PRPS1 Deficiency Spectrum

Genetic MONDO:0010533 Pathograph 29 Inborn Error of Purine Metabolism Neurological Disorder

PRPS1 deficiency is an X-linked phenotypic continuum caused by loss-of-function PRPS1 variants that reduce phosphoribosylpyrophosphate synthetase 1 (PRS-I) activity. PRS-I generates phosphoribosylpyrophosphate for purine, pyrimidine, and NAD-pathway nucleotide synthesis; reduced residual activity impairs nucleotide availability and produces a spectrum ranging from DFN2/DFNX1 nonsyndromic sensorineural hearing loss to CMTX5 peripheral neuropathy with hearing and visual loss, severe Arts syndrome with hypotonia, ataxia, developmental impairment, optic atrophy, recurrent infections, and expanded severe presentations with retinal dystrophy, diabetes insipidus, white matter disease, and growth restriction. Management is primarily supportive, with purine/NAD-pathway precursor supplementation using S-adenosylmethionine and nicotinamide riboside reported as a disease-directed option in Arts syndrome.

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1
Inheritance
5
Pathophys.
17
Phenotypes
29
Pathograph
1
Genes
3
Treatments
3
Subtypes
1
References
1
Deep Research
👪

Inheritance

1
X-linked Recessive HP:0001419
X-linked recessive inheritance
◆

Subtypes

3
Arts Syndrome (Severe PRPS1 Deficiency) MONDO:0010533
Most severe form. Early-onset ataxia, hypotonia, prelingual sensorineural hearing loss, optic atrophy, intellectual disability, recurrent infections, and early death. Minimal residual PRS-I activity.
Show evidence (1 reference)
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 defines the severe Arts syndrome cluster within PRPS1 deficiency.
Charcot-Marie-Tooth Disease X-linked 5 (Moderate Deficiency) MONDO:0010699
Moderate form. Peripheral neuropathy, optic neuropathy, and progressive sensorineural hearing loss. Partial residual PRS-I activity.
Show evidence (1 reference)
PMID:17701900 SUPPORT Human Clinical
"We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy"
Original CMTX5 family evidence links PRPS1 variants to inherited peripheral neuropathy with hearing and optic involvement.
X-linked Nonsyndromic Hearing Loss (Mild Deficiency) MONDO:0010577
Mildest form. Nonsyndromic progressive sensorineural hearing loss without neurological involvement. Highest residual PRS-I activity among the deficiency subtypes.
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"Phosphoribosylpyrophosphate synthetase (PRS) deficiency, an X-linked disorder, is a phenotypic continuum comprising three disorders previously thought to be clinically distinct: Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1)."
GeneReviews places X-linked nonsyndromic sensorineural hearing loss in the PRS deficiency continuum.
⚙

Pathophysiology

5
PRS-I loss of function
Loss-of-function PRPS1 variants reduce PRS-I enzyme activity. Residual activity helps determine severity across the DFN2, CMTX5, and Arts syndrome continuum, with undetectable activity in some severe presentations.
PRPS1 link
ribose phosphate diphosphokinase activity link ↓ DECREASED
Downstream
Impaired PRPP-dependent nucleotide biosynthesis Reduced PRS-I activity limits PRPP-dependent nucleotide biosynthesis.
PRS-I enzyme activity PRPS1 loss of function is directly observed as reduced or undetectable PRS-I enzyme activity in patient-derived assay systems.
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 cell and erythrocyte assays show that Arts syndrome variants reduce 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."
Intrafamilial continuum evidence links clinical severity to measured residual PRS-I activity.
Impaired PRPP-dependent nucleotide biosynthesis
PRS-I produces PRPP, which is used for purine, pyrimidine, and NAD-pathway nucleotide synthesis. PRPS1 loss of function therefore decreases nucleotide biosynthetic capacity and produces measurable purine and guanine nucleotide abnormalities in patients.
Neuron link
Purine nucleotide biosynthesis link ↓ DECREASED Pyrimidine nucleotide biosynthesis link ↓ DECREASED NAD+ biosynthesis link ↓ DECREASED
Downstream
Neurologic auditory and ocular vulnerability Reduced nucleotide availability is associated with neurologic, auditory, and ocular manifestations across the PRS deficiency continuum.
Immune vulnerability in Arts syndrome Severe PRPS1 deficiency can include recurrent respiratory infections and T-cell dysfunction that respond to pathway precursor supplementation.
Expanded severe multisystem involvement Some severe PRPS1 loss-of-function presentations include growth, endocrine, white-matter, and retinal findings beyond the classic three subtype clusters.
Urinary hypoxanthine Impaired purine biosynthesis is reflected by undetectable urinary hypoxanthine in affected patients.
Serum uric acid Impaired purine biosynthesis is reflected by reduced serum uric acid in affected patients.
Erythrocyte guanine nucleotides Severe PRPS1 deficiency can lower erythrocyte guanine nucleotide pools.
Show evidence (2 references)
PMID:37927483 SUPPORT Other
"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."
Human case report review explains the PRPP-dependent pathways affected by PRPS1 deficiency.
PMID:24961627 SUPPORT In Vitro
"Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate."
Severe PRPS1 deficiency patients had low erythrocyte guanine nucleotides, supporting impaired nucleotide availability.
Neurologic auditory and ocular vulnerability
PRPS1 deficiency preferentially affects hearing, peripheral and central nervous system function, and ocular tissues. The exact tissue-selective intermediates remain incompletely defined, but the manifestations track with the severity of PRS-I activity loss.
Neuron link auditory hair cell link
Downstream
Sensorineural Hearing Loss Auditory vulnerability manifests as sensorineural hearing loss across the PRPS1 deficiency continuum.
Peripheral Neuropathy Neurologic vulnerability includes peripheral neuropathy in CMTX5 and severe Arts syndrome presentations.
Ataxia Arts syndrome neurologic involvement includes early-onset ataxia.
Global Developmental Delay Severe PRPS1 deficiency produces developmental delay as part of the neurologic phenotype.
Motor Delay Severe neurologic involvement includes delayed motor development.
Intellectual Disability Severe neurologic involvement includes intellectual disability.
Hypotonia Severe neurologic involvement includes early-onset hypotonia.
Optic Atrophy Ocular vulnerability includes progressive optic atrophy.
Retinal Dystrophy Ocular vulnerability can include retinal dystrophy in the progressive ophthalmologic spectrum.
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"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) to normal cognitive abilities and..."
GeneReviews summarizes the neurologic, auditory, and ocular phenotype spectrum in affected males.
Immune vulnerability in Arts syndrome
Severe Arts syndrome includes recurrent, often respiratory, infections. Co-therapy evidence suggests that impaired purine and NAD-pathway support contributes to T-cell survival and functional defects.
T cell link
Downstream
Recurrent Respiratory Infections Immune vulnerability in severe Arts syndrome manifests as recurrent severe respiratory infections.
Muscle Weakness Infection-associated clinical worsening in Arts syndrome can include muscle weakness.
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."
Arts syndrome clinical description includes recurrent severe respiratory infections.
PMID:33532242 SUPPORT Human Clinical
"SAM and nicotinamide riboside co-therapy further improved his clinical phenotype as well as T-cell survival and function."
Human case evidence supports T-cell involvement responsive to pathway precursor supplementation.
Expanded severe multisystem involvement
Rare severe PRPS1 deficiency presentations can include intrauterine growth restriction, severe short stature, diabetes insipidus, spastic quadriparesis, white matter disease, retinal dystrophy, and low erythrocyte guanine nucleotides.
Downstream
Intrauterine Growth Restriction Severe expanded-spectrum PRPS1 deficiency includes prenatal growth restriction.
Spastic Tetraparesis Severe expanded-spectrum PRPS1 deficiency includes spastic quadriparesis, represented by spastic tetraparesis.
White Matter Disease Severe expanded-spectrum PRPS1 deficiency includes white matter disease.
Diabetes Insipidus Severe expanded-spectrum PRPS1 deficiency includes diabetes insipidus.
Short Stature Severe expanded-spectrum PRPS1 deficiency includes severe short stature.
Dysmorphic Facial Features Severe expanded-spectrum PRPS1 deficiency includes dysmorphic facial features.
Show evidence (2 references)
PMID:24961627 SUPPORT Human Clinical
"intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis."
Severe sibling cases document growth and neurologic expansion of the PRPS1 deficiency phenotype.
PMID:24961627 SUPPORT Human Clinical
"Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus."
Severe sibling cases add ocular and endocrine findings to the PRPS1 deficiency spectrum.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PRPS1 Deficiency Spectrum 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

