Arts syndrome

Mendelian MONDO:0010533 Pathograph 42 Show in embeddings browser hereditary disease syndromic disease Inborn Error of Purine Metabolism

Arts syndrome is the severe end of the PRPS1 deficiency spectrum and is an X-linked multisystem disorder characterized by early-onset sensorineural hearing impairment, ataxia, hypotonia, developmental delay, optic atrophy, retinal dystrophy, and recurrent infections.

Ask OpenScientist

Ask a research question about Arts syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Definitions
1
Inheritance
12
Pathophys.
22
Phenotypes
3
Gaps
42
Pathograph
1
Genes
5
Medical Actions
3
Differentials
2
Models
3
References
1
Deep Research
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
purine metabolism
📘

Definitions

1
Orphanet Arts syndrome definition
A severe PRPS1-deficiency presentation characterized by intellectual disability, early hypotonia and ataxia, delayed motor development, sensorineural hearing impairment, and progressive visual loss from optic atrophy.
OTHER
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"Lethal ataxia with deafness and optic atrophy (also known as Arts syndrome) is characterized by intellectual deficit, early-onset hypotonia, ataxia, delayed motor development, hearing impairment and loss of vision due to optic atrophy."
Orphanet provides a disease-specific clinical definition.
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
Arts syndrome is inherited in an X-linked manner; hemizygous males are typically more severely affected, while heterozygous females may be asymptomatic or variably affected because of X-chromosome inactivation.
X-linked recessive inheritance
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"PRS deficiency is inherited in an X-linked manner. If the mother of the proband has a PRPS1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a PRPS1 pathogenic variant, he will transmit it to all his daughters and none of his sons."
GeneReviews establishes X-linked inheritance and transmission risks.
?

Discussions and Knowledge Gaps

3
Which PRPP-dependent metabolite deficits drive the selective neural, auditory, optic, peripheral-nerve, and immune manifestations of Arts syndrome?
KNOWLEDGE GAP OPEN gap_arts_tissue_selectivity
Attached to
pathophysiology#PRPP-Dependent Biosynthetic Constraint
Human studies establish PRPS1 loss, low enzyme activity, and purine-pathway abnormalities, but do not resolve why particular high-demand tissues are affected or which purine, pyrimidine, or NAD-pathway deficit is causal.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder."
The 2026 mechanistic study explicitly identifies this limitation.
Do the single-variant iPSC model and dual-paralog zebrafish loss models reproduce the mechanisms operating across genetically diverse human Arts syndrome?
HUMAN MODEL MISMATCH OPEN mismatch_arts_models
Attached to
pathophysiology#Reduced Neural Stem Cell Proliferation pathophysiology#Neural Stem Cell Senescence-Like State pathophysiology#Impaired Neurite Outgrowth
The human neural findings derive from one patient-specific p.V42L line, while zebrafish have two prps1 paralogs and model graded transcript loss. Neither system establishes prevalence across variants or validates the cellular findings in affected human tissue.
Show evidence (2 references)
PMID:41787648 SUPPORT In Vitro
"In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies."
The study identifies the single patient-specific variant model.
PMID:27425195 SUPPORT Model Organism
"We found two paralogs in zebrafish, prps1a and prps1b and characterized each paralogous mutant individually as well as the double mutant fish."
The model-organism study documents the paralog-specific design.
Do SAMe, nicotinamide riboside, or nicotinamide mononucleotide improve survival or neurologic outcomes in controlled human studies?
KNOWLEDGE GAP OPEN gap_arts_treatment_efficacy
Attached to
pathophysiology#PRPP-Dependent Biosynthetic Constraint
SAMe and SAMe-plus-NR evidence is limited to a handful of uncontrolled cases; NMN evidence is limited to one in-vitro patient-derived model. No Arts-specific interventional trial was identified in the literature and trial-registry review current through 2026-08-05. NCT06092346 was dispositioned as not Arts-specific because its cached summary names only the broad DPPM population and does not explicitly identify PRPS1 deficiency eligibility.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted."
The report supports a preliminary signal while explicitly calling for more study.
⚙

Pathophysiology

12
PRPS1 Loss-of-Function Variants
Pathogenic PRPS1 variants reduce phosphoribosylpyrophosphate synthetase 1 function and initiate the PRPS1 deficiency cascade.
PRPS1 hgnc:9462 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PRPS1 (hgnc:9462). hgnc:9462 is a gene from the HUGO Gene Nomenclature Committee.
ribose phosphate diphosphokinase activity GO:0004749 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ribose phosphate diphosphokinase activity (GO:0004749). GO:0004749 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
PRS-I Enzyme Deficiency PRPS1 loss-of-function variants reduce phosphoribosylpyrophosphate synthetase 1 enzymatic activity.
Reduced Neural Stem Cell Proliferation A patient-derived PRPS1 p.V42L neural model showed reduced neural stem-cell proliferation, although the experiment did not isolate which downstream PRPP-dependent pathway mediates the defect.
Neural Stem Cell Senescence-Like State PRPS1 p.V42L patient-derived neural stem cells exhibited a senescence-like state with abnormal nuclear morphology.
Impaired Neurite Outgrowth Neurons differentiated from the patient-derived PRPS1 p.V42L line formed shorter, less complex neurites.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Other
"Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in PRPS1."
Directly links Arts syndrome to PRPS1 loss-of-function variants.
PRS-I Enzyme Deficiency
Loss of PRPS1 function lowers PRS-I enzyme activity and limits nucleotide precursor availability in high-demand tissues.
ribose phosphate diphosphokinase activity GO:0004749 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ribose phosphate diphosphokinase activity (GO:0004749). GO:0004749 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
PRPP-Dependent Biosynthetic Constraint Reduced PRS-I activity impairs purine biosynthesis and lowers downstream purine metabolites.
Show evidence (1 reference)
PMID:23190330 SUPPORT Other
"Lower residual activity in PRS-I leads to a more severe clinical manifestation."
Supports the severity gradient produced by progressively lower PRS-I function.
PRPP-Dependent Biosynthetic Constraint
Reduced PRS-I activity constrains PRPP-dependent biosynthesis. Impaired purine biosynthesis is supported by patient metabolites; effects on pyrimidine and nicotinamide nucleotide synthesis remain pathway-level inferences rather than measured Arts syndrome deficits.
purine nucleotide biosynthetic process GO:0006164 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased purine nucleotide biosynthetic process (GO:0006164). GO:0006164 is a biological process from the Gene Ontology. ↓ DECREASED pyrimidine nucleotide biosynthetic process GO:0006221 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased pyrimidine nucleotide biosynthetic process (GO:0006221). GO:0006221 is a biological process from the Gene Ontology. ↓ DECREASED NAD+ biosynthetic process GO:0009435 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NAD+ biosynthetic process (GO:0009435). GO:0009435 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neurodevelopmental Impairment PRPS1-related nucleotide depletion is associated with developmental impairment in affected males.
Cerebellar Dysfunction The PRPS1 deficiency phenotype includes ataxia, consistent with cerebellar-system vulnerability downstream of nucleotide depletion.
Auditory Hair Cell Dysfunction PRPS1 deficiency is associated with sensorineural hearing loss, modeled here as auditory hair-cell vulnerability.
Optic Pathway Dysfunction PRPS1 deficiency is associated with optic atrophy, modeled here as optic pathway vulnerability.
Peripheral Nerve Dysfunction Peripheral neuropathy occurs in severe PRS-I deficiency, but the intervening tissue-level mechanism is unresolved.
Immune Cell Dysfunction PRPS1 deficiency affects immune-cell function and is associated with recurrent severe respiratory infections.
Hypouricemia Impaired purine biosynthesis lowers downstream uric acid production.
Show evidence (2 references)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"This enzyme generates phospho‐ribosyl‐pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), among other metabolic pathways."
Establishes the nucleotide and NAD/NADP biosynthetic role of PRPS1.
PMID:33532242 SUPPORT Human Clinical
"PRPS1 is an initial and essential step for the synthesis of the nucleotides of purines, pyrimidines, and nicotinamide."
This Arts syndrome treatment report identifies the purine, pyrimidine, and nicotinamide nucleotide pathways affected by PRPS1 deficiency.
Reduced Neural Stem Cell Proliferation
Patient-derived PRPS1 p.V42L neural stem cells proliferate less than control cells; this is a disease-model finding, not yet a validated human biomarker.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
Experimental models
PRPS1 p.V42L patient-derived iPSC neural model IPSC DERIVED MODEL The model measures reduced proliferation in patient-derived neural stem cells.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved."
The patient-derived model directly demonstrates reduced NSC proliferation.
Neural Stem Cell Senescence-Like State
Patient-derived PRPS1 p.V42L neural stem cells show abnormal nuclear morphology and increased senescence-associated readouts.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
Experimental models
PRPS1 p.V42L patient-derived iPSC neural model IPSC DERIVED MODEL The model measures abnormal nuclear morphology and senescence-associated changes.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved."
The model directly supports a senescence-like NSC phenotype.
Impaired Neurite Outgrowth
Patient-derived neurons exhibit reduced neurite extension and branching, consistent with impaired neuronal maturation.
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
PRPS1 p.V42L patient-derived iPSC neural model IPSC DERIVED MODEL The model measures neurite length and branching in differentiated neurons.
Downstream
Neurodevelopmental Impairment Impaired neurite development is a plausible cellular contributor to the neurodevelopmental phenotype.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes."
The patient-derived neuron model directly supports this defect.
Neurodevelopmental Impairment
Purine shortage disrupts neuronal development and function, contributing to the severe developmental phenotype of Arts syndrome.
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.
Downstream
Global Developmental Delay Neurodevelopmental impairment manifests clinically as global developmental delay.
Motor delay Neurodevelopmental impairment includes delayed acquisition of motor milestones.
Hypotonia Severe central nervous system involvement includes early hypotonia.
Mild Intellectual Disability Neurodevelopmental impairment manifests as mild-to-moderate intellectual disability.
Moderate Intellectual Disability Neurodevelopmental impairment can manifest as moderate intellectual disability.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
The abstract directly frames Arts syndrome as a severe multisystem neurodevelopmental disorder downstream of PRPS1 deficiency.
Cerebellar Dysfunction
Ataxia suggests cerebellar-system dysfunction, but selective cerebellar vulnerability has not been demonstrated in Arts syndrome.
cerebellar neuron CL:1001611 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar neuron (CL:1001611). CL:1001611 is a cell type from the Cell Ontology.
Downstream
Ataxia Cerebellar dysfunction manifests as progressive ataxia in Arts syndrome.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Supports cerebellar involvement through the reported ataxia phenotype.
Auditory Hair Cell Dysfunction
Auditory hair cells have high metabolic demands and are vulnerable to PRS-I deficiency, explaining the severe sensorineural hearing impairment.
auditory hair cell CL:0000202 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves auditory hair cell (CL:0000202). CL:0000202 is a cell type from the Cell Ontology.
Downstream
Sensorineural Hearing Impairment Auditory hair-cell dysfunction produces early sensorineural hearing impairment.
Congenital Sensorineural Hearing Impairment The severe early auditory phenotype is captured more specifically as congenital sensorineural hearing impairment.
Profound Sensorineural Hearing Impairment The severe Arts phenotype can include profound hearing impairment.
Show evidence (1 reference)
PMID:26089585 SUPPORT Other
"severe PRS-I deficiency (Arts syndrome) present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment"
Directly supports the severe hearing phenotype in Arts syndrome.
Optic Pathway Dysfunction
Optic atrophy and retinal dystrophy establish ophthalmic involvement, but the vulnerable cell population and intervening mechanism remain unknown.
Downstream
Optic Atrophy Optic pathway dysfunction manifests clinically as optic atrophy.
Retinal Dystrophy Optic pathway dysfunction in the PRS deficiency spectrum can include retinal dystrophy.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports optic atrophy as a core Arts syndrome feature.
Immune Cell Dysfunction
Purine depletion can impair immune-cell function and contributes to the recurrent infection phenotype observed in severe PRPS1 deficiency.
lymphocyte CL:0000542 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves lymphocyte (CL:0000542). CL:0000542 is a cell type from the Cell Ontology.
Downstream
Recurrent Infections Immune-cell dysfunction contributes to recurrent infections in severe PRPS1 deficiency.
Severe infection Impaired immune-cell function can manifest as unusually severe infections.
Recurrent Upper Respiratory Tract Infections Arts syndrome has a marked liability to recurrent respiratory infections.
Respiratory Failure Requiring Assisted Ventilation Infection-associated deterioration and weakness can culminate in respiratory failure.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports recurrent infections as a severe complication of Arts syndrome.
Peripheral Nerve Dysfunction
Peripheral neuropathy is part of the severe PRPS1-deficiency phenotype and can be accompanied by areflexia, abnormal motor nerve conduction, chronic denervation, and progressive weakness.
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.
Downstream
Peripheral Neuropathy
Areflexia
Muscle Weakness
Show evidence (1 reference)
PMID:27256512 SUPPORT Human Clinical
"Both central nervous system involvement and peripheral neuropathy were demonstrated."
A molecularly confirmed Arts case directly documents peripheral neuropathy.
⬡

