CPT1C-Related Hereditary Spastic Paraplegia

Mendelian MONDO:0014568 Pathograph 31 Show in embeddings browser Hereditary Spastic Paraplegia

CPT1C-associated hereditary spastic paraplegia (SPG73) was defined in a three-generation family with adult-onset pure spastic paraparesis and the heterozygous p.Arg37Cys variant. CPT1C is a neuronal endoplasmic-reticulum protein involved in lipid-droplet homeostasis, nutrient-sensitive organelle transport and AMPA-receptor trafficking, rather than a conventional mitochondrial fatty-acid-oxidation enzyme. Later reports attributed childhood-onset pure or complex HSP to truncating and splice variants, but a 2026 population/cohort study found no support for loss-of-function variants as a cause of HSP. The original missense-specific association and the disputed loss-of-function model therefore require separate interpretation. Reported phenotypes span mild or improving childhood motor impairment to progressive spasticity, with additional cognitive, seizure and behavioral findings in individual candidate cases; these do not establish a uniform CPT1C loss-of-function syndrome.

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1
Mappings
1
Inheritance
10
Pathophys.
22
Phenotypes
2
Gaps
31
Pathograph
1
Genes
6
Variants
6
Medical Actions
6
Models
8
References
🏷

Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
🔗

Mappings

MONDO
MONDO:0014568 hereditary spastic paraplegia 73
skos:exactMatch MONDO
👪

Inheritance

1
Autosomal dominant HP:0000006
An autosomal dominant pedigree supports the original p.Arg37Cys association. Other reported alleles were inherited from parents with mild or absent symptoms; the pathogenicity of heterozygous loss-of-function variants is challenged by subsequent cohort data. Penetrance cannot be quantified from these small, differently ascertained reports.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:25751282 SUPPORT Human Clinical
"This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus strictly cosegregating with the disease phenotype."
Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants as causal.
DOI:10.1002/mds.70144 REFUTE Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"uncomplicated HSP is at a 50% risk of inheriting the HSP-related"
This is the conditional allele-transmission rule for a confirmed dominant diagnosis, not a penetrance estimate for disputed CPT1C alleles.
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Discussions and Knowledge Gaps

2
Do heterozygous CPT1C loss-of-function variants cause HSP, and how does their interpretation differ from p.Arg37Cys?
CONTROVERSY OPEN cpt1c-loss-of-function-causality
Attached to
genetic#CPT1C reported HSP association
Case reports and engineered transcript-decay assays were interpreted as evidence of haploinsufficiency. Subsequent UK Biobank, Canadian HSP and GENESIS analyses did not support this model. Population phenotype ascertainment can miss subtle signs, and modifiers or incomplete penetrance remain possible, but predicted loss-of-function alone is not sufficient to assign the diagnosis. The R37C missense association has distinct segregation and functional evidence and was not directly refuted by this loss-of-function study.
Show evidence (4 references)
PMID:30911584 SUPPORT In Vitro
"293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared to that of wild‐type cells"
Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
DOI:10.1002/mds.70144 REFUTE Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
DOI:10.1002/mds.70144 SUPPORT Human Clinical
"all three also carry pathogenic variants in established HSP‐associated genes."
All three GENESIS participants with HSP and CPT1C loss-of-function variants had an alternative established HSP-associated genotype.
+ 1 more reference
Which CPT1C cellular defect explains the central tract dysfunction of the original family?
HUMAN MODEL MISMATCH OPEN cpt1c-cell-to-tract-mechanism
Attached to
pathophysiology#Arg37Cys Regulatory-Domain Destabilization pathophysiology#Reduced Lipid Droplet Formation pathophysiology#Reduced Anterograde Late Endosome and Lysosome Transport pathophysiology#Reduced Axon Extension in Cortical Cultures pathophysiology#Corticospinal Tract Dysfunction
R37C changes an isolated regulatory domain, reduces lipid droplets in COS7 cells and fails cortical axon-growth rescue. These findings do not establish dominant-negative action, disruption of atlastin binding, or adult human distal axon degeneration. Nutrient-sensitive lysosome and AMPA-receptor pathways offer testable mechanisms but do not yet connect the clinical phenotype through a fully demonstrated causal chain.
Show evidence (4 references)
PMID:25751282 SUPPORT In Vitro
"We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells."
p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient motor neurons.
PMID:25751282 SUPPORT In Vitro
"The Arg37Cys mutation did not affect the ability of CPT1C to bind atlastin-1"
The specific atlastin-binding assay was negative for disruption; a generic disrupted ER interaction network is not established.
PMID:31868590 SUPPORT In Vitro
"Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S"
The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
+ 1 more reference
⚙

Pathophysiology

10
Arg37Cys Regulatory-Domain Destabilization
NMR of the isolated N-terminal regulatory domain shows destabilization by p.Arg37Cys. Altered coupling to other domains and dominant-negative activity remain proposed interpretations. Atlastin-1 binding and ER localization are retained in the tested cells.
Genetic context CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact: Regulatory-domain conformational change; dominant-negative mechanism proposed, not established.
Downstream
Reduced Lipid Droplet Formation The same R37C allele reduces lipid-droplet number and area in a separate overexpression assay; the intervening molecular mechanism is unresolved.
Reduced Axon Extension in Cortical Cultures R37C fails to restore axon extension in knockout cortical cultures. This is a functional complementation result, not direct proof of human distal axon loss.
Show evidence (2 references)
PMID:25751282 SUPPORT In Vitro
"The NMR studies indicated that the mutation altered the protein conformation"
NMR examined the isolated regulatory domain, not patient full-length protein activity.
PMID:25751282 SUPPORT In Vitro
"The Arg37Cys mutation did not affect the ability of CPT1C to bind atlastin-1"
The specific atlastin-binding assay was negative for disruption; a generic disrupted ER interaction network is not established.
Reduced Lipid Droplet Formation
R37C overexpression reduces lipid-droplet number and area in COS7 cells. Primary Cpt1c-null cortical cultures have fewer lipid droplets. These observations support altered lipid-droplet homeostasis, without demonstrating disrupted atlastin binding or identifying how the lipid change produces human HSP.
lipid droplet formation GO:0140042 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lipid droplet formation (GO:0140042). GO:0140042 is a biological process from the Gene Ontology.
Experimental models
R37C COS7 lipid-droplet assay CELL LINE Lipid-droplet number and area after R37C expression.
Cpt1c-null embryonic cortical neurons PRIMARY CELL CULTURE Reduced lipid-droplet number.
Show evidence (2 references)
PMID:25751282 SUPPORT In Vitro
"We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells."
p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient motor neurons.
PMID:25751282 SUPPORT In Vitro
"We also observed a reduction of LDs in primary cortical neurons isolated from Cpt1c−/− mice as compared with wild-type mice."
Embryo-derived knockout cortical cultures show fewer lipid droplets. This phenocopy alone does not prove dominant-negative action.
CPT1C Protein Depletion in Experimental Systems
Cpt1c knockout or knockdown depletes the protein in experimental systems. The reported p.Gln76Ter allele also causes marked transcript loss and absent detectable protein in engineered HEK293T cells, with transcript recovery after cycloheximide. Clinical causality of heterozygous loss-of-function remains disputed, and model depletion must not be equated with established human haploinsufficiency.
Genetic context CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. functional_impact: Experimental depletion or p.Gln76Ter construct-associated transcript decay; human haploinsufficiency is not established.
Experimental models
p.Gln76Ter HEK293T expression system CELL LINE Transcript decay and protein abundance.
Downstream
Reduced Anterograde Late Endosome and Lysosome Transport Knockout cortical cultures have reduced distal lysosome accumulation; nutrient-sensing experiments identify the protrudin/kinesin transfer pathway.
Increased SAC1 Phosphatase Activity Cpt1c knockout increases SAC1 phosphatase activity in brain lysates.
Show evidence (2 references)
PMID:30911584 SUPPORT In Vitro
"293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared to that of wild‐type cells"
Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
PMID:30911584 SUPPORT In Vitro
"No full‐length or truncated CPT1C proteins were detected by immunoblot in the 293T cell homogenates"
The engineered p.Gln76Ter construct lacked detectable protein in HEK293T cells.
Reduced Anterograde Late Endosome and Lysosome Transport
In cellular models, CPT1C promotes protrudin-dependent transfer of kinesin-1 to FYCO1-positive late endosomes/lysosomes under nutrient-replete conditions. CPT1C deficiency or low malonyl-CoA impairs peripheral organelle delivery. CPT1C-protrudin binding persists under stress, and CPT1C does not create the ER-lysosome contacts themselves. R37C-specific motor-transfer impairment remains inferred.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
lysosome localization GO:0032418 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal lysosome localization (GO:0032418). GO:0032418 is a biological process from the Gene Ontology.
Experimental models
CPT1C protrudin transport assays CELL LINE Peripheral lysosome distribution and anterograde transport.
Downstream
Reduced Axon Extension in Cortical Cultures The nutrient/CPT1C axis couples distal lysosome delivery to axon growth in cortical cultures; exogenous malonyl-CoA partially rescues nutrient-stressed wild-type but not knockout cultures.
Show evidence (1 reference)
PMID:31868590 SUPPORT In Vitro
"CPT1C will sense intracellular malonyl-CoA levels and promote the plus-end transport of LE/Lys through the enhancement of protrudin function."
The combined cell experiments support nutrient-dependent lysosomal transport; R37C-specific motor transfer was not directly measured.
Reduced Axon Extension in Cortical Cultures
Cpt1c-null embryonic cortical cultures grow shorter axons. Wild-type CPT1C restores growth, whereas R37C and engineered malonyl-CoA-insensitive M589S do not. Reduced dendritic arborization is also observed, but its mechanism may be independent of protrudin. These developmental culture readouts do not demonstrate adult human axon degeneration.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
axon extension GO:0048675 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased axon extension (GO:0048675). GO:0048675 is a biological process from the Gene Ontology.
Experimental models
Cpt1c-null embryonic cortical neurons PRIMARY CELL CULTURE Axon length and allelic complementation.
Show evidence (1 reference)
PMID:31868590 SUPPORT In Vitro
"Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S"
The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
Increased SAC1 Phosphatase Activity
CPT1C normally inhibits the PI4P phosphatase SAC1 in a nutrient-dependent manner. Knockout brain extracts have increased SAC1 activity. Cell assays show that malonyl-CoA depletion releases this inhibition; CPT1C-SAC1 binding itself is retained. These are gene-function findings, without direct testing of patient HSP alleles.
CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee.
phosphatase inhibitor activity GO:0019212 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphatase inhibitor activity (GO:0019212). GO:0019212 is a molecular function from the Gene Ontology.
Experimental models
CPT1C SAC1 GluA1 trafficking assays PRIMARY CELL CULTURE CPT1C-dependent SAC1 activity.
Animal models
Cpt1c-null mouse brain biochemical model Mus musculus measures SAC1 activity in knockout brain lysates.
Downstream
Reduced Trans-Golgi PI4P Increased SAC1 activity dephosphorylates PI4P; knockdown/overexpression and engineered contact-site experiments support regulation of the TGN lipid pool.
Show evidence (2 references)
PMID:32931550 SUPPORT Model Organism
"SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs"
Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than human HSP causality.
PMID:32931550 SUPPORT In Vitro
"CPT1C expression decreased SAC1 activity"
Cellular phosphatase assays support inhibition of SAC1 by CPT1C.
Reduced Trans-Golgi PI4P
CPT1C-deficient cortical neurons have reduced PI4P at the trans-Golgi network. Nutrient stress recruits CPT1C/SAC1 to ER-TGN contact sites rather than demonstrating SAC1 entry into the TGN. Wild-type CPT1C, but not engineered M589S or a C-terminal deletion, restores the lipid pool.
Experimental models
CPT1C SAC1 GluA1 trafficking assays PRIMARY CELL CULTURE TGN PI4P level.
Downstream
GluA1 Retention at the Trans-Golgi Network Reduced TGN PI4P accompanies impaired GluA1 export in the experimental CPT1C/SAC1 pathway.
Show evidence (1 reference)
PMID:32931550 SUPPORT In Vitro
"both knocking down CPT1C or treatment with TOFA resulted in a significant decrease of PI(4)P levels at the TGN."
Cortical neuronal experiments link CPT1C deficiency or inhibition of malonyl-CoA synthesis to lower TGN PI4P.
GluA1 Retention at the Trans-Golgi Network
Knockdown or knockout reduces GluA1 surface abundance and promotes retention at the TGN. Acute metabolic inhibition has little additional effect in depleted cells. The tested M589S and C-terminal deletion are engineered probes, not reported HSP alleles; this pathway is not established as the cause of seizures or intellectual disability in candidate clinical cases.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Experimental models
CPT1C SAC1 GluA1 trafficking assays PRIMARY CELL CULTURE TGN retention and surface GluA1.
Show evidence (1 reference)
PMID:32931550 SUPPORT In Vitro
"knockdown of CPT1C resulted in a similar GluA1 retention pattern at the TGN."
CPT1C knockdown causes GluA1 retention at the TGN in cortical neuronal cultures.
Corticospinal Tract Dysfunction
Prolonged central motor conduction in the original family supports corticospinal tract dysfunction despite normal peripheral conduction. How the observed lipid-droplet and axon-growth defects produce this clinical lesion remains unresolved; direct human pathology proving distal axon degeneration is absent.
upper motor neuron CL:0008048 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves upper motor neuron (CL:0008048). CL:0008048 is a cell type from the Cell Ontology.
Downstream
Spastic paraplegia Central motor tract dysfunction underlies the clinical spastic paraparesis; this does not establish which CPT1C molecular defect produces the tract lesion.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction velocities were normal in all participants examined"
Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated histologically.
Dorsal Column Dysfunction
Abnormal sensory evoked potentials and reduced ankle vibration in the original family support dorsal-column involvement. Peripheral nerve conduction was normal. This sensory tract finding is distinct from the corticospinal motor dysfunction.
Downstream
Impaired vibration sensation at ankles Dorsal-column dysfunction is consistent with the distal vibration deficit in the same clinical family.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction velocities were normal in all participants examined"
Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated histologically.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CPT1C-Related Hereditary Spastic Paraplegia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

22
Genitourinary 1
Urinary dysfunction Abnormality of the lower urinary tract HP:0010936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the lower urinary tract (HP:0010936). HP:0010936 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"| Urinary dysfunction | Mild phenotype |"
The source gives an unspecified urinary functional abnormality.
Limbs 5
Lower limb muscle weakness HP:0007340 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb muscle weakness (HP:0007340). HP:0007340 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"| Weakness | Mild phenotype, proximal |"
The clinical table documents mild proximal weakness.
Pes cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30911584 SUPPORT Human Clinical
"Bilateral pes cavus was obvious."
Pes cavus was directly documented in the index child.
Ankle clonus HP:0011448 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankle clonus (HP:0011448). HP:0011448 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"bilateral lower leg spasticity, ankle clonus, a positive Babinski sign"
Case1 examination.
Ankle contracture HP:0034677 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ankle contracture (HP:0034677). HP:0034677 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"leading to contractures of the ankles, muscle wasting, and significant spontaneous ankle clonus"
Case2 examination; not a frequency estimate.
Foot deformity Structural foot deformity HP:0010219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Structural foot deformity (HP:0010219). HP:0010219 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"| Additional features (No. of individuals/total individuals) | Foot deformity (2/5) |"
This is a family-specific proportion, not population frequency.
Musculoskeletal 4
Spastic paraplegia HP:0001258 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic paraplegia (HP:0001258). HP:0001258 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"adult-onset, and pure spastic paraplegia of unknown genetic cause"
The original pedigree had pure spastic paraplegia.
Lower limb spasticity HP:0002061 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb spasticity (HP:0002061). HP:0002061 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"| Spasticity | Moderate/severe phenotype |"
The founding family clinical table documents spasticity.
Spastic gait HP:0002064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic gait (HP:0002064). HP:0002064 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25751282 SUPPORT Human Clinical
"The disease was slowly progressive, leading to impairment or loss of ambulation 10 to 15 years after the onset of symptoms."
Family-specific natural history.
PMID:30911584 SUPPORT Human Clinical
"spasticity of lower limbs still affected his gaits"
The reported Q76Ter boy retained gait impairment despite later improvement.
Skeletal muscle atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25751282 SUPPORT Human Clinical
"| Muscle wasting | Mild phenotype |"
The founding family clinical table documents mild wasting.
PMID:39737739 SUPPORT Human Clinical
"leading to contractures of the ankles, muscle wasting, and significant spontaneous ankle clonus"
Muscle wasting in the second candidate case.
Nervous System 12
Lower limb hyperreflexia HP:0002395 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb hyperreflexia (HP:0002395). HP:0002395 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30911584 SUPPORT Human Clinical
"Deep tendon reflexes were brisk in the lower extremities."
Direct examination in the reported Q76Ter family.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"Lower-extremity hyperreflexia and extensor plantar responses may be demonstrated on neurologic examination."
General uncomplicated HSP clinical context; CPT1C-specific findings are supported by the family reports.
Babinski sign HP:0003487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Babinski sign (HP:0003487). HP:0003487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"| Plantar reflex | Extensor |"
The founding family table records extensor plantar responses.
Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30911584 SUPPORT Human Clinical
"walking independently at age 3.5"
The reported Q76Ter index child had delayed independent walking.
Chiari malformation HP:0002308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari malformation (HP:0002308). HP:0002308 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"MR imaging of the brain showed a Chiari 1 malformation but was otherwise unremarkable."
Single candidate-case imaging observation.
Moderate intellectual disability HP:0002342 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Moderate intellectual disability (HP:0002342). HP:0002342 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"His IQ testing suggests moderate cognitive impairment (full scale IQ: 57)"
Case2 measured cognition, not both reported boys.
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39737739 SUPPORT Human Clinical
"Further evaluation led to a diagnosis of attention‐deficit/hyperactivity disorder."
Case1 had ADHD.
PMID:39737739 SUPPORT Human Clinical
"Diagnoses include ADHD, anxiety disorder, depressive disorder, disruptive mood dysregulation disorder, conduct disorder, and autism spectrum disorder."
Case2 had multiple neurobehavioral diagnoses; their causal connection to CPT1C is unresolved.
Anxiety HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"continued significant anxiety as he aged leading to a formal diagnosis of anxiety disorder"
Case1 had an anxiety disorder.
Autism HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Diagnoses include ADHD, anxiety disorder, depressive disorder, disruptive mood dysregulation disorder, conduct disorder, and autism spectrum disorder."
Case2’s diagnostic list includes autism spectrum disorder.
Depression HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Diagnoses include ADHD, anxiety disorder, depressive disorder, disruptive mood dysregulation disorder, conduct disorder, and autism spectrum disorder."
Depressive disorder was reported in case 2.
Aggressive behavior HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"a history of aggressive and impulsive behavior from a young age"
Case2 behavioral history.
Impaired vibration sensation at ankles HP:0006938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired vibration sensation at ankles (HP:0006938). HP:0006938 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25751282 SUPPORT Human Clinical
"| Vibration sensation at ankles | Decreased |"
Direct table observation in the original family.
Bilateral tonic-clonic seizures HP:0002069 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral tonic-clonic seizure (HP:0002069). HP:0002069 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"a history of generalized tonic–clonic seizures, first occurring at age 5"
Single candidate-case seizure history; genotype attribution remains unresolved.
🧬

Genetic Associations

1
CPT1C reported HSP association (Allele-dependent association; heterozygous loss-of-function causality challenged)
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:25751282 SUPPORT Human Clinical
"This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus strictly cosegregating with the disease phenotype."
Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants as causal.
DOI:10.1002/mds.70144 REFUTE Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
DOI:10.1002/mds.70144 SUPPORT Human Clinical
"all three also carry pathogenic variants in established HSP‐associated genes."
All three GENESIS participants with HSP and CPT1C loss-of-function variants had an alternative established HSP-associated genotype.
Variants (6)
p.Arg37Cys
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: missense
NM_001136052:c.109C>T; original adult-onset pure HSP pedigree. Segregation, isolated-domain NMR, COS7 lipid-droplet assays and failed rescue of knockout cortical axon growth provide allele-specific support. Dominant-negative action remains proposed.
Show evidence (3 references)
PMID:25751282 SUPPORT Human Clinical
"This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus strictly cosegregating with the disease phenotype."
Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants as causal.
PMID:25751282 SUPPORT In Vitro
"We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells."
p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient motor neurons.
PMID:31868590 SUPPORT In Vitro
"Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S"
The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
p.Gln76Ter
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: nonsense
c.226C>T; reported in a family with childhood motor delay, subsequent improvement and a minimally affected mother, and in another child summarized by Brooks et al. Engineered construct assays demonstrate transcript/protein loss, but later population data challenge causal loss-of-function interpretation.
Show evidence (3 references)
PMID:30911584 SUPPORT In Vitro
"293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared to that of wild‐type cells"
Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
PMID:30911584 SUPPORT In Vitro
"No full‐length or truncated CPT1C proteins were detected by immunoblot in the 293T cell homogenates"
The engineered p.Gln76Ter construct lacked detectable protein in HEK293T cells.
DOI:10.1002/mds.70144 REFUTE Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
p.Ile686SerfsTer8
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. deletion
Variant detail: frameshift
NM_001199753.2:c.2057_2061del; maternally inherited in Brooks case 1. Original authors classified the variant as pathogenic, but no functional study was performed and the later loss-of-function challenge applies.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Variant c.2057_2061del (Ile686SerfsTer8) in CPT1C (NM_001199753.2) was identified through multi‐gene panel testing and classified as Pathogenic"
Historical author classification, not an independent current pathogenicity assertion.
c.2020-1G>C
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: splice site
NM_001199753.2:c.2020-1G>C; maternally inherited in Brooks case 2. Original authors called it likely pathogenic; splicing was not experimentally established and clinical causality remains uncertain.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Genetic testing identified a likely pathogenic variant in CPT1C (NM_001199753.2: c.2020‐1G>C)"
The report describes a candidate splice-site allele; its functional and clinical interpretation needs reassessment.
c.2133+1G>A
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: splice site
NM_001199752:c.2133+1G>A; heterozygous in patient 2 of the 2018 Italian cohort, listed among author-assigned confirmed diagnoses. No focal splice assay is reported in the main article.
Show evidence (1 reference)
PMID:30564185 SUPPORT Human Clinical
"| Pt2 | CPT1C | NM_001199752 | c.2133+1G>A (het) |"
Table2 lists this variant among the historically assigned diagnoses, rather than among that study’s VUS group.
p.Thr601Met
Gene: CPT1C hgnc:18540 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in CPT1C (hgnc:18540). hgnc:18540 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
Variant detail: missense
NM_001199752:c.1802C>T; heterozygous in patient 23 of the 2018 Italian cohort, listed among author-assigned confirmed diagnoses. Functional and segregation details are insufficient in the main article to generalize the original R37C mechanism.
Show evidence (1 reference)
PMID:30564185 SUPPORT Human Clinical
"| Pt23 | CPT1C | NM_001199752 | c.1802C>T (het) | NP_001186681 | p.Thr601Met |"
This is a second reported missense allele, not direct functional replication of R37C.
💊

Medical Actions

6
Supportive multidisciplinary care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
General HSP care aims to maintain mobility and daily function, manage spasticity and associated symptoms, and provide psychological and social support. No CPT1C-specific disease-modifying intervention was demonstrated in the reviewed clinical reports.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
General uncomplicated HSP management, not a CPT1C-specific trial.
Physical therapy and mobility support
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Individualized stretching, strengthening, aerobic exercise, gait training and occupational therapy follow general HSP practice. Orthotics and walking aids are selected by need; Brooks case 2 used orthotics and a wheelchair for longer distances.
Mechanism Target:
MODULATES Spastic gait — Symptomatic management of the reported manifestation; no disease-modifying effect is established.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Spasticity is currently managed with baclofen and physical therapy."
Direct management reported in case 1.
Show evidence (4 references)
PMID:39737739 SUPPORT Human Clinical
"Spasticity is currently managed with baclofen and physical therapy."
Direct management reported in case 1.
PMID:39737739 SUPPORT Human Clinical
"He now requires orthotics and wheelchair assistance for longer distances"
Direct mobility support reported in case 2.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"Supportive care to improve quality of life, maximize function, and reduce complications is recommended."
General uncomplicated HSP management, not a CPT1C-specific trial.
+ 1 more reference
Baclofen and other antispasmodic therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: baclofen CHEBI:2972 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baclofen (CHEBI:2972). CHEBI:2972 is a therapeutic agent from Chemical Entities of Biological Interest.
Baclofen was used in Brooks case 1. General HSP guidance also discusses intrathecal baclofen, botulinum toxin and tizanidine according to individual need; these are symptomatic approaches without CPT1C-specific efficacy trials. GeneReviews cautions against dantrolene in ambulatory individuals because it may cause irreversible weakness.
Mechanism Target:
MODULATES Lower limb spasticity — Symptomatic management of the reported manifestation; no disease-modifying effect is established.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Spasticity is currently managed with baclofen and physical therapy."
Reported symptomatic treatment.
Show evidence (3 references)
PMID:39737739 SUPPORT Human Clinical
"Spasticity is currently managed with baclofen and physical therapy."
Reported symptomatic treatment.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness that can adversely affect overall mobility."
General HSP treatment precaution.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"Baclofen can be tried first and can be used with an intrathecal pump in some individuals."
General HSP antispasticity management; individual drug selection is symptom-driven.
Management of associated seizures
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Brooks case 2 received an unnamed antiseizure medication regimen, later discontinued after two years of seizure freedom. Drug choice and discontinuation are individual clinical decisions; the report does not demonstrate a CPT1C-specific antiseizure response.
Mechanism Target:
MODULATES Bilateral tonic-clonic seizures — Symptomatic management of the reported manifestation; no disease-modifying effect is established.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Antiseizure medications were initially prescribed but discontinued after 2 years of seizure freedom."
Single candidate-case treatment course.
Show evidence (1 reference)
PMID:39737739 SUPPORT Human Clinical
"Antiseizure medications were initially prescribed but discontinued after 2 years of seizure freedom."
Single candidate-case treatment course.
Management of behavioral and psychiatric symptoms
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: amphetamine CHEBI:2679 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses amphetamine (CHEBI:2679). CHEBI:2679 is a therapeutic agent from Chemical Entities of Biological Interest. sertraline CHEBI:9123 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sertraline (CHEBI:9123). CHEBI:9123 is a therapeutic agent from Chemical Entities of Biological Interest. lurasidone CHEBI:70735 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lurasidone (CHEBI:70735). CHEBI:70735 is a therapeutic agent from Chemical Entities of Biological Interest. olanzapine CHEBI:7735 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses olanzapine (CHEBI:7735). CHEBI:7735 is a therapeutic agent from Chemical Entities of Biological Interest.
Brooks case 1 received amphetamine/dextroamphetamine and sertraline; case 2 received sertraline, lurasidone and olanzapine with apparent benefit but persistent daily impairment. These are descriptive case observations, not comparative treatment recommendations or evidence of a CPT1C-specific response.
Show evidence (2 references)
PMID:39737739 SUPPORT Human Clinical
"Current medications include amphetamine/dextroamphetamine (Adderall) and sertraline."
Case1 medication list.
PMID:39737739 SUPPORT Human Clinical
"Current pharmacotherapy includes sertraline, lurasidone, and olanzapine, which appear effective."
Case2 reported treatment response without a controlled comparison.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling depends on establishing the causal diagnosis and interpreting family segregation. A heterozygous allele has a 50% transmission probability, but this must not be presented as 50% HSP risk for a disputed CPT1C loss-of-function finding. Reproductive testing requires a well-supported familial pathogenic variant.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"Genetic counseling and risk assessment depend on determination of the specific genetic cause of uncomplicated HSP in an individual."
General HSP counseling principle is especially relevant to the CPT1C loss-of-function controversy.
DOI:10.1002/mds.70144 SUPPORT Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/ SUPPORT Other
"uncomplicated HSP is at a 50% risk of inheriting the HSP-related"
This is the conditional allele-transmission rule for a confirmed dominant diagnosis, not a penetrance estimate for disputed CPT1C alleles.
🔬

Diagnosis

3
Clinical and neurophysiologic assessment
Document the distribution and course of spasticity and weakness, pyramidal signs, sensory findings and urinary symptoms. Central motor/sensory evoked potentials may be abnormal despite normal peripheral conduction. Normal brain or spinal MRI does not exclude the reported pure presentations.
Show evidence (2 references)
PMID:25751282 SUPPORT Human Clinical
"indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction velocities were normal in all participants examined"
Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated histologically.
PMID:30911584 SUPPORT Human Clinical
"Cerebral and spinal MRI were normal."
Normal structural imaging in the reported Q76Ter family.
Genetic testing and causal reassessment
Use an HSP-focused panel or broader genomic testing with appropriate copy-number analysis and family segregation. A CPT1C finding should not end the search for an established HSP cause, particularly for heterozygous truncating/splice alleles. Reassess variant-level evidence and alternative diagnoses rather than equating predicted loss-of-function with confirmed SPG73.
Show evidence (5 references)
DOI:10.1002/mds.70144 SUPPORT Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
DOI:10.1002/mds.70144 SUPPORT Human Clinical
"all three also carry pathogenic variants in established HSP‐associated genes."
All three GENESIS participants with HSP and CPT1C loss-of-function variants had an alternative established HSP-associated genotype.
PMID:30911584 SUPPORT Human Clinical
"No copy number variation in exons was found in the SPAST, REEP1, or ATL1 gene."
The case report investigated selected alternative HSP genes; a negative limited workup does not exclude every alternative.
+ 2 more references
Evaluation of complex features
When seizures, developmental/cognitive impairment, behavioral problems or structural brain changes coexist, characterize these individually and evaluate alternative or additional diagnoses. These findings in candidate CPT1C cases do not yet establish a validated complex loss-of-function subtype.
Show evidence (2 references)
PMID:39737739 SUPPORT Human Clinical
"with EEG findings revealing sharp waves in the temporal region"
Case2 underwent EEG assessment after seizures.
DOI:10.1002/mds.70144 SUPPORT Human Clinical
"Our study does not support a causal role for CPT1C LOF variants in HSP."
The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does not directly test the original missense-specific mechanism.
🧫

Experimental Models

5
R37C COS7 lipid-droplet assay CELL_LINE
Overexpression reduces lipid-droplet number and area; coimmunoprecipitation shows preserved atlastin-1 binding.
Cell source
COS7 cells expressing wild-type or R37C CPT1C
Pathograph links
Reduced Lipid Droplet Formation measures fidelity: unknown Lipid-droplet number and area after R37C expression.
Limitations: Non-neuronal overexpression; no demonstrated human axon loss.
Show evidence (2 references)
PMID:25751282 SUPPORT In Vitro
"We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells."
p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient motor neurons.
+ 1 more reference
Cpt1c-null embryonic cortical neurons PRIMARY_CELL_CULTURE
Cultures support lipid-droplet and axon-growth phenotypes. Wild-type re-expression restores growth; R37C and engineered M589S fail.
Cell source
Primary cortical cultures from Cpt1c-null mouse embryos
Pathograph links
Reduced Lipid Droplet Formation measures fidelity: unknown Reduced lipid-droplet number.
Limitations: Embryonic culture, not an adult in-vivo HSP phenotype.
Show evidence (1 reference)
PMID:25751282 SUPPORT In Vitro
"We also observed a reduction of LDs in primary cortical neurons isolated from Cpt1c−/− mice as compared with wild-type mice."
Embryo-derived knockout cortical cultures show fewer lipid droplets. This phenocopy alone does not prove dominant-negative action.
Reduced Axon Extension in Cortical Cultures measures fidelity: unknown Axon length and allelic complementation.
Limitations: R37C failure to rescue is not a demonstration of dominant-negative action in a heterozygote.
Show evidence (1 reference)
PMID:31868590 SUPPORT In Vitro
"Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S"
The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
p.Gln76Ter HEK293T expression system CELL_LINE
The mutant construct produces much less transcript and no detectable full-length or truncated protein; cycloheximide restores transcript abundance.
Cell source
Engineered GFP-CPT1C constructs in HEK293T cells
Pathograph links
CPT1C Protein Depletion in Experimental Systems measures fidelity: unknown Transcript decay and protein abundance.
Limitations: Not patient-derived cells; does not establish clinical haploinsufficiency.
Show evidence (2 references)
PMID:30911584 SUPPORT In Vitro
"293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared to that of wild‐type cells"
Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
+ 1 more reference
CPT1C protrudin transport assays CELL_LINE
Biochemical interactions, live vesicle tracking and lysosome positioning support nutrient-sensitive kinesin transfer.
Cell source
HeLa and HEK293 cells with CPT1C, protrudin and FYCO1 manipulations
Pathograph links
Reduced Anterograde Late Endosome and Lysosome Transport measures fidelity: unknown Peripheral lysosome distribution and anterograde transport.
Limitations: R37C-specific motor transfer is not directly assayed; engineered M589S is a mechanistic probe.
Show evidence (1 reference)
PMID:31868590 SUPPORT In Vitro
"CPT1C will sense intracellular malonyl-CoA levels and promote the plus-end transport of LE/Lys through the enhancement of protrudin function."
The combined cell experiments support nutrient-dependent lysosomal transport; R37C-specific motor transfer was not directly measured.
CPT1C SAC1 GluA1 trafficking assays PRIMARY_CELL_CULTURE
Knockdown/knockout and rescue experiments interrogate SAC1, PI4P and GluA1 localization. Engineered ER-TGN contacts provide complementary pathway perturbation.
Cell source
Mouse cortical neurons, with complementary engineered HEK293 and HeLa assays
Pathograph links
Increased SAC1 Phosphatase Activity measures fidelity: unknown CPT1C-dependent SAC1 activity.
Limitations: Normal gene function; patient HSP alleles were not directly tested.
Show evidence (1 reference)
PMID:32931550 SUPPORT In Vitro
"CPT1C expression decreased SAC1 activity"
Cell assays show negative regulation of SAC1.
Reduced Trans-Golgi PI4P measures fidelity: unknown TGN PI4P level.
Limitations: No established causal connection to complex clinical features.
Show evidence (1 reference)
PMID:32931550 SUPPORT In Vitro
"both knocking down CPT1C or treatment with TOFA resulted in a significant decrease of PI(4)P levels at the TGN."
Cortical neuronal experiments link CPT1C deficiency or inhibition of malonyl-CoA synthesis to lower TGN PI4P.
GluA1 Retention at the Trans-Golgi Network measures fidelity: unknown TGN retention and surface GluA1.
Limitations: Nutrient challenges and engineered mutants are not treatments or patient variants.
Show evidence (1 reference)
PMID:32931550 SUPPORT In Vitro
"knockdown of CPT1C resulted in a similar GluA1 retention pattern at the TGN."
CPT1C knockdown causes GluA1 retention at the TGN in cortical neuronal cultures.
🐁

Animal Models

1
Cpt1c-null mouse brain biochemical model
Adult knockout brain lysates show increased SAC1 phosphatase activity and reduced phosphatidylinositol monophosphate. These biochemical findings support CPT1C function, without recapitulating an established heterozygous human loss-of-function HSP mechanism.
Species
Mus musculus
Genotype
Cpt1c−/−
Pathograph links
Increased SAC1 Phosphatase Activity measures fidelity: unknown SAC1 activity in knockout brain lysates.
Limitations: Complete gene knockout differs from human heterozygosity; the clinical loss-of-function model is disputed.
Show evidence (1 reference)
PMID:32931550 SUPPORT Model Organism
"SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs"
Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than human HSP causality.
Show evidence (1 reference)
PMID:32931550 SUPPORT Model Organism
"SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs"
Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than human HSP causality.
{ }

Source YAML

click to show 
name: CPT1C-Related Hereditary Spastic Paraplegia
creation_date: '2026-07-07T00:00:00Z'
description: >-
  CPT1C-associated hereditary spastic paraplegia (SPG73) was defined in a three-generation family with
  adult-onset pure spastic paraparesis and the heterozygous p.Arg37Cys variant. CPT1C is a neuronal endoplasmic-reticulum
  protein involved in lipid-droplet homeostasis, nutrient-sensitive organelle transport and AMPA-receptor
  trafficking, rather than a conventional mitochondrial fatty-acid-oxidation enzyme. Later reports attributed
  childhood-onset pure or complex HSP to truncating and splice variants, but a 2026 population/cohort
  study found no support for loss-of-function variants as a cause of HSP. The original missense-specific
  association and the disputed loss-of-function model therefore require separate interpretation. Reported
  phenotypes span mild or improving childhood motor impairment to progressive spasticity, with additional
  cognitive, seizure and behavioral findings in individual candidate cases; these do not establish a uniform
  CPT1C loss-of-function syndrome.
synonyms:
- SPG73
- Hereditary spastic paraplegia 73
- CPT1C-related autosomal dominant pure spastic paraplegia
- Autosomal dominant spastic paraplegia type 73
category: Mendelian
disease_term:
  preferred_term: hereditary spastic paraplegia 73
  term:
    id: MONDO:0014568
    label: hereditary spastic paraplegia 73
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014568
      label: hereditary spastic paraplegia 73
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- Hereditary Spastic Paraplegia
inheritance:
- name: Autosomal dominant
  description: >-
    An autosomal dominant pedigree supports the original p.Arg37Cys association. Other reported alleles
    were inherited from parents with mild or absent symptoms; the pathogenicity of heterozygous loss-of-function
    variants is challenged by subsequent cohort data. Penetrance cannot be quantified from these small,
    differently ascertained reports.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus
      strictly cosegregating with the disease phenotype.
    explanation: >-
      Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants
      as causal.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
    explanation: >-
      The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
      not directly test the original missense-specific mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: uncomplicated HSP is at a 50% risk of inheriting the HSP-related
    explanation: >-
      This is the conditional allele-transmission rule for a confirmed dominant diagnosis, not a penetrance
      estimate for disputed CPT1C alleles.
pathophysiology:
- name: Arg37Cys Regulatory-Domain Destabilization
  description: >-
    NMR of the isolated N-terminal regulatory domain shows destabilization by p.Arg37Cys. Altered coupling
    to other domains and dominant-negative activity remain proposed interpretations. Atlastin-1 binding
    and ER localization are retained in the tested cells.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The NMR studies indicated that the mutation altered the protein conformation
    explanation: NMR examined the isolated regulatory domain, not patient full-length protein activity.
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The Arg37Cys mutation did not affect the ability of CPT1C to bind atlastin-1
    explanation: >-
      The specific atlastin-binding assay was negative for disruption; a generic disrupted ER interaction
      network is not established.
  role: trigger
  genetic_context:
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    functional_impact: Regulatory-domain conformational change; dominant-negative mechanism proposed, not established.
  downstream:
  - target: Reduced Lipid Droplet Formation
    description: >-
      The same R37C allele reduces lipid-droplet number and area in a separate overexpression assay; the
      intervening molecular mechanism is unresolved.
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells.
      explanation: >-
        p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient
        motor neurons.
  - target: Reduced Axon Extension in Cortical Cultures
    description: >-
      R37C fails to restore axon extension in knockout cortical cultures. This is a functional complementation
      result, not direct proof of human distal axon loss.
    evidence:
    - reference: PMID:31868590
      reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S
      explanation: The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
- name: Reduced Lipid Droplet Formation
  description: >-
    R37C overexpression reduces lipid-droplet number and area in COS7 cells. Primary Cpt1c-null cortical
    cultures have fewer lipid droplets. These observations support altered lipid-droplet homeostasis,
    without demonstrating disrupted atlastin binding or identifying how the lipid change produces human
    HSP.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells.
    explanation: >-
      p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient
      motor neurons.
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also observed a reduction of LDs in primary cortical neurons isolated from Cpt1c−/− mice as compared
      with wild-type mice.
    explanation: >-
      Embryo-derived knockout cortical cultures show fewer lipid droplets. This phenocopy alone does not
      prove dominant-negative action.
  biological_processes:
  - preferred_term: lipid droplet formation
    term:
      id: GO:0140042
      label: lipid droplet formation
    modifier: DECREASED
- name: CPT1C Protein Depletion in Experimental Systems
  description: >-
    Cpt1c knockout or knockdown depletes the protein in experimental systems. The reported p.Gln76Ter
    allele also causes marked transcript loss and absent detectable protein in engineered HEK293T cells,
    with transcript recovery after cycloheximide. Clinical causality of heterozygous loss-of-function
    remains disputed, and model depletion must not be equated with established human haploinsufficiency.
  evidence:
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared
      to that of wild‐type cells
    explanation: Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: No full‐length or truncated CPT1C proteins were detected by immunoblot in the 293T cell homogenates
    explanation: The engineered p.Gln76Ter construct lacked detectable protein in HEK293T cells.
  role: trigger
  genetic_context:
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    functional_impact: >-
      Experimental depletion or p.Gln76Ter construct-associated transcript decay; human haploinsufficiency
      is not established.
  downstream:
  - target: Reduced Anterograde Late Endosome and Lysosome Transport
    description: >-
      Knockout cortical cultures have reduced distal lysosome accumulation; nutrient-sensing experiments
      identify the protrudin/kinesin transfer pathway.
    evidence:
    - reference: PMID:31868590
      reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        CPT1C will sense intracellular malonyl-CoA levels and promote the plus-end transport of LE/Lys
        through the enhancement of protrudin function.
      explanation: >-
        The combined cell experiments support nutrient-dependent lysosomal transport; R37C-specific motor
        transfer was not directly measured.
  - target: Increased SAC1 Phosphatase Activity
    description: Cpt1c knockout increases SAC1 phosphatase activity in brain lysates.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs
      explanation: >-
        Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than
        human HSP causality.
- name: Reduced Anterograde Late Endosome and Lysosome Transport
  description: >-
    In cellular models, CPT1C promotes protrudin-dependent transfer of kinesin-1 to FYCO1-positive late
    endosomes/lysosomes under nutrient-replete conditions. CPT1C deficiency or low malonyl-CoA impairs
    peripheral organelle delivery. CPT1C-protrudin binding persists under stress, and CPT1C does not create
    the ER-lysosome contacts themselves. R37C-specific motor-transfer impairment remains inferred.
  evidence:
  - reference: PMID:31868590
    reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CPT1C will sense intracellular malonyl-CoA levels and promote the plus-end transport of LE/Lys through
      the enhancement of protrudin function.
    explanation: >-
      The combined cell experiments support nutrient-dependent lysosomal transport; R37C-specific motor
      transfer was not directly measured.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: lysosome localization
    term:
      id: GO:0032418
      label: lysosome localization
    modifier: ABNORMAL
  downstream:
  - target: Reduced Axon Extension in Cortical Cultures
    description: >-
      The nutrient/CPT1C axis couples distal lysosome delivery to axon growth in cortical cultures; exogenous
      malonyl-CoA partially rescues nutrient-stressed wild-type but not knockout cultures.
    evidence:
    - reference: PMID:31868590
      reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: axon growth was partially restored in all conditions
      explanation: Malonyl-CoA supplementation partially restored axon growth after metabolic stress in wild-type cultures.
- name: Reduced Axon Extension in Cortical Cultures
  description: >-
    Cpt1c-null embryonic cortical cultures grow shorter axons. Wild-type CPT1C restores growth, whereas
    R37C and engineered malonyl-CoA-insensitive M589S do not. Reduced dendritic arborization is also observed,
    but its mechanism may be independent of protrudin. These developmental culture readouts do not demonstrate
    adult human axon degeneration.
  evidence:
  - reference: PMID:31868590
    reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S
    explanation: The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: axon extension
    term:
      id: GO:0048675
      label: axon extension
    modifier: DECREASED
- name: Increased SAC1 Phosphatase Activity
  description: >-
    CPT1C normally inhibits the PI4P phosphatase SAC1 in a nutrient-dependent manner. Knockout brain extracts
    have increased SAC1 activity. Cell assays show that malonyl-CoA depletion releases this inhibition;
    CPT1C-SAC1 binding itself is retained. These are gene-function findings, without direct testing of
    patient HSP alleles.
  evidence:
  - reference: PMID:32931550
    reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs
    explanation: >-
      Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than
      human HSP causality.
  - reference: PMID:32931550
    reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: CPT1C expression decreased SAC1 activity
    explanation: Cellular phosphatase assays support inhibition of SAC1 by CPT1C.
  gene:
    preferred_term: CPT1C
    term:
      id: hgnc:18540
      label: CPT1C
  molecular_functions:
  - preferred_term: phosphatase inhibitor activity
    term:
      id: GO:0019212
      label: phosphatase inhibitor activity
    modifier: DECREASED
  downstream:
  - target: Reduced Trans-Golgi PI4P
    description: >-
      Increased SAC1 activity dephosphorylates PI4P; knockdown/overexpression and engineered contact-site
      experiments support regulation of the TGN lipid pool.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        both knocking down CPT1C or treatment with TOFA resulted in a significant decrease of PI(4)P levels
        at the TGN.
      explanation: >-
        Cortical neuronal experiments link CPT1C deficiency or inhibition of malonyl-CoA synthesis to
        lower TGN PI4P.
- name: Reduced Trans-Golgi PI4P
  description: >-
    CPT1C-deficient cortical neurons have reduced PI4P at the trans-Golgi network. Nutrient stress recruits
    CPT1C/SAC1 to ER-TGN contact sites rather than demonstrating SAC1 entry into the TGN. Wild-type CPT1C,
    but not engineered M589S or a C-terminal deletion, restores the lipid pool.
  evidence:
  - reference: PMID:32931550
    reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      both knocking down CPT1C or treatment with TOFA resulted in a significant decrease of PI(4)P levels
      at the TGN.
    explanation: >-
      Cortical neuronal experiments link CPT1C deficiency or inhibition of malonyl-CoA synthesis to lower
      TGN PI4P.
  downstream:
  - target: GluA1 Retention at the Trans-Golgi Network
    description: Reduced TGN PI4P accompanies impaired GluA1 export in the experimental CPT1C/SAC1 pathway.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: knockdown of CPT1C resulted in a similar GluA1 retention pattern at the TGN.
      explanation: CPT1C knockdown causes GluA1 retention at the TGN in cortical neuronal cultures.
- name: GluA1 Retention at the Trans-Golgi Network
  description: >-
    Knockdown or knockout reduces GluA1 surface abundance and promotes retention at the TGN. Acute metabolic
    inhibition has little additional effect in depleted cells. The tested M589S and C-terminal deletion
    are engineered probes, not reported HSP alleles; this pathway is not established as the cause of seizures
    or intellectual disability in candidate clinical cases.
  evidence:
  - reference: PMID:32931550
    reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: knockdown of CPT1C resulted in a similar GluA1 retention pattern at the TGN.
    explanation: CPT1C knockdown causes GluA1 retention at the TGN in cortical neuronal cultures.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
- name: Corticospinal Tract Dysfunction
  description: >-
    Prolonged central motor conduction in the original family supports corticospinal tract dysfunction
    despite normal peripheral conduction. How the observed lipid-droplet and axon-growth defects produce
    this clinical lesion remains unresolved; direct human pathology proving distal axon degeneration is
    absent.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction
      velocities were normal in all participants examined
    explanation: >-
      Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated
      histologically.
  cell_types:
  - preferred_term: upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  downstream:
  - target: Spastic paraplegia
    description: >-
      Central motor tract dysfunction underlies the clinical spastic paraparesis; this does not establish
      which CPT1C molecular defect produces the tract lesion.
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction
        velocities were normal in all participants examined
      explanation: >-
        Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated
        histologically.
- name: Dorsal Column Dysfunction
  description: >-
    Abnormal sensory evoked potentials and reduced ankle vibration in the original family support dorsal-column
    involvement. Peripheral nerve conduction was normal. This sensory tract finding is distinct from the
    corticospinal motor dysfunction.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction
      velocities were normal in all participants examined
    explanation: >-
      Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated
      histologically.
  downstream:
  - target: Impaired vibration sensation at ankles
    description: Dorsal-column dysfunction is consistent with the distal vibration deficit in the same clinical family.
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction
        velocities were normal in all participants examined
      explanation: >-
        Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated
        histologically.
phenotypes:
- name: Spastic paraplegia
  category: Neurological
  description: >-
    Adult-onset pure spastic paraplegia in the original R37C family; childhood presentations were reported
    with other alleles whose causality remains uncertain.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: adult-onset, and pure spastic paraplegia of unknown genetic cause
    explanation: The original pedigree had pure spastic paraplegia.
- name: Lower limb spasticity
  category: Neurological
  description: Moderate to severe in the founding family; also reported in childhood candidate cases.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Spasticity | Moderate/severe phenotype |'
    explanation: The founding family clinical table documents spasticity.
- name: Spastic gait
  category: Neurological
  description: >-
    Slow progression to impaired or lost ambulation over 10–15 years in the original family. This course
    is not universal: the reported Q76Ter siblings improved around age 10.
  phenotype_term:
    preferred_term: Spastic gait
    term:
      id: HP:0002064
      label: Spastic gait
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease was slowly progressive, leading to impairment or loss of ambulation 10 to 15 years after
      the onset of symptoms.
    explanation: Family-specific natural history.
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: spasticity of lower limbs still affected his gaits
    explanation: The reported Q76Ter boy retained gait impairment despite later improvement.
- name: Lower limb muscle weakness
  category: Neurological
  description: Mild proximal weakness in the founding family; dorsiflexion weakness in the reported Q76Ter children.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Weakness | Mild phenotype, proximal |'
    explanation: The clinical table documents mild proximal weakness.
- name: Lower limb hyperreflexia
  category: Neurological
  description: Increased lower-limb reflexes in the clinical reports.
  phenotype_term:
    preferred_term: Lower limb hyperreflexia
    term:
      id: HP:0002395
      label: Lower limb hyperreflexia
  evidence:
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Deep tendon reflexes were brisk in the lower extremities.
    explanation: Direct examination in the reported Q76Ter family.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Lower-extremity hyperreflexia and extensor plantar responses may be demonstrated on neurologic examination.
    explanation: General uncomplicated HSP clinical context; CPT1C-specific findings are supported by the family reports.
- name: Babinski sign
  category: Neurological
  description: Extensor plantar responses were documented in the original family and candidate childhood cases.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Plantar reflex | Extensor |'
    explanation: The founding family table records extensor plantar responses.
- name: Pes cavus
  category: Musculoskeletal
  description: >-
    Bilateral pes cavus in the reported Q76Ter siblings; the original family had unspecified foot deformity
    in 2/5 examined individuals, which should not be assumed to be pes cavus.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bilateral pes cavus was obvious.
    explanation: Pes cavus was directly documented in the index child.
- name: Motor delay
  category: Neurological
  description: >-
    Reported Q76Ter siblings achieved independent walking at 3–3.5 years. Delayed milestones are not a
    universal feature of the original adult-onset family.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: walking independently at age 3.5
    explanation: The reported Q76Ter index child had delayed independent walking.
- name: Ankle clonus
  category: Neurological
  description: Documented in both Brooks candidate cases; genotype causality remains unresolved.
  phenotype_term:
    preferred_term: Ankle clonus
    term:
      id: HP:0011448
      label: Ankle clonus
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bilateral lower leg spasticity, ankle clonus, a positive Babinski sign
    explanation: Case1 examination.
- name: Ankle contracture
  category: Musculoskeletal
  description: Brooks case 2 developed ankle contractures in the setting of progressive spasticity.
  phenotype_term:
    preferred_term: Ankle contracture
    term:
      id: HP:0034677
      label: Ankle contracture
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: leading to contractures of the ankles, muscle wasting, and significant spontaneous ankle clonus
    explanation: Case2 examination; not a frequency estimate.
- name: Chiari malformation
  category: Neurological
  description: >-
    Chiari 1 malformation in Brooks case 1; an association with CPT1C is unproven and other imaged cases
    had normal MRI.
  phenotype_term:
    preferred_term: Chiari malformation
    term:
      id: HP:0002308
      label: Chiari malformation
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MR imaging of the brain showed a Chiari 1 malformation but was otherwise unremarkable.
    explanation: Single candidate-case imaging observation.
- name: Moderate intellectual disability
  category: Neurological
  description: >-
    Brooks case 2 had full-scale IQ 57 and impaired adaptive function. Case1 cognition was normal in the
    table, despite broader wording in the abstract/discussion. Causation by CPT1C remains uncertain.
  phenotype_term:
    preferred_term: Moderate intellectual disability
    term:
      id: HP:0002342
      label: Moderate intellectual disability
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'His IQ testing suggests moderate cognitive impairment (full scale IQ: 57)'
    explanation: Case2 measured cognition, not both reported boys.
- name: Attention deficit hyperactivity disorder
  category: Behavioral
  description: Diagnosed in both Brooks candidate cases.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Further evaluation led to a diagnosis of attention‐deficit/hyperactivity disorder.
    explanation: Case1 had ADHD.
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnoses include ADHD, anxiety disorder, depressive disorder, disruptive mood dysregulation disorder,
      conduct disorder, and autism spectrum disorder.
    explanation: Case2 had multiple neurobehavioral diagnoses; their causal connection to CPT1C is unresolved.
- name: Anxiety
  category: Behavioral
  description: Anxiety disorders in both Brooks candidate cases.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: continued significant anxiety as he aged leading to a formal diagnosis of anxiety disorder
    explanation: Case1 had an anxiety disorder.
- name: Autism
  category: Behavioral
  description: >-
    Autism spectrum disorder in Brooks case 2; not established for case 1 or as a characteristic CPT1C
    phenotype.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnoses include ADHD, anxiety disorder, depressive disorder, disruptive mood dysregulation disorder,
      conduct disorder, and autism spectrum disorder.
    explanation: Case2’s diagnostic list includes autism spectrum disorder.
- name: Depression
  category: Behavioral
  description: Depressive disorder in Brooks case 2, with unresolved genotype attribution.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnoses include ADHD, anxiety disorder, depressive disorder, disruptive mood dysregulation disorder,
      conduct disorder, and autism spectrum disorder.
    explanation: Depressive disorder was reported in case 2.
- name: Aggressive behavior
  category: Behavioral
  description: Aggressive and impulsive behavior in Brooks case 2.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a history of aggressive and impulsive behavior from a young age
    explanation: Case2 behavioral history.
- name: Skeletal muscle atrophy
  category: Neurological
  description: >-
    Mild muscle wasting in the original adult family; also documented in Brooks case 2, whereas case 1
    had no wasting.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Muscle wasting | Mild phenotype |'
    explanation: The founding family clinical table documents mild wasting.
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: leading to contractures of the ankles, muscle wasting, and significant spontaneous ankle clonus
    explanation: Muscle wasting in the second candidate case.
- name: Urinary dysfunction
  category: Neurological
  description: >-
    Mild urinary dysfunction in the founding family, without enough detail to identify urgency, incontinence
    or a specific bladder mechanism.
  phenotype_term:
    preferred_term: Abnormality of the lower urinary tract
    term:
      id: HP:0010936
      label: Abnormality of the lower urinary tract
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Urinary dysfunction | Mild phenotype |'
    explanation: The source gives an unspecified urinary functional abnormality.
- name: Impaired vibration sensation at ankles
  category: Neurological
  description: >-
    Reduced ankle vibration in the founding adult family, consistent with the neurophysiologic sensory
    tract findings.
  phenotype_term:
    preferred_term: Impaired vibration sensation at ankles
    term:
      id: HP:0006938
      label: Impaired vibration sensation at ankles
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Vibration sensation at ankles | Decreased |'
    explanation: Direct table observation in the original family.
- name: Foot deformity
  category: Musculoskeletal
  description: >-
    Unspecified foot deformity in 2/5 examined members of the founding family. The source does not identify
    the precise deformity.
  phenotype_term:
    preferred_term: Structural foot deformity
    term:
      id: HP:0010219
      label: Structural foot deformity
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Additional features (No. of individuals/total individuals) | Foot deformity (2/5) |'
    explanation: This is a family-specific proportion, not population frequency.
- name: Bilateral tonic-clonic seizures
  category: Neurological
  description: >-
    Brooks case 2 had seizures described as generalized tonic-clonic from age 5, with temporal sharp waves
    on EEG. Onset classification is insufficient to distinguish generalized from focal-to-bilateral seizures.
  phenotype_term:
    preferred_term: Bilateral tonic-clonic seizure
    term:
      id: HP:0002069
      label: Bilateral tonic-clonic seizure
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a history of generalized tonic–clonic seizures, first occurring at age 5
    explanation: Single candidate-case seizure history; genotype attribution remains unresolved.
genetic:
- name: CPT1C reported HSP association
  gene_term:
    preferred_term: CPT1C
    term:
      id: hgnc:18540
      label: CPT1C
  association: Allele-dependent association; heterozygous loss-of-function causality challenged
  notes: >-
    The original missense pedigree and cellular complementation differ from the later truncating/splice
    case reports. UK Biobank and HSP cohort analyses did not support a causal loss-of-function model;
    alternative established HSP genotypes explained all three GENESIS HSP cases carrying CPT1C loss-of-function
    alleles. Mild phenotypes, modifiers or incomplete penetrance are not excluded. A functional loss in
    a model is insufficient to establish a variant as the explanation for a patient’s HSP. No curator-assigned
    gene-validity tier is asserted.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus
      strictly cosegregating with the disease phenotype.
    explanation: >-
      Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants
      as causal.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
    explanation: >-
      The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
      not directly test the original missense-specific mechanism.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: all three also carry pathogenic variants in established HSP‐associated genes.
    explanation: >-
      All three GENESIS participants with HSP and CPT1C loss-of-function variants had an alternative established
      HSP-associated genotype.
  variants:
  - name: p.Arg37Cys
    variant_type: single nucleotide variant
    description: >-
      NM_001136052:c.109C>T; original adult-onset pure HSP pedigree. Segregation, isolated-domain NMR,
      COS7 lipid-droplet assays and failed rescue of knockout cortical axon growth provide allele-specific
      support. Dominant-negative action remains proposed.
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus
        strictly cosegregating with the disease phenotype.
      explanation: >-
        Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants
        as causal.
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells.
      explanation: >-
        p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient
        motor neurons.
    - reference: PMID:31868590
      reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S
      explanation: The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
    type: missense
  - name: p.Gln76Ter
    variant_type: single nucleotide variant
    description: >-
      c.226C>T; reported in a family with childhood motor delay, subsequent improvement and a minimally
      affected mother, and in another child summarized by Brooks et al. Engineered construct assays demonstrate
      transcript/protein loss, but later population data challenge causal loss-of-function interpretation.
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    evidence:
    - reference: PMID:30911584
      reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared
        to that of wild‐type cells
      explanation: Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
    - reference: PMID:30911584
      reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: No full‐length or truncated CPT1C proteins were detected by immunoblot in the 293T cell homogenates
      explanation: The engineered p.Gln76Ter construct lacked detectable protein in HEK293T cells.
    - reference: DOI:10.1002/mds.70144
      reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
      explanation: >-
        The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
        not directly test the original missense-specific mechanism.
    type: nonsense
  - name: p.Ile686SerfsTer8
    variant_type: deletion
    description: >-
      NM_001199753.2:c.2057_2061del; maternally inherited in Brooks case 1. Original authors classified
      the variant as pathogenic, but no functional study was performed and the later loss-of-function
      challenge applies.
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    evidence:
    - reference: PMID:39737739
      reference_title: >-
        Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
        case series.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Variant c.2057_2061del (Ile686SerfsTer8) in CPT1C (NM_001199753.2) was identified through multi‐gene
        panel testing and classified as Pathogenic
      explanation: Historical author classification, not an independent current pathogenicity assertion.
    type: frameshift
  - name: c.2020-1G>C
    variant_type: single nucleotide variant
    description: >-
      NM_001199753.2:c.2020-1G>C; maternally inherited in Brooks case 2. Original authors called it likely
      pathogenic; splicing was not experimentally established and clinical causality remains uncertain.
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    evidence:
    - reference: PMID:39737739
      reference_title: >-
        Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
        case series.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Genetic testing identified a likely pathogenic variant in CPT1C (NM_001199753.2: c.2020‐1G>C)'
      explanation: >-
        The report describes a candidate splice-site allele; its functional and clinical interpretation
        needs reassessment.
    type: splice site
  - name: c.2133+1G>A
    variant_type: single nucleotide variant
    description: >-
      NM_001199752:c.2133+1G>A; heterozygous in patient 2 of the 2018 Italian cohort, listed among author-assigned
      confirmed diagnoses. No focal splice assay is reported in the main article.
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    evidence:
    - reference: PMID:30564185
      reference_title: 'Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '| Pt2 | CPT1C | NM_001199752 | c.2133+1G>A (het) |'
      explanation: >-
        Table2 lists this variant among the historically assigned diagnoses, rather than among that study’s
        VUS group.
    type: splice site
  - name: p.Thr601Met
    variant_type: single nucleotide variant
    description: >-
      NM_001199752:c.1802C>T; heterozygous in patient 23 of the 2018 Italian cohort, listed among author-assigned
      confirmed diagnoses. Functional and segregation details are insufficient in the main article to
      generalize the original R37C mechanism.
    gene:
      preferred_term: CPT1C
      term:
        id: hgnc:18540
        label: CPT1C
    evidence:
    - reference: PMID:30564185
      reference_title: 'Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: '| Pt23 | CPT1C | NM_001199752 | c.1802C>T (het) | NP_001186681 | p.Thr601Met |'
      explanation: This is a second reported missense allele, not direct functional replication of R37C.
    type: missense
treatments:
- name: Supportive multidisciplinary care
  description: >-
    General HSP care aims to maintain mobility and daily function, manage spasticity and associated symptoms,
    and provide psychological and social support. No CPT1C-specific disease-modifying intervention was
    demonstrated in the reviewed clinical reports.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
    explanation: General uncomplicated HSP management, not a CPT1C-specific trial.
- name: Physical therapy and mobility support
  description: >-
    Individualized stretching, strengthening, aerobic exercise, gait training and occupational therapy
    follow general HSP practice. Orthotics and walking aids are selected by need; Brooks case 2 used orthotics
    and a wheelchair for longer distances.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Spasticity is currently managed with baclofen and physical therapy.
    explanation: Direct management reported in case 1.
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He now requires orthotics and wheelchair assistance for longer distances
    explanation: Direct mobility support reported in case 2.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
    explanation: General uncomplicated HSP management, not a CPT1C-specific trial.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Stretching exercises to improve flexibility
    explanation: General HSP physical therapy includes stretching, strengthening and aerobic exercise.
  target_mechanisms:
  - target: Spastic gait
    treatment_effect: MODULATES
    description: Symptomatic management of the reported manifestation; no disease-modifying effect is established.
    evidence:
    - reference: PMID:39737739
      reference_title: >-
        Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
        case series.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Spasticity is currently managed with baclofen and physical therapy.
      explanation: Direct management reported in case 1.
- name: Baclofen and other antispasmodic therapy
  description: >-
    Baclofen was used in Brooks case 1. General HSP guidance also discusses intrathecal baclofen, botulinum
    toxin and tizanidine according to individual need; these are symptomatic approaches without CPT1C-specific
    efficacy trials. GeneReviews cautions against dantrolene in ambulatory individuals because it may
    cause irreversible weakness.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Spasticity is currently managed with baclofen and physical therapy.
    explanation: Reported symptomatic treatment.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness
      that can adversely affect overall mobility.
    explanation: General HSP treatment precaution.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Baclofen can be tried first and can be used with an intrathecal pump in some individuals.
    explanation: General HSP antispasticity management; individual drug selection is symptom-driven.
  target_mechanisms:
  - target: Lower limb spasticity
    treatment_effect: MODULATES
    description: Symptomatic management of the reported manifestation; no disease-modifying effect is established.
    evidence:
    - reference: PMID:39737739
      reference_title: >-
        Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
        case series.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Spasticity is currently managed with baclofen and physical therapy.
      explanation: Reported symptomatic treatment.
- name: Management of associated seizures
  description: >-
    Brooks case 2 received an unnamed antiseizure medication regimen, later discontinued after two years
    of seizure freedom. Drug choice and discontinuation are individual clinical decisions; the report
    does not demonstrate a CPT1C-specific antiseizure response.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Antiseizure medications were initially prescribed but discontinued after 2 years of seizure freedom.
    explanation: Single candidate-case treatment course.
  target_mechanisms:
  - target: Bilateral tonic-clonic seizures
    treatment_effect: MODULATES
    description: Symptomatic management of the reported manifestation; no disease-modifying effect is established.
    evidence:
    - reference: PMID:39737739
      reference_title: >-
        Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
        case series.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Antiseizure medications were initially prescribed but discontinued after 2 years of seizure freedom.
      explanation: Single candidate-case treatment course.
- name: Management of behavioral and psychiatric symptoms
  description: >-
    Brooks case 1 received amphetamine/dextroamphetamine and sertraline; case 2 received sertraline, lurasidone
    and olanzapine with apparent benefit but persistent daily impairment. These are descriptive case observations,
    not comparative treatment recommendations or evidence of a CPT1C-specific response.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amphetamine
      term:
        id: CHEBI:2679
        label: amphetamine
    - preferred_term: sertraline
      term:
        id: CHEBI:9123
        label: sertraline
    - preferred_term: lurasidone
      term:
        id: CHEBI:70735
        label: lurasidone
    - preferred_term: olanzapine
      term:
        id: CHEBI:7735
        label: olanzapine
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Current medications include amphetamine/dextroamphetamine (Adderall) and sertraline.
    explanation: Case1 medication list.
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Current pharmacotherapy includes sertraline, lurasidone, and olanzapine, which appear effective.
    explanation: Case2 reported treatment response without a controlled comparison.
- name: Genetic counseling
  description: >-
    Counseling depends on establishing the causal diagnosis and interpreting family segregation. A heterozygous
    allele has a 50% transmission probability, but this must not be presented as 50% HSP risk for a disputed
    CPT1C loss-of-function finding. Reproductive testing requires a well-supported familial pathogenic
    variant.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic counseling and risk assessment depend on determination of the specific genetic cause of
      uncomplicated HSP in an individual.
    explanation: General HSP counseling principle is especially relevant to the CPT1C loss-of-function controversy.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
    explanation: >-
      The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
      not directly test the original missense-specific mechanism.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: uncomplicated HSP is at a 50% risk of inheriting the HSP-related
    explanation: >-
      This is the conditional allele-transmission rule for a confirmed dominant diagnosis, not a penetrance
      estimate for disputed CPT1C alleles.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: adult-onset, and pure spastic paraplegia of unknown genetic cause
      explanation: The founding pedigree had a central motor disorder.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus
        strictly cosegregating with the disease phenotype.
      explanation: >-
        Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants
        as causal.
diagnosis:
- name: Clinical and neurophysiologic assessment
  description: >-
    Document the distribution and course of spasticity and weakness, pyramidal signs, sensory findings
    and urinary symptoms. Central motor/sensory evoked potentials may be abnormal despite normal peripheral
    conduction. Normal brain or spinal MRI does not exclude the reported pure presentations.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction
      velocities were normal in all participants examined
    explanation: >-
      Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated
      histologically.
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cerebral and spinal MRI were normal.
    explanation: Normal structural imaging in the reported Q76Ter family.
- name: Genetic testing and causal reassessment
  description: >-
    Use an HSP-focused panel or broader genomic testing with appropriate copy-number analysis and family
    segregation. A CPT1C finding should not end the search for an established HSP cause, particularly
    for heterozygous truncating/splice alleles. Reassess variant-level evidence and alternative diagnoses
    rather than equating predicted loss-of-function with confirmed SPG73.
  evidence:
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
    explanation: >-
      The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
      not directly test the original missense-specific mechanism.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: all three also carry pathogenic variants in established HSP‐associated genes.
    explanation: >-
      All three GENESIS participants with HSP and CPT1C loss-of-function variants had an alternative established
      HSP-associated genotype.
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No copy number variation in exons was found in the SPAST, REEP1, or ATL1 gene.
    explanation: >-
      The case report investigated selected alternative HSP genes; a negative limited workup does not
      exclude every alternative.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic counseling and risk assessment depend on determination of the specific genetic cause of
      uncomplicated HSP in an individual.
    explanation: The general HSP evaluation seeks a causal diagnosis rather than accepting any rare variant.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
    reference_title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas
      genomic testing does not.
    explanation: General HSP testing includes multigene panels and comprehensive genomic approaches.
- name: Evaluation of complex features
  description: >-
    When seizures, developmental/cognitive impairment, behavioral problems or structural brain changes
    coexist, characterize these individually and evaluate alternative or additional diagnoses. These findings
    in candidate CPT1C cases do not yet establish a validated complex loss-of-function subtype.
  evidence:
  - reference: PMID:39737739
    reference_title: >-
      Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
      case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with EEG findings revealing sharp waves in the temporal region
    explanation: Case2 underwent EEG assessment after seizures.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
    explanation: >-
      The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
      not directly test the original missense-specific mechanism.
experimental_models:
- name: R37C COS7 lipid-droplet assay
  experimental_model_type: CELL_LINE
  cell_source: COS7 cells expressing wild-type or R37C CPT1C
  description: >-
    Overexpression reduces lipid-droplet number and area; coimmunoprecipitation shows preserved atlastin-1
    binding.
  modeled_mechanisms:
  - target: Reduced Lipid Droplet Formation
    relationship: MEASURES
    description: Lipid-droplet number and area after R37C expression.
    fidelity: UNKNOWN
    limitations: Non-neuronal overexpression; no demonstrated human axon loss.
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells.
      explanation: >-
        p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient
        motor neurons.
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The Arg37Cys mutation did not affect the ability of CPT1C to bind atlastin-1
      explanation: >-
        The specific atlastin-binding assay was negative for disruption; a generic disrupted ER interaction
        network is not established.
- name: Cpt1c-null embryonic cortical neurons
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Primary cortical cultures from Cpt1c-null mouse embryos
  description: >-
    Cultures support lipid-droplet and axon-growth phenotypes. Wild-type re-expression restores growth;
    R37C and engineered M589S fail.
  modeled_mechanisms:
  - target: Reduced Lipid Droplet Formation
    relationship: MEASURES
    description: Reduced lipid-droplet number.
    fidelity: UNKNOWN
    limitations: Embryonic culture, not an adult in-vivo HSP phenotype.
    evidence:
    - reference: PMID:25751282
      reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We also observed a reduction of LDs in primary cortical neurons isolated from Cpt1c−/− mice as
        compared with wild-type mice.
      explanation: >-
        Embryo-derived knockout cortical cultures show fewer lipid droplets. This phenocopy alone does
        not prove dominant-negative action.
  - target: Reduced Axon Extension in Cortical Cultures
    relationship: MEASURES
    description: Axon length and allelic complementation.
    fidelity: UNKNOWN
    limitations: R37C failure to rescue is not a demonstration of dominant-negative action in a heterozygote.
    evidence:
    - reference: PMID:31868590
      reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S
      explanation: The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
- name: p.Gln76Ter HEK293T expression system
  experimental_model_type: CELL_LINE
  cell_source: Engineered GFP-CPT1C constructs in HEK293T cells
  description: >-
    The mutant construct produces much less transcript and no detectable full-length or truncated protein;
    cycloheximide restores transcript abundance.
  modeled_mechanisms:
  - target: CPT1C Protein Depletion in Experimental Systems
    relationship: MEASURES
    description: Transcript decay and protein abundance.
    fidelity: UNKNOWN
    limitations: Not patient-derived cells; does not establish clinical haploinsufficiency.
    evidence:
    - reference: PMID:30911584
      reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared
        to that of wild‐type cells
      explanation: Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
    - reference: PMID:30911584
      reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: No full‐length or truncated CPT1C proteins were detected by immunoblot in the 293T cell homogenates
      explanation: The engineered p.Gln76Ter construct lacked detectable protein in HEK293T cells.
- name: CPT1C protrudin transport assays
  experimental_model_type: CELL_LINE
  cell_source: HeLa and HEK293 cells with CPT1C, protrudin and FYCO1 manipulations
  description: >-
    Biochemical interactions, live vesicle tracking and lysosome positioning support nutrient-sensitive
    kinesin transfer.
  modeled_mechanisms:
  - target: Reduced Anterograde Late Endosome and Lysosome Transport
    relationship: MEASURES
    description: Peripheral lysosome distribution and anterograde transport.
    fidelity: UNKNOWN
    limitations: R37C-specific motor transfer is not directly assayed; engineered M589S is a mechanistic probe.
    evidence:
    - reference: PMID:31868590
      reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        CPT1C will sense intracellular malonyl-CoA levels and promote the plus-end transport of LE/Lys
        through the enhancement of protrudin function.
      explanation: >-
        The combined cell experiments support nutrient-dependent lysosomal transport; R37C-specific motor
        transfer was not directly measured.
- name: CPT1C SAC1 GluA1 trafficking assays
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Mouse cortical neurons, with complementary engineered HEK293 and HeLa assays
  description: >-
    Knockdown/knockout and rescue experiments interrogate SAC1, PI4P and GluA1 localization. Engineered
    ER-TGN contacts provide complementary pathway perturbation.
  modeled_mechanisms:
  - target: Increased SAC1 Phosphatase Activity
    relationship: MEASURES
    description: CPT1C-dependent SAC1 activity.
    fidelity: UNKNOWN
    limitations: Normal gene function; patient HSP alleles were not directly tested.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: CPT1C expression decreased SAC1 activity
      explanation: Cell assays show negative regulation of SAC1.
  - target: Reduced Trans-Golgi PI4P
    relationship: MEASURES
    description: TGN PI4P level.
    fidelity: UNKNOWN
    limitations: No established causal connection to complex clinical features.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        both knocking down CPT1C or treatment with TOFA resulted in a significant decrease of PI(4)P levels
        at the TGN.
      explanation: >-
        Cortical neuronal experiments link CPT1C deficiency or inhibition of malonyl-CoA synthesis to
        lower TGN PI4P.
  - target: GluA1 Retention at the Trans-Golgi Network
    relationship: MEASURES
    description: TGN retention and surface GluA1.
    fidelity: UNKNOWN
    limitations: Nutrient challenges and engineered mutants are not treatments or patient variants.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: knockdown of CPT1C resulted in a similar GluA1 retention pattern at the TGN.
      explanation: CPT1C knockdown causes GluA1 retention at the TGN in cortical neuronal cultures.
animal_models:
- name: Cpt1c-null mouse brain biochemical model
  species: Mus musculus
  genotype: Cpt1c−/−
  description: >-
    Adult knockout brain lysates show increased SAC1 phosphatase activity and reduced phosphatidylinositol
    monophosphate. These biochemical findings support CPT1C function, without recapitulating an established
    heterozygous human loss-of-function HSP mechanism.
  evidence:
  - reference: PMID:32931550
    reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs
    explanation: >-
      Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than
      human HSP causality.
  modeled_mechanisms:
  - target: Increased SAC1 Phosphatase Activity
    relationship: MEASURES
    description: SAC1 activity in knockout brain lysates.
    fidelity: UNKNOWN
    limitations: >-
      Complete gene knockout differs from human heterozygosity; the clinical loss-of-function model is
      disputed.
    evidence:
    - reference: PMID:32931550
      reference_title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: SAC1 phosphatase activity is significantly increased in CPT1C−/− brains compared with WTs
      explanation: >-
        Knockout brain lysates show greater SAC1 activity; the assay measures gene function rather than
        human HSP causality.
discussions:
- discussion_id: cpt1c-loss-of-function-causality
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Do heterozygous CPT1C loss-of-function variants cause HSP, and how does their interpretation differ
    from p.Arg37Cys?
  attaches_to:
  - genetic#CPT1C reported HSP association
  rationale: >-
    Case reports and engineered transcript-decay assays were interpreted as evidence of haploinsufficiency.
    Subsequent UK Biobank, Canadian HSP and GENESIS analyses did not support this model. Population phenotype
    ascertainment can miss subtle signs, and modifiers or incomplete penetrance remain possible, but predicted
    loss-of-function alone is not sufficient to assign the diagnosis. The R37C missense association has
    distinct segregation and functional evidence and was not directly refuted by this loss-of-function
    study.
  evidence:
  - reference: PMID:30911584
    reference_title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      293T cells carrying the p.Q76X variant indeed contained only about 5% CPT1C mRNA transcript compared
      to that of wild‐type cells
    explanation: Engineered HEK293T constructs support transcript loss; this does not resolve clinical causality.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Our study does not support a causal role for CPT1C LOF variants in HSP.
    explanation: >-
      The population/cohort study challenges heterozygous loss-of-function as a cause of HSP. It does
      not directly test the original missense-specific mechanism.
  - reference: DOI:10.1002/mds.70144
    reference_title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: all three also carry pathogenic variants in established HSP‐associated genes.
    explanation: >-
      All three GENESIS participants with HSP and CPT1C loss-of-function variants had an alternative established
      HSP-associated genotype.
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This variant was also absent in the other unaffected participants (III-1, IV-2, and IV-3), thus
      strictly cosegregating with the disease phenotype.
    explanation: >-
      Segregation supports the original p.Arg37Cys association; it does not establish all CPT1C variants
      as causal.
- discussion_id: cpt1c-cell-to-tract-mechanism
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Which CPT1C cellular defect explains the central tract dysfunction of the original family?
  attaches_to:
  - pathophysiology#Arg37Cys Regulatory-Domain Destabilization
  - pathophysiology#Reduced Lipid Droplet Formation
  - pathophysiology#Reduced Anterograde Late Endosome and Lysosome Transport
  - pathophysiology#Reduced Axon Extension in Cortical Cultures
  - pathophysiology#Corticospinal Tract Dysfunction
  rationale: >-
    R37C changes an isolated regulatory domain, reduces lipid droplets in COS7 cells and fails cortical
    axon-growth rescue. These findings do not establish dominant-negative action, disruption of atlastin
    binding, or adult human distal axon degeneration. Nutrient-sensitive lysosome and AMPA-receptor pathways
    offer testable mechanisms but do not yet connect the clinical phenotype through a fully demonstrated
    causal chain.
  evidence:
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We showed that mutant CPT1C markedly reduces the number and size of LDs in transfected cells.
    explanation: >-
      p.Arg37Cys overexpression reduces lipid droplets in COS7 cells; this is not a measurement in patient
      motor neurons.
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The Arg37Cys mutation did not affect the ability of CPT1C to bind atlastin-1
    explanation: >-
      The specific atlastin-binding assay was negative for disruption; a generic disrupted ER interaction
      network is not established.
  - reference: PMID:31868590
    reference_title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Axon length was rescued by CPT1C re-expression but not by CPT1CR37C or CPT1CM589S
    explanation: The HSP-associated R37C construct failed to rescue axon growth in mouse cortical cultures.
  - reference: PMID:25751282
    reference_title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicating abnormalities of the corticospinal tract and the dorsal column. Peripheral nerve conduction
      velocities were normal in all participants examined
    explanation: >-
      Human neurophysiology supports central tract dysfunction; distal axon degeneration was not demonstrated
      histologically.
notes: >-
  Reported childhood loss-of-function phenotypes are included as observations with unresolved genotype
  attribution, not validated SPG73 subtypes. The general GeneReviews HSP chapter informs examination,
  testing, supportive care and conditional genetic counseling; its generic frequencies and prognosis are
  not transferred to CPT1C. Brooks et al. additionally summarize Wang et al. children with severe motor
  delay, visual impairment, cortical dysplasia or callosal/periventricular abnormalities; those details
  are secondary summaries rather than independently replicated genotype–phenotype associations. These
  isolated complex presentations do not establish a characteristic loss-of-function syndrome.
references:
- reference: DOI:10.1002/mds.70144
  title: "Loss‐of‐Function Variants in\n                    <scp>\n                      <i>CPT1C</i>\n                    </scp>\n                    : No Support for a Causal Role in Hereditary Spastic Paraplegia"
- reference: PMID:25751282
  title: Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
- reference: PMID:30564185
  title: 'Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.'
- reference: PMID:30911584
  title: A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
- reference: PMID:31868590
  title: Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
- reference: PMID:32931550
  title: Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
- reference: PMID:39737739
  title: >-
    Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a
    case series.
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
  title: Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
📚

References & Deep Research

References

8
DOI:10.1002/mds.70144
Loss‐of‐Function Variants in <scp> <i>CPT1C</i> </scp> : No Support for a Causal Role in Hereditary Spastic Paraplegia
No top-level findings curated for this source.
PMID:25751282
Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
No top-level findings curated for this source.
PMID:30564185
Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.
No top-level findings curated for this source.
PMID:30911584
A novel CPT1C variant causes pure hereditary spastic paraplegia with benign clinical course.
No top-level findings curated for this source.
PMID:31868590
Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth.
No top-level findings curated for this source.
PMID:32931550
Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking.
No top-level findings curated for this source.
PMID:39737739
Expanding molecular and clinical spectrum of CPT1C-associated hereditary spastic paraplegia (SPG73)-a case series.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/books/NBK1509/
Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.