17
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment (HP:0000407)
Show evidence (2 references)
PMID:20301738 SUPPORT Other
"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) to normal cognitive abilities and..."
GeneReviews describes hearing loss from severe congenital to milder later-onset presentations.
PMID:23190330 SUPPORT Other
"Hearing loss in male patients with PRPS1 mutations is bilateral, moderate to profound, and can be prelingual or postlingual, progressive or non-progressive."
Characterizes hearing loss across the PRPS1 spectrum.
Endocrine 1
Diabetes Insipidus Diabetes insipidus (HP:0000873)
Show evidence (1 reference)
PMID:24961627 SUPPORT Human Clinical
"Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus."
Severe sibling cases directly report diabetes insipidus.
Eye 2
Optic Atrophy Optic atrophy (HP:0000648)
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 Arts syndrome family evidence explicitly includes optic atrophy.
PMID:27256512 SUPPORT Human Clinical
"Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections."
Case report evidence supports progressive optic atrophy in Arts syndrome.
Retinal Dystrophy Retinal dystrophy (HP:0000556)
Show evidence (2 references)
PMID:20301738 SUPPORT Other
"progressive ophthalmologic involvement (retinal dystrophy and optic atrophy)"
GeneReviews directly lists retinal dystrophy as part of progressive ophthalmologic involvement.
PMID:24961627 SUPPORT Human Clinical
"Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus."
Severe sibling cases explicitly include retinal dystrophy.
Head and Neck 1
Dysmorphic Facial Features Abnormal facial shape (HP:0001999)
Show evidence (1 reference)
PMID:24961627 SUPPORT Human Clinical
"intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis."
Severe sibling cases directly report dysmorphic facial features.
Immune 1
Recurrent Respiratory Infections Recurrent respiratory infections (HP:0002205)
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."
Arts syndrome therapy case report describes recurrent severe respiratory infections in affected males.
PMID:37927483 SUPPORT Human Clinical
"developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline"
Case report review emphasizes recurrent infections and their contribution to severe clinical decline.
Musculoskeletal 2
Hypotonia Hypotonia (HP:0001252)
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 Arts syndrome family evidence explicitly includes early-onset hypotonia.
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."
Case report identifies hypotonia as an initial symptom in Arts syndrome.
Muscle Weakness Muscle weakness (HP:0001324)
Show evidence (1 reference)
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."
Arts syndrome case report documents recurrent infection-triggered muscle weakness as a clinical feature.
Nervous System 6
Ataxia Ataxia (HP:0001251)
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 Arts syndrome family evidence explicitly names ataxia.
PMID:27256512 SUPPORT Human Clinical
"Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections."
Case report evidence confirms ataxia as part of Arts syndrome.
Peripheral Neuropathy Peripheral neuropathy (HP:0009830)
Show evidence (2 references)
PMID:17701900 SUPPORT Human Clinical
"We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy"
CMTX5 original report directly links PRPS1 variants to inherited peripheral neuropathy.
PMID:26089585 SUPPORT Other
"moderate PRS-I deficiency (CMTX5) and severe PRS-I deficiency (Arts syndrome) present with peripheral or optic neuropathy, prelingual progressive sensorineural hearing loss, and central nervous system impairment"
Describes peripheral neuropathy as a feature of moderate and severe PRPS1 deficiency.
Intellectual Disability Intellectual disability (HP:0001249)
Show evidence (2 references)
PMID:27256512 SUPPORT Human Clinical
"Arts syndrome is characterized by early-onset hypotonia, ataxia, intellectual disability, sensorineural hearing impairment, progressive optic atrophy, and a tendency to develop infections."
Arts syndrome case report directly lists intellectual disability.
PMID:24961627 SUPPORT Human Clinical
"intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis."
Expanded severe PRPS1 deficiency cases document severe intellectual disability.
Global Developmental Delay Global developmental delay (HP:0001263)
Show evidence (2 references)
PMID:20301738 SUPPORT Other
"severe congenital profound sensorineural hearing loss, intellectual disability, delayed motor development, and progressive ophthalmologic involvement"
GeneReviews directly includes delayed motor development in severe affected males.
PMID:37927483 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"
Arts syndrome treatment case report review lists developmental delays in severe PRPS1 deficiency.
Motor Delay Motor delay (HP:0001270)
Show evidence (1 reference)
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 Arts syndrome family evidence explicitly includes delayed motor development.
White Matter Disease Leukoencephalopathy (HP:0002352)
Show evidence (1 reference)
PMID:24961627 SUPPORT Human Clinical
"Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders."
The indexed title for the severe sibling report explicitly names white matter disease in the PRPS1-related disorder spectrum.
Growth 2
Intrauterine Growth Restriction Intrauterine growth retardation (HP:0001511)
Show evidence (1 reference)
PMID:24961627 SUPPORT Human Clinical
"intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis."
Severe sibling cases directly report intrauterine growth restriction.
Short Stature Short stature (HP:0004322)
Show evidence (1 reference)
PMID:24961627 SUPPORT Human Clinical
"Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus."
Severe sibling cases explicitly report severe short stature in expanded-spectrum PRPS1 deficiency.
Other 1
Spastic Tetraparesis Spastic tetraparesis (HP:0001285)
Show evidence (1 reference)
PMID:24961627 SUPPORT Human Clinical
"intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis."
Severe sibling cases report spastic quadriparesis, represented by the current HPO spastic tetraparesis term.
🧬

Genetic Associations

1
PRPS1 Loss-of-Function Variants (Pathogenic Variants)
X-linked Recessive
Show evidence (2 references)
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 supports hemizygous PRPS1 pathogenic variants as diagnostic in affected males.
PMID:23190330 SUPPORT Other
"the loss-of-function mutations result in X-linked nonsyndromic sensorineural deafness type 2 (DFN2), or in syndromic deafness including Arts syndrome and X-linked Charcot-Marie-Tooth disease-5 (CMTX5)"
LOF mutations cause the deficiency spectrum.
💊

Treatments

3
Purine and NAD Pathway Precursor Supplementation
Action: dietary intervention MAXO:0000088
S-adenosylmethionine can replenish purine nucleotides, and combined S-adenosylmethionine plus nicotinamide riboside has been reported to further improve clinical phenotype and T-cell survival/function in Arts syndrome. This is an emerging disease-directed option that bypasses some PRPP-dependent reactions; evidence remains limited to case reports and small literature reviews.
Mechanism Target:
BYPASSES Impaired PRPP-dependent nucleotide biosynthesis — SAM and nicotinamide riboside supplement downstream purine and NAD pathways outside the defective PRPP-dependent step.
Show evidence (1 reference)
PMID:37927483 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)."
Case report and literature review supports the bypass rationale for SAMe and NR supplementation.
Show evidence (4 references)
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."
Human case evidence supports SAM and nicotinamide riboside co-therapy as a disease-directed approach in Arts syndrome.
PMID:37927483 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."
Case report and literature review supports SAMe/NR as a potential treatment option while noting the limited evidence base.
PMID:26089585 SUPPORT Other
"purine replacement via S-adenosylmethionine (SAM) supplementation in patients with Arts syndrome appears to improve their condition"
SAM supplementation as potential therapy for PRPS1 deficiency.
+ 1 more reference
Multidisciplinary Supportive Care
Action: supportive care MAXO:0000950
There is no cure for PRS deficiency, so management includes coordinated neurologic, rehabilitation, hearing, vision, education, and genetics care to maximize function and reduce complications.
Mechanism Target:
MODULATES Neurologic auditory and ocular vulnerability — Supportive care treats consequences of neurologic, auditory, and ocular involvement without correcting PRS-I loss of function.
Show evidence (1 reference)
PMID:20301738 SUPPORT Other
"There is no cure for PRS deficiency. 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..."
GeneReviews supports multidisciplinary supportive management for PRS deficiency.
Genetic Counseling
Action: Genetic counseling Ontology label: genetic counseling MAXO:0000079
Genetic counseling regarding X-linked recessive inheritance and carrier testing for at-risk females.
Show evidence (2 references)
PMID:20301738 SUPPORT Other
"PRS deficiency is inherited in an X-linked manner."
GeneReviews supports X-linked counseling for PRS deficiency.
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 carrier testing and reproductive counseling once the familial variant is known.
🔬

Biochemical Markers

4
PRS-I enzyme activity (DECREASED)
Context: Reduced phosphoribosylpyrophosphate synthetase 1 activity is the proximal biochemical defect in PRPS1 deficiency and correlates with severity across the continuum.
Pathograph Readouts
Readout Of PRS-I loss of function Negative Diagnostic
Reduced PRS-I enzyme activity directly reports the proximal PRPS1 loss-of-function mechanism.
Show evidence (1 reference)
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 assays support PRS-I enzyme activity as a direct biochemical readout of the proximal mechanism.
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 study documents a biochemical activity gradient matching clinical severity.
Urinary hypoxanthine (DECREASED)
Context: Undetectable urinary hypoxanthine supports impaired purine biosynthesis in Arts syndrome due to PRPS1 loss of function.
Pathograph Readouts
Readout Of Impaired PRPP-dependent nucleotide biosynthesis Negative Diagnostic
Undetectable urinary hypoxanthine reports impaired purine biosynthesis downstream of PRPP 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."
Patient biochemical findings support urinary hypoxanthine as a readout of impaired purine biosynthesis.
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 Impaired PRPP-dependent nucleotide biosynthesis Negative Diagnostic
Reduced serum uric acid reports impaired purine biosynthesis downstream of PRPP 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."
Patient biochemical findings support serum uric acid as a readout of impaired purine biosynthesis.
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 guanine nucleotides (DECREASED)
Context: Abnormally low erythrocyte GTP and GDP in severe PRPS1 deficiency support impaired nucleotide biosynthetic capacity.
Pathograph Readouts
Readout Of Impaired PRPP-dependent nucleotide biosynthesis Negative Diagnostic
Low erythrocyte GTP and GDP report impaired nucleotide availability in severe PRPS1 deficiency.
Show evidence (1 reference)
PMID:24961627 SUPPORT In Vitro
"Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate."
Patient erythrocyte analysis supports guanine nucleotide levels as a readout of impaired nucleotide biosynthesis.
Show evidence (1 reference)
PMID:24961627 SUPPORT In Vitro
"Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate."
Severe sibling cases had reduced erythrocyte guanine nucleotides.
{ }

Source YAML

click to show 
name: PRPS1 Deficiency Spectrum
creation_date: "2026-04-04T00:00:00Z"
updated_date: "2026-05-21T22:12:29Z"
description: >-
  PRPS1 deficiency is an X-linked phenotypic continuum caused by
  loss-of-function PRPS1 variants that reduce phosphoribosylpyrophosphate
  synthetase 1 (PRS-I) activity. PRS-I generates phosphoribosylpyrophosphate
  for purine, pyrimidine, and NAD-pathway nucleotide synthesis; reduced
  residual activity impairs nucleotide availability and produces a spectrum
  ranging from DFN2/DFNX1 nonsyndromic sensorineural hearing loss to CMTX5
  peripheral neuropathy with hearing and visual loss, severe Arts syndrome
  with hypotonia, ataxia, developmental impairment, optic atrophy, recurrent
  infections, and expanded severe presentations with retinal dystrophy,
  diabetes insipidus, white matter disease, and growth restriction. Management
  is primarily supportive, with purine/NAD-pathway precursor supplementation
  using S-adenosylmethionine and nicotinamide riboside reported as a
  disease-directed option in Arts syndrome.
category: Genetic
parents:
- Inborn Error of Purine Metabolism
- Neurological Disorder
disease_term:
  preferred_term: Arts syndrome
  term:
    id: MONDO:0010533
    label: Arts syndrome
has_subtypes:
- name: Arts Syndrome
  display_name: Arts Syndrome (Severe PRPS1 Deficiency)
  description: >-
    Most severe form. Early-onset ataxia, hypotonia, prelingual
    sensorineural hearing loss, optic atrophy, intellectual disability,
    recurrent infections, and early death. Minimal residual PRS-I activity.
  subtype_term:
    preferred_term: Arts syndrome
    term:
      id: MONDO:0010533
      label: Arts syndrome
  evidence:
  - reference: PMID:17701896
    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 defines the severe Arts syndrome cluster within
      PRPS1 deficiency.
- name: CMTX5
  display_name: Charcot-Marie-Tooth Disease X-linked 5 (Moderate Deficiency)
  description: >-
    Moderate form. Peripheral neuropathy, optic neuropathy, and
    progressive sensorineural hearing loss. Partial residual PRS-I
    activity.
  subtype_term:
    preferred_term: Charcot-Marie-Tooth disease X-linked recessive 5
    term:
      id: MONDO:0010699
      label: Charcot-Marie-Tooth disease X-linked recessive 5
  evidence:
  - reference: PMID:17701900
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified missense mutations at conserved amino acids in the
      PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited
      peripheral neuropathy
    explanation: >-
      Original CMTX5 family evidence links PRPS1 variants to inherited
      peripheral neuropathy with hearing and optic involvement.
- name: DFN2
  display_name: X-linked Nonsyndromic Hearing Loss (Mild Deficiency)
  description: >-
    Mildest form. Nonsyndromic progressive sensorineural hearing loss
    without neurological involvement. Highest residual PRS-I activity
    among the deficiency subtypes.
  subtype_term:
    preferred_term: X-linked hearing loss 1
    term:
      id: MONDO:0010577
      label: hearing loss, X-linked 1
  evidence:
  - reference: PMID:20301738
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Phosphoribosylpyrophosphate synthetase (PRS) deficiency, an X-linked
      disorder, is a phenotypic continuum comprising three disorders previously
      thought to be clinically distinct: Arts syndrome, Charcot-Marie-Tooth
      neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural
      hearing loss (DFNX1).
    explanation: >-
      GeneReviews places X-linked nonsyndromic sensorineural hearing loss in
      the PRS deficiency continuum.
prevalence:
- population: Global
  percentage: Rare
inheritance:
- name: X-linked Recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
pathophysiology:
- name: PRS-I loss of function
  description: >-
    Loss-of-function PRPS1 variants reduce PRS-I enzyme activity. Residual
    activity helps determine severity across the DFN2, CMTX5, and Arts
    syndrome continuum, with undetectable activity in some severe presentations.
  genes:
  - preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  molecular_functions:
  - preferred_term: ribose phosphate diphosphokinase activity
    term:
      id: GO:0004749
      label: ribose phosphate diphosphokinase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:17701896
    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 cell and erythrocyte assays show that Arts syndrome
      variants reduce PRS-I activity.
  - reference: PMID:24528855
    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: >-
      Intrafamilial continuum evidence links clinical severity to measured
      residual PRS-I activity.
  downstream:
  - target: Impaired PRPP-dependent nucleotide biosynthesis
    description: >-
      Reduced PRS-I activity limits PRPP-dependent nucleotide biosynthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17701896
      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: >-
        Enzyme loss is linked to impaired purine biosynthesis and downstream
        purine-metabolite abnormalities.
  - target: PRS-I enzyme activity
    description: >-
      PRPS1 loss of function is directly observed as reduced or undetectable
      PRS-I enzyme activity in patient-derived assay systems.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24528855
      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 assays show that PRPS1 deficiency directly lowers PRS-I
        enzyme activity.
- name: Impaired PRPP-dependent nucleotide biosynthesis
  description: >-
    PRS-I produces PRPP, which is used for purine, pyrimidine, and NAD-pathway
    nucleotide synthesis. PRPS1 loss of function therefore decreases nucleotide
    biosynthetic capacity and produces measurable purine and guanine nucleotide
    abnormalities in patients.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Purine nucleotide biosynthesis
    term:
      id: GO:0006164
      label: purine nucleotide biosynthetic process
    modifier: DECREASED
  - preferred_term: Pyrimidine nucleotide biosynthesis
    term:
      id: GO:0006221
      label: pyrimidine nucleotide biosynthetic process
    modifier: DECREASED
  - preferred_term: NAD+ biosynthesis
    term:
      id: GO:0009435
      label: NAD+ biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:37927483
    supports: SUPPORT
    evidence_source: OTHER
    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: >-
      Human case report review explains the PRPP-dependent pathways affected by
      PRPS1 deficiency.
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nucleotide analysis in erythrocytes revealed abnormally low guanosine
      triphosphate and guanosine diphosphate.
    explanation: >-
      Severe PRPS1 deficiency patients had low erythrocyte guanine nucleotides,
      supporting impaired nucleotide availability.
  downstream:
  - target: Neurologic auditory and ocular vulnerability
    description: >-
      Reduced nucleotide availability is associated with neurologic, auditory,
      and ocular manifestations across the PRS deficiency continuum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301738
      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) to normal cognitive
        abilities and relatively later-onset, somewhat milder manifestations,
        such as mild sensorineural hearing loss, peripheral neuropathy, and
        gait ataxia.
      explanation: >-
        GeneReviews links PRS deficiency to neurologic, auditory, and ocular
        involvement across the clinical continuum.
  - target: Immune vulnerability in Arts syndrome
    description: >-
      Severe PRPS1 deficiency can include recurrent respiratory infections and
      T-cell dysfunction that respond to pathway precursor supplementation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33532242
      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: >-
        Human Arts syndrome treatment evidence connects nucleotide
        replenishment to improved T-cell survival and function.
  - target: Expanded severe multisystem involvement
    description: >-
      Some severe PRPS1 loss-of-function presentations include growth,
      endocrine, white-matter, and retinal findings beyond the classic three
      subtype clusters.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This presentation is the most severe form of PRPS1-deficiency syndrome
        described to date and expands the spectrum of PRPS1-related disorders.
      explanation: >-
        Severe sibling cases expand the clinical spectrum beyond classic Arts,
        CMTX5, and DFN2 clusters.
  - target: Urinary hypoxanthine
    description: >-
      Impaired purine biosynthesis is reflected by undetectable urinary
      hypoxanthine in affected patients.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17701896
      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 biochemical findings connect impaired purine biosynthesis to
        low urinary hypoxanthine.
  - target: Serum uric acid
    description: >-
      Impaired purine biosynthesis is reflected by reduced serum uric acid in
      affected patients.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17701896
      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 biochemical findings connect impaired purine biosynthesis to
        reduced serum uric acid.
  - target: Erythrocyte guanine nucleotides
    description: >-
      Severe PRPS1 deficiency can lower erythrocyte guanine nucleotide pools.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Nucleotide analysis in erythrocytes revealed abnormally low guanosine
        triphosphate and guanosine diphosphate.
      explanation: >-
        Patient erythrocyte nucleotide analysis supports reduced guanine
        nucleotides as a readout of impaired nucleotide availability.
- name: Neurologic auditory and ocular vulnerability
  description: >-
    PRPS1 deficiency preferentially affects hearing, peripheral and central
    nervous system function, and ocular tissues. The exact tissue-selective
    intermediates remain incompletely defined, but the manifestations track with
    the severity of PRS-I activity loss.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  evidence:
  - reference: PMID:20301738
    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) to normal cognitive
      abilities and relatively later-onset, somewhat milder manifestations,
      such as mild sensorineural hearing loss, peripheral neuropathy, and gait
      ataxia.
    explanation: >-
      GeneReviews summarizes the neurologic, auditory, and ocular phenotype
      spectrum in affected males.
  downstream:
  - target: Sensorineural Hearing Loss
    description: >-
      Auditory vulnerability manifests as sensorineural hearing loss across the
      PRPS1 deficiency continuum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23190330
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Hearing loss in male patients with PRPS1 mutations is bilateral,
        moderate to profound, and can be prelingual or postlingual, progressive
        or non-progressive.
      explanation: >-
        Review evidence supports sensorineural hearing loss as a downstream
        manifestation of PRPS1 deficiency.
  - target: Peripheral Neuropathy
    description: >-
      Neurologic vulnerability includes peripheral neuropathy in CMTX5 and severe
      Arts syndrome presentations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26089585
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        moderate PRS-I deficiency (CMTX5) and severe PRS-I deficiency (Arts
        syndrome) present with peripheral or optic neuropathy, prelingual
        progressive sensorineural hearing loss, and central nervous system
        impairment
      explanation: >-
        Review evidence links PRS-I deficiency severity to peripheral neuropathy.
  - target: Ataxia
    description: >-
      Arts syndrome neurologic involvement includes early-onset ataxia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17701896
      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 Arts syndrome family evidence includes ataxia downstream of
        PRPS1 deficiency.
  - target: Global Developmental Delay
    description: >-
      Severe PRPS1 deficiency produces developmental delay as part of the
      neurologic phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37927483
      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
      explanation: >-
        Case report review lists developmental delays in severe PRPS1 deficiency.
  - target: Motor Delay
    description: >-
      Severe neurologic involvement includes delayed motor development.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:17701896
      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 Arts syndrome family evidence supports delayed motor development
        as a downstream neurologic manifestation.
  - target: Intellectual Disability
    description: >-
      Severe neurologic involvement includes intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27256512
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome is characterized by early-onset hypotonia, ataxia,
        intellectual disability, sensorineural hearing impairment, progressive