Pathograph

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

Phenotypes

22
Ear 2
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports the hearing phenotype in Arts syndrome.
Profound Sensorineural Hearing Impairment FREQUENT HP:0011476 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Profound sensorineural hearing impairment (HP:0011476). HP:0011476 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0011476 | Profound sensorineural hearing impairment | Frequent (79-30%)"
Orphanet supports both the phenotype and frequency band.
Eye 3
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports optic atrophy as part of the Arts syndrome phenotype.
Retinal Dystrophy HP:0000556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is retinal dystrophy (HP:0000556). HP:0000556 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"progressive ophthalmologic involvement (retinal dystrophy and optic atrophy)"
GeneReviews reports retinal dystrophy as an ophthalmologic feature of the PRS deficiency spectrum.
Nystagmus FREQUENT HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0000639 | Nystagmus | Frequent (79-30%)"
Orphanet supports both the phenotype and frequency band.
Immune 1
Recurrent Infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports recurrent infections as a recognized complication of severe Arts syndrome.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports hypotonia as a core Arts syndrome feature.
Muscle Weakness VERY_FREQUENT HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:1187 SUPPORT Other
"HP:0001324 | Muscle weakness | Very frequent (99-80%)"
Orphanet supports both the phenotype and frequency band.
PMID:27256512 SUPPORT Human Clinical
"The initial symptoms of the 1-year-old proband were hypotonia and ataxia, worsening recurrent infection-triggered muscle weakness, motor and intellectual developmental delay, and hearing loss."
A molecularly confirmed case documents infection-triggered worsening.
Nervous System 6
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports ataxia as a core Arts syndrome feature.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Directly supports developmental delay as part of the syndrome.
Motor delay FREQUENT 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 (2 references)
PMID:17701896 SUPPORT Human Clinical
"Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy."
Original family evidence reports delayed motor development in Arts syndrome.
ORPHA:1187 SUPPORT Other
"HP:0001270 | Motor delay | Frequent (79-30%)"
Orphanet records motor delay as frequent in Arts syndrome.
Mild Intellectual Disability FREQUENT HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"
Orphanet supports both the phenotype and frequency band.
Peripheral Neuropathy FREQUENT HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27256512 SUPPORT Human Clinical
"Both central nervous system involvement and peripheral neuropathy were demonstrated."
A molecularly confirmed Arts case documents peripheral neuropathy.
ORPHA:1187 SUPPORT Other
"HP:0009830 | Peripheral neuropathy | Frequent (79-30%)"
Orphanet supports the frequency band.
Areflexia FREQUENT HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0001284 | Areflexia | Frequent (79-30%)"
Orphanet supports both the phenotype and frequency band.
Other 8
Congenital Sensorineural Hearing Impairment VERY_FREQUENT HP:0008527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital sensorineural hearing impairment (HP:0008527). HP:0008527 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
Case report review directly lists congenital sensorineural hearing loss in severe PRPS1 deficiency.
ORPHA:1187 SUPPORT Other
"HP:0008527 | Congenital sensorineural hearing impairment | Very frequent (99-80%)"
Orphanet records congenital sensorineural hearing impairment as very frequent in Arts syndrome.
Severe infection VERY_FREQUENT HP:0032169 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe infection (HP:0032169). HP:0032169 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33532242 SUPPORT Human Clinical
"Classically, affected males present with sensorineural hearing loss, optic atrophy, muscular hypotonia, developmental impairment, and recurrent severe respiratory infections early in life."
Human case evidence supports severe respiratory infections in Arts syndrome.
ORPHA:1187 SUPPORT Other
"HP:0032169 | Severe infection | Very frequent (99-80%)"
Orphanet records severe infection as very frequent in Arts syndrome.
Hypouricemia FREQUENT HP:0003537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypouricemia (HP:0003537). HP:0003537 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17701896 SUPPORT Human Clinical
"impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients."
Patient biochemical evidence documents reduced serum uric acid.
ORPHA:1187 SUPPORT Other
"HP:0003537 | Hypouricemia | Frequent (79-30%)"
Orphanet records hypouricemia as frequent in Arts syndrome.
Moderate Intellectual Disability FREQUENT 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)
ORPHA:1187 SUPPORT Other
"HP:0002342 | Intellectual disability, moderate | Frequent (79-30%)"
Orphanet supports both the phenotype and frequency band.
Decreased Motor Nerve Conduction Velocity VERY_FREQUENT HP:0003431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased motor nerve conduction velocity (HP:0003431). HP:0003431 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0003431 | Decreased motor nerve conduction velocity | Very frequent (99-80%)"
Orphanet supports both the investigation finding and frequency band.
EMG Chronic Denervation Signs VERY_FREQUENT HP:0003444 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EMG chronic denervation signs, annotated with EMG: chronic denervation signs (HP:0003444). HP:0003444 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0003444 | EMG: chronic denervation signs | Very frequent (99-80%)"
Orphanet supports both the investigation finding and frequency band.
Recurrent Upper Respiratory Tract Infections VERY_FREQUENT HP:0002788 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent upper respiratory tract infections (HP:0002788). HP:0002788 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0002788 | Recurrent upper respiratory tract infections | Very frequent (99-80%)"
Orphanet supports both the phenotype and frequency band.
Respiratory Failure Requiring Assisted Ventilation FREQUENT HP:0004887 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure requiring assisted ventilation (HP:0004887). HP:0004887 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
Orphanet supports both the phenotype and frequency band.
🧬

Genetic Associations

1
PRPS1 (Causative)
Gene: PRPS1 hgnc:9462 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRPS1 (hgnc:9462). hgnc:9462 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in PRPS1."
Directly supports PRPS1 as the causative gene and loss of function as the disease mechanism.
💊

Medical Actions

5
S-Adenosylmethionine Supplementation
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Agent: S-adenosyl-L-methionine CHEBI:15414 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses S-adenosyl-L-methionine (CHEBI:15414). CHEBI:15414 is a therapeutic agent from Chemical Entities of Biological Interest.
SAM supplementation is the best-described reported intervention for Arts syndrome and has been associated with stabilization or improvement.
Mechanism Target:
BYPASSES PRPP-Dependent Biosynthetic Constraint — SAMe supplementation provides purine-pathway support outside the defective PRPP-dependent step.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Supplementation of the purine and NAD pathways outside of PRPP‐dependent reactions is a logical approach and has been reported in a handful of patients, two with S‐adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR)."
The case-review abstract directly supports the bypass rationale for SAMe and NR supplementation.
Show evidence (2 references)
PMID:26089585 SUPPORT Other
"Currently, purine replacement via S-adenosylmethionine (SAM) supplementation in patients with Arts syndrome appears to improve their condition."
Supports SAM as a disease-relevant dietary supplementation strategy.
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted."
Reinforces the reported benefit of SAMe-containing regimens.
Nicotinamide Riboside Supplementation
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Agent: nicotinamide riboside CHEBI:15927 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nicotinamide riboside, annotated with N-ribosylnicotinamide (CHEBI:15927). CHEBI:15927 is a therapeutic agent from Chemical Entities of Biological Interest.
Nicotinamide riboside has been reported in combination with SAMe in Arts syndrome and is mechanistically relevant because PRPS1 deficiency affects NAD-related metabolism.
Mechanism Target:
BYPASSES PRPP-Dependent Biosynthetic Constraint — Nicotinamide riboside is intended to support NAD-pathway metabolism downstream of the PRPP-dependent PRPS1 block.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Supplementation of the purine and NAD pathways outside of PRPP‐dependent reactions is a logical approach and has been reported in a handful of patients, two with S‐adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR)."
The case-review abstract supports nicotinamide riboside as part of a purine/NAD pathway bypass strategy.
Show evidence (1 reference)
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"Supplementation of the purine and NAD pathways outside of PRPP‐dependent reactions is a logical approach and has been reported in a handful of patients, two with S‐adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR)."
Supports NR as part of a reported supplementation regimen, though the abstract describes combination use rather than NR monotherapy.
Nicotinamide Mononucleotide (Preclinical)
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: nicotinamide mononucleotide CHEBI:50383 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nicotinamide mononucleotide (CHEBI:50383). CHEBI:50383 is a therapeutic agent from Chemical Entities of Biological Interest.
NMN partially rescued neural stem-cell and neuronal morphology defects in one patient-derived iPSC model. It has not been shown to be safe or effective as an Arts syndrome treatment in humans.
Mechanism Target:
RESTORES Reduced Neural Stem Cell Proliferation — NMN partially restores proliferation in PRPS1-mutant neural stem cells.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology."
The cellular study directly supports partial rescue of proliferation.
RESTORES Impaired Neurite Outgrowth — NMN partially improves neuronal morphology in the patient-derived model.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology."
The cellular study supports partial rescue of neuronal morphology.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology."
This supports only preclinical cellular rescue, not human efficacy.
Multidisciplinary Supportive 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
There is no curative therapy. Supportive management addresses neurologic, mobility, hearing, visual, developmental, respiratory, and genetic needs.
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"Supportive care to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in neurology, physiatry, physical therapy, occupational therapy, audiology, otolaryngology, ophthalmology and low vision services, education, and medical genetics."
GeneReviews supplies the multidisciplinary management baseline.
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. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling is appropriate for an X-linked disorder with carrier testing implications.
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"Once the PRPS1 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible."
GeneReviews supports counseling and reproductive testing options.
🔬

