy is progressive on serial MRI.
Course: chronic and lifelong. Remission does not occur.
Critical period: early childhood, before axonal loss. This is the presumed window for allele-specific or ASO therapy (inferred).
Suggested progression: phases: infantile hypotonia and developmental delay → childhood spasticity and seizures → adolescent/adult loss of ambulation and vision.

9. Inheritance and population

Prevalence: unknown. Hundreds to more than 1,000 diagnosed individuals are known worldwide through KIF1A.ORG.
Recommended record: prevalence_class: NOT_YET_DOCUMENTED or RARE with measure_type: UNKNOWN.
In the Dutch exome cohort, KIF1A explained 6–7% of mostly pure HSP. ✅ PMID:31488895: "KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%)." This figure is a candidate for case_fractions, not population prevalence.
Inheritance:
autosomal dominant: mostly de novo (64/115 confirmed); SPG30A can be inherited;
autosomal recessive: SPG30B, HSN2C.
Penetrance: high for de novo motor-domain variants; reduced or variable penetrance in inherited dominant HSP families.
Expressivity: highly variable, even for the same variant.
Other inheritance features:
no anticipation;
germline mosaicism is possible;
founder alleles appear in consanguineous recessive families (Palestinian, Afghan).
Sex ratio: about 1:1 (47 F / 53 M in Boyle).
Ancestry: reported worldwide, with no enrichment.

10. Diagnostics

Genetic testing (definitive):
exome or genome sequencing, or a multigene panel (HSP, epilepsy, NDD, ataxia, or neuropathy panels);
CNV analysis for rare deletions;
parental testing to establish de novo status.
GeneReviews: diagnosis rests on "a heterozygous pathogenic variant or, less commonly, biallelic pathogenic variants in KIF1A identified by molecular genetic testing."
Imaging: MRI for cerebellar (vermian) atrophy, thin corpus callosum, and optic nerve thinning.
Ophthalmology: OCT of the RNFL/GCL and visual evoked potentials (VEP). ✅ PMID:39009236: "VEPs showed findings consistent with optic neuropathy and visual dysfunction even in the absence of obvious structural changes on OCT."
Electrophysiology:
EEG (absence seizures, generalized epileptiform activity);
nerve conduction/EMG (axonal sensorimotor neuropathy).
Muscle biopsy: non-specific oxidative changes (PMID:34487232).
Laboratory biomarkers: none validated. Neurofilament light chain has been proposed and is under study in KOALA (unpublished).
Clinical criteria: none are standardized.
Differential diagnosis:
other complicated HSPs (SPG11, SPG4/SPAST, SPG7);
Rett syndrome (MECP2, CDKL5, FOXG1);
PEHO syndrome;
congenital ataxias;
other HSAN genes (WNK1/HSN2, RETREG1/FAM134B);
cerebral palsy, the most common misdiagnosis;
other kinesinopathies (KIF5A, KIF1B, KIF1C).
Screening: no newborn screening exists. Prenatal or preimplantation testing is available for known familial variants.

11. Outcome and prognosis

Survival: KAND is described as "neurodegenerative and often lethal" (✅ PMID:39122967). Life-expectancy data are lacking; the oldest reported cohort members were in their 30s to 60s (dominant HSP).
Morbidity:
wheelchair dependence by the 20s in severe forms;
progressive visual loss;
refractory epilepsy in some patients;
aspiration and feeding problems (10% need enteral nutrition).
Prognostic factors:
variant location (P-loop/switch I/II = worse);
molecular class (rigor = worst);
earlier onset (associated with microcephaly);
p.Glu253Lys (most severe).
Recovery: none. Cognition is generally stable and does not regress.

12. Treatment

No disease-modifying therapy is approved. Management is symptomatic and delivered by a multidisciplinary team.

Intervention	Details	Candidate NCIT term (verify)	Modality
Antiseizure medication	Selected by seizure type; absence seizures are common	NCIT:C15986 Pharmacotherapy + `therapeutic_agent`	SMALL_MOLECULE
Spasticity drugs	Baclofen, tizanidine; botulinum toxin injection	NCIT:C15986	SMALL_MOLECULE / biologic
Orthopedic surgery	Tendon lengthening (15%), scoliosis surgery	NCIT:C16186 Orthopedic Surgical Procedure	SURGERY
Physical, occupational, speech therapy		NCIT:C15302 / NCIT:C121351 / NCIT:C159273	BEHAVIORAL
Gastrostomy and nutritional support	GERD management	NCIT:C15433 Nutritional Support (not BEHAVIORAL; see CLAUDE.md)	—
Vision support, strabismus management		NCIT:C15747 Supportive Care	—
Genetic counseling		NCIT:C15240 Genetic Counseling	—
Allele-specific ASO (n-of-1; experimental)	p.Pro305Leu; intrathecal gapmer from n-Lorem	NCIT:C15986 + `oligonucleotide_details` (`RNASE_H_KNOCKDOWN`, target hgnc:888)	ANTISENSE_OLIGONUCLEOTIDE

ASO case (✅ PMID:39122967, Ziegler et al. 2024, Nat Med): - "treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele." - "the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved." - Adverse event: an epidural CSF collection after the first lumbar puncture, which resolved spontaneously. - The design rationale is that silencing the dominant-negative allele preserves wild-type function. This depends on the patient tolerating 50% dosage, which haploinsufficient HSP families suggest may itself cause mild disease. That tension is worth recording in a KNOWLEDGE_GAP discussion.