        optic atrophy, and a tendency to develop infections.
      explanation: >-
        Case report evidence includes intellectual disability in Arts syndrome.
  - target: Hypotonia
    description: >-
      Severe neurologic involvement includes early-onset hypotonia.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27256512
      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: >-
        Case report evidence identifies hypotonia as an initial symptom.
  - target: Optic Atrophy
    description: >-
      Ocular vulnerability includes progressive optic atrophy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27256512
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Arts syndrome is characterized by early-onset hypotonia, ataxia,
        intellectual disability, sensorineural hearing impairment, progressive
        optic atrophy, and a tendency to develop infections.
      explanation: >-
        Case report evidence links Arts syndrome to progressive optic atrophy.
  - target: Retinal Dystrophy
    description: >-
      Ocular vulnerability can include retinal dystrophy in the progressive
      ophthalmologic spectrum.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301738
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        progressive ophthalmologic involvement (retinal dystrophy and optic
        atrophy)
      explanation: >-
        GeneReviews identifies retinal dystrophy as part of progressive
        ophthalmologic involvement.
- name: Immune vulnerability in Arts syndrome
  description: >-
    Severe Arts syndrome includes recurrent, often respiratory, infections.
    Co-therapy evidence suggests that impaired purine and NAD-pathway support
    contributes to T-cell survival and functional defects.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:33532242
    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: >-
      Arts syndrome clinical description includes recurrent severe respiratory
      infections.
  - reference: PMID:33532242
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SAM and nicotinamide riboside co-therapy further improved his clinical
      phenotype as well as T-cell survival and function.
    explanation: >-
      Human case evidence supports T-cell involvement responsive to pathway
      precursor supplementation.
  downstream:
  - target: Recurrent Respiratory Infections
    description: >-
      Immune vulnerability in severe Arts syndrome manifests as recurrent severe
      respiratory infections.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33532242
      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 connects Arts syndrome with recurrent severe
        respiratory infections.
  - target: Muscle Weakness
    description: >-
      Infection-associated clinical worsening in Arts syndrome can include muscle
      weakness.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27256512
      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: >-
        Case report evidence supports infection-triggered muscle weakness as a
        downstream severe Arts syndrome manifestation.
- name: Expanded severe multisystem involvement
  description: >-
    Rare severe PRPS1 deficiency presentations can include intrauterine growth
    restriction, severe short stature, diabetes insipidus, spastic
    quadriparesis, white matter disease, retinal dystrophy, and low erythrocyte
    guanine nucleotides.
  evidence:
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intrauterine growth restriction, dysmorphic facial features, severe
      intellectual disability and spastic quadraparesis.
    explanation: >-
      Severe sibling cases document growth and neurologic expansion of the
      PRPS1 deficiency phenotype.
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional phenotypic features include macular coloboma-like lesions with
      retinal dystrophy, severe short stature and diabetes insipidus.
    explanation: >-
      Severe sibling cases add ocular and endocrine findings to the PRPS1
      deficiency spectrum.
  downstream:
  - target: Intrauterine Growth Restriction
    description: >-
      Severe expanded-spectrum PRPS1 deficiency includes prenatal growth
      restriction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        intrauterine growth restriction, dysmorphic facial features, severe
        intellectual disability and spastic quadraparesis.
      explanation: >-
        Severe sibling cases document intrauterine growth restriction in the
        expanded PRPS1 deficiency spectrum.
  - target: Spastic Tetraparesis
    description: >-
      Severe expanded-spectrum PRPS1 deficiency includes spastic quadriparesis,
      represented by spastic tetraparesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        intrauterine growth restriction, dysmorphic facial features, severe
        intellectual disability and spastic quadraparesis.
      explanation: >-
        Severe sibling cases document spastic quadriparesis/tetraparesis.
  - target: White Matter Disease
    description: >-
      Severe expanded-spectrum PRPS1 deficiency includes white matter disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Prenatal growth restriction, retinal dystrophy, diabetes insipidus and
        white matter disease: expanding the spectrum of PRPS1-related disorders.
      explanation: >-
        The severe sibling report title explicitly places white matter disease in
        the PRPS1-related disorder spectrum.
  - target: Diabetes Insipidus
    description: >-
      Severe expanded-spectrum PRPS1 deficiency includes diabetes insipidus.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additional phenotypic features include macular coloboma-like lesions with
        retinal dystrophy, severe short stature and diabetes insipidus.
      explanation: >-
        Severe sibling cases document diabetes insipidus in the expanded PRPS1
        deficiency spectrum.
  - target: Short Stature
    description: >-
      Severe expanded-spectrum PRPS1 deficiency includes severe short stature.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Additional phenotypic features include macular coloboma-like lesions with
        retinal dystrophy, severe short stature and diabetes insipidus.
      explanation: >-
        Severe sibling cases document severe short stature in the expanded PRPS1
        deficiency spectrum.
  - target: Dysmorphic Facial Features
    description: >-
      Severe expanded-spectrum PRPS1 deficiency includes dysmorphic facial
      features.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        intrauterine growth restriction, dysmorphic facial features, severe
        intellectual disability and spastic quadraparesis.
      explanation: >-
        Severe sibling cases document dysmorphic facial features in the expanded
        PRPS1 deficiency spectrum.
phenotypes:
- category: Hearing
  name: Sensorineural Hearing Loss
  description: >-
    Sensorineural hearing loss is present across the PRPS1 deficiency
    continuum. It may be congenital or later-onset, prelingual or postlingual,
    progressive or non-progressive, and can also occur as isolated or milder
    hearing impairment in heterozygous females.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:20301738
    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) to normal cognitive
      abilities and relatively later-onset, somewhat milder manifestations,
      such as mild sensorineural hearing loss, peripheral neuropathy, and gait
      ataxia.
    explanation: >-
      GeneReviews describes hearing loss from severe congenital to milder
      later-onset presentations.
  - reference: PMID:23190330
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hearing loss in male patients with PRPS1 mutations is bilateral,
      moderate to profound, and can be prelingual or postlingual,
      progressive or non-progressive.
    explanation: >-
      Characterizes hearing loss across the PRPS1 spectrum.
- category: Neurological
  name: Ataxia
  subtype: Arts Syndrome
  description: >-
    Ataxia is a neurologic feature of Arts syndrome and is also described as a
    milder later-onset manifestation in the PRS deficiency continuum.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:17701896
    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 Arts syndrome family evidence explicitly names ataxia.
  - reference: PMID:27256512
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome is characterized by early-onset hypotonia, ataxia,
      intellectual disability, sensorineural hearing impairment, progressive
      optic atrophy, and a tendency to develop infections.
    explanation: >-
      Case report evidence confirms ataxia as part of Arts syndrome.
- category: Neurological
  name: Peripheral Neuropathy
  subtypes:
  - CMTX5
  - Arts Syndrome
  description: >-
    Peripheral neuropathy is central to CMTX5 and can also be demonstrated in
    severe Arts syndrome cases.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:17701900
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified missense mutations at conserved amino acids in the
      PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited
      peripheral neuropathy
    explanation: >-
      CMTX5 original report directly links PRPS1 variants to inherited
      peripheral neuropathy.
  - reference: PMID:26089585
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      moderate PRS-I deficiency (CMTX5) and severe PRS-I deficiency (Arts
      syndrome) present with peripheral or optic neuropathy, prelingual
      progressive sensorineural hearing loss, and central nervous system
      impairment
    explanation: >-
      Describes peripheral neuropathy as a feature of moderate and severe
      PRPS1 deficiency.
- category: Ophthalmologic
  name: Optic Atrophy
  description: >-
    Optic neuropathy and atrophy in Arts syndrome and CMTX5 subtypes.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:17701896
    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 Arts syndrome family evidence explicitly includes optic atrophy.
  - reference: PMID:27256512
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome is characterized by early-onset hypotonia, ataxia,
      intellectual disability, sensorineural hearing impairment, progressive
      optic atrophy, and a tendency to develop infections.
    explanation: >-
      Case report evidence supports progressive optic atrophy in Arts syndrome.
- category: Neurological
  name: Hypotonia
  subtype: Arts Syndrome
  description: >-
    Early-onset muscular hypotonia is a characteristic severe Arts syndrome
    feature and can worsen with recurrent infections.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:17701896
    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 Arts syndrome family evidence explicitly includes early-onset
      hypotonia.
  - reference: PMID:27256512
    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: >-
      Case report identifies hypotonia as an initial symptom in Arts syndrome.
- category: Ophthalmologic
  name: Retinal Dystrophy
  description: >-
    Retinal dystrophy is part of progressive ophthalmologic involvement in
    PRPS1 deficiency and is prominent in some severe expanded-spectrum cases.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:20301738
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      progressive ophthalmologic involvement (retinal dystrophy and optic
      atrophy)
    explanation: >-
      GeneReviews directly lists retinal dystrophy as part of progressive
      ophthalmologic involvement.
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional phenotypic features include macular coloboma-like lesions with
      retinal dystrophy, severe short stature and diabetes insipidus.
    explanation: >-
      Severe sibling cases explicitly include retinal dystrophy.
- category: Neurodevelopmental
  name: Intellectual Disability
  subtype: Arts Syndrome
  description: >-
    Intellectual disability is part of severe Arts syndrome and may be severe in
    expanded PRPS1-deficiency presentations.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:27256512
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arts syndrome is characterized by early-onset hypotonia, ataxia,
      intellectual disability, sensorineural hearing impairment, progressive
      optic atrophy, and a tendency to develop infections.
    explanation: >-
      Arts syndrome case report directly lists intellectual disability.
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intrauterine growth restriction, dysmorphic facial features, severe
      intellectual disability and spastic quadraparesis.
    explanation: >-
      Expanded severe PRPS1 deficiency cases document severe intellectual
      disability.
- category: Neurodevelopmental
  name: Global Developmental Delay
  subtype: Arts Syndrome
  description: >-
    Developmental delay in PRPS1 deficiency includes delayed motor development
    and broader developmental impairment, especially in severe Arts syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301738
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      severe congenital profound sensorineural hearing loss, intellectual
      disability, delayed motor development, and progressive ophthalmologic
      involvement
    explanation: >-
      GeneReviews directly includes delayed motor development in severe affected
      males.
  - reference: PMID:37927483
    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
    explanation: >-
      Arts syndrome treatment case report review lists developmental delays in
      severe PRPS1 deficiency.
- category: Neurological
  name: Motor Delay
  subtype: Arts Syndrome
  description: >-
    Motor developmental delay is a core severe Arts syndrome manifestation.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:17701896
    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 Arts syndrome family evidence explicitly includes delayed motor
      development.
- category: Immunologic
  name: Recurrent Respiratory Infections
  subtype: Arts Syndrome
  description: >-
    Severe Arts syndrome often includes recurrent severe respiratory infections
    early in life, contributing to progressive clinical decline.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:33532242
    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: >-
      Arts syndrome therapy case report describes recurrent severe respiratory
      infections in affected males.
  - reference: PMID:37927483
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      developmental delays, ataxia, hypotonia, and recurrent infections that
      can cause progressive clinical decline
    explanation: >-
      Case report review emphasizes recurrent infections and their contribution
      to severe clinical decline.
- category: Growth
  name: Intrauterine Growth Restriction
  description: >-
    Intrauterine growth restriction is described in severe expanded-spectrum
    PRPS1 deficiency.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intrauterine growth restriction, dysmorphic facial features, severe
      intellectual disability and spastic quadraparesis.
    explanation: >-
      Severe sibling cases directly report intrauterine growth restriction.
- category: Neurological
  name: Spastic Tetraparesis
  description: >-
    Spastic quadriparesis/tetraparesis is reported in severe expanded-spectrum
    PRPS1 deficiency.
  phenotype_term:
    preferred_term: Spastic tetraparesis
    term:
      id: HP:0001285
      label: Spastic tetraparesis
  evidence:
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intrauterine growth restriction, dysmorphic facial features, severe
      intellectual disability and spastic quadraparesis.
    explanation: >-
      Severe sibling cases report spastic quadriparesis, represented by the
      current HPO spastic tetraparesis term.
- category: Neurological
  name: White Matter Disease
  description: >-
    White matter disease/leukoencephalopathy is described in severe
    expanded-spectrum PRPS1 deficiency.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal growth restriction, retinal dystrophy, diabetes insipidus and
      white matter disease: expanding the spectrum of PRPS1-related disorders.
    explanation: >-
      The indexed title for the severe sibling report explicitly names white
      matter disease in the PRPS1-related disorder spectrum.
- category: Endocrine
  name: Diabetes Insipidus
  description: >-
    Diabetes insipidus has been reported in severe expanded-spectrum PRPS1
    deficiency.
  phenotype_term:
    preferred_term: Diabetes insipidus
    term:
      id: HP:0000873
      label: Diabetes insipidus
  evidence:
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional phenotypic features include macular coloboma-like lesions with
      retinal dystrophy, severe short stature and diabetes insipidus.
    explanation: >-
      Severe sibling cases directly report diabetes insipidus.
- category: Growth
  name: Short Stature
  description: >-
    Severe postnatal short stature is reported in expanded-spectrum PRPS1
    deficiency, beyond the prenatal-onset intrauterine growth restriction.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24961627
    reference_title: "Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional phenotypic features include macular coloboma-like lesions with
      retinal dystrophy, severe short stature and diabetes insipidus.
    explanation: >-
      Severe sibling cases explicitly report severe short stature in
      expanded-spectrum PRPS1 deficiency.
- category: Neurological
  name: Muscle Weakness
  description: >-
    Muscle weakness, often triggered or worsened by recurrent infections, is
    described in Arts syndrome alongside hypotonia and ataxia.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  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: >-
      Arts syndrome case report documents recurrent infection-triggered muscle
      weakness as a clinical feature.
- category: Craniofacial
  name: Dysmorphic Facial Features
  description: >-
    Dysmorphic facial features are reported in severe expanded-spectrum PRPS1
    deficiency presentations.
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:24961627
    reference_title: "Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intrauterine growth restriction, dysmorphic facial features, severe
      intellectual disability and spastic quadraparesis.
    explanation: >-
      Severe sibling cases directly report dysmorphic facial features.
biochemical:
- name: PRS-I enzyme activity
  presence: DECREASED
  context: >-
    Reduced phosphoribosylpyrophosphate synthetase 1 activity is the proximal
    biochemical defect in PRPS1 deficiency and correlates with severity across
    the continuum.
  readouts:
  - target: PRS-I loss of function
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced PRS-I enzyme activity directly reports the proximal PRPS1 loss-of-function mechanism.
    evidence:
    - reference: PMID:24528855
      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 assays support PRS-I enzyme activity as a direct biochemical
        readout of the proximal mechanism.
  evidence:
  - reference: PMID:17701896
    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
    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 study documents a biochemical activity gradient matching clinical
      severity.
- name: Urinary hypoxanthine
  biomarker_term:
    preferred_term: Urinary 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: Impaired PRPP-dependent nucleotide biosynthesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Undetectable urinary hypoxanthine reports impaired purine biosynthesis downstream of PRPP deficiency.
    evidence:
    - reference: PMID:17701896
      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 findings support urinary hypoxanthine as a readout of
        impaired purine biosynthesis.
  evidence:
  - reference: PMID:17701896
    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: Serum 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: Impaired PRPP-dependent nucleotide biosynthesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced serum uric acid reports impaired purine biosynthesis downstream of PRPP deficiency.
    evidence:
    - reference: PMID:17701896
      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 findings support serum uric acid as a readout of
        impaired purine biosynthesis.
  evidence:
  - reference: PMID:17701896
    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 guanine nucleotides
  biomarker_term:
    preferred_term: Erythrocyte guanine nucleotides
    term:
      id: CHEBI:61292
      label: guanyl nucleotide
  presence: DECREASED
  context: >-
    Abnormally low erythrocyte GTP and GDP in severe PRPS1 deficiency support
    impaired nucleotide biosynthetic capacity.
  readouts:
  - target: Impaired PRPP-dependent nucleotide biosynthesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low erythrocyte GTP and GDP report impaired nucleotide availability in severe PRPS1 deficiency.
    evidence:
    - reference: PMID:24961627
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Nucleotide analysis in erythrocytes revealed abnormally low guanosine
        triphosphate and guanosine diphosphate.
      explanation: >-
        Patient erythrocyte analysis supports guanine nucleotide levels as a
        readout of impaired nucleotide biosynthesis.
  evidence:
  - reference: PMID:24961627
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nucleotide analysis in erythrocytes revealed abnormally low guanosine
      triphosphate and guanosine diphosphate.
    explanation: >-
      Severe sibling cases had reduced erythrocyte guanine nucleotides.
genetic:
- name: PRPS1 Loss-of-Function Variants
  association: Pathogenic Variants
  gene_term:
    preferred_term: PRPS1
    term:
      id: hgnc:9462
      label: PRPS1
  inheritance:
  - name: X-linked Recessive
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
  features: >-
    Hemizygous PRPS1 pathogenic variants in males and heterozygous variants in
    females establish the diagnosis in clinically suggestive individuals.
    Severity correlates with residual PRS-I activity, and heterozygous females
    may be asymptomatic or show isolated/milder manifestations.
  evidence:
  - reference: PMID:20301738
    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 supports hemizygous PRPS1 pathogenic variants as diagnostic
      in affected males.
  - reference: PMID:23190330
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the loss-of-function mutations result in X-linked nonsyndromic
      sensorineural deafness type 2 (DFN2), or in syndromic deafness
      including Arts syndrome and X-linked Charcot-Marie-Tooth
      disease-5 (CMTX5)
    explanation: >-
      LOF mutations cause the deficiency spectrum.
treatments:
- name: Purine and NAD Pathway Precursor Supplementation
  description: >-
    S-adenosylmethionine can replenish purine nucleotides, and combined
    S-adenosylmethionine plus nicotinamide riboside has been reported to
    further improve clinical phenotype and T-cell survival/function in Arts
    syndrome. This is an emerging disease-directed option that bypasses some
    PRPP-dependent reactions; evidence remains limited to case reports and
    small literature reviews.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Impaired PRPP-dependent nucleotide biosynthesis
    treatment_effect: BYPASSES
    description: >-
      SAM and nicotinamide riboside supplement downstream purine and NAD
      pathways outside the defective PRPP-dependent step.
    evidence:
    - reference: PMID:37927483
      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: >-
        Case report and literature review supports the bypass rationale for
        SAMe and NR supplementation.
  evidence:
  - reference: PMID:33532242
    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: >-
      Human case evidence supports SAM and nicotinamide riboside co-therapy as
      a disease-directed approach in Arts syndrome.
  - reference: PMID:37927483
    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: >-
      Case report and literature review supports SAMe/NR as a potential
      treatment option while noting the limited evidence base.
  - reference: PMID:26089585
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      purine replacement via S-adenosylmethionine (SAM) supplementation
      in patients with Arts syndrome appears to improve their condition
    explanation: >-
      SAM supplementation as potential therapy for PRPS1 deficiency.
  - reference: PMID:23190330
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SAM could compensate for PRS-I deficiency
    explanation: >-
      Confirms SAM as a potential therapeutic approach.
- name: Multidisciplinary Supportive Care
  description: >-
    There is no cure for PRS deficiency, so management includes coordinated
    neurologic, rehabilitation, hearing, vision, education, and genetics care to
    maximize function and reduce complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Neurologic auditory and ocular vulnerability
    treatment_effect: MODULATES
    description: >-
      Supportive care treats consequences of neurologic, auditory, and ocular
      involvement without correcting PRS-I loss of function.
  evidence:
  - reference: PMID:20301738
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is no cure for PRS deficiency. 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 supports multidisciplinary supportive management for PRS
      deficiency.
- name: Genetic Counseling
  description: >-
    Genetic counseling regarding X-linked recessive inheritance and
    carrier testing for at-risk females.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301738
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PRS deficiency is inherited in an X-linked manner.
    explanation: >-
      GeneReviews supports X-linked counseling for PRS deficiency.
  - reference: PMID:20301738
    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 carrier testing and reproductive counseling once the
      familial variant is known.
datasets:
references:
- reference: PMID:20301738
  title: Phosphoribosylpyrophosphate Synthetase Deficiency.
  tags:
  - GeneReviews
  found_in:
  - PRPS1_Deficiency_Spectrum-deep-research-falcon.md
📚

References & Deep Research

References

1
PMID:20301738
Phosphoribosylpyrophosphate Synthetase Deficiency.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 41 citations 2026-04-04T12:36:35.345416

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: PRPS1 Deficiency Spectrum
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on PRPS1 Deficiency Spectrum covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

PRPS1 Deficiency Spectrum (PRS-I deficiency) — Comprehensive Disease Characteristics Report (Genetic)

Executive summary

PRPS1 deficiency (also called PRS-I/PRS deficiency) is an X-linked inborn error of nucleotide metabolism caused by loss-of-function variants in PRPS1, encoding phosphoribosyl pyrophosphate synthetase 1 (PRS-I), a key enzyme producing phosphoribosyl pyrophosphate (PRPP). Contemporary literature conceptualizes PRPS1 deficiency as a phenotypic continuum spanning X-linked nonsyndromic hearing loss (DFNX1) to Charcot–Marie–Tooth neuropathy with optic involvement (CMTX5) and severe multisystem disease (Arts syndrome), with severity broadly correlating with residual enzymatic activity and, in females, X-chromosome inactivation patterns. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, nassogne2024neurologicalpresentationsof pages 2-3, camici2023inbornerrorsof pages 4-7)

A key recent (2023–2024) development is consolidation of diagnostic biochemical signatures for purine/pyrimidine disorders (including PRPS1 deficiency), and new mechanistic work on post-translational regulation of PRPS1 (O-GlcNAcylation/AMPK phosphorylation) that also links an Arts-syndrome-associated PRPS1 mutant to reduced PRPS1 activity. (nassogne2024neurologicalpresentationsof pages 2-3, chen2024directstimulationof pages 1-2, chen2024directstimulationof pages 21-25)

Therapeutically, there is no established disease-modifying therapy, but small numbers of Arts syndrome patients have been treated with S-adenosylmethionine (SAMe) ± nicotinamide riboside (NR) with reported clinical stability/improvement and improved immune cell function in a mechanistic case study. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, lenherr2021cotherapywithsadenosylmethionine pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 4-6)

Key recent sources and statistics (2023–2024)

Category Entity/Source Identifier(s) Publication/Key dates Hallmark features or main contribution URL/DOI Citation
Spectrum entity DFNX1 (X-linked nonsyndromic hearing loss 1) OMIM #304500 — Mild end of PRPS1 deficiency spectrum; primarily progressive sensorineural hearing loss, often congenital-to-childhood onset; hearing loss may range from moderate to profound. https://omim.org/entry/304500 (nassogne2024neurologicalpresentationsof pages 2-3, feng2024genomicandphenotypic pages 4-5)
Spectrum entity CMTX5 (Charcot-Marie-Tooth disease X-linked type 5) OMIM #311070 — Intermediate phenotype with sensorineural hearing loss plus peripheral neuropathy, ataxia/hypotonia, and optic neuropathy/optic atrophy. https://omim.org/entry/311070 (nassogne2024neurologicalpresentationsof pages 2-3, nassogne2024neurologicalpresentationsof pages 3-4)
Spectrum entity Arts syndrome OMIM #301835; ORPHA:1187 — Most severe PRPS1 deficiency phenotype; congenital sensorineural hearing loss, developmental delay/intellectual disability, hypotonia, ataxia, optic atrophy/retinal disease, recurrent respiratory infections, and early mortality in severe untreated cases. https://omim.org/entry/301835 ; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=1187 (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, lenherr2021cotherapywithsadenosylmethionine pages 1-2, brouwer2007artssyndromeis pages 3-4)
Recent source Lee et al., JIMD Reports DOI: 10.1002/jmd2.12395 Sep 2023 Case report + literature review of SAMe and nicotinamide riboside (NR) therapy in Arts syndrome; notes fewer than 25 reported cases in literature; across treated patients, symptoms were stable or improved, including reduced infection burden and gains in strength/endurance. https://doi.org/10.1002/jmd2.12395 (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, lee2023s‐adenosylmethionineandnicotinamide pages 2-4, lee2023s‐adenosylmethionineandnicotinamide pages 4-6)
Recent source Camici et al., Metabolites DOI: 10.3390/metabo13070787 Jun 2023 Review framing PRPS1 deficiency as an X-linked phenotypic continuum (DFNX1-CMTX5-Arts syndrome); severity correlates with residual enzyme activity; summarizes hearing loss, neuropathy, optic involvement, and recurrent infections. https://doi.org/10.3390/metabo13070787 (camici2023inbornerrorsof pages 4-7)
Recent source Nassogne et al., Eur J Paediatr Neurol DOI: 10.1016/j.ejpn.2023.11.013 Jan 2024 Review highlighting diagnostic biochemical markers: decreased PRS activity, decreased plasma uric acid, low urinary hypoxanthine/other purine metabolites, increased urinary orotic acid, and reduced RBC ATP/GTP/NAD/NADP; explicitly lists Arts syndrome OMIM #301835, CMTX5 #311070, DFNX1 #304500. https://doi.org/10.1016/j.ejpn.2023.11.013 (nassogne2024neurologicalpresentationsof pages 2-3)
Recent source Feng et al., Orphanet J Rare Dis DOI: 10.1186/s13023-024-03338-z Sep 2024 Hearing-loss cohort of 3,646 unrelated patients: overall diagnostic rate 52.72% (1,922/3,646); X-linked genes accounted for ~1.14% (22/1,922) of solved cases; PRPS1 variants were mainly missense; paper notes 30 reported PRPS1 coding mutations overall, including 11 DFNX1, 10 CMTX5, and 5 Arts syndrome. https://doi.org/10.1186/s13023-024-03338-z (feng2024genomicandphenotypic pages 4-5, feng2024genomicandphenotypic pages 2-4, feng2024genomicandphenotypic pages 1-2)
Recent source Chen et al., Nature Chemical Biology DOI: 10.1038/s41589-023-01354-x Jun 2024 Mechanistic study: OGT-mediated O-GlcNAcylation of PRPS1 promotes active hexamer formation, relieves ADP/GDP feedback inhibition, increases PRPP/nucleotide/NAD synthesis, and antagonizes AMPK-mediated inhibitory phosphorylation; Arts-associated R196W showed decreased O-GlcNAcylation and reduced activity. https://doi.org/10.1038/s41589-023-01354-x (chen2024directstimulationof pages 1-2, chen2024directstimulationof pages 21-25, chen2024directstimulationof pages 2-3)
Natural history study NCT06092346, NHGRI observational cohort ClinicalTrials.gov: NCT06092346 First posted 2023-10-23; study start 2023-12-19; recruiting; primary completion estimated 2099-01-01 Prospective natural history study of purine/pyrimidine metabolism disorders; explicitly includes PRPS1-related entries (PRPS1 deficiency/Arts syndrome/CMT); annual clinical evaluation and biospecimen collection to define genomic, clinical, laboratory, pharmacological, and dietary determinants of outcomes. https://clinicaltrials.gov/ct2/show/NCT06092346 (NCT06092346 chunk 1, NCT06092346 chunk 2)

Table: This table condenses the main clinical entities within the PRPS1 deficiency spectrum and the most relevant recent 2023-2024 sources, including diagnostics, mechanisms, treatment evidence, and the active NIH natural history study.

1. Disease information

What is the disease?

PRPS1 deficiency spectrum is a set of allelic X-linked disorders due to reduced PRS-I activity, leading to impaired PRPP generation and downstream deficits in purine nucleotide and NAD/NADP-related metabolism; clinically it manifests as a continuum from isolated/progressive sensorineural hearing loss to neuropathy/optic involvement and severe neurodevelopmental + immunologic disease. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, nassogne2024neurologicalpresentationsof pages 2-3, camici2023inbornerrorsof pages 4-7)

Key identifiers (evidence-backed from retrieved sources)

  • Gene: PRPS1 (OMIM *311850) (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, NCT06092346 chunk 1)
  • Arts syndrome: OMIM #301835; Orphanet ORPHA:1187 (nassogne2024neurologicalpresentationsof pages 2-3, lenherr2021cotherapywithsadenosylmethionine pages 1-2)
  • CMTX5: OMIM #311070 (nassogne2024neurologicalpresentationsof pages 2-3)
  • DFNX1: OMIM #304500 (nassogne2024neurologicalpresentationsof pages 2-3)

Not found in the retrieved full texts: MONDO ID, MeSH descriptor, ICD-10/ICD-11 code(s). This report therefore does not assert them.

Synonyms and alternative names

  • PRPS1 deficiency; PRS-I deficiency; PRS deficiency; phosphoribosyl pyrophosphate synthetase 1 deficiency; phosphoribosylpyrophosphate synthetase deficiency spectrum (nassogne2024neurologicalpresentationsof pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 1-2)
  • Arts syndrome (severe PRPS1 deficiency), CMTX5, DFNX1 (nassogne2024neurologicalpresentationsof pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 1-2)

Evidence provenance

The majority of information is derived from aggregated literature/reviews and case reports/series, plus one large hearing loss cohort study for contribution statistics. (feng2024genomicandphenotypic pages 4-5, lee2023s‐adenosylmethionineandnicotinamide pages 1-2, nassogne2024neurologicalpresentationsof pages 2-3)

2. Etiology

Disease causal factors

  • Primary cause: germline loss-of-function PRPS1 variants that reduce PRS-I activity and PRPP production (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, nassogne2024neurologicalpresentationsof pages 2-3, camici2023inbornerrorsof pages 4-7)
  • Inheritance: X-linked; females can be affected with variable severity influenced by X-inactivation and/or mosaicism (nassogne2024neurologicalpresentationsof pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 6-7)

Risk factors

  • Genetic: hemizygous PRPS1 pathogenic variants in males; heterozygous females may exhibit milder features depending on X-inactivation (nassogne2024neurologicalpresentationsof pages 2-3)

Protective factors

No evidence-based protective variants or environmental protective factors were identified in the retrieved texts.

Gene–environment interactions

Direct gene–environment interaction evidence specific to PRPS1 deficiency was not identified in the retrieved corpus. However, several reports emphasize infection-triggered clinical declines in severe PRPS1 deficiency (Arts syndrome), consistent with physiologic stress exacerbating downstream consequences of nucleotide/NAD deficiency. (lee2023s‐adenosylmethionineandnicotinamide pages 2-4)

3. Phenotypes (clinical spectrum)

Spectrum concept (current understanding)

Recent reviews explicitly describe PRPS1 deficiency phenotypes as a “continuum disease spectrum”, with severity broadly correlating with residual PRS activity and (in females) X-inactivation. (nassogne2024neurologicalpresentationsof pages 2-3)

Core phenotypes by syndrome (hallmarks)

Arts syndrome (severe PRPS1 deficiency) - Congenital sensorineural hearing loss; optic atrophy/retinal dystrophy; developmental delay/intellectual disability; hypotonia; ataxia; peripheral neuropathy; recurrent respiratory infections/immune dysfunction; potentially early death in severe untreated cases. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, lee2023s‐adenosylmethionineandnicotinamide pages 4-6, brouwer2007artssyndromeis pages 3-4) - Foundational natural-history detail: in the original AJHG cohort, severe outcomes included early deaths and neuropathologic evidence of profound CNS involvement (e.g., myelin loss). (brouwer2007artssyndromeis pages 3-4)

CMTX5 (intermediate) - Sensorineural hearing loss plus peripheral neuropathy (CMT) and optic neuropathy; ataxia/hypotonia can occur. (nassogne2024neurologicalpresentationsof pages 3-4, nassogne2024neurologicalpresentationsof pages 2-3)

DFNX1 (milder end) - Predominant phenotype: sensorineural hearing loss (often progressive; onset variable). (feng2024genomicandphenotypic pages 4-5, nassogne2024neurologicalpresentationsof pages 2-3)

Example genotype–biochemical–phenotype correlation

In a study of PRPS1-associated X-linked hearing loss with mild peripheral neuropathy, affected males carrying different PRPS1 missense variants had markedly reduced erythrocyte PRS-I activity relative to controls, and severity of enzyme impairment differed by variant, supporting a functional basis for variable expressivity. (robusto2015theexpandingspectrum pages 4-6)

Suggested HPO terms (non-exhaustive; for knowledge base use)

  • Sensorineural hearing impairment HP:0000407
  • Optic atrophy HP:0000648; Retinal dystrophy HP:0000556
  • Peripheral neuropathy HP:0009830; Abnormal nerve conduction velocity HP:0003430
  • Ataxia HP:0001251; Hypotonia HP:0001252
  • Global developmental delay HP:0001263; Intellectual disability HP:0001249
  • Recurrent respiratory infections HP:0002205

Phenotype frequencies: robust, cross-study percentage frequencies were not extractable from the retrieved sources; most evidence is case-based. A single recent cohort provides X-linked contributions to a hearing-loss cohort, but not syndrome-specific penetrance/frequency across PRPS1 deficiency spectrum. (feng2024genomicandphenotypic pages 4-5)

4. Genetic / molecular information

Causal gene

  • PRPS1 (PRS-I), Xq22.3 (lenherr2021cotherapywithsadenosylmethionine pages 1-2)

Variant types and genotype–phenotype notes

  • Recent cohort/review synthesis notes that PRPS1 disease-associated variants are predominantly missense, consistent with the requirement for some residual activity compatible with development. (camici2023inbornerrorsof pages 4-7, feng2024genomicandphenotypic pages 4-5)
  • A 2024 review lists the spectrum entities and explicitly ties severity to residual PRS activity, reinforcing a genotype→activity→phenotype model. (nassogne2024neurologicalpresentationsof pages 2-3)

Reported mutation counts (literature synthesis; 2024)

A 2024 hearing-loss cohort study states that 30 coding-region PRPS1 mutations had been reported (as summarized there), with distribution across phenotypes including DFNX1 and CMTX5 and fewer for Arts syndrome, and notes that variants are mainly missense. (feng2024genomicandphenotypic pages 4-5)

Functional consequences

  • Loss-of-function PRPS1 variants reduce PRS activity and impair PRPP-dependent metabolic flux; severe cases show multiple downstream nucleotide/cofactor deficiencies. (nassogne2024neurologicalpresentationsof pages 2-3, camici2023inbornerrorsof pages 4-7)

Modifier genes / epigenetics: No direct evidence for modifier genes or epigenetic signatures specific to PRPS1 deficiency were identified in the retrieved corpus.

5. Environmental information

No disease-specific environmental or lifestyle contributing factors were identified from the retrieved sources. Clinical deterioration in severe disease can occur with infections (clinical stressors). (lee2023s‐adenosylmethionineandnicotinamide pages 2-4)

6. Mechanism / pathophysiology

Biochemical role of PRPS1 (upstream)

PRPS1 deficiency is secondary to loss-of-function PRPS1 variants; PRS-I generates PRPP, which is utilized in purine synthesis and in NAD/NADP-related pathways, among others. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2)

Direct abstract-quote evidence (2023): - “Phospho‐ribosyl‐pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in PRPS1. This enzyme generates phospho‐ribosyl‐pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP) …” (lee2023s‐adenosylmethionineandnicotinamide pages 1-2)

Downstream biochemical abnormalities (diagnostically relevant)

A 2024 review of purine/pyrimidine disorders provides a concise biochemical signature for PRPS1 deficiency, including: - decreased PRS activity (RBC/fibroblasts/lymphocytes) - decreased plasma uric acid - decreased urinary hypoxanthine and other purine-related metabolites - increased urinary orotic acid - decreased RBC ATP, GTP, NAD, and NADP (nassogne2024neurologicalpresentationsof pages 2-3)

Cellular processes and tissue vulnerability

  • Severe disease includes immune dysfunction with recurrent infections; mechanistic case work links nucleotide/NAD replenishment strategies to improved T-cell survival/function. (lenherr2021cotherapywithsadenosylmethionine pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 4-6)

Recent mechanistic development (2024): PRPS1 regulation by O-GlcNAcylation/AMPK

A 2024 Nature Chemical Biology study demonstrated a regulatory mechanism in which OGT-mediated O-GlcNAcylation promotes PRPS1 hexamer formation and relieves feedback inhibition, and also connects an Arts-syndrome-associated PRPS1 mutant to reduced activity.

Direct abstract-quote evidence (2024): - “Phosphoribosyl pyrophosphate synthetase (PRPS1)… was found to be O-GlcNAcylated, which increases PRPS1 activity …” and “Arts-syndrome-associated PRPS1 R196W mutant exhibits decreased PRPS1 O-GlcNAcylation and activity …” (chen2024directstimulationof pages 1-2)

Mechanistic chain (condensed): PRPS1 LOF → ↓PRPP → ↓purine nucleotides and ↓NAD/NADP pools → impaired energy/redox balance and biosynthetic capacity → vulnerability in high-demand tissues (auditory system, nervous system, optic/retinal tissues) and immune dysfunction in severe cases. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, nassogne2024neurologicalpresentationsof pages 2-3, lenherr2021cotherapywithsadenosylmethionine pages 2-3)

Suggested GO terms (examples)

  • GO:0006164 purine nucleotide biosynthetic process
  • GO:0006739 NADP metabolic process
  • GO:0006766 vitamin metabolic process (for nicotinamide-related pathways)
  • GO:0046034 ATP metabolic process

Suggested CL (cell types) and UBERON (anatomy)

  • CL:0000545 T cell; CL:0000625 CD8-positive, alpha-beta T cell; CL:0000624 CD4-positive, alpha-beta T cell (supported by immune-cell functional assays in Arts syndrome) (lenherr2021cotherapywithsadenosylmethionine pages 2-3)
  • UBERON:0002107 cochlea; UBERON:0000955 brain; UBERON:0000047 retina; UBERON:0000966 optic nerve; UBERON:0001021 peripheral nerve

7. Anatomical structures affected

Primary systems implicated across the spectrum include: - Auditory system (sensorineural hearing loss) (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, feng2024genomicandphenotypic pages 4-5) - Nervous system (peripheral neuropathy, ataxia, hypotonia, neurodevelopmental impairment) (nassogne2024neurologicalpresentationsof pages 2-3, brouwer2007artssyndromeis pages 3-4) - Visual system (optic atrophy/retinal dystrophy) (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, nassogne2024neurologicalpresentationsof pages 2-3) - Immune/respiratory involvement in severe disease (recurrent respiratory infections; T-cell dysfunction) (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, lenherr2021cotherapywithsadenosylmethionine pages 2-3)

8. Temporal development

  • Onset: often congenital/early childhood for hearing loss; severe Arts syndrome presents in early childhood and can be progressive. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, feng2024genomicandphenotypic pages 4-5)
  • Course: severe cases may worsen with recurrent infections; treated reports describe more stable trajectories in limited numbers of patients. (lee2023s‐adenosylmethionineandnicotinamide pages 4-6)

9. Inheritance and population

Inheritance pattern

  • X-linked inheritance is consistently reported; female phenotype variability is linked to X-inactivation and mosaicism. (nassogne2024neurologicalpresentationsof pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 6-7)

Population statistics (recent)

A large Chinese hearing-loss cohort study (n=3,646) reported: - overall genetic diagnostic rate 52.72% (1,922/3,646) - X-linked gene diagnoses contributed ~1.14% (22/1,922) of solved cases (feng2024genomicandphenotypic pages 1-2)

This study also describes PRPS1’s contribution as low in that cohort and summarizes the known mutational spectrum (mostly missense; literature-reported coding mutations). (feng2024genomicandphenotypic pages 4-5, feng2024genomicandphenotypic pages 9-10)

Prevalence/incidence: no population prevalence/incidence for PRPS1 deficiency spectrum (or Arts syndrome specifically) was extractable from retrieved sources.

10. Diagnostics

Clinical testing and biomarkers

A recent review provides a coherent set of biochemical findings supporting diagnosis, including decreased PRS activity and low uric acid with characteristic urinary metabolite changes and reduced RBC nucleotides/cofactors. (nassogne2024neurologicalpresentationsof pages 2-3)

However, biochemical markers can be inconsistent: a 2020 case report explicitly notes that normal serum/urine purine/pyrimidine metabolite levels do not exclude PRPS1-related disorders, emphasizing the importance of enzyme testing and/or genetics. (puusepp2020atypicalpresentationof pages 1-2)

Genetic testing (real-world)

  • PRPS1 is “found on many commercially available genetic panels” relevant to hearing loss, intellectual disability, and optic atrophy (lee2023s‐adenosylmethionineandnicotinamide pages 4-6)
  • WES has been used as a discovery/diagnostic tool in genetically heterogeneous hearing loss (robusto2015theexpandingspectrum pages 1-2)
  • Targeted panel sequencing plus confirmatory enzyme assays (erythrocyte PRS activity) has been used in clinical diagnosis (puusepp2020atypicalpresentationof pages 1-2)

Differential diagnosis

The diagnostic workup in reported cases includes audiologic, neurophysiologic, ophthalmologic and neuroimaging evaluations to distinguish PRPS1-related syndromic disease from other causes of hearing loss, neuropathy, and retinal disease. (puusepp2020atypicalpresentationof pages 1-2)

11. Outcome / prognosis

  • Severe Arts syndrome is associated with progressive decline and early mortality in historical cohorts; the foundational 2007 AJHG report describes early deaths in multiple affected males in the families studied. (brouwer2007artssyndromeis pages 3-4)
  • Limited treated case reports suggest improved stability/trajectory, but evidence is low (case-based; no controlled trials). (lee2023s‐adenosylmethionineandnicotinamide pages 4-6)

12. Treatment

Current management (real-world)

  • Predominantly supportive/symptomatic management (e.g., addressing sensory impairment and neurological complications); hypouricemic drugs are relevant for PRPS1 superactivity but do not improve hearing/neurodevelopment in PRPS1 deficiency phenotypes. (camici2023inbornerrorsof pages 4-7)

Experimental / emerging: SAMe and nicotinamide riboside

A 2023 case report plus literature review summarizes the rationale and limited clinical experience: - rationale: bypass PRPP-dependent steps by supplying downstream precursors to purine and NAD pathways (lee2023s‐adenosylmethionineandnicotinamide pages 1-2) - direct abstract-quote evidence (2023): “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.” (lee2023s‐adenosylmethionineandnicotinamide pages 1-2)

Mechanistic/immune outcomes in Arts syndrome (case-based): - SAM+NR co-therapy improved T-cell survival/function and partially rescued cytokine responses; biochemical measurements indicated persistent NAD deficiency with partial NADP restoration and improved erythrocyte ATP/GTP. (lenherr2021cotherapywithsadenosylmethionine pages 2-3)

Visual evidence (treatment case summaries): - Lee et al. Table 1 summarizes prior Arts syndrome patients treated with SAMe ± NR and reported outcomes. (lee2023s‐adenosylmethionineandnicotinamide media 265985d2, lee2023s‐adenosylmethionineandnicotinamide media 29d0cecc)

Clinical trials / studies

  • NCT06092346 (NHGRI): observational prospective natural history study of purine/pyrimidine metabolism disorders; explicitly lists PRPS1 deficiency/Arts syndrome/CMT among included conditions; first posted 2023-10-23; study start 2023-12-19; recruiting. URL: https://clinicaltrials.gov/ct2/show/NCT06092346 (NCT06092346 chunk 1, NCT06092346 chunk 2)

Suggested MAXO terms (examples)

  • MAXO:0000472 dietary supplementation
  • MAXO:0000782 cochlear implantation (for hearing loss management)
  • MAXO:0001175 genetic counseling
  • MAXO:0001298 physical therapy

Uridine therapy: no uridine intervention evidence was identified in the retrieved corpus; this report does not claim uridine use.

13. Prevention

  • Primary prevention: not applicable in the traditional sense for monogenic disorders; focus is on family planning and carrier detection.
  • Secondary prevention: early diagnosis through genetic testing in individuals with suggestive phenotypes (hearing loss ± optic/neuropathy/immunodeficiency) can enable earlier supportive interventions and consideration of experimental supplementation in severe disease. (lee2023s‐adenosylmethionineandnicotinamide pages 4-6)
  • Genetic counseling (X-linked): counseling is critical given X-linked inheritance, potential female manifestations, and intrafamilial variability influenced by X-inactivation/mosaicism. (nassogne2024neurologicalpresentationsof pages 2-3, lee2023s‐adenosylmethionineandnicotinamide pages 6-7)

14. Other species / natural disease

No naturally occurring PRPS1 deficiency analogs in non-human species were identified in the retrieved sources.

15. Model organisms

No PRPS1-deficiency-specific animal model details were retrieved in the current evidence set. The report therefore does not assert specific model phenotypes.

Expert opinion / analysis (evidence-constrained)

The most authoritative recent synthesis supports a pragmatic diagnostic stance: because biochemical markers can be inconsistent, combined molecular testing and functional enzymology are emphasized across purine metabolism disorders, including PRPS1-related disease. (puusepp2020atypicalpresentationof pages 1-2, dewulf2022disordersofpurine pages 4-4)

Therapeutic evidence for SAMe/NR remains limited to case reports and small series; nevertheless, the combination of (i) mechanistic plausibility (bypassing PRPP-dependent steps), (ii) reported clinical stability/improvement, and (iii) immune-cell functional rescue in an Arts syndrome case argues that carefully monitored supplementation protocols may be reasonable in selected severe cases while awaiting more systematic natural-history data and interventional trials. (lee2023s‐adenosylmethionineandnicotinamide pages 1-2, lenherr2021cotherapywithsadenosylmethionine pages 2-3, NCT06092346 chunk 1)

References (URLs and publication dates)

  • Lee A et al. JIMD Reports. Sep 2023. “S‐adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review.” https://doi.org/10.1002/jmd2.12395 (lee2023s‐adenosylmethionineandnicotinamide pages 1-2)
  • Nassogne M-C et al. European Journal of Paediatric Neurology. Jan 2024. https://doi.org/10.1016/j.ejpn.2023.11.013 (nassogne2024neurologicalpresentationsof pages 2-3)
  • Feng H et al. Orphanet Journal of Rare Diseases. Sep 2024. https://doi.org/10.1186/s13023-024-03338-z (feng2024genomicandphenotypic pages 1-2)
  • Chen L et al. Nature Chemical Biology. Jun 2024. https://doi.org/10.1038/s41589-023-01354-x (chen2024directstimulationof pages 1-2)
  • de Brouwer APM et al. American Journal of Human Genetics. Sep 2007. https://doi.org/10.1086/520706 (brouwer2007artssyndromeis pages 1-2)
  • Lenherr N et al. Molecular Genetics and Metabolism Reports. Mar 2021. https://doi.org/10.1016/j.ymgmr.2021.100709 (lenherr2021cotherapywithsadenosylmethionine pages 1-2)
  • Puusepp S et al. Molecular Genetics and Metabolism Reports. Dec 2020. https://doi.org/10.1016/j.ymgmr.2020.100677 (puusepp2020atypicalpresentationof pages 1-2)
  • ClinicalTrials.gov NCT06092346. First posted 2023-10-23. https://clinicaltrials.gov/ct2/show/NCT06092346 (NCT06092346 chunk 1)

References

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