Biochemical Markers

4
PRS-I enzyme activity (DECREASED)
Context: Reduced phosphoribosylpyrophosphate synthetase 1 activity is the proximal biochemical defect in Arts syndrome and tracks PRPS1 deficiency severity.
Pathograph Readouts
Readout Of PRS-I Enzyme Deficiency Positive Diagnostic
Low PRS-I activity directly reports the enzyme-deficiency node in the Arts syndrome pathograph.
Show evidence (1 reference)
PMID:17701896 SUPPORT In Vitro
"Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients."
Patient erythrocyte and fibroblast assays directly support decreased PRS-I activity as a readout.
Show evidence (2 references)
PMID:17701896 SUPPORT In Vitro
"Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients."
Patient-derived erythrocyte and fibroblast assays show reduced PRS-I activity.
PMID:24528855 SUPPORT In Vitro
"Enzymatically, PRS-I activity was undetectable in the index subject, reduced in his less affected sister, and normal in his unaffected mother."
Family enzyme testing documents a residual-activity gradient across the PRPS1 deficiency continuum.
Urinary hypoxanthine (DECREASED)
Context: Undetectable urinary hypoxanthine supports impaired purine biosynthesis in Arts syndrome due to PRPS1 loss of function.
Pathograph Readouts
Readout Of PRPP-Dependent Biosynthetic Constraint Positive Diagnostic
Low urinary hypoxanthine reports the impaired purine-biosynthesis branch downstream of PRS-I deficiency.
Show evidence (1 reference)
PMID:17701896 SUPPORT Human Clinical
"impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients."
Original patient evidence directly reports undetectable urinary hypoxanthine.
Show evidence (1 reference)
PMID:17701896 SUPPORT Human Clinical
"impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients."
Original patient evidence reports undetectable urinary hypoxanthine.
Serum uric acid (DECREASED)
Context: Reduced serum uric acid is a downstream purine-metabolism marker in Arts syndrome due to impaired purine biosynthesis.
Pathograph Readouts
Readout Of PRPP-Dependent Biosynthetic Constraint Positive Diagnostic
Low serum uric acid reports impaired purine biosynthesis downstream of PRS-I deficiency.
Show evidence (1 reference)
PMID:17701896 SUPPORT Human Clinical
"impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients."
Original patient evidence directly reports reduced serum uric acid.
Show evidence (1 reference)
PMID:17701896 SUPPORT Human Clinical
"impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients."
Original patient evidence reports reduced serum uric acid levels.
Erythrocyte purine nucleotides (DECREASED)
Context: Erythrocyte purine nucleotides are a pharmacodynamic readout of purine pathway replenishment during SAMe therapy.
Pathograph Readouts
Readout Of PRPP-Dependent Biosynthetic Constraint Positive Pharmacodynamic
Replenishment of erythrocyte adenosine and guanosine nucleotides reports bypass of the purine nucleotide depletion branch.
Show evidence (1 reference)
PMID:33532242 SUPPORT Human Clinical
"Treatment of a 3-year old boy with S-adenosylmethionine (SAM) replenished erythrocyte purine nucleotides of adenosine and guanosine, while SAM and nicotinamide riboside co-therapy further improved his clinical phenotype as well as T-cell survival and function."
Treatment-associated erythrocyte purine nucleotide replenishment supports this pharmacodynamic readout.
Show evidence (1 reference)
PMID:33532242 SUPPORT Human Clinical
"Treatment of a 3-year old boy with S-adenosylmethionine (SAM) replenished erythrocyte purine nucleotides of adenosine and guanosine, while SAM and nicotinamide riboside co-therapy further improved his clinical phenotype as well as T-cell survival and function."
The clinical report identifies erythrocyte purine nucleotides as a treatment-responsive biochemical readout.
🔬

Diagnosis

1
Molecular genetic testing for PRPS1 variants (A hemizygous pathogenic PRPS1 variant confirms PRS deficiency in an affected male.)
Molecular confirmation is the key diagnostic step; a variant of uncertain significance alone does not establish Arts syndrome.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"The diagnosis of PRS deficiency is established in a male proband with suggestive findings and a hemizygous pathogenic variant in PRPS1 identified by molecular genetic testing."
GeneReviews directly states the molecular diagnostic criterion.
📈

Progression

2
Neonatal period and infancy
Age: Neonatal period through infancy
Hypotonia, ataxia, developmental delay, and profound hearing impairment begin early.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"- Age of onset: Infancy - Age of onset: Neonatal"
Orphanet records both infancy and neonatal onset periods.
Early-childhood progression and infection-triggered deterioration
Age: Infancy through early childhood
Baseline neurologic weakness progresses, with acute infection-triggered worsening that may lead to ventilatory failure and early death in severe cases.
Show evidence (2 references)
PMID:27256512 SUPPORT Human Clinical
"The initial symptoms of the 1-year-old proband were hypotonia and ataxia, worsening recurrent infection-triggered muscle weakness, motor and intellectual developmental delay, and hearing loss."
The case documents the characteristic infection-triggered deterioration.
DOI:10.1002/jmd2.12395 SUPPORT Human Clinical
"recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age."
The review summarizes the severe early-childhood prognosis.
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet reports worldwide point prevalence below 1 per 1,000,000.
Show evidence (1 reference)
ORPHA:1187 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:27256512"
Orphanet supplies the point-prevalence class without an exact rate.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Arts syndrome:

Charcot-Marie-Tooth disease X-linked recessive 5 Not Yet Curated MONDO:0010699
Overlapping Features CMTX5 is the intermediate PRPS1 deficiency phenotype and can resemble Arts syndrome, but tends to present with less severe neurodevelopmental and infectious involvement.
Distinguishing Features
  • Peripheral neuropathy and optic neuropathy are more prominent than the severe multisystem childhood phenotype.
  • Residual PRS-I activity is higher than in Arts syndrome.
Show evidence (1 reference)
PMID:26089585 SUPPORT Other
"decreased activity leads to X-linked nonsyndromic sensorineural deafness (DFNX-2), Charcot-Marie-Tooth disease-5 (CMTX5), and Arts syndrome depending on the residual activity of PRS-I"
Places CMTX5 and Arts syndrome on the same severity spectrum and supports CMTX5 as a close differential.
X-linked nonsyndromic hearing loss 1 Not Yet Curated MONDO:0010577
Overlapping Features Mild PRPS1 deficiency can present as isolated X-linked hearing loss without the severe neurologic, optic, or infectious manifestations of Arts syndrome.
Distinguishing Features
  • Hearing loss is the main feature; ataxia, hypotonia, and recurrent infections are absent or minimal.
  • Higher residual PRS-I activity separates this phenotype from Arts syndrome.
Show evidence (1 reference)
PMID:23190330 SUPPORT Other
"Mutations in PRPS1 are associated with a spectrum of non-syndromic to syndromic hearing loss."
Supports isolated X-linked hearing loss as the mild end of the PRPS1 spectrum and a differential for Arts syndrome.
PRPS1 superactivity MONDO:0010395
Overlapping Features PRPS1 gain-of-function causes a distinct hyperuricemic disorder; uric-acid overproduction and increased PRS-I activity distinguish it from Arts syndrome.
Distinguishing Features
  • Uric acid overproduction rather than low-normal serum uric acid.
  • PRS-I superactivity rather than loss of enzyme activity.
Show evidence (1 reference)
PMID:20380929 SUPPORT Other
"Patients with PRS-I superactivity primarily present with uric acid overproduction, mental retardation, ataxia, hypotonia, and hearing impairment."
The review distinguishes the gain-of-function hyperuricemic phenotype.
🧫

Experimental Models

1
PRPS1 p.V42L patient-derived iPSC neural model IPSC_DERIVED_MODEL
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient PBMC-derived iPSCs differentiated into neural stem cells and neurons
Publication
PMID:41787648
Pathograph links
Reduced Neural Stem Cell Proliferation The model measures reduced proliferation in patient-derived neural stem cells.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved."
The model directly measures reduced neural stem-cell proliferation.
Neural Stem Cell Senescence-Like State The model measures abnormal nuclear morphology and senescence-associated changes.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved."
The model directly measures the senescence-like state.
Impaired Neurite Outgrowth The model measures neurite length and branching in differentiated neurons.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes."
The model directly measures neurite outgrowth and branching.
Findings
Patient-derived NSCs show reduced proliferation and a senescence-like phenotype.
"Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved."
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved."
The abstract directly supports the finding.
Patient-derived neurons show impaired neurite outgrowth and branching.
"Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes."
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes."
The abstract directly supports the finding.
Show evidence (1 reference)
PMID:41787648 SUPPORT In Vitro
"In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies."
This directly establishes the patient-derived neural model.
🐁

Animal Models

1
prps1a and prps1b single and double loss-of-function mutants Zebrafish (Danio rerio)
Additive loss of the two zebrafish paralogs produces graded eye, hair-cell, motor-neuron, innervation, and leukocyte abnormalities resembling features of the human PRPS1-deficiency spectrum.
Smaller eyes Reduced hair cell number Abnormal primary motor-neuron development Abnormal hair-cell innervation Reduced leukocytes
Species
Zebrafish (Danio rerio)
Genotype
prps1a and prps1b single and double loss-of-function mutants
Show evidence (1 reference)
PMID:27425195 SUPPORT Model Organism
"The double mutant also showed abnormal development of primary motor neurons, hair cell innervation, and reduced leukocytes, consistent with the neuropathy and recurrent infection of the human patients possessing the most severe reductions of PRPS1 activity."
The zebrafish model recapitulates neurologic, auditory, and immune features.
{ }

Source YAML

click to show 
name: Arts syndrome
creation_date: "2026-04-16T00:00:00Z"
description: >-
  Arts syndrome is the severe end of the PRPS1 deficiency spectrum and is an
  X-linked multisystem disorder characterized by early-onset sensorineural
  hearing impairment, ataxia, hypotonia, developmental delay, optic atrophy,
  retinal dystrophy, and recurrent infections.
category: Mendelian
parents:
- hereditary disease
- syndromic disease
- Inborn Error of Purine Metabolism
classifications:
  icimd_category:
  - classification_value: purine_metabolism
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders of
      purine metabolism" under category "Disorders of nucleobase, nucleotide
      and nucleic acid metabolism". Arts syndrome is the severe PRPS1
      deficiency presentation with impaired purine biosynthesis.
disease_term:
  preferred_term: Arts syndrome
  term:
    id: MONDO:0010533
    label: Arts syndrome
definitions:
- name: Orphanet Arts syndrome definition
  definition_type: OTHER
  description: >-
    A severe PRPS1-deficiency presentation characterized by intellectual
    disability, early hypotonia and ataxia, delayed motor development,
    sensorineural hearing impairment, and progressive visual loss from optic
    atrophy.
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Lethal ataxia with deafness and optic atrophy (also known as Arts syndrome)
      is characterized by intellectual deficit, early-onset hypotonia, ataxia,
      delayed motor development, hearing impairment and loss of vision due to
      optic atrophy.
    explanation: Orphanet provides a disease-specific clinical definition.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet reports worldwide point prevalence below 1 per 1,000,000.
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:27256512"
    explanation: Orphanet supplies the point-prevalence class without an exact rate.
inheritance:
- name: X-linked recessive inheritance
  description: >-
    Arts syndrome is inherited in an X-linked manner; hemizygous males are
    typically more severely affected, while heterozygous females may be
    asymptomatic or variably affected because of X-chromosome inactivation.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:20301738
    reference_title: Phosphoribosylpyrophosphate Synthetase Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PRS deficiency is inherited in an X-linked manner. If the mother of the
      proband has a PRPS1 pathogenic variant, the chance of transmitting it in
      each pregnancy is 50%; if the father of the proband has a PRPS1 pathogenic
      variant, he will transmit it to all his daughters and none of his sons.
    explanation: GeneReviews establishes X-linked inheritance and transmission risks.
pathophysiology:
- name: PRPS1 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Pathogenic PRPS1 variants reduce phosphoribosylpyrophosphate synthetase 1
    function and initiate the PRPS1 deficiency cascade.
  genes:
  - preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  molecular_functions:
  - preferred_term: ribose phosphate diphosphokinase activity
    modifier: DECREASED
    term:
      id: GO:0004749
      label: ribose phosphate diphosphokinase activity
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary
      to loss of function variants in PRPS1.
    explanation: >-
      Directly links Arts syndrome to PRPS1 loss-of-function variants.
  downstream:
  - target: PRS-I Enzyme Deficiency
    description: >-
      PRPS1 loss-of-function variants reduce phosphoribosylpyrophosphate
      synthetase 1 enzymatic activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Both mutations result in a loss of phosphoribosyl pyrophosphate
        synthetase 1 activity, as was shown in silico by molecular modeling and
        was shown in vitro by phosphoribosyl pyrophosphate synthetase activity
        assays in erythrocytes and fibroblasts from patients.
      explanation: >-
        Patient-derived erythrocyte and fibroblast assays directly link PRPS1
        variants to reduced PRS-I activity.
  - target: Reduced Neural Stem Cell Proliferation
    description: >-
      A patient-derived PRPS1 p.V42L neural model showed reduced neural stem-cell
      proliferation, although the experiment did not isolate which downstream
      PRPP-dependent pathway mediates the defect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient-derived NSCs demonstrated significantly reduced proliferative
        capacity, aberrant nuclear morphology, and increased neuronal senescence,
        while mitochondrial integrity and function were largely preserved.
      explanation: Patient-derived NSCs directly demonstrate the proliferation defect.
  - target: Neural Stem Cell Senescence-Like State
    description: >-
      PRPS1 p.V42L patient-derived neural stem cells exhibited a senescence-like
      state with abnormal nuclear morphology.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient-derived NSCs demonstrated significantly reduced proliferative
        capacity, aberrant nuclear morphology, and increased neuronal senescence,
        while mitochondrial integrity and function were largely preserved.
      explanation: The patient-derived cellular model directly supports this state.
  - target: Impaired Neurite Outgrowth
    description: >-
      Neurons differentiated from the patient-derived PRPS1 p.V42L line formed
      shorter, less complex neurites.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Neurons differentiated from these NSCs exhibited impaired neurite
        outgrowth and reduced branching complexity, indicative of disrupted
        neurodevelopmental processes.
      explanation: Patient-derived neurons directly demonstrate impaired maturation.
- name: PRS-I Enzyme Deficiency
  biological_scale: MOLECULAR
  description: >-
    Loss of PRPS1 function lowers PRS-I enzyme activity and limits nucleotide
    precursor availability in high-demand tissues.
  molecular_functions:
  - preferred_term: ribose phosphate diphosphokinase activity
    modifier: DECREASED
    term:
      id: GO:0004749
      label: ribose phosphate diphosphokinase activity
  evidence:
  - reference: PMID:23190330
    reference_title: "Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Lower residual activity in PRS-I leads to a more severe clinical
      manifestation.
    explanation: >-
      Supports the severity gradient produced by progressively lower PRS-I
      function.
  downstream:
  - target: PRPP-Dependent Biosynthetic Constraint
    description: >-
      Reduced PRS-I activity impairs purine biosynthesis and lowers downstream
      purine metabolites.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The loss-of-function mutations of PRPS1 likely result in impaired
        purine biosynthesis, which is supported by the undetectable
        hypoxanthine in urine and the reduced uric acid levels in serum from
        patients.
      explanation: >-
        Patient metabolite findings link PRPS1 loss of function to impaired
        purine biosynthesis.
- name: PRPP-Dependent Biosynthetic Constraint
  biological_scale: MOLECULAR
  description: >-
    Reduced PRS-I activity constrains PRPP-dependent biosynthesis. Impaired
    purine biosynthesis is supported by patient metabolites; effects on
    pyrimidine and nicotinamide nucleotide synthesis remain pathway-level
    inferences rather than measured Arts syndrome deficits.
  biological_processes:
  - preferred_term: purine nucleotide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006164
      label: purine nucleotide biosynthetic process
  - preferred_term: pyrimidine nucleotide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006221
      label: pyrimidine nucleotide biosynthetic process
  - preferred_term: NAD+ biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0009435
      label: NAD+ biosynthetic process
  chemical_entities:
  - preferred_term: phosphoribosyl pyrophosphate
    modifier: DYSREGULATED
    term:
      id: CHEBI:17111
      label: 5-O-phosphono-alpha-D-ribofuranosyl diphosphate
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This enzyme generates phospho‐ribosyl‐pyrophosphate (PRPP), which is
      utilized in the synthesis of purines, nicotinamide adenine dinucleotide
      (NAD), and NAD phosphate (NADP), among other metabolic pathways.
    explanation: >-
      Establishes the nucleotide and NAD/NADP biosynthetic role of PRPS1.
  - reference: PMID:33532242
    reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PRPS1 is an initial and essential step for the synthesis of the
      nucleotides of purines, pyrimidines, and nicotinamide.
    explanation: >-
      This Arts syndrome treatment report identifies the purine, pyrimidine,
      and nicotinamide nucleotide pathways affected by PRPS1 deficiency.
  downstream:
  - target: Neurodevelopmental Impairment
    description: >-
      PRPS1-related nucleotide depletion is associated with developmental
      impairment in affected males.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Classically, affected males present with sensorineural hearing loss,
        optic atrophy, muscular hypotonia, developmental impairment, and
        recurrent severe respiratory infections early in life.
      explanation: >-
        The report links PRPS1 deficiency to developmental impairment and other
        downstream Arts syndrome manifestations.
  - target: Cerebellar Dysfunction
    description: >-
      The PRPS1 deficiency phenotype includes ataxia, consistent with
      cerebellar-system vulnerability downstream of nucleotide depletion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
        characterized by congenital sensorineural hearing loss, optic atrophy,
        developmental delays, ataxia, hypotonia, and recurrent infections that
        can cause progressive clinical decline, often resulting in death before
        5 years of age.
      explanation: >-
        The review places ataxia downstream of severe PRPS1 deficiency.
  - target: Auditory Hair Cell Dysfunction
    description: >-
      PRPS1 deficiency is associated with sensorineural hearing loss, modeled
      here as auditory hair-cell vulnerability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Classically, affected males present with sensorineural hearing loss,
        optic atrophy, muscular hypotonia, developmental impairment, and
        recurrent severe respiratory infections early in life.
      explanation: >-
        The report links PRPS1 deficiency to sensorineural hearing loss.
  - target: Optic Pathway Dysfunction
    description: >-
      PRPS1 deficiency is associated with optic atrophy, modeled here as optic
      pathway vulnerability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Classically, affected males present with sensorineural hearing loss,
        optic atrophy, muscular hypotonia, developmental impairment, and
        recurrent severe respiratory infections early in life.
      explanation: >-
        The report links PRPS1 deficiency to optic atrophy.
  - target: Peripheral Nerve Dysfunction
    description: >-
      Peripheral neuropathy occurs in severe PRS-I deficiency, but the
      intervening tissue-level mechanism is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26089585
      reference_title: "Association of PRPS1 Mutations with Disease Phenotypes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        severe PRS-I deficiency (Arts syndrome) present with peripheral or optic
        neuropathy, prelingual progressive sensorineural hearing loss, and central
        nervous system impairment
      explanation: The PRPS1 phenotype review associates severe PRS-I deficiency with peripheral neuropathy.
  - target: Immune Cell Dysfunction
    description: >-
      PRPS1 deficiency affects immune-cell function and is associated with
      recurrent severe respiratory infections.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment of a 3-year old boy with S-adenosylmethionine (SAM)
        replenished erythrocyte purine nucleotides of adenosine and guanosine,
        while SAM and nicotinamide riboside co-therapy further improved his
        clinical phenotype as well as T-cell survival and function.
      explanation: >-
        The improvement of T-cell survival and function after purine/NAD
        pathway supplementation supports immune-cell vulnerability downstream
        of PRPS1 deficiency.
  - target: Hypouricemia
    description: >-
      Impaired purine biosynthesis lowers downstream uric acid production.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        impaired purine biosynthesis, which is supported by the undetectable
        hypoxanthine in urine and the reduced uric acid levels in serum from
        patients.
      explanation: >-
        Patient biochemical data link PRPS1-driven purine-biosynthesis failure
        to reduced serum uric acid.
- name: Reduced Neural Stem Cell Proliferation
  biological_scale: CELLULAR
  description: >-
    Patient-derived PRPS1 p.V42L neural stem cells proliferate less than control
    cells; this is a disease-model finding, not yet a validated human biomarker.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient-derived NSCs demonstrated significantly reduced proliferative
      capacity, aberrant nuclear morphology, and increased neuronal senescence,
      while mitochondrial integrity and function were largely preserved.
    explanation: The patient-derived model directly demonstrates reduced NSC proliferation.
- name: Neural Stem Cell Senescence-Like State
  biological_scale: CELLULAR
  description: >-
    Patient-derived PRPS1 p.V42L neural stem cells show abnormal nuclear
    morphology and increased senescence-associated readouts.
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient-derived NSCs demonstrated significantly reduced proliferative
      capacity, aberrant nuclear morphology, and increased neuronal senescence,
      while mitochondrial integrity and function were largely preserved.
    explanation: The model directly supports a senescence-like NSC phenotype.
- name: Impaired Neurite Outgrowth
  biological_scale: CELLULAR
  description: >-
    Patient-derived neurons exhibit reduced neurite extension and branching,
    consistent with impaired neuronal maturation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Neurons differentiated from these NSCs exhibited impaired neurite
      outgrowth and reduced branching complexity, indicative of disrupted
      neurodevelopmental processes.
    explanation: The patient-derived neuron model directly supports this defect.
  downstream:
  - target: Neurodevelopmental Impairment
    description: >-
      Impaired neurite development is a plausible cellular contributor to the
      neurodevelopmental phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Neurons differentiated from these NSCs exhibited impaired neurite
        outgrowth and reduced branching complexity, indicative of disrupted
        neurodevelopmental processes.
      explanation: The authors interpret the patient-derived neuronal phenotype as evidence of disrupted neurodevelopmental processes.
- name: Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >-
    Purine shortage disrupts neuronal development and function, contributing to
    the severe developmental phenotype of Arts syndrome.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      The abstract directly frames Arts syndrome as a severe multisystem
      neurodevelopmental disorder downstream of PRPS1 deficiency.
  downstream:
  - target: Global Developmental Delay
    description: >-
      Neurodevelopmental impairment manifests clinically as global
      developmental delay.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
        characterized by congenital sensorineural hearing loss, optic atrophy,
        developmental delays, ataxia, hypotonia, and recurrent infections that
        can cause progressive clinical decline, often resulting in death before
        5 years of age.
      explanation: >-
        The review directly lists developmental delays among Arts syndrome
        features.
  - target: Motor delay
    description: >-
      Neurodevelopmental impairment includes delayed acquisition of motor
      milestones.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome is an X-linked disorder characterized by mental retardation,
        early-onset hypotonia, ataxia, delayed motor development, hearing
        impairment, and optic atrophy.
      explanation: >-
        Original family evidence includes delayed motor development in Arts
        syndrome.
  - target: Hypotonia
    description: >-
      Severe central nervous system involvement includes early hypotonia.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
        characterized by congenital sensorineural hearing loss, optic atrophy,
        developmental delays, ataxia, hypotonia, and recurrent infections that
        can cause progressive clinical decline, often resulting in death before
        5 years of age.
      explanation: >-
        The review directly lists hypotonia among Arts syndrome features.
  - target: Mild Intellectual Disability
    description: Neurodevelopmental impairment manifests as mild-to-moderate intellectual disability.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301738
      reference_title: Phosphoribosylpyrophosphate Synthetase Deficiency.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In affected males, the PRS deficiency phenotypic spectrum ranges from
        severe congenital profound sensorineural hearing loss, intellectual
        disability, delayed motor development, and progressive ophthalmologic
        involvement (retinal dystrophy and optic atrophy)
      explanation: GeneReviews directly supports intellectual disability in affected males.
  - target: Moderate Intellectual Disability
    description: Neurodevelopmental impairment can manifest as moderate intellectual disability.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002342 | Intellectual disability, moderate | Frequent (79-30%)"
      explanation: Orphanet specifically records moderate intellectual disability in Arts syndrome.
- name: Cerebellar Dysfunction
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Ataxia suggests cerebellar-system dysfunction, but selective cerebellar
    vulnerability has not been demonstrated in Arts syndrome.
  cell_types:
  - preferred_term: cerebellar neuron
    term:
      id: CL:1001611
      label: cerebellar neuron
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that
      can cause progressive clinical decline, often resulting in death before 5
      years of age.
    explanation: >-
      Supports cerebellar involvement through the reported ataxia phenotype.
  downstream:
  - target: Ataxia
    description: >-
      Cerebellar dysfunction manifests as progressive ataxia in Arts syndrome.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
        characterized by congenital sensorineural hearing loss, optic atrophy,
        developmental delays, ataxia, hypotonia, and recurrent infections that
        can cause progressive clinical decline, often resulting in death before
        5 years of age.
      explanation: >-
        The review directly lists ataxia among Arts syndrome features.
- name: Auditory Hair Cell Dysfunction
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Auditory hair cells have high metabolic demands and are vulnerable to PRS-I
    deficiency, explaining the severe sensorineural hearing impairment.
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  evidence:
  - reference: PMID:26089585
    reference_title: "Association of PRPS1 Mutations with Disease Phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      severe PRS-I deficiency (Arts syndrome) present with peripheral or optic
      neuropathy, prelingual progressive sensorineural hearing loss, and central
      nervous system impairment
    explanation: >-
      Directly supports the severe hearing phenotype in Arts syndrome.
  downstream:
  - target: Sensorineural Hearing Impairment
    description: >-
      Auditory hair-cell dysfunction produces early sensorineural hearing
      impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26089585
      reference_title: "Association of PRPS1 Mutations with Disease Phenotypes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        severe PRS-I deficiency (Arts syndrome) present with peripheral or optic
        neuropathy, prelingual progressive sensorineural hearing loss, and
        central nervous system impairment
      explanation: >-
        PRPS1 phenotype review directly reports prelingual progressive
        sensorineural hearing loss in severe PRS-I deficiency.
  - target: Congenital Sensorineural Hearing Impairment
    description: >-
      The severe early auditory phenotype is captured more specifically as
      congenital sensorineural hearing impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
        characterized by congenital sensorineural hearing loss, optic atrophy,
        developmental delays, ataxia, hypotonia, and recurrent infections that
        can cause progressive clinical decline, often resulting in death before
        5 years of age.
      explanation: >-
        Case report review supports congenital sensorineural hearing loss as a
        severe Arts syndrome phenotype.
  - target: Profound Sensorineural Hearing Impairment
    description: The severe Arts phenotype can include profound hearing impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011476 | Profound sensorineural hearing impairment | Frequent (79-30%)"
      explanation: Orphanet directly supports the profound hearing phenotype and its frequency band.
- name: Optic Pathway Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Optic atrophy and retinal dystrophy establish ophthalmic involvement, but
    the vulnerable cell population and intervening mechanism remain unknown.
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports optic atrophy as a core Arts syndrome feature.
  downstream:
  - target: Optic Atrophy
    description: >-
      Optic pathway dysfunction manifests clinically as optic atrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
        characterized by congenital sensorineural hearing loss, optic atrophy,
        developmental delays, ataxia, hypotonia, and recurrent infections that
        can cause progressive clinical decline, often resulting in death before
        5 years of age.
      explanation: >-
        The review directly lists optic atrophy among Arts syndrome features.
  - target: Retinal Dystrophy
    description: >-
      Optic pathway dysfunction in the PRS deficiency spectrum can include
      retinal dystrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301738
      reference_title: "Phosphoribosylpyrophosphate Synthetase Deficiency."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        progressive ophthalmologic involvement (retinal dystrophy and optic
        atrophy)
      explanation: >-
        GeneReviews lists retinal dystrophy and optic atrophy as progressive
        ophthalmologic manifestations in the PRS deficiency spectrum.
- name: Immune Cell Dysfunction
  biological_scale: CELLULAR
  description: >-
    Purine depletion can impair immune-cell function and contributes to the
    recurrent infection phenotype observed in severe PRPS1 deficiency.
  cell_types:
  - preferred_term: lymphocyte
    term:
      id: CL:0000542
      label: lymphocyte
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports recurrent infections as a severe complication of Arts
      syndrome.
  downstream:
  - target: Recurrent Infections
    description: >-
      Immune-cell dysfunction contributes to recurrent infections in severe
      PRPS1 deficiency.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Classically, affected males present with sensorineural hearing loss,
        optic atrophy, muscular hypotonia, developmental impairment, and
        recurrent severe respiratory infections early in life.
      explanation: >-
        The treatment report directly lists recurrent severe respiratory
        infections in classic Arts syndrome.
  - target: Severe infection
    description: >-
      Impaired immune-cell function can manifest as unusually severe infections.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Classically, affected males present with sensorineural hearing loss,
        optic atrophy, muscular hypotonia, developmental impairment, and
        recurrent severe respiratory infections early in life.
      explanation: >-
        Human case evidence supports severe respiratory infections as part of
        the classic Arts syndrome presentation.
  - target: Recurrent Upper Respiratory Tract Infections
    description: Arts syndrome has a marked liability to recurrent respiratory infections.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002788 | Recurrent upper respiratory tract infections | Very frequent (99-80%)"
      explanation: Orphanet directly records this phenotype and frequency band.
  - target: Respiratory Failure Requiring Assisted Ventilation
    description: Infection-associated deterioration and weakness can culminate in respiratory failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
      explanation: Orphanet directly records assisted-ventilation respiratory failure and its frequency band.
- name: Peripheral Nerve Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Peripheral neuropathy is part of the severe PRPS1-deficiency phenotype and
    can be accompanied by areflexia, abnormal motor nerve conduction, chronic
    denervation, and progressive weakness.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:27256512
    reference_title: "Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both central nervous system involvement and peripheral neuropathy were demonstrated.
    explanation: A molecularly confirmed Arts case directly documents peripheral neuropathy.
  downstream:
  - target: Peripheral Neuropathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27256512
      reference_title: "Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Both central nervous system involvement and peripheral neuropathy were demonstrated.
      explanation: The molecularly confirmed case directly establishes peripheral neuropathy.
  - target: Areflexia
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001284 | Areflexia | Frequent (79-30%)"
      explanation: Areflexia is an established manifestation of the documented peripheral neuropathy phenotype.
  - target: Muscle Weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27256512
      reference_title: "Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The initial symptoms of the 1-year-old proband were hypotonia and ataxia,
        worsening recurrent infection-triggered muscle weakness, motor and
        intellectual developmental delay, and hearing loss.
      explanation: The case supports muscle weakness in the setting of central and peripheral neurologic involvement without resolving the intervening mechanism.
phenotypes:
- category: Hearing
  name: Sensorineural Hearing Impairment
  description: >-
    Severe, early-onset sensorineural hearing impairment is a core feature of
    Arts syndrome.
  phenotype_term:
    preferred_term: sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports the hearing phenotype in Arts syndrome.
- category: Hearing
  name: Congenital Sensorineural Hearing Impairment
  frequency: VERY_FREQUENT
  description: >-
    Congenital sensorineural hearing impairment is a severe early hearing
    phenotype in Arts syndrome.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Case report review directly lists congenital sensorineural hearing loss
      in severe PRPS1 deficiency.
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008527 | Congenital sensorineural hearing impairment | Very frequent (99-80%)"
    explanation: Orphanet records congenital sensorineural hearing impairment as very frequent in Arts syndrome.
- category: Neurologic
  name: Ataxia
  description: >-
    Progressive cerebellar ataxia is a hallmark neurologic manifestation of
    Arts syndrome.
  phenotype_term:
    preferred_term: ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports ataxia as a core Arts syndrome feature.
- category: Neurologic
  name: Hypotonia
  description: >-
    Early hypotonia reflects severe central nervous system involvement in Arts
    syndrome.
  phenotype_term:
    preferred_term: hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports hypotonia as a core Arts syndrome feature.
- category: Developmental
  name: Global Developmental Delay
  description: >-
    Global developmental delay is part of the severe childhood neurodevelopmental
    presentation.
  phenotype_term:
    preferred_term: global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports developmental delay as part of the syndrome.
- category: Developmental
  name: Motor delay
  frequency: FREQUENT
  description: >-
    Delayed motor development is a component of the Arts syndrome
    neurodevelopmental phenotype.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:17701896
    reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome is an X-linked disorder characterized by mental retardation,
      early-onset hypotonia, ataxia, delayed motor development, hearing
      impairment, and optic atrophy.
    explanation: Original family evidence reports delayed motor development in Arts syndrome.
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001270 | Motor delay | Frequent (79-30%)"
    explanation: Orphanet records motor delay as frequent in Arts syndrome.
- category: Ophthalmologic
  name: Optic Atrophy
  description: >-
    Optic atrophy contributes to the visual impairment observed in Arts
    syndrome.
  phenotype_term:
    preferred_term: optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports optic atrophy as part of the Arts syndrome phenotype.
- category: Ophthalmologic
  name: Retinal Dystrophy
  description: >-
    Retinal dystrophy has been described within the PRPS1 deficiency spectrum
    together with optic atrophy.
  phenotype_term:
    preferred_term: retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:20301738
    reference_title: "Phosphoribosylpyrophosphate Synthetase Deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      progressive ophthalmologic involvement (retinal dystrophy and optic
      atrophy)
    explanation: >-
      GeneReviews reports retinal dystrophy as an ophthalmologic feature of
      the PRS deficiency spectrum.
- category: Immunologic
  name: Recurrent Infections
  description: >-
    Recurrent infections are common in severe PRPS1 deficiency and contribute to
    morbidity.
  phenotype_term:
    preferred_term: recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome, or severe PRPS1 deficiency, is an X‐linked condition
      characterized by congenital sensorineural hearing loss, optic atrophy,
      developmental delays, ataxia, hypotonia, and recurrent infections that can
      cause progressive clinical decline, often resulting in death before 5 years
      of age.
    explanation: >-
      Directly supports recurrent infections as a recognized complication of
      severe Arts syndrome.
- category: Immunologic
  name: Severe infection
  frequency: VERY_FREQUENT
  description: >-
    Arts syndrome can involve unusually severe infections in addition to
    recurrent infections.
  phenotype_term:
    preferred_term: Severe infection
    term:
      id: HP:0032169
      label: Severe infection
  evidence:
  - reference: PMID:33532242
    reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classically, affected males present with sensorineural hearing loss,
      optic atrophy, muscular hypotonia, developmental impairment, and
      recurrent severe respiratory infections early in life.
    explanation: Human case evidence supports severe respiratory infections in Arts syndrome.
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0032169 | Severe infection | Very frequent (99-80%)"
    explanation: Orphanet records severe infection as very frequent in Arts syndrome.
- category: Metabolic
  name: Hypouricemia
  frequency: FREQUENT
  description: >-
    Low serum uric acid is a downstream purine-metabolism manifestation of
    PRPS1 loss-of-function.
  phenotype_term:
    preferred_term: Hypouricemia
    term:
      id: HP:0003537
      label: Hypouricemia
  evidence:
  - reference: PMID:17701896
    reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      impaired purine biosynthesis, which is supported by the undetectable
      hypoxanthine in urine and the reduced uric acid levels in serum from
      patients.
    explanation: Patient biochemical evidence documents reduced serum uric acid.
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003537 | Hypouricemia | Frequent (79-30%)"
    explanation: Orphanet records hypouricemia as frequent in Arts syndrome.
- category: Nervous System
  name: Mild Intellectual Disability
  frequency: FREQUENT
  description: Mild intellectual disability is reported in a substantial subset.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001256 | Intellectual disability, mild | Frequent (79-30%)"
    explanation: Orphanet supports both the phenotype and frequency band.
- category: Nervous System
  name: Moderate Intellectual Disability
  frequency: FREQUENT
  description: Moderate intellectual disability is also reported in Arts syndrome.
  phenotype_term:
    preferred_term: Moderate intellectual disability
    term:
      id: HP:0002342
      label: Moderate intellectual disability
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002342 | Intellectual disability, moderate | Frequent (79-30%)"
    explanation: Orphanet supports both the phenotype and frequency band.
- category: Musculature
  name: Muscle Weakness
  frequency: VERY_FREQUENT
  description: >-
    Muscle weakness is prominent and may acutely worsen during recurrent infection.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Very frequent (99-80%)"
    explanation: Orphanet supports both the phenotype and frequency band.
  - reference: PMID:27256512
    reference_title: "Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The initial symptoms of the 1-year-old proband were hypotonia and ataxia,
      worsening recurrent infection-triggered muscle weakness, motor and
      intellectual developmental delay, and hearing loss.
    explanation: A molecularly confirmed case documents infection-triggered worsening.
- category: Nervous System
  name: Peripheral Neuropathy
  frequency: FREQUENT
  description: Peripheral neuropathy accompanies central neurologic involvement.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:27256512
    reference_title: "Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both central nervous system involvement and peripheral neuropathy were demonstrated.
    explanation: A molecularly confirmed Arts case documents peripheral neuropathy.
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009830 | Peripheral neuropathy | Frequent (79-30%)"
    explanation: Orphanet supports the frequency band.
- category: Nervous System
  name: Areflexia
  frequency: FREQUENT
  description: Loss of deep-tendon reflexes is a peripheral-neuropathy manifestation.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001284 | Areflexia | Frequent (79-30%)"
    explanation: Orphanet supports both the phenotype and frequency band.
- category: Nervous System
  name: Decreased Motor Nerve Conduction Velocity
  frequency: VERY_FREQUENT
  description: Abnormal motor nerve-conduction studies provide an objective neuropathy readout.
  phenotype_term:
    preferred_term: Decreased motor nerve conduction velocity
    term:
      id: HP:0003431
      label: Decreased motor nerve conduction velocity
  reports_on:
  - target: Peripheral Nerve Dysfunction
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003431 | Decreased motor nerve conduction velocity | Very frequent (99-80%)"
      explanation: The objective nerve-conduction finding is a readout of peripheral nerve dysfunction.
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003431 | Decreased motor nerve conduction velocity | Very frequent (99-80%)"
    explanation: Orphanet supports both the investigation finding and frequency band.
- category: Nervous System
  name: EMG Chronic Denervation Signs
  frequency: VERY_FREQUENT
  description: Chronic denervation on electromyography is an objective neuropathy readout.
  phenotype_term:
    preferred_term: EMG chronic denervation signs
    term:
      id: HP:0003444
      label: "EMG: chronic denervation signs"
  reports_on:
  - target: Peripheral Nerve Dysfunction
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    evidence:
    - reference: ORPHA:1187
      reference_title: "Lethal ataxia with deafness and optic atrophy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003444 | EMG: chronic denervation signs | Very frequent (99-80%)"
      explanation: Chronic denervation on EMG is an objective readout of peripheral nerve dysfunction.
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003444 | EMG: chronic denervation signs | Very frequent (99-80%)"
    explanation: Orphanet supports both the investigation finding and frequency band.
- category: Immunologic
  name: Recurrent Upper Respiratory Tract Infections
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent upper respiratory tract infections
    term:
      id: HP:0002788
      label: Recurrent upper respiratory tract infections
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002788 | Recurrent upper respiratory tract infections | Very frequent (99-80%)"
    explanation: Orphanet supports both the phenotype and frequency band.
- category: Respiratory
  name: Respiratory Failure Requiring Assisted Ventilation
  frequency: FREQUENT
  severity: SEVERE
  description: Severe infection-associated deterioration may require assisted ventilation.
  phenotype_term:
    preferred_term: Respiratory failure requiring assisted ventilation
    term:
      id: HP:0004887
      label: Respiratory failure requiring assisted ventilation
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0004887 | Respiratory failure requiring assisted ventilation | Frequent (79-30%)"
    explanation: Orphanet supports both the phenotype and frequency band.
- category: Hearing
  name: Profound Sensorineural Hearing Impairment
  frequency: FREQUENT
  severity: SEVERE
  phenotype_term:
    preferred_term: Profound sensorineural hearing impairment
    term:
      id: HP:0011476
      label: Profound sensorineural hearing impairment
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011476 | Profound sensorineural hearing impairment | Frequent (79-30%)"
    explanation: Orphanet supports both the phenotype and frequency band.
- category: Eye
  name: Nystagmus
  frequency: FREQUENT
  description: Nystagmus is reported in Arts syndrome.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Frequent (79-30%)"
    explanation: Orphanet supports both the phenotype and frequency band.
biochemical:
- name: PRS-I enzyme activity
  presence: DECREASED
  context: >-
    Reduced phosphoribosylpyrophosphate synthetase 1 activity is the proximal
    biochemical defect in Arts syndrome and tracks PRPS1 deficiency severity.
  readouts:
  - target: PRS-I Enzyme Deficiency
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low PRS-I activity directly reports the enzyme-deficiency node in the
      Arts syndrome pathograph.
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Both mutations result in a loss of phosphoribosyl pyrophosphate
        synthetase 1 activity, as was shown in silico by molecular modeling and
        was shown in vitro by phosphoribosyl pyrophosphate synthetase activity
        assays in erythrocytes and fibroblasts from patients.
      explanation: >-
        Patient erythrocyte and fibroblast assays directly support decreased
        PRS-I activity as a readout.
  evidence:
  - reference: PMID:17701896
    reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both mutations result in a loss of phosphoribosyl pyrophosphate
      synthetase 1 activity, as was shown in silico by molecular modeling and
      was shown in vitro by phosphoribosyl pyrophosphate synthetase activity
      assays in erythrocytes and fibroblasts from patients.
    explanation: >-
      Patient-derived erythrocyte and fibroblast assays show reduced PRS-I
      activity.
  - reference: PMID:24528855
    reference_title: "X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Enzymatically, PRS-I activity was undetectable in the index subject,
      reduced in his less affected sister, and normal in his unaffected mother.
    explanation: >-
      Family enzyme testing documents a residual-activity gradient across the
      PRPS1 deficiency continuum.
- name: Urinary hypoxanthine
  biomarker_term:
    preferred_term: hypoxanthine
    term:
      id: CHEBI:17368
      label: hypoxanthine
  presence: DECREASED
  context: >-
    Undetectable urinary hypoxanthine supports impaired purine biosynthesis in
    Arts syndrome due to PRPS1 loss of function.
  readouts:
  - target: PRPP-Dependent Biosynthetic Constraint
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low urinary hypoxanthine reports the impaired purine-biosynthesis branch
      downstream of PRS-I deficiency.
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        impaired purine biosynthesis, which is supported by the undetectable
        hypoxanthine in urine and the reduced uric acid levels in serum from
        patients.
      explanation: >-
        Original patient evidence directly reports undetectable urinary
        hypoxanthine.
  evidence:
  - reference: PMID:17701896
    reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      impaired purine biosynthesis, which is supported by the undetectable
      hypoxanthine in urine and the reduced uric acid levels in serum from
      patients.
    explanation: >-
      Original patient evidence reports undetectable urinary hypoxanthine.
- name: Serum uric acid
  biomarker_term:
    preferred_term: uric acid
    term:
      id: CHEBI:27226
      label: uric acid
  presence: DECREASED
  context: >-
    Reduced serum uric acid is a downstream purine-metabolism marker in Arts
    syndrome due to impaired purine biosynthesis.
  readouts:
  - target: PRPP-Dependent Biosynthetic Constraint
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Low serum uric acid reports impaired purine biosynthesis downstream of
      PRS-I deficiency.
    evidence:
    - reference: PMID:17701896
      reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        impaired purine biosynthesis, which is supported by the undetectable
        hypoxanthine in urine and the reduced uric acid levels in serum from
        patients.
      explanation: >-
        Original patient evidence directly reports reduced serum uric acid.
  evidence:
  - reference: PMID:17701896
    reference_title: "Arts syndrome is caused by loss-of-function mutations in PRPS1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      impaired purine biosynthesis, which is supported by the undetectable
      hypoxanthine in urine and the reduced uric acid levels in serum from
      patients.
    explanation: >-
      Original patient evidence reports reduced serum uric acid levels.
- name: Erythrocyte purine nucleotides
  biomarker_term:
    preferred_term: purine nucleotide
    term:
      id: CHEBI:26395
      label: purine nucleotide
  presence: DECREASED
  context: >-
    Erythrocyte purine nucleotides are a pharmacodynamic readout of purine
    pathway replenishment during SAMe therapy.
  readouts:
  - target: PRPP-Dependent Biosynthetic Constraint
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PHARMACODYNAMIC
    interpretation: >-
      Replenishment of erythrocyte adenosine and guanosine nucleotides reports
      bypass of the purine nucleotide depletion branch.
    evidence:
    - reference: PMID:33532242
      reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment of a 3-year old boy with S-adenosylmethionine (SAM)
        replenished erythrocyte purine nucleotides of adenosine and guanosine,
        while SAM and nicotinamide riboside co-therapy further improved his
        clinical phenotype as well as T-cell survival and function.
      explanation: >-
        Treatment-associated erythrocyte purine nucleotide replenishment
        supports this pharmacodynamic readout.
  evidence:
  - reference: PMID:33532242
    reference_title: "Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of a 3-year old boy with S-adenosylmethionine (SAM)
      replenished erythrocyte purine nucleotides of adenosine and guanosine,
      while SAM and nicotinamide riboside co-therapy further improved his
      clinical phenotype as well as T-cell survival and function.
    explanation: >-
      The clinical report identifies erythrocyte purine nucleotides as a
      treatment-responsive biochemical readout.
genetic:
- name: PRPS1
  gene_term:
    preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  association: Causative
  notes: >-
    Arts syndrome is caused by PRPS1 loss-of-function variants and represents
    the severe end of the PRPS1 deficiency spectrum.
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary
      to loss of function variants in PRPS1.
    explanation: >-
      Directly supports PRPS1 as the causative gene and loss of function as the
      disease mechanism.
diagnosis:
- name: Molecular genetic testing for PRPS1 variants
  presence: A hemizygous pathogenic PRPS1 variant confirms PRS deficiency in an affected male.
  description: >-
    Molecular confirmation is the key diagnostic step; a variant of uncertain
    significance alone does not establish Arts syndrome.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: PRPS1
        term:
          id: hgnc:9462
          label: PRPS1
  evidence:
  - reference: PMID:20301738
    reference_title: Phosphoribosylpyrophosphate Synthetase Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of PRS deficiency is established in a male proband with
      suggestive findings and a hemizygous pathogenic variant in PRPS1
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews directly states the molecular diagnostic criterion.
differential_diagnoses:
- name: Charcot-Marie-Tooth disease X-linked recessive 5
  disease_term:
    preferred_term: Charcot-Marie-Tooth disease X-linked recessive 5
    term:
      id: MONDO:0010699
      label: Charcot-Marie-Tooth disease X-linked recessive 5
  description: >-
    CMTX5 is the intermediate PRPS1 deficiency phenotype and can resemble Arts
    syndrome, but tends to present with less severe neurodevelopmental and
    infectious involvement.
  distinguishing_features:
  - Peripheral neuropathy and optic neuropathy are more prominent than the severe multisystem childhood phenotype.
  - Residual PRS-I activity is higher than in Arts syndrome.
  evidence:
  - reference: PMID:26089585
    reference_title: "Association of PRPS1 Mutations with Disease Phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      decreased activity leads to X-linked nonsyndromic sensorineural deafness
      (DFNX-2), Charcot-Marie-Tooth disease-5 (CMTX5), and Arts syndrome
      depending on the residual activity of PRS-I
    explanation: >-
      Places CMTX5 and Arts syndrome on the same severity spectrum and supports
      CMTX5 as a close differential.
- name: X-linked nonsyndromic hearing loss 1
  disease_term:
    preferred_term: X-linked hearing loss 1
    term:
      id: MONDO:0010577
      label: hearing loss, X-linked 1
  description: >-
    Mild PRPS1 deficiency can present as isolated X-linked hearing loss without
    the severe neurologic, optic, or infectious manifestations of Arts syndrome.
  distinguishing_features:
  - Hearing loss is the main feature; ataxia, hypotonia, and recurrent infections are absent or minimal.
  - Higher residual PRS-I activity separates this phenotype from Arts syndrome.
  evidence:
  - reference: PMID:23190330
    reference_title: "Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations in PRPS1 are associated with a spectrum of non-syndromic to
      syndromic hearing loss.
    explanation: >-
      Supports isolated X-linked hearing loss as the mild end of the PRPS1
      spectrum and a differential for Arts syndrome.
- name: PRPS1 superactivity
  disease_term:
    preferred_term: PRPS1 superactivity
    term:
      id: MONDO:0010395
      label: phosphoribosylpyrophosphate synthetase superactivity
  description: >-
    PRPS1 gain-of-function causes a distinct hyperuricemic disorder; uric-acid
    overproduction and increased PRS-I activity distinguish it from Arts syndrome.
  distinguishing_features:
  - Uric acid overproduction rather than low-normal serum uric acid.
  - PRS-I superactivity rather than loss of enzyme activity.
  evidence:
  - reference: PMID:20380929
    reference_title: "PRPS1 mutations: four distinct syndromes and potential treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with PRS-I superactivity primarily present with uric acid
      overproduction, mental retardation, ataxia, hypotonia, and hearing impairment.
    explanation: >-
      The review distinguishes the gain-of-function hyperuricemic phenotype.
progression:
- phase: Neonatal period and infancy
  age_range: Neonatal period through infancy
  notes: Hypotonia, ataxia, developmental delay, and profound hearing impairment begin early.
  evidence:
  - reference: ORPHA:1187
    reference_title: "Lethal ataxia with deafness and optic atrophy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      - Age of onset: Infancy
      - Age of onset: Neonatal
    explanation: Orphanet records both infancy and neonatal onset periods.
- phase: Early-childhood progression and infection-triggered deterioration
  age_range: Infancy through early childhood
  notes: >-
    Baseline neurologic weakness progresses, with acute infection-triggered
    worsening that may lead to ventilatory failure and early death in severe cases.
  evidence:
  - reference: PMID:27256512
    reference_title: "Arts syndrome with a novel missense mutation in the PRPS1 gene: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The initial symptoms of the 1-year-old proband were hypotonia and ataxia,
      worsening recurrent infection-triggered muscle weakness, motor and
      intellectual developmental delay, and hearing loss.
    explanation: The case documents the characteristic infection-triggered deterioration.
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recurrent infections that can cause progressive clinical decline, often
      resulting in death before 5 years of age.
    explanation: The review summarizes the severe early-childhood prognosis.
experimental_models:
- name: PRPS1 p.V42L patient-derived iPSC neural model
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  cell_source: Patient PBMC-derived iPSCs differentiated into neural stem cells and neurons
  publication: PMID:41787648
  modeled_mechanisms:
  - target: Reduced Neural Stem Cell Proliferation
    description: The model measures reduced proliferation in patient-derived neural stem cells.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient-derived NSCs demonstrated significantly reduced proliferative
        capacity, aberrant nuclear morphology, and increased neuronal senescence,
        while mitochondrial integrity and function were largely preserved.
      explanation: The model directly measures reduced neural stem-cell proliferation.
  - target: Neural Stem Cell Senescence-Like State
    description: The model measures abnormal nuclear morphology and senescence-associated changes.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient-derived NSCs demonstrated significantly reduced proliferative
        capacity, aberrant nuclear morphology, and increased neuronal senescence,
        while mitochondrial integrity and function were largely preserved.
      explanation: The model directly measures the senescence-like state.
  - target: Impaired Neurite Outgrowth
    description: The model measures neurite length and branching in differentiated neurons.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Neurons differentiated from these NSCs exhibited impaired neurite
        outgrowth and reduced branching complexity, indicative of disrupted
        neurodevelopmental processes.
      explanation: The model directly measures neurite outgrowth and branching.
  findings:
  - statement: Patient-derived NSCs show reduced proliferation and a senescence-like phenotype.
    supporting_text: >-
      Patient-derived NSCs demonstrated significantly reduced proliferative
      capacity, aberrant nuclear morphology, and increased neuronal senescence,
      while mitochondrial integrity and function were largely preserved.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Patient-derived NSCs demonstrated significantly reduced proliferative
        capacity, aberrant nuclear morphology, and increased neuronal senescence,
        while mitochondrial integrity and function were largely preserved.
      explanation: The abstract directly supports the finding.
  - statement: Patient-derived neurons show impaired neurite outgrowth and branching.
    supporting_text: >-
      Neurons differentiated from these NSCs exhibited impaired neurite outgrowth
      and reduced branching complexity, indicative of disrupted neurodevelopmental processes.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Neurons differentiated from these NSCs exhibited impaired neurite
        outgrowth and reduced branching complexity, indicative of disrupted
        neurodevelopmental processes.
      explanation: The abstract directly supports the finding.
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we generated patient-specific induced pluripotent stem cells
      harboring the PRPS1 p.V42L variant and differentiated them into neural stem
      cells (NSCs) and neurons to elucidate disease mechanisms and explore potential
      therapeutic strategies.
    explanation: This directly establishes the patient-derived neural model.
animal_models:
- species: Zebrafish (Danio rerio)
  genotype: prps1a and prps1b single and double loss-of-function mutants
  description: >-
    Additive loss of the two zebrafish paralogs produces graded eye, hair-cell,
    motor-neuron, innervation, and leukocyte abnormalities resembling features
    of the human PRPS1-deficiency spectrum.
  associated_phenotypes:
  - Smaller eyes
  - Reduced hair cell number
  - Abnormal primary motor-neuron development
  - Abnormal hair-cell innervation
  - Reduced leukocytes
  evidence:
  - reference: PMID:27425195
    reference_title: Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The double mutant also showed abnormal development of primary motor neurons,
      hair cell innervation, and reduced leukocytes, consistent with the neuropathy
      and recurrent infection of the human patients possessing the most severe
      reductions of PRPS1 activity.
    explanation: The zebrafish model recapitulates neurologic, auditory, and immune features.
clinical_trials: []
treatments:
- name: S-Adenosylmethionine Supplementation
  description: >-
    SAM supplementation is the best-described reported intervention for Arts
    syndrome and has been associated with stabilization or improvement.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: S-adenosyl-L-methionine
      term:
        id: CHEBI:15414
        label: S-adenosyl-L-methionine
  target_mechanisms:
  - target: PRPP-Dependent Biosynthetic Constraint
    treatment_effect: BYPASSES
    description: >-
      SAMe supplementation provides purine-pathway support outside the
      defective PRPP-dependent step.
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Supplementation of the purine and NAD pathways outside of
        PRPP‐dependent reactions is a logical approach and has been reported in
        a handful of patients, two with S‐adenosylmethionine (SAMe) and one
        with SAMe and nicotinamide riboside (NR).
      explanation: >-
        The case-review abstract directly supports the bypass rationale for
        SAMe and NR supplementation.
  evidence:
  - reference: PMID:26089585
    reference_title: "Association of PRPS1 Mutations with Disease Phenotypes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently, purine replacement via S-adenosylmethionine (SAM)
      supplementation in patients with Arts syndrome appears to improve their
      condition.
    explanation: >-
      Supports SAM as a disease-relevant dietary supplementation strategy.
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had stability or improvement of symptoms, suggesting that SAMe
      and NR can be a treatment option in Arts syndrome, though further studies
      are warranted.
    explanation: >-
      Reinforces the reported benefit of SAMe-containing regimens.
- name: Nicotinamide Riboside Supplementation
  description: >-
    Nicotinamide riboside has been reported in combination with SAMe in Arts
    syndrome and is mechanistically relevant because PRPS1 deficiency affects
    NAD-related metabolism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: nicotinamide riboside
      term:
        id: CHEBI:15927
        label: N-ribosylnicotinamide
  target_mechanisms:
  - target: PRPP-Dependent Biosynthetic Constraint
    treatment_effect: BYPASSES
    description: >-
      Nicotinamide riboside is intended to support NAD-pathway metabolism
      downstream of the PRPP-dependent PRPS1 block.
    evidence:
    - reference: DOI:10.1002/jmd2.12395
      reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Supplementation of the purine and NAD pathways outside of
        PRPP‐dependent reactions is a logical approach and has been reported in
        a handful of patients, two with S‐adenosylmethionine (SAMe) and one
        with SAMe and nicotinamide riboside (NR).
      explanation: >-
        The case-review abstract supports nicotinamide riboside as part of a
        purine/NAD pathway bypass strategy.
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Supplementation of the purine and NAD pathways outside of PRPP‐dependent
      reactions is a logical approach and has been reported in a handful of
      patients, two with S‐adenosylmethionine (SAMe) and one with SAMe and
      nicotinamide riboside (NR).
    explanation: >-
      Supports NR as part of a reported supplementation regimen, though the
      abstract describes combination use rather than NR monotherapy.
- name: Nicotinamide Mononucleotide (Preclinical)
  description: >-
    NMN partially rescued neural stem-cell and neuronal morphology defects in
    one patient-derived iPSC model. It has not been shown to be safe or effective
    as an Arts syndrome treatment in humans.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nicotinamide mononucleotide
      term:
        id: CHEBI:50383
        label: nicotinamide mononucleotide
  target_mechanisms:
  - target: Reduced Neural Stem Cell Proliferation
    treatment_effect: RESTORES
    description: NMN partially restores proliferation in PRPS1-mutant neural stem cells.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Notably, supplementation with nicotinamide mononucleotide, a precursor of
        nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in
        NSC proliferation, nuclear architecture, and neuronal morphology.
      explanation: The cellular study directly supports partial rescue of proliferation.
  - target: Impaired Neurite Outgrowth
    treatment_effect: RESTORES
    description: NMN partially improves neuronal morphology in the patient-derived model.
    evidence:
    - reference: PMID:41787648
      reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Notably, supplementation with nicotinamide mononucleotide, a precursor of
        nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in
        NSC proliferation, nuclear architecture, and neuronal morphology.
      explanation: The cellular study supports partial rescue of neuronal morphology.
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Notably, supplementation with nicotinamide mononucleotide, a precursor of
      nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in
      NSC proliferation, nuclear architecture, and neuronal morphology.
    explanation: This supports only preclinical cellular rescue, not human efficacy.
- name: Multidisciplinary Supportive Care
  description: >-
    There is no curative therapy. Supportive management addresses neurologic,
    mobility, hearing, visual, developmental, respiratory, and genetic needs.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301738
    reference_title: Phosphoribosylpyrophosphate Synthetase Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Supportive care to improve quality of life, maximize function, and reduce
      complications can include multidisciplinary care by specialists in
      neurology, physiatry, physical therapy, occupational therapy, audiology,
      otolaryngology, ophthalmology and low vision services, education, and
      medical genetics.
    explanation: GeneReviews supplies the multidisciplinary management baseline.
- name: Genetic Counseling
  description: >-
    Genetic counseling is appropriate for an X-linked disorder with carrier
    testing implications.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301738
    reference_title: Phosphoribosylpyrophosphate Synthetase Deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once the PRPS1 pathogenic variant has been identified in an affected
      family member, heterozygote testing for at-risk female relatives and
      prenatal and preimplantation genetic testing are possible.
    explanation: GeneReviews supports counseling and reproductive testing options.
discussions:
- discussion_id: gap_arts_tissue_selectivity
  prompt: >-
    Which PRPP-dependent metabolite deficits drive the selective neural,
    auditory, optic, peripheral-nerve, and immune manifestations of Arts syndrome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#PRPP-Dependent Biosynthetic Constraint
  rationale: >-
    Human studies establish PRPS1 loss, low enzyme activity, and purine-pathway
    abnormalities, but do not resolve why particular high-demand tissues are
    affected or which purine, pyrimidine, or NAD-pathway deficit is causal.
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      therapeutic interventions remain limited, largely due to an incomplete
      understanding of the cellular pathophysiology underlying the disorder.
    explanation: The 2026 mechanistic study explicitly identifies this limitation.
- discussion_id: mismatch_arts_models
  prompt: >-
    Do the single-variant iPSC model and dual-paralog zebrafish loss models
    reproduce the mechanisms operating across genetically diverse human Arts syndrome?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Neural Stem Cell Proliferation
  - pathophysiology#Neural Stem Cell Senescence-Like State
  - pathophysiology#Impaired Neurite Outgrowth
  rationale: >-
    The human neural findings derive from one patient-specific p.V42L line, while
    zebrafish have two prps1 paralogs and model graded transcript loss. Neither
    system establishes prevalence across variants or validates the cellular
    findings in affected human tissue.
  evidence:
  - reference: PMID:41787648
    reference_title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study, we generated patient-specific induced pluripotent stem cells
      harboring the PRPS1 p.V42L variant and differentiated them into neural stem
      cells (NSCs) and neurons to elucidate disease mechanisms and explore potential
      therapeutic strategies.
    explanation: The study identifies the single patient-specific variant model.
  - reference: PMID:27425195
    reference_title: Additive reductions in zebrafish PRPS1 activity result in a spectrum of deficiencies modeling several human PRPS1-associated diseases.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found two paralogs in zebrafish, prps1a and prps1b and characterized
      each paralogous mutant individually as well as the double mutant fish.
    explanation: The model-organism study documents the paralog-specific design.
- discussion_id: gap_arts_treatment_efficacy
  prompt: >-
    Do SAMe, nicotinamide riboside, or nicotinamide mononucleotide improve
    survival or neurologic outcomes in controlled human studies?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#PRPP-Dependent Biosynthetic Constraint
  rationale: >-
    SAMe and SAMe-plus-NR evidence is limited to a handful of uncontrolled cases;
    NMN evidence is limited to one in-vitro patient-derived model. No Arts-specific
    interventional trial was identified in the literature and trial-registry review
    current through 2026-08-05. NCT06092346 was dispositioned as not Arts-specific
    because its cached summary names only the broad DPPM population and does not
    explicitly identify PRPS1 deficiency eligibility.
  evidence:
  - reference: DOI:10.1002/jmd2.12395
    reference_title: "S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had stability or improvement of symptoms, suggesting that SAMe
      and NR can be a treatment option in Arts syndrome, though further studies
      are warranted.
    explanation: The report supports a preliminary signal while explicitly calling for more study.
datasets: []
references:
- reference: PMID:20301738
  title: Phosphoribosylpyrophosphate Synthetase Deficiency.
  tags:
  - GeneReviews
- reference: PMID:37670898
  title: Clinical and genetic characteristics of a patient with phosphoribosyl pyrophosphate synthetase 1 deficiency and a systematic literature review.
- reference: PMID:41787648
  title: "PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation."
📚

References & Deep Research

References

3
PMID:20301738
Phosphoribosylpyrophosphate Synthetase Deficiency.
No top-level findings curated for this source.
PMID:37670898
Clinical and genetic characteristics of a patient with phosphoribosyl pyrophosphate synthetase 1 deficiency and a systematic literature review.
No top-level findings curated for this source.
PMID:41787648
PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Arts syndrome. Core disease mechanisms, molecular and cellular pathways, i...
Asta Scientific Corpus Retrieval 19 citations 2026-04-16T14:41:35.931211

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Arts syndrome. Core disease mechanisms, molecular and cellular pathways, i...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[2] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[3] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.376) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[4] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.372) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[5] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

  • Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
  • Year: 2023
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
  • DOI: 10.3390/genes14091734
  • PMID: 37761876
  • PMCID: 10531442
  • Citations: 11
  • Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.371) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[6] Drug Repurposing in Rare Diseases: An Integrative Study of Drug Screening and Transcriptomic Analysis in Nephropathic Cystinosis

  • Authors: F. Bellomo, Ester De Leo, A. Taranta, L. Giaquinto, G. di Giovamberardino et al.
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/5e45caf9d574a1dc3ebf53a7fcb57c10bb2373f8
  • DOI: 10.3390/ijms222312829
  • PMID: 34884638
  • PMCID: 8657658
  • Citations: 18
  • Summary: A drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases is shown, combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels.
  • Evidence snippets:
  • Snippet 1 (score: 0.370) > Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.

[7] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

  • Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
  • Year: 2024
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
  • DOI: 10.3389/fmed.2024.1425038
  • PMID: 39135718
  • PMCID: 11317438
  • Citations: 1
  • Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.369) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[8] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 9
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[9] Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD

  • Authors: D. Drakulić, S. Djurovic, Y. A. Syed, Sebastiano Trattaro, N. Caporale et al.
  • Year: 2020
  • Venue: Molecular Autism
  • URL: https://www.semanticscholar.org/paper/c6cac51304043d34c93254007adca11883e387cd
  • DOI: 10.1186/s13229-020-00343-4
  • PMID: 32487215
  • PMCID: 7268297
  • Citations: 23
  • Influential citations: 1
  • Summary: Here, it is examined how iPSCs derived from ASD patients with an associated CNV inform the understanding of the genetic and biological mechanisms underlying the aetiology of ASD.
  • Evidence snippets:
  • Snippet 1 (score: 0.367) > external factors. These complications hinder identification of the basic pathophysiological mechanisms that lead to ASD and hence hamper development of effective therapies. > Molecular and cellular analysis of human patients is generally prospective with data mostly derived from post-mortem tissue. As mentioned above, such studies are subject to the confounds of secondary effects and record the outcomes of underlying disease mechanism rather than directly probe the causative mechanisms. Animal models can be highly informative for the study of a basic mechanism; however, it is difficult to directly translate between observed patient phenotype and animal models. A particular weakness is the ability to capture the phenotypic variation across the patient population. > Human stem cell models offer an opportunity to directly study the molecular and cellular mechanisms of diseases. Key to this approach is the generation of human-induced pluripotent stem cells (iPSCs) derived from patient cells. These are generated by reprogramming of somatic cells into pluripotent stem cells from which many cell types can be differentiated, including neurons and glial cells. Importantly, they can be easily obtained in the clinic from fibroblasts (skin biopsies), keratinocytes (hair roots) [3], T lymphocytes (peripheral blood) [4,5] and exfoliated renal epithelial cells from urine samples [6,7]. Importantly, patient iPSCs enable the in vitro study of different cells types in isolation or co-culture in order to investigate cell function. Uniquely they can track the development profile of patient cell differentiation. More recently the capacity of iPSCs to form 3D organoids has opened up the possibility to investigate the interaction of multiple cell types in a more brain-like microenvironment. Methods for increasing reproducibility of brain organoid differentiation are improving substantially [8,9] and being exploited to mechanistically dissect the effect of genetic lesions causing ASD and ID [10][11][12], as well as the role of specific genes and molecular modules key to human-specific neuronal differentiation trajectories and pathophysiology [13]. > The major question is how to identify the relevant cellular phenotypes that converge on the common pathophysiological mechanisms underlying patient aeti

[10] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

  • Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
  • DOI: 10.2174/1570159X17666191021141057
  • PMID: 31631822
  • PMCID: 7327943
  • Citations: 12
  • Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.364) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[11] Recent Evidences of Epigenetic Alterations in Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review

  • Authors: R. Ragusa, Pasquale Bufano, A. Tognetti, M. Laurino, Chiara Caselli
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2660cdbbe1f205c631fe890e5c6a3c8d9b81ce5f
  • DOI: 10.3390/ijms26062571
  • PMID: 40141213
  • PMCID: 11942187
  • Citations: 4
  • Summary: A systematic review of the latest knowledge on epigenetic modifications that characterize COPD, summarizing epigenetic factors that could serve as potential novel biomarkers and therapeutic targets for the treatment of COPD patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > The papers included were clustered according to epigenetic mechanisms involved in COPD (molecular and cellular processes, as biomarker or therapeutic target). Tables 4-9 describe the extracted information, including the following: Study = name of first author et al., year; Country (Region) = where the study took place; Number of participants = sample size; Type of sample = biological sample employed; Gene affected = gene or group of genes whose expression can be "regulated" by epigenetic mechanisms; Epigenetic alteration = type of epigenetic alteration observed in the presence of disease; Activity in COPD = involvement of epigenetic elements in different molecular and cellular mechanisms associated with COPD; and Role of epigenetic mechanisms = epigenetic modifications that can be used to explain the pathophysiology of COPD or as biomarkers and therapeutic targets.

[12] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

  • Authors: Debopam Samanta
  • Year: 2025
  • Venue: Children
  • URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
  • DOI: 10.3390/children12040481
  • PMID: 40310132
  • PMCID: 12025602
  • Citations: 19
  • Influential citations: 1
  • Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.
  • Snippet 2 (score: 0.360) > A key advantage of disease-modifying therapies is their potential to target pathogenic mechanisms early in the disease course, potentially preventing the progression of some infantile epileptic encephalopathies to LGS. > This narrative review explores precision therapeutic strategies based on specific monogenic causes and disease mechanisms relevant to LGS. A comprehensive literature search (PubMed, MEDLINE, ClinicalTrials.gov, conference abstracts from the American Academy of Neurology and American Epilepsy Society, and gray literature) was conducted through 19 February 2025 to identify established ASMs, repurposed and novel drugs, as well as various gene therapy approaches with potential relevance to LGS. Given that over 900 monogenic causes of DEEs have been identified-implicating diverse cellular components such as ion channels, receptors, synaptic proteins, signaling pathways, metabolic processes, and epigenetic regulators-this review discusses current and emerging precision therapeutics based on shared molecular mechanisms and the pathophysiology of select genes associated with LGS [17] (Table 1).

[13] Chromatin modifiers in neurodevelopment

  • Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
  • Year: 2025
  • Venue: Frontiers in Molecular Neuroscience
  • URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
  • DOI: 10.3389/fnmol.2025.1551107
  • PMID: 40469903
  • PMCID: 12133960
  • Citations: 2
  • Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[14] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

  • Authors: I. Condò
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
  • DOI: 10.3390/ijms23126525
  • PMID: 35742964
  • PMCID: 9223693
  • Citations: 16
  • Influential citations: 2
  • Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
  • Evidence snippets:
  • Snippet 1 (score: 0.361) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[15] Editorial: Molecular mechanisms of neuropsychiatric diseases

  • Authors: M. Moreira-Rodrigues, Melanie J. Grubisha
  • Year: 2022
  • Venue: Frontiers in Molecular Neuroscience
  • URL: https://www.semanticscholar.org/paper/9ea80cf42a6ccc00550e8abd24f116e79963a1c3
  • DOI: 10.3389/fnmol.2022.1102296
  • PMID: 36568276
  • PMCID: 9773978
  • Citations: 5
  • Summary: Molecular mechanisms of neuropsychiatric diseases are studied through a probabilistic approach and the results show clear patterns of disease progression that are consistent with known mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.360) > Neuropsychiatric disorders, such as depression, schizophrenia, bipolar disorder, obsessive compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder and others are estimated to impair millions of individuals globally. Despite the high global prevalence, much remains unknown about the underlying molecular mechanisms that lead to these and other neuropsychiatric diseases. The likelihood of developing these disorders may depend on a variety of genetic, developmental and environmental factors. The molecular alterations produced by these factors may contribute to both disease onset or the persistence of a specific pathology. Identifying the molecular mechanisms of a disease will increase our understanding of the underlying pathophysiology and ultimately lead to the rational design of targeted treatments. The goal of this Research Topic was to explore fundamental molecular mechanisms underlying neuropsychiatric diseases, and how these mechanisms may be exploited for potential therapeutic benefit. > A longstanding challenge in the elucidation of molecular mechanisms underlying neuropsychiatric disease has been the initial paucity of anatomical and/or molecular findings. Distinguished American neurologist Dr. Fred Plum once referred to schizophrenia as "the graveyard of neuropathologists." This Topic features multiple papers that serve to tackle this and other challenges and link clinical entities to anatomical and molecular abnormalities. > Ren et al. showed that schizophrenia patients with auditory verbal hallucinations exhibit a decrease in cortical thickness in orbitofrontal cortices, which was negatively correlated with severity of these symptoms. Seeking to discover molecular aberrations in a depression-relevant model, Chen et al. employed a large-scale-omics approach to achieve metabolic profiling in the olfactory bulb of a chronic mild stress mouse model. They discovered an abnormal metabolism of the tryptophan pathway in the olfactory bulb, which may mediate the occurrence of a depression-like phenotype in a chronic mild stress model. On the other way, Martinho, Oliveira et al. sought to identify specific molecular abnormalities underlying contextual fear memory relevant to PTSD, and that modulating this system can reverse fear-related phenotypic changes.

[16] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

  • Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
  • Year: 2021
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
  • DOI: 10.1002/mgg3.1809
  • PMID: 34519438
  • PMCID: 8580094
  • Citations: 12
  • Influential citations: 2
  • Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[17] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 3
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[18] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[19] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.357) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.