Other experimental programs: - further n-Lorem ASOs for other private variants; - AAV gene-replacement preclinical work; - the KOALA natural-history and endpoint study, which is pre-trial and currently moving from Columbia to Boston Children's (KIF1A.ORG).

I found no registered interventional NCT trial. Search ClinicalTrials.gov directly before claiming that none exists.

13. Prevention

Primary prevention: not possible for de novo cases.
Reproductive options: genetic counseling; prenatal or preimplantation diagnosis for familial or recessive variants. Recurrence risk after a de novo case is low but above zero because of parental mosaicism.
Tertiary prevention:
seizure control;
contracture and scoliosis surveillance;
regular ophthalmology (OCT/VEP);
aspiration prevention.

14. Other species and natural disease

I found no naturally occurring KIF1A disease in OMIA. This should be confirmed in OMIA.
KIF1A is highly conserved. The C. elegans ortholog is unc-104 (the founding kinesin-3), and the Drosophila ortholog is unc-104/imac.

15. Model organisms

Model	Phenotype and fidelity	Source
Kif1a−/− mouse	Neonatal lethal; SVP transport loss; sensory/motor deficits; neuronal death. Models complete loss of function only, which no human patient has.	PMID:9548721 (Yonekawa 1998, J Cell Biol)
Kif1a^Lgdg (C3H "legs at odd angles"-type) mouse	Progressive spasticity, hind-limb paralysis, cerebellar axonal torpedoes. Partially recapitulates human disease.	search summary; primary PMID needed
Kif1a+/− mouse	Sensory neuron/TrkA defects (Tanaka 2016)	PMID to confirm
C. elegans CRISPR KAND knock-ins (unc-104 carrying human variants)	Reduced axonal transport in heterozygotes and homozygotes; a suppressor screen identified a rescue mutation. ✅ PMID:35917346	MODEL_ORGANISM
C. elegans SPG-allele knock-ins	Hyperactive SVP transport (Chiba 2019)	MODEL_ORGANISM
Rat/mouse hippocampal neurons, in vitro TIRF motility	Reduced velocity, processivity and force; rigor binding	PMID:33880452; Budaitis 2021; IN_VITRO
Patient iPSC-derived neurons	In development (KIF1A.ORG-funded); unpublished	—

Limitations to record as HUMAN_MODEL_MISMATCH: - the knockout mouse is lethal while human disease is heterozygous and dominant-negative; - no mouse knock-in of a common human allele (e.g. T99M, E253K) has been fully characterized in a peer-reviewed publication; - the worm studies lack the optic nerve, cerebellum and corticospinal biology.

Remaining work before using this in the YAML

Fetch these sources so their quotes can be verified against cached text: GeneReviews NBK621569 (and run just check-genereviews), Chiba 2019, Budaitis 2021, Guedes-Dias 2019, and Yonekawa 1998 (PMID:9548721).
Re-quote the truncated ✅ snippets from their complete sentences in the cache: PMID:21820098, PMID:31488895, and PMID:34487232.
Look up every HP/GO/CL/UBERON/NCIT/ORPHA CURIE above with runoak or the term cache. I wrote them from memory.
Check ClinGen for KIF1A–NESCAV/SPG30 CGGV: assertions before recording any gene-disease validity tier.

Sources: - GeneReviews NBK621569 - KAND overview (PMC9962247) - Chiba et al. 2019, PNAS (PMC6744892) - Budaitis et al. 2021, eLife (PMC7844421) - Guedes-Dias et al. 2019 (PMC6342647) - Yonekawa et al. 1998, J Cell Biol - OMIM SPG30B 620607 (mirror) - OMIM HSN2C 614213 (mirror) - MONDO:0700055 (SAIL concept library) - MalaCards - Frontiers in Medicine 2025 - KOALA study (KIF1A.ORG) - n-Lorem press release - Ziegler et al. 2024, Nat Med (PubMed 39122967) - Genomics England PanelApp: KIF1A - Local references_cache/ files: PMID 21487076, 21820098, 25265257, 31488895, 32737135, 33880452, 34487232, 35917346, 39009236, 39122967, 42500835.

Two connector notes: - The claude.ai Google Drive connector needs authorization in claude.ai's connector settings before it can be used. - The GeneReviews page could not be fetched here because of a reCAPTCHA.

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	17
Resolved	17
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	3
Quoted claims found in source	3
Quoted claims not found in source	0
References weighed for topical relevance	17
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	77
Resolved	76
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	8
Terms named correctly	5
Terms named as a different term	2
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0700055 (7 mentions) - the report calls it "MONDO", "SAIL concept library"; MONDO calls it KIF1A related neurological disorder
NCIT:C15986 (3 mentions) - the report calls it "Baclofen, tizanidine; botulinum toxin injection"; NCIT calls it Pharmacotherapy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

UBERON:0000941 (1 mention) - the report calls it "optic nerve"; UBERON calls it cranial nerve II, and lists "optic nerve" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0700055 - called "MONDO", "SAIL concept library"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

Ask OpenScientist

OpenScientist Report

Mappings

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

References

Deep Research

KIF1A-Related Neurological Disorder (KAND; MONDO:0700055): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Suggested ontology bindings (verify all)

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Remaining work before using this in the YAML

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver