ALDH18A1-Related Spastic Paraplegia and Neurocutaneous Spectrum

Mendelian MONDO:0100126 Pathograph 24 Hereditary Spastic Paraplegia Metabolic Disease Neurodegenerative Disease

ALDH18A1-related spastic paraplegia and neurocutaneous spectrum encompasses autosomal dominant spastic paraplegia type 9A (SPG9A), autosomal recessive spastic paraplegia type 9B (SPG9B), and autosomal recessive cutis laxa type 3A (ARCL3A, De Barsy syndrome). All are caused by loss-of-function or dominant-negative mutations in ALDH18A1, encoding delta-1-pyrroline-5-carboxylate synthase (P5CS), the bifunctional mitochondrial enzyme catalyzing the first two steps of proline and ornithine biosynthesis from glutamate. SPG9A (autosomal dominant) presents with pure or complex hereditary spastic paraplegia, cataracts, and gastroesophageal reflux, while SPG9B (autosomal recessive biallelic) is clinically more severe with earlier onset, marked cognitive impairment, dysmorphic features, and cutaneous involvement overlapping with ARCL3A. Metabolic features include reduced plasma levels of proline, ornithine, citrulline, and arginine, along with decreased glutathione and altered antioxidant metabolism.

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2
Inheritance
8
Pathophys.
13
Phenotypes
24
Pathograph
1
Genes
2
Treatments
2
Subtypes
8
References
1
Deep Research
👪

Inheritance

2
Autosomal Dominant (SPG9A) HP:0000006
Heterozygous (monoallelic) ALDH18A1 mutations cause SPG9A and segregate with autosomal dominant pure or complex hereditary spastic paraplegia.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:26026163 SUPPORT Human Clinical
"identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia,"
Identifies monoallelic ALDH18A1 mutations in autosomal dominant pedigrees.
Autosomal Recessive (SPG9B / ARCL3A) HP:0000007
Biallelic loss-of-function mutations cause SPG9B and ARCL3A, with partial P5CS deficiency and a more severe clinical phenotype than the dominant form.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:26026163 SUPPORT Human Clinical
"families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality."
Identifies biallelic ALDH18A1 mutations in autosomal recessive spastic paraplegia families.
PMID:24767728 SUPPORT Human Clinical
"Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease."
Confirms autosomal recessive inheritance for ALDH18A1-related cutis laxa.
◆

Subtypes

2
Spastic Paraplegia 9A (Autosomal Dominant)
Autosomal dominant form caused by heterozygous ALDH18A1 mutations acting through a proposed dominant-negative mechanism on P5CS oligomer architecture. Presents as pure or complex hereditary spastic paraplegia with cataracts and sometimes gastroesophageal reflux. Generally less severe than SPG9B, with later onset and preserved cognition.
Show evidence (1 reference)
PMID:26026163 SUPPORT Human Clinical
"identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia, as well as in two sporadic patients."
Establishes SPG9A as an autosomal dominant form of ALDH18A1-related spastic paraplegia.
Spastic Paraplegia 9B (Autosomal Recessive)
Autosomal recessive form caused by biallelic ALDH18A1 mutations resulting in partial P5CS deficiency. Clinically more severe than SPG9A with earlier onset, greater disability, marked cognitive impairment, growth retardation, and dysmorphic features. Overlaps phenotypically with ARCL3A (De Barsy syndrome).
Show evidence (2 references)
PMID:31402623 SUPPORT Human Clinical
"conclude that both mutations are disease-causing, that SPG9B associates with partial P5CS deficiency and that it is clinically more severe than SPG9A, as reflected in onset age, disability, cognitive status, growth, and dysmorphic traits."
Clinical comparison confirms SPG9B is more severe than SPG9A across multiple clinical domains.
PMID:36067040 SUPPORT Human Clinical
"developmental delay, neurological deficits and loose skin."
Homozygous ALDH18A1 patients demonstrate the overlap of neurological and cutaneous features in recessive disease.
⚙

Pathophysiology

8
Dominant-negative disruption of P5CS oligomer (SPG9A)
In the autosomal dominant form, heterozygous missense mutations do not abolish P5CS protein production but are proposed to disrupt P5CS oligomer architecture via a dominant-negative effect, reducing enzymatic activity despite normal protein localization.
Downstream
P5CS deficiency and proline biosynthesis impairment
Show evidence (1 reference)
PMID:31402623 SUPPORT Other
"leading to the proposal that dominant mutations cause ALDH18A1 pathologies by a dominant negative effect"
Literature review within this study proposes that dominant ALDH18A1 mutations cause disease through a dominant-negative mechanism.
P5CS oligomerization and protein stability defects
Biallelic ALDH18A1 variants can reduce P5CS oligomer incorporation, protein stability, or both, producing a partial loss-of-function state in patient cells.
Downstream
P5CS deficiency and proline biosynthesis impairment
Cellular lipid droplet dysregulation
Show evidence (2 references)
PMID:36067040 SUPPORT In Vitro
"reduced incorporation of the monomer into P5CS oligomers."
Patient-cell and complemented-cell experiments show impaired oligomer assembly for a homozygous ALDH18A1 variant.
PMID:25077174 SUPPORT In Vitro
"mutations alter a conserved C-terminal domain of the encoded protein and reduce protein stability as determined through Western blot analysis of patient fibroblasts."
Patient fibroblast Western blotting supports reduced P5CS protein stability for ARCL3A-associated variants.
P5CS deficiency and proline biosynthesis impairment
Loss-of-function mutations in ALDH18A1 reduce P5CS enzymatic activity and impair de novo biosynthesis of proline and ornithine from glutamate. Human plasma amino-acid studies and patient-cell metabolomics show reduced glutamate-derived metabolites, providing the metabolic bridge to downstream antioxidant, extracellular-matrix, and neurodevelopmental abnormalities.
L-proline biosynthetic process link ↓ DECREASED Ornithine biosynthetic process link ↓ DECREASED L-arginine biosynthetic process link ↓ DECREASED
Downstream
Antioxidant metabolism impairment
Urea-cycle amino acid depletion
Extracellular matrix-related cellular dysregulation
Neurodevelopmental and corticospinal motor-system involvement
Plasma proline
Cellular glutathione
Cellular putrescine
Show evidence (3 references)
PMID:11092761 SUPPORT Human Clinical
"delta(1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine."
The original P5CS deficiency report anchors the blocked proline, ornithine, and arginine biosynthetic branch.
PMID:26026163 SUPPORT Human Clinical
"as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."
Metabolic profiling demonstrates reduced amino acid levels downstream of P5CS.
PMID:36067040 SUPPORT In Vitro
"identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione."
Metabolomics in patient fibroblasts confirms broad impairment of glutamate-derived amino acid and antioxidant pathways.
Urea-cycle amino acid depletion
P5CS deficiency lowers ornithine, citrulline, and arginine availability, linking the blocked glutamate-derived amino-acid pathway to impaired nitrogen handling. Classic P5CS deficiency can therefore manifest downstream as hyperammonemia together with hypoornithinemia, hypocitrullinemia, hypoargininemia, and hypoprolinemia.
Ornithine biosynthetic process link ↓ DECREASED Citrulline biosynthetic process link ↓ DECREASED L-arginine biosynthetic process link ↓ DECREASED
Downstream
Hyperammonemia Reduced urea-cycle amino acid availability manifests as hyperammonemia in classic P5CS deficiency.
Blood ammonia Hyperammonemia is measured clinically as increased blood ammonia.
Plasma ornithine Hypoornithinemia is a direct biochemical readout of the urea-cycle amino acid branch.
Plasma citrulline Hypocitrullinemia is reported with the same low urea-cycle amino acid profile.
Plasma arginine Hypoargininemia reports downstream impairment of arginine biosynthesis.
Show evidence (2 references)
PMID:11092761 SUPPORT Human Clinical
"Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia."
The original sibling report directly documents the low urea-cycle amino acids and hyperammonemia branch.
PMID:26026163 SUPPORT Human Clinical
"Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."
Later SPG9 families show the same plasma ornithine, citrulline, arginine, and proline depletion pattern.
Antioxidant metabolism impairment
P5CS deficiency leads to reduced glutathione levels and decreased polyamine (putrescine) biosynthesis from ornithine, impairing cellular antioxidant defenses. This oxidative vulnerability may contribute to neuronal degeneration in motor neurons and cortical neurons.
Glutamate metabolic process link ↓ DECREASED
Downstream
Cellular glutathione
Cellular putrescine
Show evidence (2 references)
PMID:36067040 SUPPORT In Vitro
"identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione. Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts,"
Patient-cell metabolomics shows decreased glutathione and putrescine, connecting the primary metabolic block to antioxidant dysfunction.
PMID:36067040 SUPPORT In Vitro
"Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts, highlighting the functional consequence on another metabolic pathway involved in antioxidant responses in the cell."
Decreased putrescine biosynthesis demonstrates P5CS deficiency impacts antioxidant pathways beyond proline synthesis.
Neurodevelopmental and corticospinal motor-system involvement
ALDH18A1-related P5CS deficiency produces a neurological disease spectrum spanning hereditary spastic paraplegia, cognitive impairment, developmental delay, and microcephaly, with recessive SPG9B generally more severe than dominant SPG9A.
Downstream
Spastic paraplegia
Spastic paraplegia with cognitive impairment
Intellectual disability
Global developmental delay
Microcephaly
Show evidence (2 references)
PMID:26026163 SUPPORT Human Clinical
"Hereditary spastic paraplegias are heterogeneous neurological disorders characterized by a pyramidal syndrome with symptoms predominantly affecting the lower limbs."
Clinical series establishes the corticospinal motor-system phenotype framing ALDH18A1-associated hereditary spastic paraplegia.
PMID:36067040 SUPPORT Human Clinical
"developmental delay, neurological deficits and loose skin."
Homozygous ALDH18A1 cases support neurodevelopmental involvement in the recessive spectrum.
Cellular lipid droplet dysregulation
ALDH18A1-mutant fibroblasts show enlarged lipid droplets after oleate loading, a cellular phenotype similar to findings reported in Warburg Micro syndrome models.
Show evidence (1 reference)
PMID:25077174 SUPPORT In Vitro
"Patient fibroblasts exhibit a lipid droplet phenotype similar to that recently reported in Warburg Micro syndrome, a disorder with similar features but hitherto unrelated cellular etiology."
Patient fibroblast assays identify lipid droplet dysregulation as a cellular consequence associated with ALDH18A1 loss of function.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ALDH18A1-Related Spastic Paraplegia and Neurocutaneous 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

13
Eye 1
Cataracts Cataract (HP:0000518)
Show evidence (1 reference)
PMID:25077174 SUPPORT Human Clinical
"bilateral cataracts have been seen in 6/10 cases and so appear more frequent than in patients with PYCR1 mutations"
Cataracts are a common feature of ALDH18A1-related disorders, more frequent than in the related PYCR1-related cutis laxa.
Head and Neck 1
Microcephaly Microcephaly (HP:0000252)
Show evidence (1 reference)
PMID:25077174 SUPPORT Human Clinical
"Microcephaly has been reported in 7/10 cases, a similar proportion to that seen in patients with PYCR1 mutations."
Microcephaly is a frequent neurological feature of ARCL3A.
Integument 1
Cutis laxa Cutis laxa (HP:0000973)
Show evidence (1 reference)
PMID:24767728 SUPPORT Human Clinical
"Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay."
Cutis laxa is a recognized feature of ARCL3A with variable distribution.
Metabolism 1
Hyperammonemia Hyperammonemia (HP:0001987)
Show evidence (1 reference)
PMID:11092761 SUPPORT Human Clinical
"Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia."
The original human P5CS deficiency report directly includes hyperammonemia in the metabolic phenotype.
Musculoskeletal 3
Spastic paraplegia Spastic paraplegia (HP:0001258)
Show evidence (1 reference)
PMID:26026163 SUPPORT Human Clinical
"identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia,"
Spastic paraplegia is the defining feature of SPG9A, ranging from pure to complex forms.
Spastic paraplegia with cognitive impairment Spastic paraplegia (HP:0001258)
Show evidence (1 reference)
PMID:26026163 SUPPORT Human Clinical
"families with autosomal recessive transmission of ALDH18A1 mutations, and predominant complex hereditary spastic paraplegia with marked cognitive impairment, without any cutaneous abnormality."
SPG9B is characterized by complex HSP with prominent cognitive impairment.
Joint hypermobility Joint hypermobility (HP:0001382)
Show evidence (1 reference)
PMID:24767728 SUPPORT Human Clinical
"Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay."
The clinical report and literature review include joint laxity, an exact synonym of HP:0001382 joint hypermobility.
Nervous System 3
Intellectual disability Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:31402623 SUPPORT Human Clinical
"conclude that both mutations are disease-causing, that SPG9B associates with partial P5CS deficiency and that it is clinically more severe than SPG9A, as reflected in onset age, disability, cognitive status, growth, and dysmorphic traits."
Cognitive impairment is a defining feature distinguishing SPG9B severity from SPG9A.
Global developmental delay Global developmental delay (HP:0001263)
Show evidence (1 reference)
PMID:36067040 SUPPORT Human Clinical
"developmental delay, neurological deficits and loose skin."
Developmental delay is a consistent feature of biallelic ALDH18A1 disease.
Delayed speech and language development Delayed speech and language development (HP:0000750)
Show evidence (1 reference)
PMID:24767728 SUPPORT Human Clinical
"cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay."
The ARCL3A clinical report and literature review document severe developmental and speech delay.
Growth 2
Growth retardation Short stature (HP:0004322)
Show evidence (1 reference)
PMID:24767728 SUPPORT Human Clinical
"Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay."
Short stature and failure to thrive are consistent features of ARCL3A.
Failure to thrive Failure to thrive (HP:0001508)
Show evidence (1 reference)
PMID:24767728 SUPPORT Human Clinical
"cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay."
The ARCL3A clinical report and literature review document failure to thrive among the recognized features.
Other 1
Prominent superficial veins Prominent superficial veins (HP:0001015)
Show evidence (1 reference)
PMID:24767728 SUPPORT Human Clinical
"cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay."
The ARCL3A clinical report and literature review document visible superficial veins on the thorax and abdomen.
🧬

Genetic Associations

1
ALDH18A1 (Causative)
Autosomal Dominant Autosomal Recessive
Show evidence (3 references)
PMID:29754261 SUPPORT Human Clinical
"Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary spastic paraplegia and autosomal recessive and dominant cutis laxa."
Establishes that ALDH18A1 mutations cause both dominant and recessive forms of spastic paraplegia and cutis laxa.
PMID:26026163 SUPPORT Human Clinical
"catalyses the first and common step of proline and ornithine biosynthesis from glutamate."
Defines the enzymatic function of the ALDH18A1 gene product.
CGGV:assertion_7bfbe962-beb3-4553-9909-a83a3aac2d55-2021-05-18T211134.377Z SUPPORT Other
"ALDH18A1 | HGNC:9722 | P5CS deficiency | MONDO:0100126 | SD | Definitive"
ClinGen classifies the ALDH18A1-P5CS deficiency gene-disease relationship as definitive with semidominant inheritance.
💊

Treatments

2
Genetic Counseling
Action: genetic counseling MAXO:0000079
Genetic counseling for families regarding autosomal dominant versus recessive inheritance patterns and recurrence risk. Amino acid chromatography is recommended in the diagnostic workup of hereditary spastic paraplegia.
Show evidence (1 reference)
PMID:26026163 SUPPORT Human Clinical
"we therefore suggest including amino acid chromatography in the clinico-genetic work-up of hereditary spastic paraplegia, particularly in dominant cases, as the associated phenotype is not distinct from other causative genes."
Authors recommend metabolic screening as part of the diagnostic approach for HSP.
Supportive Care
Action: supportive care MAXO:0000950
Multidisciplinary management including physiotherapy for spasticity, ophthalmological care for cataracts, developmental support, and nutritional optimization.
🔬

Biochemical Markers

7
Plasma proline (DECREASED)
Context: Reduced plasma proline levels serve as a potential biomarker, particularly when mutations affect the G5K domain. Mutations in the G5PR domain may not alter plasma amino acid levels.
Pathograph Readouts
Readout Of P5CS deficiency and proline biosynthesis impairment Negative Diagnostic
Lower plasma proline reports impaired P5CS-dependent proline biosynthesis.
Show evidence (2 references)
PMID:26026163 SUPPORT Human Clinical
"as well as in two sporadic patients. Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."
Plasma amino acid profiling reveals P5CS deficiency biomarkers in affected individuals.
PMID:29754261 PARTIAL Human Clinical
"childhood and temporal lobe epilepsy, but normal levels of proline, ornithine and arginine."
Demonstrates that amino acid levels may be normal when mutations affect the G5PR domain.
Plasma ornithine (DECREASED)
Context: Reduced plasma ornithine is part of the amino-acid profile suggesting P5CS deficiency and reflects impaired ornithine biosynthesis from glutamate.
Pathograph Readouts
Readout Of Urea-cycle amino acid depletion Negative Diagnostic
Lower plasma ornithine reports the urea-cycle amino acid depletion branch downstream of P5CS deficiency.
Show evidence (2 references)
PMID:11092761 SUPPORT Human Clinical
"Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia."
The original P5CS deficiency report documents hypoornithinemia as part of the metabolic phenotype.
PMID:26026163 SUPPORT Human Clinical
"Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."
ALDH18A1-related SPG families show reduced plasma ornithine in the diagnostic amino-acid profile.
Plasma citrulline (DECREASED)
Context: Reduced plasma citrulline accompanies reduced ornithine and arginine in the P5CS deficiency amino-acid profile, linking the primary biosynthetic block to the urea-cycle related branch.
Pathograph Readouts
Readout Of Urea-cycle amino acid depletion Negative Diagnostic
Lower plasma citrulline reports downstream urea-cycle amino acid depletion.
Show evidence (2 references)
PMID:11092761 SUPPORT Human Clinical
"Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia."
The original P5CS deficiency report documents hypocitrullinemia.
PMID:26026163 SUPPORT Human Clinical
"Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."
ALDH18A1-related SPG families show reduced plasma citrulline.
Plasma arginine (DECREASED)
Context: Reduced plasma arginine is reported with reduced ornithine, citrulline, and proline in P5CS deficiency, reflecting impaired arginine biosynthetic support from the glutamate-derived pathway.
Pathograph Readouts
Readout Of Urea-cycle amino acid depletion Negative Diagnostic
Lower plasma arginine reports downstream impairment of the arginine biosynthetic branch.
Show evidence (2 references)
PMID:11092761 SUPPORT Human Clinical
"Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia."
The original P5CS deficiency report documents hypoargininemia.
PMID:26026163 SUPPORT Human Clinical
"Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."
ALDH18A1-related SPG families show reduced plasma arginine.
Blood ammonia (INCREASED)
Context: Increased blood ammonia reflects the hyperammonemia branch reported in the original P5CS deficiency siblings with combined low ornithine, citrulline, arginine, and proline.
Pathograph Readouts
Readout Of Urea-cycle amino acid depletion Positive Diagnostic
Elevated ammonia reports impaired nitrogen handling in the severe P5CS deficiency branch.
Show evidence (1 reference)
PMID:11092761 SUPPORT Human Clinical
"Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia."
The original P5CS deficiency report directly documents hyperammonemia.
Cellular glutathione (DECREASED)
Context: Metabolomic profiling in patient fibroblasts shows reduced glutathione, indicating impaired glutamate-derived antioxidant metabolism.
Pathograph Readouts
Readout Of Antioxidant metabolism impairment Negative
Lower cellular glutathione reports the antioxidant-metabolism branch in ALDH18A1-deficient cells.
Show evidence (1 reference)
PMID:36067040 SUPPORT In Vitro
"identified reduced abundance of glutamate and several metabolites derived from glutamate, including proline and glutathione."
Patient-cell metabolomics directly identifies reduced glutathione.
Cellular putrescine (DECREASED)
Context: Metabolomic profiling in patient fibroblasts shows reduced biosynthesis of putrescine from ornithine, tying the P5CS ornithine branch to antioxidant pathway dysfunction.
Pathograph Readouts
Readout Of Antioxidant metabolism impairment Negative
Lower cellular putrescine reports impaired ornithine-derived polyamine biosynthesis in the antioxidant branch.
Show evidence (1 reference)
PMID:36067040 SUPPORT In Vitro
"Biosynthesis of the polyamine putrescine, derived from ornithine, was also decreased in patient fibroblasts,"
Patient fibroblast metabolomics directly identifies decreased putrescine biosynthesis.
{ }

Source YAML

click to show 
name: ALDH18A1-Related Spastic Paraplegia and Neurocutaneous Spectrum
creation_date: "2026-04-04T00:00:00Z"
updated_date: "2026-05-20T11:21:46Z"
category: Mendelian
description: >
  ALDH18A1-related spastic paraplegia and neurocutaneous spectrum encompasses
  autosomal dominant spastic paraplegia type 9A (SPG9A), autosomal recessive
  spastic paraplegia type 9B (SPG9B), and autosomal recessive cutis laxa type 3A
  (ARCL3A, De Barsy syndrome). All are caused by loss-of-function or
  dominant-negative mutations in ALDH18A1, encoding delta-1-pyrroline-5-carboxylate
  synthase (P5CS), the bifunctional mitochondrial enzyme catalyzing the first two
  steps of proline and ornithine biosynthesis from glutamate. SPG9A (autosomal
  dominant) presents with pure or complex hereditary spastic paraplegia, cataracts,
  and gastroesophageal reflux, while SPG9B (autosomal recessive biallelic) is
  clinically more severe with earlier onset, marked cognitive impairment,
  dysmorphic features, and cutaneous involvement overlapping with ARCL3A. Metabolic
  features include reduced plasma levels of proline, ornithine, citrulline, and
  arginine, along with decreased glutathione and altered antioxidant metabolism.
disease_term:
  preferred_term: P5CS deficiency
  term:
    id: MONDO:0100126
    label: P5CS deficiency
synonyms:
- SPG9A
- SPG9B
- Autosomal recessive cutis laxa type 3A
- ARCL3A
- De Barsy syndrome due to ALDH18A1
- P5CS deficiency
parents:
- Hereditary Spastic Paraplegia
- Metabolic Disease
- Neurodegenerative Disease
notes: >-
  This entry is intentionally curated at the spectrum level and groups the
  ALDH18A1-related SPG9A, SPG9B, and ARCL3A/de Barsy presentations under the
  broader MONDO term P5CS deficiency (MONDO:0100126), which explicitly covers
  the full ALDH18A1 neurocutaneous and motor phenotype spectrum.
has_subtypes:
- name: SPG9A
  display_name: Spastic Paraplegia 9A (Autosomal Dominant)
  description: >
    Autosomal dominant form caused by heterozygous ALDH18A1 mutations acting
    through a proposed dominant-negative mechanism on P5CS oligomer
    architecture. Presents as pure or complex hereditary spastic paraplegia
    with cataracts and sometimes gastroesophageal reflux. Generally less
    severe than SPG9B, with later onset and preserved cognition.
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      identified monoallelic ALDH18A1 mutations segregating in three independent
      families with autosomal dominant pure or complex hereditary spastic paraplegia,
      as well as in two sporadic patients.
    explanation: Establishes SPG9A as an autosomal dominant form of ALDH18A1-related spastic paraplegia.
- name: SPG9B
  display_name: Spastic Paraplegia 9B (Autosomal Recessive)
  description: >
    Autosomal recessive form caused by biallelic ALDH18A1 mutations resulting in
    partial P5CS deficiency. Clinically more severe than SPG9A with earlier onset,
    greater disability, marked cognitive impairment, growth retardation, and
    dysmorphic features. Overlaps phenotypically with ARCL3A (De Barsy syndrome).
  evidence:
  - reference: PMID:31402623
    reference_title: "P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      conclude that both mutations are disease-causing, that SPG9B associates with
      partial P5CS deficiency and that it is clinically more severe than SPG9A, as
      reflected in onset age, disability, cognitive status, growth, and dysmorphic
      traits.
    explanation: Clinical comparison confirms SPG9B is more severe than SPG9A across multiple clinical domains.
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay, neurological deficits and loose skin."
    explanation: Homozygous ALDH18A1 patients demonstrate the overlap of neurological and cutaneous features in recessive disease.
inheritance:
- name: Autosomal Dominant (SPG9A)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Heterozygous (monoallelic) ALDH18A1 mutations cause SPG9A and segregate with
    autosomal dominant pure or complex hereditary spastic paraplegia.
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      identified monoallelic ALDH18A1 mutations segregating in three independent
      families with autosomal dominant pure or complex hereditary spastic paraplegia,
    explanation: Identifies monoallelic ALDH18A1 mutations in autosomal dominant pedigrees.
- name: Autosomal Recessive (SPG9B / ARCL3A)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Biallelic loss-of-function mutations cause SPG9B and ARCL3A, with partial P5CS
    deficiency and a more severe clinical phenotype than the dominant form.
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      families with autosomal recessive transmission of ALDH18A1 mutations, and
      predominant complex hereditary spastic paraplegia with marked cognitive
      impairment, without any cutaneous abnormality.
    explanation: Identifies biallelic ALDH18A1 mutations in autosomal recessive spastic paraplegia families.
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder
      characterized by wrinkled, inelastic skin, frequently associated with a
      neurologic involvement and multisystem disease.
    explanation: Confirms autosomal recessive inheritance for ALDH18A1-related cutis laxa.
genetic:
- name: ALDH18A1
  gene_term:
    preferred_term: ALDH18A1
    term:
      id: hgnc:9722
      label: ALDH18A1
  association: Causative
  features: >
    ALDH18A1 encodes the bifunctional mitochondrial enzyme P5CS (delta-1-pyrroline-
    5-carboxylate synthetase) composed of glutamate 5-kinase (G5K) and
    gamma-glutamyl phosphate reductase (G5PR) domains. Mutations in either domain
    can cause disease. Dominant mutations are proposed to disrupt P5CS oligomer
    architecture via a dominant-negative effect. Biallelic mutations cause partial
    P5CS deficiency.
    Mutations in the G5K domain tend to reduce plasma proline, citrulline, and
    arginine levels, while G5PR domain mutations may not affect plasma amino acid
    levels.
  inheritance:
  - name: Autosomal Dominant
  - name: Autosomal Recessive
  evidence:
  - reference: PMID:29754261
    reference_title: "Compound heterozygous mutations in two different domains of ALDH18A1 do not affect the amino acid levels in a patient with hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary
      spastic paraplegia and autosomal recessive and dominant cutis laxa.
    explanation: Establishes that ALDH18A1 mutations cause both dominant and recessive forms of spastic paraplegia and cutis laxa.
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      catalyses the first and common step of proline and ornithine biosynthesis from
      glutamate.
    explanation: Defines the enzymatic function of the ALDH18A1 gene product.
  - reference: CGGV:assertion_7bfbe962-beb3-4553-9909-a83a3aac2d55-2021-05-18T211134.377Z
    reference_title: "ALDH18A1 / P5CS deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALDH18A1 | HGNC:9722 | P5CS deficiency | MONDO:0100126 | SD | Definitive"
    explanation: ClinGen classifies the ALDH18A1-P5CS deficiency gene-disease relationship as definitive with semidominant inheritance.
pathophysiology:
- name: Dominant-negative disruption of P5CS oligomer (SPG9A)
  description: >
    In the autosomal dominant form, heterozygous missense mutations do not abolish
    P5CS protein production but are proposed to disrupt P5CS oligomer architecture
    via a dominant-negative effect, reducing enzymatic activity despite normal
    protein localization.
  gene:
    preferred_term: ALDH18A1
    modifier: ABNORMAL
    term:
      id: hgnc:9722
      label: ALDH18A1
  evidence:
  - reference: PMID:31402623
    reference_title: "P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "leading to the proposal that dominant mutations cause ALDH18A1 pathologies by a dominant negative effect"
    explanation: Literature review within this study proposes that dominant ALDH18A1 mutations cause disease through a dominant-negative mechanism.
  downstream:
  - target: P5CS deficiency and proline biosynthesis impairment
- name: P5CS oligomerization and protein stability defects
  description: >
    Biallelic ALDH18A1 variants can reduce P5CS oligomer incorporation, protein
    stability, or both, producing a partial loss-of-function state in patient
    cells.
  gene:
    preferred_term: ALDH18A1
    modifier: DECREASED
    term:
      id: hgnc:9722
      label: ALDH18A1
  evidence:
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "reduced incorporation of the monomer into P5CS oligomers."
    explanation: Patient-cell and complemented-cell experiments show impaired oligomer assembly for a homozygous ALDH18A1 variant.
  - reference: PMID:25077174
    reference_title: "Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      mutations alter a conserved C-terminal domain of the encoded protein and reduce
      protein stability as determined through Western blot analysis of patient
      fibroblasts.
    explanation: Patient fibroblast Western blotting supports reduced P5CS protein stability for ARCL3A-associated variants.
  downstream:
  - target: P5CS deficiency and proline biosynthesis impairment
  - target: Cellular lipid droplet dysregulation
- name: P5CS deficiency and proline biosynthesis impairment
  description: >
    Loss-of-function mutations in ALDH18A1 reduce P5CS enzymatic activity and
    impair de novo biosynthesis of proline and ornithine from glutamate. Human
    plasma amino-acid studies and patient-cell metabolomics show reduced
    glutamate-derived metabolites, providing the metabolic bridge to downstream
    antioxidant, extracellular-matrix, and neurodevelopmental abnormalities.
  gene:
    preferred_term: ALDH18A1
    modifier: DECREASED
    term:
      id: hgnc:9722
      label: ALDH18A1
  biological_processes:
  - preferred_term: L-proline biosynthetic process
    term:
      id: GO:0055129
      label: L-proline biosynthetic process
    modifier: DECREASED
  - preferred_term: Ornithine biosynthetic process
    term:
      id: GO:0006592
      label: ornithine biosynthetic process
    modifier: DECREASED
  - preferred_term: L-arginine biosynthetic process
    term:
      id: GO:0006526
      label: L-arginine biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-proline
    term:
      id: CHEBI:17203
      label: L-proline
    modifier: DECREASED
  - preferred_term: L-ornithine
    term:
      id: CHEBI:15729
      label: L-ornithine
    modifier: DECREASED
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      delta(1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and
      NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to
      delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of
      proline, ornithine and arginine.
    explanation: The original P5CS deficiency report anchors the blocked proline, ornithine, and arginine biosynthetic branch.
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      as well as in two sporadic patients. Low levels of plasma ornithine, citrulline,
      arginine and proline in four individuals from two families suggested P5CS
      deficiency.
    explanation: Metabolic profiling demonstrates reduced amino acid levels downstream of P5CS.
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      identified reduced abundance of glutamate and several metabolites derived from
      glutamate, including proline and glutathione.
    explanation: Metabolomics in patient fibroblasts confirms broad impairment of glutamate-derived amino acid and antioxidant pathways.
  downstream:
  - target: Antioxidant metabolism impairment
  - target: Urea-cycle amino acid depletion
  - target: Extracellular matrix-related cellular dysregulation
  - target: Neurodevelopmental and corticospinal motor-system involvement
  - target: Plasma proline
  - target: Cellular glutathione
  - target: Cellular putrescine
- name: Urea-cycle amino acid depletion
  description: >
    P5CS deficiency lowers ornithine, citrulline, and arginine availability, linking
    the blocked glutamate-derived amino-acid pathway to impaired nitrogen handling.
    Classic P5CS deficiency can therefore manifest downstream as hyperammonemia
    together with hypoornithinemia, hypocitrullinemia, hypoargininemia, and
    hypoprolinemia.
  biological_processes:
  - preferred_term: Ornithine biosynthetic process
    term:
      id: GO:0006592
      label: ornithine biosynthetic process
    modifier: DECREASED
  - preferred_term: Citrulline biosynthetic process
    term:
      id: GO:0019240
      label: citrulline biosynthetic process
    modifier: DECREASED
  - preferred_term: L-arginine biosynthetic process
    term:
      id: GO:0006526
      label: L-arginine biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: L-ornithine
    term:
      id: CHEBI:15729
      label: L-ornithine
    modifier: DECREASED
  - preferred_term: L-citrulline
    term:
      id: CHEBI:16349
      label: L-citrulline
    modifier: DECREASED
  - preferred_term: L-arginine
    term:
      id: CHEBI:16467
      label: L-arginine
    modifier: DECREASED
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Their metabolic phenotype includes hyperammonemia, hypoornithinemia,
      hypocitrullinemia, hypoargininemia and hypoprolinemia.
    explanation: The original sibling report directly documents the low urea-cycle amino acids and hyperammonemia branch.
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Low levels of plasma ornithine, citrulline,
      arginine and proline in four individuals from two families suggested P5CS
      deficiency.
    explanation: Later SPG9 families show the same plasma ornithine, citrulline, arginine, and proline depletion pattern.
  downstream:
  - target: Hyperammonemia
    causal_link_type: DIRECT
    description: Reduced urea-cycle amino acid availability manifests as hyperammonemia in classic P5CS deficiency.
  - target: Blood ammonia
    causal_link_type: DIRECT
    description: Hyperammonemia is measured clinically as increased blood ammonia.
  - target: Plasma ornithine
    causal_link_type: DIRECT
    description: Hypoornithinemia is a direct biochemical readout of the urea-cycle amino acid branch.
  - target: Plasma citrulline
    causal_link_type: DIRECT
    description: Hypocitrullinemia is reported with the same low urea-cycle amino acid profile.
  - target: Plasma arginine
    causal_link_type: DIRECT
    description: Hypoargininemia reports downstream impairment of arginine biosynthesis.
- name: Antioxidant metabolism impairment
  description: >
    P5CS deficiency leads to reduced glutathione levels and decreased polyamine
    (putrescine) biosynthesis from ornithine, impairing cellular antioxidant
    defenses. This oxidative vulnerability may contribute to neuronal degeneration
    in motor neurons and cortical neurons.
  biological_processes:
  - preferred_term: Glutamate metabolic process
    term:
      id: GO:0006536
      label: glutamate metabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
    modifier: DECREASED
  - preferred_term: putrescine
    term:
      id: CHEBI:17148
      label: putrescine
    modifier: DECREASED
  evidence:
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      identified reduced abundance of glutamate and several metabolites derived from
      glutamate, including proline and glutathione. Biosynthesis of the polyamine
      putrescine, derived from ornithine, was also decreased in patient fibroblasts,
    explanation: Patient-cell metabolomics shows decreased glutathione and putrescine, connecting the primary metabolic block to antioxidant dysfunction.
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      Biosynthesis of the polyamine
      putrescine, derived from ornithine, was also decreased in patient fibroblasts,
      highlighting the functional consequence on another metabolic pathway involved in
      antioxidant responses in the cell.
    explanation: Decreased putrescine biosynthesis demonstrates P5CS deficiency impacts antioxidant pathways beyond proline synthesis.
  downstream:
  - target: Cellular glutathione
  - target: Cellular putrescine
- name: Extracellular matrix-related cellular dysregulation
  description: >
    Impaired P5CS function is associated with extracellular matrix-related
    transcript changes in patient fibroblasts and with the wrinkled, inelastic
    skin phenotype of ALDH18A1-related cutis laxa.
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      revealed transcript abundance changes in several metabolic and extracellular
      matrix-related genes, adding further insight into pathogenic processes
      associated with impaired P5CS function.
    explanation: Patient fibroblast transcriptomics link impaired P5CS function to extracellular matrix-related cellular dysregulation.
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder
      characterized by wrinkled, inelastic skin, frequently associated with a
      neurologic involvement and multisystem disease.
    explanation: Clinical description anchors the extracellular matrix-related cellular findings to cutis laxa connective-tissue disease.
  downstream:
  - target: Cutis laxa
  - target: Joint hypermobility
- name: Neurodevelopmental and corticospinal motor-system involvement
  description: >
    ALDH18A1-related P5CS deficiency produces a neurological disease spectrum
    spanning hereditary spastic paraplegia, cognitive impairment, developmental
    delay, and microcephaly, with recessive SPG9B generally more severe than
    dominant SPG9A.
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Hereditary spastic paraplegias are heterogeneous neurological disorders
      characterized by a pyramidal syndrome with symptoms predominantly affecting the
      lower limbs.
    explanation: Clinical series establishes the corticospinal motor-system phenotype framing ALDH18A1-associated hereditary spastic paraplegia.
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay, neurological deficits and loose skin."
    explanation: Homozygous ALDH18A1 cases support neurodevelopmental involvement in the recessive spectrum.
  downstream:
  - target: Spastic paraplegia
  - target: Spastic paraplegia with cognitive impairment
  - target: Intellectual disability
  - target: Global developmental delay
  - target: Microcephaly
- name: Cellular lipid droplet dysregulation
  description: >
    ALDH18A1-mutant fibroblasts show enlarged lipid droplets after oleate loading,
    a cellular phenotype similar to findings reported in Warburg Micro syndrome
    models.
  evidence:
  - reference: PMID:25077174
    reference_title: "Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      Patient fibroblasts exhibit a lipid droplet phenotype similar to
      that recently reported in Warburg Micro syndrome, a disorder with similar
      features but hitherto unrelated cellular etiology.
    explanation: Patient fibroblast assays identify lipid droplet dysregulation as a cellular consequence associated with ALDH18A1 loss of function.
phenotypes:
- category: Neurological
  name: Spastic paraplegia
  subtype: SPG9A
  description: >
    Progressive spasticity of the lower limbs is the hallmark feature, presenting
    as pure hereditary spastic paraplegia in some dominant families and complex
    HSP with additional neurological features in others.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      identified monoallelic ALDH18A1 mutations segregating in three independent
      families with autosomal dominant pure or complex hereditary spastic paraplegia,
    explanation: Spastic paraplegia is the defining feature of SPG9A, ranging from pure to complex forms.
- category: Neurological
  name: Spastic paraplegia with cognitive impairment
  subtype: SPG9B
  description: >
    Biallelic mutations cause complex spastic paraplegia with marked cognitive
    impairment, earlier onset, and greater disability than the dominant form.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      families with autosomal recessive transmission of ALDH18A1 mutations, and
      predominant complex hereditary spastic paraplegia with marked cognitive
      impairment, without any cutaneous abnormality.
    explanation: SPG9B is characterized by complex HSP with prominent cognitive impairment.
- category: Neurological
  name: Intellectual disability
  subtype: SPG9B
  description: >
    Cognitive impairment ranging from mild to severe intellectual disability,
    more prominent in biallelic SPG9B and ARCL3A than in dominant SPG9A.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31402623
    reference_title: "P5CS expression study in a new family with ALDH18A1-associated hereditary spastic paraplegia SPG9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      conclude that both mutations are disease-causing, that SPG9B associates with
      partial P5CS deficiency and that it is clinically more severe than SPG9A, as
      reflected in onset age, disability, cognitive status, growth, and dysmorphic
      traits.
    explanation: Cognitive impairment is a defining feature distinguishing SPG9B severity from SPG9A.
- category: Neurological
  name: Global developmental delay
  subtype: SPG9B
  description: >
    Developmental delay is prominent in the recessive form, with variable severity.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay, neurological deficits and loose skin."
    explanation: Developmental delay is a consistent feature of biallelic ALDH18A1 disease.
- category: Dermatological
  name: Cutis laxa
  subtype: SPG9B
  description: >
    Wrinkled, inelastic skin with visible veins is a feature of ARCL3A and some
    SPG9B patients, reflecting deficient proline-dependent collagen synthesis.
    The degree of skin involvement is variable.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Features of our patient that
      have been described in literature included cutis laxa on hands and feet, visible
      veins on thorax and abdomen, joint laxity, failure to thrive, short stature,
      microcephaly, and severe developmental and speech delay.
    explanation: Cutis laxa is a recognized feature of ARCL3A with variable distribution.
- category: Musculoskeletal
  name: Joint hypermobility
  subtype: SPG9B
  description: >
    Joint laxity or hypermobility is part of the connective-tissue phenotype in
    ALDH18A1-related ARCL3A/de Barsy-spectrum disease, occurring with cutis laxa,
    visible veins, growth failure, microcephaly, and developmental delay.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Features of our patient that
      have been described in literature included cutis laxa on hands and feet, visible
      veins on thorax and abdomen, joint laxity, failure to thrive, short stature,
      microcephaly, and severe developmental and speech delay.
    explanation: The clinical report and literature review include joint laxity, an exact synonym of HP:0001382 joint hypermobility.
- category: Ophthalmological
  name: Cataracts
  description: >
    Bilateral cataracts are frequent in both dominant and recessive forms,
    reported in approximately 60% of ARCL3A patients and in some SPG9A families.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:25077174
    reference_title: "Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral cataracts have been seen in 6/10 cases and so appear more frequent than in patients with PYCR1 mutations"
    explanation: Cataracts are a common feature of ALDH18A1-related disorders, more frequent than in the related PYCR1-related cutis laxa.
- category: Growth
  name: Growth retardation
  subtype: SPG9B
  description: >
    Short stature and failure to thrive are prominent in SPG9B and ARCL3A,
    reflecting impaired proline-dependent growth processes.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Features of our patient that
      have been described in literature included cutis laxa on hands and feet, visible
      veins on thorax and abdomen, joint laxity, failure to thrive, short stature,
      microcephaly, and severe developmental and speech delay.
    explanation: Short stature and failure to thrive are consistent features of ARCL3A.
- category: Neurological
  name: Microcephaly
  subtype: SPG9B
  description: >
    Microcephaly is reported in approximately 70% of ARCL3A patients and
    reflects impaired brain growth.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:25077174
    reference_title: "Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly has been reported in 7/10 cases, a similar proportion to that seen in patients with PYCR1 mutations."
    explanation: Microcephaly is a frequent neurological feature of ARCL3A.
- category: Metabolic
  name: Hyperammonemia
  description: >
    Hyperammonemia was part of the original biallelic P5CS deficiency metabolic
    phenotype together with reduced ornithine, citrulline, arginine, and proline.
    It should be interpreted as a reported branch of the severe neurocutaneous
    spectrum rather than a universal feature of every ALDH18A1 presentation.
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Their metabolic phenotype includes hyperammonemia, hypoornithinemia,
      hypocitrullinemia, hypoargininemia and hypoprolinemia.
    explanation: The original human P5CS deficiency report directly includes hyperammonemia in the metabolic phenotype.
- category: Dermatological
  name: Prominent superficial veins
  subtype: SPG9B
  description: >
    Visible superficial veins through the thin, inelastic skin are part of the
    connective-tissue phenotype of ALDH18A1-related cutis laxa.
  phenotype_term:
    preferred_term: Prominent superficial veins
    term:
      id: HP:0001015
      label: Prominent superficial veins
  evidence:
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      cutis laxa on hands and feet, visible
      veins on thorax and abdomen, joint laxity, failure to thrive, short stature,
      microcephaly, and severe developmental and speech delay.
    explanation: The ARCL3A clinical report and literature review document visible superficial veins on the thorax and abdomen.
- category: Growth
  name: Failure to thrive
  subtype: SPG9B
  description: >
    Failure to thrive occurs in ARCL3A/de Barsy-spectrum disease alongside short
    stature and the broader growth-failure phenotype.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      cutis laxa on hands and feet, visible
      veins on thorax and abdomen, joint laxity, failure to thrive, short stature,
      microcephaly, and severe developmental and speech delay.
    explanation: The ARCL3A clinical report and literature review document failure to thrive among the recognized features.
- category: Neurological
  name: Delayed speech and language development
  subtype: SPG9B
  description: >
    Severe speech and language delay accompanies the global developmental delay
    in ALDH18A1-related cutis laxa.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:24767728
    reference_title: "Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      cutis laxa on hands and feet, visible
      veins on thorax and abdomen, joint laxity, failure to thrive, short stature,
      microcephaly, and severe developmental and speech delay.
    explanation: The ARCL3A clinical report and literature review document severe developmental and speech delay.
biochemical:
- name: Plasma proline
  presence: DECREASED
  context: >-
    Reduced plasma proline levels serve as a potential biomarker, particularly
    when mutations affect the G5K domain. Mutations in the G5PR domain may not
    alter plasma amino acid levels.
  biomarker_term:
    preferred_term: L-proline
    term:
      id: CHEBI:17203
      label: L-proline
  readouts:
  - target: P5CS deficiency and proline biosynthesis impairment
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower plasma proline reports impaired P5CS-dependent proline biosynthesis.
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      as well as in two sporadic patients. Low levels of plasma ornithine, citrulline,
      arginine and proline in four individuals from two families suggested P5CS
      deficiency.
    explanation: Plasma amino acid profiling reveals P5CS deficiency biomarkers in affected individuals.
  - reference: PMID:29754261
    reference_title: "Compound heterozygous mutations in two different domains of ALDH18A1 do not affect the amino acid levels in a patient with hereditary spastic paraplegia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      childhood and temporal lobe epilepsy, but normal levels of proline, ornithine
      and arginine.
    explanation: Demonstrates that amino acid levels may be normal when mutations affect the G5PR domain.
- name: Plasma ornithine
  presence: DECREASED
  context: >-
    Reduced plasma ornithine is part of the amino-acid profile suggesting P5CS
    deficiency and reflects impaired ornithine biosynthesis from glutamate.
  biomarker_term:
    preferred_term: L-ornithine
    term:
      id: CHEBI:15729
      label: L-ornithine
  readouts:
  - target: Urea-cycle amino acid depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower plasma ornithine reports the urea-cycle amino acid depletion branch downstream of P5CS deficiency.
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Their metabolic phenotype includes hyperammonemia, hypoornithinemia,
      hypocitrullinemia, hypoargininemia and hypoprolinemia.
    explanation: The original P5CS deficiency report documents hypoornithinemia as part of the metabolic phenotype.
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Low levels of plasma ornithine, citrulline,
      arginine and proline in four individuals from two families suggested P5CS
      deficiency.
    explanation: ALDH18A1-related SPG families show reduced plasma ornithine in the diagnostic amino-acid profile.
- name: Plasma citrulline
  presence: DECREASED
  context: >-
    Reduced plasma citrulline accompanies reduced ornithine and arginine in the
    P5CS deficiency amino-acid profile, linking the primary biosynthetic block to
    the urea-cycle related branch.
  biomarker_term:
    preferred_term: L-citrulline
    term:
      id: CHEBI:16349
      label: L-citrulline
  readouts:
  - target: Urea-cycle amino acid depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower plasma citrulline reports downstream urea-cycle amino acid depletion.
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Their metabolic phenotype includes hyperammonemia, hypoornithinemia,
      hypocitrullinemia, hypoargininemia and hypoprolinemia.
    explanation: The original P5CS deficiency report documents hypocitrullinemia.
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Low levels of plasma ornithine, citrulline,
      arginine and proline in four individuals from two families suggested P5CS
      deficiency.
    explanation: ALDH18A1-related SPG families show reduced plasma citrulline.
- name: Plasma arginine
  presence: DECREASED
  context: >-
    Reduced plasma arginine is reported with reduced ornithine, citrulline, and
    proline in P5CS deficiency, reflecting impaired arginine biosynthetic support
    from the glutamate-derived pathway.
  biomarker_term:
    preferred_term: L-arginine
    term:
      id: CHEBI:16467
      label: L-arginine
  readouts:
  - target: Urea-cycle amino acid depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Lower plasma arginine reports downstream impairment of the arginine biosynthetic branch.
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Their metabolic phenotype includes hyperammonemia, hypoornithinemia,
      hypocitrullinemia, hypoargininemia and hypoprolinemia.
    explanation: The original P5CS deficiency report documents hypoargininemia.
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Low levels of plasma ornithine, citrulline,
      arginine and proline in four individuals from two families suggested P5CS
      deficiency.
    explanation: ALDH18A1-related SPG families show reduced plasma arginine.
- name: Blood ammonia
  presence: INCREASED
  context: >-
    Increased blood ammonia reflects the hyperammonemia branch reported in the
    original P5CS deficiency siblings with combined low ornithine, citrulline,
    arginine, and proline.
  biomarker_term:
    preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
  readouts:
  - target: Urea-cycle amino acid depletion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated ammonia reports impaired nitrogen handling in the severe P5CS deficiency branch.
  evidence:
  - reference: PMID:11092761
    reference_title: "Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Their metabolic phenotype includes hyperammonemia, hypoornithinemia,
      hypocitrullinemia, hypoargininemia and hypoprolinemia.
    explanation: The original P5CS deficiency report directly documents hyperammonemia.
- name: Cellular glutathione
  presence: DECREASED
  context: >-
    Metabolomic profiling in patient fibroblasts shows reduced glutathione,
    indicating impaired glutamate-derived antioxidant metabolism.
  biomarker_term:
    preferred_term: glutathione
    term:
      id: CHEBI:16856
      label: glutathione
  readouts:
  - target: Antioxidant metabolism impairment
    relationship: READOUT_OF
    direction: NEGATIVE
    interpretation: Lower cellular glutathione reports the antioxidant-metabolism branch in ALDH18A1-deficient cells.
  evidence:
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      identified reduced abundance of glutamate and several metabolites derived from
      glutamate, including proline and glutathione.
    explanation: Patient-cell metabolomics directly identifies reduced glutathione.
- name: Cellular putrescine
  presence: DECREASED
  context: >-
    Metabolomic profiling in patient fibroblasts shows reduced biosynthesis of
    putrescine from ornithine, tying the P5CS ornithine branch to antioxidant
    pathway dysfunction.
  biomarker_term:
    preferred_term: putrescine
    term:
      id: CHEBI:17148
      label: putrescine
  readouts:
  - target: Antioxidant metabolism impairment
    relationship: READOUT_OF
    direction: NEGATIVE
    interpretation: Lower cellular putrescine reports impaired ornithine-derived polyamine biosynthesis in the antioxidant branch.
  evidence:
  - reference: PMID:36067040
    reference_title: "Functional assessment of homozygous ALDH18A1 variants reveals alterations in amino acid and antioxidant metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: |-
      Biosynthesis of the polyamine
      putrescine, derived from ornithine, was also decreased in patient fibroblasts,
    explanation: Patient fibroblast metabolomics directly identifies decreased putrescine biosynthesis.
treatments:
- name: Genetic Counseling
  description: >
    Genetic counseling for families regarding autosomal dominant versus recessive
    inheritance patterns and recurrence risk. Amino acid chromatography is
    recommended in the diagnostic workup of hereditary spastic paraplegia.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:26026163
    reference_title: "Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      we therefore suggest including
      amino acid chromatography in the clinico-genetic work-up of hereditary spastic
      paraplegia, particularly in dominant cases, as the associated phenotype is not
      distinct from other causative genes.
    explanation: Authors recommend metabolic screening as part of the diagnostic approach for HSP.
- name: Supportive Care
  description: >
    Multidisciplinary management including physiotherapy for spasticity,
    ophthalmological care for cataracts, developmental support, and
    nutritional optimization.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
references:
- reference: DOI:10.1002/acn3.50821
  title: P5CS expression study in a new family with <i>ALDH18A1</i>‐associated hereditary spastic paraplegia SPG9
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia.
    supporting_text: In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia.
    evidence:
    - reference: DOI:10.1002/acn3.50821
      reference_title: P5CS expression study in a new family with <i>ALDH18A1</i>‐associated hereditary spastic paraplegia SPG9
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.1002/jimd.12220
  title: 'Δ<sup>1</sup>‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder'
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998.
    supporting_text: The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998.
    evidence:
    - reference: DOI:10.1002/jimd.12220
      reference_title: 'Δ<sup>1</sup>‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.1007/s10545-017-0063-1
  title: Amino acid synthesis deficiencies
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: In recent years the number of disorders known to affect amino acid synthesis has grown rapidly.
    supporting_text: In recent years the number of disorders known to affect amino acid synthesis has grown rapidly.
    evidence:
    - reference: DOI:10.1007/s10545-017-0063-1
      reference_title: Amino acid synthesis deficiencies
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In recent years the number of disorders known to affect amino acid synthesis has grown rapidly.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.1055/s-0040-1701671
  title: Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability.
    supporting_text: Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability.
    evidence:
    - reference: DOI:10.1055/s-0040-1701671
      reference_title: Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.1093/hmg/ddac226
  title: Functional assessment of homozygous <i>ALDH18A1</i> variants reveals alterations in amino acid and antioxidant metabolism
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia.
    supporting_text: Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia.
    evidence:
    - reference: DOI:10.1093/hmg/ddac226
      reference_title: Functional assessment of homozygous <i>ALDH18A1</i> variants reveals alterations in amino acid and antioxidant metabolism
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.1177/20503121231221941
  title: 'Hereditary spastic paraplegia: Novel insights into the pathogenesis and management'
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs.
    supporting_text: Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs.
    evidence:
    - reference: DOI:10.1177/20503121231221941
      reference_title: 'Hereditary spastic paraplegia: Novel insights into the pathogenesis and management'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.3389/fneur.2021.627531
  title: Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B).
    supporting_text: Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B).
    evidence:
    - reference: DOI:10.3389/fneur.2021.627531
      reference_title: Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B).
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
- reference: DOI:10.3389/fneur.2023.1239725
  title: The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia
  found_in:
  - ALDH18A1_De_Barsy_Spectrum-deep-research-falcon.md
  findings:
  - statement: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans.
    supporting_text: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans.
    evidence:
    - reference: DOI:10.3389/fneur.2023.1239725
      reference_title: The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans.
      explanation: Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
📚

References & Deep Research

References

8
DOI:10.1002/acn3.50821
P5CS expression study in a new family with <i>ALDH18A1</i>‐associated hereditary spastic paraplegia SPG9
1 finding
In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia.
"In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia."
Show evidence (1 reference)
DOI:10.1002/acn3.50821 SUPPORT Human Clinical
"In 2015–2016, we and others reported ALDH18A1 mutations causing dominant (SPG9A) or recessive (SPG9B) spastic paraplegia."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.1002/jimd.12220
Δ<sup>1</sup>‐Pyrroline‐5‐carboxylate synthetase deficiency: An emergent multifaceted urea cycle‐related disorder
1 finding
The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998.
"The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998."
Show evidence (1 reference)
DOI:10.1002/jimd.12220 SUPPORT Human Clinical
"The bifunctional homooligomeric enzyme Δ1‐pyrroline‐5‐carboxylate synthetase (P5CS) and its encoding gene ALDH18A1 were associated with disease in 1998."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.1007/s10545-017-0063-1
Amino acid synthesis deficiencies
1 finding
In recent years the number of disorders known to affect amino acid synthesis has grown rapidly.
"In recent years the number of disorders known to affect amino acid synthesis has grown rapidly."
Show evidence (1 reference)
DOI:10.1007/s10545-017-0063-1 SUPPORT Human Clinical
"In recent years the number of disorders known to affect amino acid synthesis has grown rapidly."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.1055/s-0040-1701671
Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA
1 finding
Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability.
"Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability."
Show evidence (1 reference)
DOI:10.1055/s-0040-1701671 SUPPORT Human Clinical
"Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.1093/hmg/ddac226
Functional assessment of homozygous <i>ALDH18A1</i> variants reveals alterations in amino acid and antioxidant metabolism
1 finding
Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia.
"Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia."
Show evidence (1 reference)
DOI:10.1093/hmg/ddac226 SUPPORT Human Clinical
"Mono- and bi-allelic variants in ALDH18A1 cause a spectrum of human disorders associated with cutaneous and neurological findings that overlap with both cutis laxa and spastic paraplegia."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.1177/20503121231221941
Hereditary spastic paraplegia: Novel insights into the pathogenesis and management
1 finding
Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs.
"Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs."
Show evidence (1 reference)
DOI:10.1177/20503121231221941 SUPPORT Other
"Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.3389/fneur.2021.627531
Novel Compound Missense and Intronic Splicing Mutation in ALDH18A1 Causes Autosomal Recessive Spastic Paraplegia
1 finding
Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B).
"Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B)."
Show evidence (1 reference)
DOI:10.3389/fneur.2021.627531 SUPPORT Human Clinical
"Hereditary spastic paraplegia (HSP) caused by mutations in ALDH18A1 have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B)."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.
DOI:10.3389/fneur.2023.1239725
The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia
1 finding
Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans.
"Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans."
Show evidence (1 reference)
DOI:10.3389/fneur.2023.1239725 SUPPORT Human Clinical
"Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN) and spastic ataxias in Europeans."
Deep research cited this publication as relevant literature for ALDH18A1 De Barsy Spectrum.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 36 citations 2026-05-08T07:51:27.206605

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: ALDH18A1-Related Spastic Paraplegia and Neurocutaneous Spectrum
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on ALDH18A1-Related Spastic Paraplegia and Neurocutaneous 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

Comprehensive research report: ALDH18A1‑Related Spastic Paraplegia and Neurocutaneous Spectrum (P5CS deficiency continuum)

Executive summary

ALDH18A1 encodes the mitochondrial bifunctional enzyme Δ1‑pyrroline‑5‑carboxylate synthase (P5CS), which catalyzes conversion of glutamate to pyrroline‑5‑carboxylate (P5C), a branch point for proline and ornithine/arginine‑urea‑cycle–linked metabolism. Pathogenic ALDH18A1 variants produce a continuous clinicogenetic spectrum spanning neurocutaneous cutis laxa / de Barsy–like presentations and hereditary spastic paraplegia (HSP) type 9 (SPG9), with dominant forms frequently proposed to act by dominant‑negative loss‑of‑function and recessive forms by partial/marked deficiency. A widely cited synthesis proposes severity ordering SPG9A < SPG9B < ADCL3 ≤ ARCL3A as a single disease entity (“P5CS deficiency”). (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

Recent (2023) multi‑omics work in patient fibroblasts with a homozygous ALDH18A1 variant demonstrates broad alterations in amino‑acid and antioxidant metabolism, including reduced glutamate‑derived metabolites (proline, glutathione) and decreased ornithine‑derived putrescine, providing a modern mechanistic and biomarker framework for this Mendelian spectrum. (colonna2023functionalassessmentof pages 1-1)

1. Disease information (definitions, identifiers, synonyms)

1.1 Disease concept

ALDH18A1‑related spastic paraplegia and neurocutaneous spectrum refers to Mendelian disorders caused by mono‑ or biallelic pathogenic variants in ALDH18A1, producing a phenotype continuum that includes: - Hereditary spastic paraplegia type 9: SPG9A (AD) and SPG9B (AR). - Cutis laxa 3: autosomal dominant cutis laxa 3 (ADCL3) and autosomal recessive cutis laxa type IIIA (ARCL3A). - ALDH18A1‑related de Barsy syndrome as a neurocutaneous entity overlapping the cutis laxa/progeroid spectrum.

A central definition from a 2020 expert review states that ALDH18A1 mutations cause “two neurocutaneous syndromes … and two SPG9 syndromes” and that they “represent a continuum of increasing severity … of the same disease, P5CS deficiency.” (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

1.2 Key identifiers

  • Gene: ALDH18A1 at 10q24.1 (OMIM gene entry cited as OMIM 138250 in a SPG9B case report). (kalmar2021tremorasan pages 1-2)
  • SPG9A: OMIM/MIM 601162. (kalmar2021tremorasan pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • SPG9B: OMIM/MIM 616586. (kalmar2021tremorasan pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2)
  • ADCL3: OMIM/MIM 616603. (kalmar2021tremorasan pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • ARCL3A: OMIM/MIM 219150. (kalmar2021tremorasan pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • De Barsy syndrome (DBS): discussed within ARCL3 / ARCL3A spectrum; DBS listed with MIM 219150 within a cutis laxa diagnostic/nosology paper. (gardeitchik2014clinicalandbiochemical pages 1-2)

MONDO (via Open Targets association evidence): - MONDO:0009053 “ALDH18A1‑related de Barsy syndrome” - MONDO:0014702 “autosomal recessive complex spastic paraplegia type 9B” - MONDO:0014706 “cutis laxa, autosomal dominant 3” - MONDO:0015091 “autosomal dominant spastic paraplegia type 9” (OpenTargets Search: -ALDH18A1)

1.3 Synonyms and alternative names

  • P5CS deficiency / Δ1‑pyrroline‑5‑carboxylate synthetase deficiency (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • ALDH18A1‑related cutis laxa (dominant or recessive) (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • ALDH18A1‑associated HSP / spastic paraplegia 9 (chen2021novelcompoundmissense pages 1-2)
  • De Barsy‑like progeroid cutis laxa phenotype (fischerzirnsak2015recurrentdenovo pages 1-2)

1.4 Evidence source types

Most information in the available corpus is derived from aggregated disease‑level resources and literature synthesis (e.g., JIMD review) (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) and primary case series (e.g., Am J Hum Genet Arg138 de novo cohort) (fischerzirnsak2015recurrentdenovo pages 1-2, fischerzirnsak2015recurrentdenovo media 44a36465), complemented by functional studies in patient cells (colonna2023functionalassessmentof pages 1-1) and clinical cohort sequencing studies (mahungu2023themutationalprofile pages 1-2).

2. Etiology

2.1 Disease causal factors

Primary cause is genetic: pathogenic variants in ALDH18A1. The encoded enzyme P5CS catalyzes the first and common step of proline and ornithine biosynthesis from glutamate, linking glutamate metabolism to urea cycle and broader amino‑acid/polyamine metabolism. (coutelier2015alterationofornithine pages 1-2, colonna2023functionalassessmentof pages 1-2)

2.2 Risk factors

  • Genetic: Monoallelic variants (dominant) or biallelic variants (recessive) in ALDH18A1. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2)
  • Environmental/lifestyle risk factors are not established in the retrieved disease‑specific literature.

2.3 Protective factors / gene–environment interactions

The initial ARCL3A description included “paradoxical hyperammonemia (alleviated by protein),” indicating dietary protein intake can acutely modify a biochemical phenotype in severe P5CS deficiency. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

3. Phenotypes (clinical spectrum)

3.1 Overarching phenotype architecture

A key modern framing is that ALDH18A1 disorders encompass at least two named syndromic groupings—SPG9A/B and cutis laxa 3 (ADCL3/ARCL3A)—with overlapping neurological and cutaneous findings. (colonna2023functionalassessmentof pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

Entity/synonym Inheritance Typical onset Core neuro features Core cutaneous/connective-tissue features Key biochemical clues Notes/quantitative stats Key references
SPG9A / autosomal dominant spastic paraplegia type 9 / dominant ALDH18A1-related HSP Autosomal dominant; monoallelic ALDH18A1 variants, with dominant-negative loss-of-function proposed (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, panza2016aldh18a1genemutations pages 8-8) Generally later-onset than recessive/neurocutaneous forms; upper motor neuron syndrome with progressive course (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) Progressive spastic paraparesis/paraplegia; can be pure or complex HSP; corticospinal tract involvement; tremor can occur in ALDH18A1-related HSP spectrum (coutelier2015alterationofornithine pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, kalmar2021tremorasan pages 1-2) Typically lacks overt cutis laxa/joint hypermobility seen in neurocutaneous forms (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) Plasma ornithine, citrulline, arginine, and proline may be low or low-normal; amino-acid chromatography suggested as a trait biomarker in ALDH18A1 HSP (coutelier2015alterationofornithine pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) Review cited 50 total SPG9 patients, of whom 36 were monoallelic; SPG9A framed as the mildest end of the ALDH18A1/P5CS deficiency continuum (SPG9A < SPG9B < ADCL3 ≤ ARCL3A) (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) Coutelier et al., 2015, Brain, https://doi.org/10.1093/brain/awv143; Panza et al., 2016, Brain, https://doi.org/10.1093/brain/awv247; Marco-Marín et al., 2020, JIMD, https://doi.org/10.1002/jimd.12220
SPG9B / autosomal recessive complex spastic paraplegia type 9B / recessive ALDH18A1-related HSP Autosomal recessive; biallelic ALDH18A1 variants (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2, kalmar2021tremorasan pages 1-2) Usually childhood onset; clinically more severe than SPG9A, but milder than cutis laxa neurocutaneous forms overall (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2, kalmar2021tremorasan pages 1-2) Complex HSP with spasticity, developmental delay/intellectual impairment in some cases, tremor as early sign in at least one child, white-matter reduction/corpus callosum hypoplasia reported, variable cognitive involvement (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2, kalmar2021tremorasan pages 1-2) Usually no frank cutis laxa; may have growth issues/dysmorphic traits in more severe cases (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, kalmar2021tremorasan pages 1-2) P5CS concentration can be significantly decreased in plasma; amino-acid abnormalities may include low or low-normal ornithine/citrulline/arginine/proline, but can also be normal except mild hypocitrullinemia; RNA splicing analysis can clarify intronic variants (coutelier2015alterationofornithine pages 1-2, chen2021novelcompoundmissense pages 1-2, kalmar2021tremorasan pages 1-2) Review cited 50 total SPG9 patients, 14 biallelic; Chen 2021 reported novel c.880T>C (p.S294P) plus c.-28-13A>G in one AR family; Kalmár 2021 detailed early tremor (~2 months), DQ 45 at 2 years, MRI abnormalities, normal fasting ammonia, normal proline/ornithine/arginine, slightly decreased citrulline (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2, kalmar2021tremorasan pages 1-2) Magini et al., 2019, Ann Clin Transl Neurol, https://doi.org/10.1002/acn3.50821; Chen et al., 2021, Front Neurol, https://doi.org/10.3389/fneur.2021.627531; Kalmár et al., 2021, Brain Dev, https://doi.org/10.1016/j.braindev.2020.07.015
ADCL3 / cutis laxa, autosomal dominant 3 / progeroid autosomal-dominant cutis laxa due to ALDH18A1 Autosomal dominant, typically de novo heterozygous ALDH18A1 variants; recurrent Arg138 substitutions highlighted (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, fischerzirnsak2015recurrentdenovo pages 1-2) Congenital/prenatal to early infancy; growth restriction often prenatal and postnatal (fischerzirnsak2015recurrentdenovo pages 1-2) Developmental/psychomotor delay common; neurodevelopmental impairment; vascular tortuosity reported in some; overlaps with De Barsy-like neurocutaneous phenotype (fischerzirnsak2015recurrentdenovo pages 1-2) Lax thin skin, progeroid appearance, joint hyperlaxity; cataracts frequent; adducted thumbs in many patients (fischerzirnsak2015recurrentdenovo pages 1-2) Reduced P5CS enzymatic activity; delayed proline accumulation; altered sub-mitochondrial distribution of mutant P5CS (fischerzirnsak2015recurrentdenovo pages 1-2) In a cohort of 8 unrelated individuals, all had lax thin skin and joint hyperlaxity; all had prenatal growth restriction and 7/8 postnatal growth restriction; 6/8 had cataracts; 5/8 adducted thumbs; 4/8 cranial vessel tortuosity; de novo origin confirmed in all 6 probands with parental DNA available (fischerzirnsak2015recurrentdenovo pages 1-2, fischerzirnsak2015recurrentdenovo media 44a36465) Fischer-Zirnsak et al., 2015, Am J Hum Genet, https://doi.org/10.1016/j.ajhg.2015.08.001; Marco-Marín et al., 2020, JIMD, https://doi.org/10.1002/jimd.12220
ARCL3A / cutis laxa, autosomal recessive type IIIA / recessive neurocutaneous P5CS deficiency Autosomal recessive; homozygous or compound heterozygous ALDH18A1 variants (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, lugli2022autosomalrecessivecutis pages 6-6, gardeitchik2014clinicalandbiochemical pages 1-2) Usually congenital/infantile; often severe, including fetal presentations in some reports (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, lugli2022autosomalrecessivecutis pages 6-6) Developmental disability/intellectual disability, severe neurologic involvement in many cases, growth restriction, cataracts; corpus callosum agenesis/dysgenesis and dystonic posturing associated in broader cutis laxa diagnostic series (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, lugli2022autosomalrecessivecutis pages 6-6, gardeitchik2014clinicalandbiochemical pages 1-2) Cutis laxa, connective-tissue laxity, joint laxity, hernias; systemic involvement typical (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, lugli2022autosomalrecessivecutis pages 6-6) Plasma proline, arginine, citrulline, and ornithine can be decreased or low-normal; hyperammonemia reported in classic P5CS deficiency; considered a multifaceted urea-cycle-related disorder (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, lugli2022autosomalrecessivecutis pages 6-6) Review cited 32 neurocutaneous patients: 21 familial with homozygous/compound heterozygous variants and 11 sporadic with de novo heterozygous variants across the broader neurocutaneous spectrum; ARCL3A considered among the most severe manifestations (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) Gardeitchik et al., 2014, Eur J Hum Genet, https://doi.org/10.1038/ejhg.2013.154; Angelini et al., 2020, Neuropediatrics, https://doi.org/10.1055/s-0040-1701671; Lugli et al., 2022, Eur J Med Genet, https://doi.org/10.1016/j.ejmg.2022.104568
ALDH18A1-related de Barsy syndrome / De Barsy-like neurocutaneous syndrome / P5CS deficiency spectrum Usually autosomal recessive in classic de Barsy-like presentations, but ALDH18A1-related disease spans recessive neurocutaneous forms and de novo dominant cutis laxa phenotypes (lugli2022autosomalrecessivecutis pages 6-6, fischerzirnsak2015recurrentdenovo pages 1-2, OpenTargets Search: -ALDH18A1) Congenital to infantile in classic neurocutaneous presentations (lugli2022autosomalrecessivecutis pages 6-6, fischerzirnsak2015recurrentdenovo pages 1-2) Neurodevelopmental delay, cataracts, neurodegeneration/neurologic deficits; overlap with spastic paraplegia and broader ALDH18A1 neurocutaneous disease (OpenTargets Search: -ALDH18A1, lugli2022autosomalrecessivecutis pages 6-6, fischerzirnsak2015recurrentdenovo pages 1-2) Cutis laxa/progeroid appearance, joint laxity, connective-tissue manifestations; fat pads/retinopathy and cardiovascular involvement reported in broader ALDH18A1 literature (lugli2022autosomalrecessivecutis pages 6-6, panza2016aldh18a1genemutations pages 8-8) Hyperammonemia with reduced ornithine, citrulline, arginine, and proline described in classic P5CS deficiency; recent work also shows altered amino-acid and antioxidant metabolism, including reduced glutamate, proline, glutathione, and putrescine (fischerzirnsak2026neurocutaneousdisordersduea pages 20-22, colonna2023functionalassessmentof pages 1-1) Open Targets links ALDH18A1 to MONDO:0009053 “ALDH18A1-related de Barsy syndrome”; named disease concept overlaps substantially with ARCL3A/ADCL3 and is best understood as part of a continuous ALDH18A1/P5CS deficiency spectrum rather than a sharply separate entity (OpenTargets Search: -ALDH18A1, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) Colonna et al., 2023, Hum Mol Genet, https://doi.org/10.1093/hmg/ddac226; Fischer-Zirnsak et al., 2015, Am J Hum Genet, https://doi.org/10.1016/j.ajhg.2015.08.001; Open Targets disease association (OpenTargets Search: -ALDH18A1)

Table: This table summarizes the named ALDH18A1/P5CS deficiency entities across the spastic paraplegia and neurocutaneous spectrum, including inheritance, onset, core features, biochemical clues, and available quantitative cohort data. It is useful for comparing how SPG9 and cutis laxa/de Barsy-like presentations fit into a single mechanistic disease continuum.

3.2 Neurocutaneous / cutis laxa / de Barsy‑like phenotypes (ADCL3; ARCL3A; ALDH18A1‑related de Barsy)

Core clinical features in an autosomal‑dominant progeroid cutis laxa cohort (8 unrelated individuals) include: - Lax thin skin with visible veins and joint hyperlaxity in all individuals - Prenatal growth restriction in all; postnatal growth restriction in 7/8 - Cataracts in 6/8 - Adducted thumbs in 5/8 - Cranial vessel tortuosity in 4/8 - Psychomotor development delayed in all probands These individuals carried heterozygous de novo ALDH18A1 variants affecting Arg138 of P5CS. (fischerzirnsak2015recurrentdenovo pages 1-2, fischerzirnsak2015recurrentdenovo media 44a36465)

The same paper provides a concise abstract statement (useful for knowledge‑base evidence quoting): it reports “eight unrelated individuals … clinically diagnosed with DBS or wrinkly skin syndrome” with “three heterozygous mutations in ALDH18A1 … Arg138,” and notes reduced enzymatic activity and delayed proline accumulation, concluding that these recurrent de novo variants “cause an autosomal‑dominant form of cutis laxa with progeroid features” and “will have immediate impact on diagnostics and genetic counseling.” (fischerzirnsak2015recurrentdenovo pages 1-2)

Suggested HPO terms (examples): - Cutis laxa (HP:0000973) - Joint hypermobility (HP:0001382) - Cataract (HP:0000518) - Prenatal growth restriction / IUGR (HP:0001511) - Postnatal growth retardation (HP:0008897) - Developmental delay (HP:0001263) - Arterial/cerebral vessel tortuosity (HP:0005116)

3.3 Spastic paraplegia phenotypes (SPG9A/B)

SPG9 clinical definition and spectrum: HSP due to ALDH18A1 can be pure (lower‑limb spasticity with mild urinary symptoms and distal vibration impairment) or complicated (cognitive impairment, seizures, neuropathy, amyotrophy, short stature, vision abnormalities, etc.). (chen2021novelcompoundmissense pages 1-2)

Primary HSP series evidence: In 2015, ALDH18A1 variants were found to cause both recessive and dominant HSP; low plasma ornithine/citrulline/arginine/proline suggested P5CS deficiency, and fibroblast glutamine‑loading tests confirmed a metabolic block at P5CS. The authors propose amino‑acid chromatography in the clinico‑genetic work‑up. (coutelier2015alterationofornithine pages 1-2)

Example SPG9B natural history (case report): a child with compound heterozygous ALDH18A1 variants had tremor onset at ~2 months, developmental delay (unable to sit at 10 months, stand at 12 months), DQ 45 at age 2 years, MRI showing reduced white matter and corpus callosum hypoplasia, and slightly decreased citrulline with otherwise normal proline/ornithine/arginine and normal fasting ammonia. (kalmar2021tremorasan pages 1-2)

Suggested HPO terms (examples): - Spastic paraplegia (HP:0001258) - Hyperreflexia (HP:0001347) - Urinary urgency (HP:0000012) - Tremor (HP:0001337) - Corpus callosum hypoplasia/dysgenesis (HP:0002079) - White matter abnormality / hypomyelination (HP:0002500) - Intellectual disability / developmental delay (HP:0001249, HP:0001263)

3.4 Quality of life impact

Disease‑specific QoL instruments were not present in the retrieved ALDH18A1‑specific sources. For HSP broadly, the disease “significantly impairs … quality of life” and worsens with severity/age. (awuah2024hereditaryspasticparaplegia pages 1-2)

4. Genetic/molecular information

4.1 Causal gene

  • ALDH18A1 encodes P5CS (Δ1‑pyrroline‑5‑carboxylate synthetase), a bifunctional mitochondrial enzyme. (colonna2023functionalassessmentof pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

4.2 Pathogenic variants and variant classes (examples)

  • Autosomal dominant progeroid cutis laxa (ADCL3): recurrent heterozygous de novo missense variants affecting Arg138 (amino‑acid substitutions of the same conserved residue). (fischerzirnsak2015recurrentdenovo pages 1-2)
  • Autosomal recessive SPG9B: compound missense plus intronic splicing variants (e.g., c.880T>C p.S294P and c.-28-13A>G) with reduced P5CS concentration in plasma by ELISA. (chen2021novelcompoundmissense pages 1-2)
  • Biallelic ARCL3A / neurocutaneous: early reports include biallelic variants and biochemical evidence of impaired ornithine/proline synthesis and paradoxical hyperammonemia. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

4.3 Functional consequences and inheritance mechanisms

A 2020 review concludes that dominant mutations “cause loss‑of‑function by dominant‑negative mechanisms,” and that decreased P5CS function underlies all four named syndromes. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

A primary study of Arg138 de novo variants shows the mutant protein can interact with wild‑type P5CS but has altered sub‑mitochondrial distribution and reduced enzymatic activity, consistent with a dominant negative/complex destabilization model. (fischerzirnsak2015recurrentdenovo pages 1-2)

4.4 Population frequencies, modifier genes, epigenetics

No gnomAD‑style allele frequencies, established modifier genes, or disease‑specific epigenetic mechanisms were available in the retrieved sources.

5. Environmental information

No specific environmental toxins/lifestyle exposures were implicated in the retrieved ALDH18A1‑specific literature. Diet can modulate biochemical expression in severe cases (protein alleviating paradoxical hyperammonemia). (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

6. Mechanism / pathophysiology

6.1 Core metabolic pathway and causal chain

ALDH18A1/P5CS converts glutamate → P5C, which then supports: - Proline synthesis via PYCR1 - Ornithine synthesis via OAT, connecting to urea‑cycle amino acids (citrulline, arginine) This connects P5CS to the urea cycle and TCA cycle and to synthesis of polyamines and glutathione (redox). (colonna2023functionalassessmentof pages 1-2)

Causal chain (simplified): 1) Pathogenic ALDH18A1 variant → reduced P5CS function/complex formation (fischerzirnsak2015recurrentdenovo pages 1-2, colonna2023functionalassessmentof pages 1-1) 2) Reduced de novo proline/ornithine production → low/low‑normal plasma proline/ornithine/citrulline/arginine (trait biomarker) and, in severe cases, paradoxical hyperammonemia (coutelier2015alterationofornithine pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 5-9) 3) Downstream consequences: - Connective tissue/skin: impaired proline availability plausibly limits collagen/elastin production → cutis laxa/progeroid appearance (colonna2023functionalassessmentof pages 1-2) - Neurodevelopment/neurodegeneration: not fully understood mechanistically, but may relate to metabolic/redox stress and selective neuronal vulnerability (colonna2023functionalassessmentof pages 1-2) - Antioxidant pathway: reduced glutathione and polyamine metabolism → impaired cellular antioxidant responses (colonna2023functionalassessmentof pages 1-1)

6.2 Recent mechanistic developments (2023)

A 2023 Human Molecular Genetics functional study of a homozygous ALDH18A1 variant (p.Thr331Pro) used NMR metabolomics and showed reduced glutamate and glutamate‑derived metabolites “including proline and glutathione,” and decreased biosynthesis of putrescine (ornithine‑derived), with RNA‑seq changes in metabolic and ECM‑related genes. (colonna2023functionalassessmentof pages 1-1)

6.3 Suggested ontology terms

  • GO biological process (examples): proline biosynthetic process; ornithine biosynthetic process; glutathione metabolic process; polyamine biosynthetic process.
  • GO cellular component: mitochondrion.
  • CHEBI (examples): L‑proline, L‑ornithine, L‑arginine, L‑citrulline, glutamate, glutathione, putrescine.
  • Cell types (CL): upper motor neuron (for HSP manifestations; specific CL mapping not provided in retrieved texts).

7. Anatomical structures affected

  • Nervous system: corticospinal tract degeneration/upper motor neuron syndrome in SPG9; brain structural abnormalities (white matter, corpus callosum) in some complex cases. (awuah2024hereditaryspasticparaplegia pages 1-2, kalmar2021tremorasan pages 1-2)
  • Skin/connective tissue: cutis laxa, joint hyperlaxity. (fischerzirnsak2015recurrentdenovo pages 1-2)
  • Eye: cataracts/corneal clouding common in neurocutaneous and some SPG9 cases. (fischerzirnsak2015recurrentdenovo pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • Vasculature: cranial vessel tortuosity in a subset of ADCL3 Arg138 cases. (fischerzirnsak2015recurrentdenovo pages 1-2, fischerzirnsak2015recurrentdenovo media 44a36465)

Suggested UBERON (examples): skin; brain; corpus callosum; corticospinal tract; eye lens; arteries.

8. Temporal development

  • ARCL3A / severe neurocutaneous: typically congenital/early onset; can be very severe; associated with growth restriction and early systemic involvement. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • ADCL3 Arg138: prenatal growth restriction and early postnatal manifestations; psychomotor delay. (fischerzirnsak2015recurrentdenovo pages 1-2)
  • SPG9A/SPG9B: generally later onset upper motor neuron syndrome, with SPG9B typically more severe than SPG9A in growth/cognitive features per review synthesis. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

9. Inheritance and population

9.1 Inheritance

  • Autosomal dominant: SPG9A; ADCL3 (often de novo). (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, fischerzirnsak2015recurrentdenovo pages 1-2)
  • Autosomal recessive: SPG9B; ARCL3A. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5, chen2021novelcompoundmissense pages 1-2)

9.2 Epidemiology and statistics

ALDH18A1‑specific prevalence is not established in the retrieved sources. Available proxy statistics: - Cutis laxa (overall) estimated incidence: 1:2–400,000. (gardeitchik2014clinicalandbiochemical pages 1-2) - HSP (overall): global incidence reported as 3.6 per 100,000 in a 2024 review; HSP “does not reduce a person’s lifespan.” (awuah2024hereditaryspasticparaplegia pages 1-2) - Literature case counts compiled in a 2020 review: 32 neurocutaneous patients (21 familial biallelic; 11 sporadic de novo heterozygous) and 50 SPG9 patients (14 biallelic; 36 monoallelic). (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) - Detection benchmarking in cohorts: ALDH18A1 heterozygous variants in 2/530 screened HSP patients in one 2015 study. (coutelier2015alterationofornithine pages 5-5)

10. Diagnostics

10.1 Clinical and biochemical testing

  • Plasma amino acids: low ornithine/citrulline/arginine/proline may suggest P5CS deficiency. (coutelier2015alterationofornithine pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • Functional confirmation: glutamine loading tests in patient fibroblasts can show a metabolic block at P5CS. (coutelier2015alterationofornithine pages 1-2)
  • Protein quantification: ELISA can show significantly decreased plasma P5CS concentration in SPG9B (used to support variant pathogenicity). (chen2021novelcompoundmissense pages 1-2)

10.2 Imaging

  • Corpus callosum dysgenesis/hypoplasia and white‑matter reduction are reported in PYCR1/ALDH18A1‑related cutis laxa spectrum and in an SPG9B child. (gardeitchik2014clinicalandbiochemical pages 1-2, kalmar2021tremorasan pages 1-2)

10.3 Genetic testing and real‑world implementation

  • Whole‑exome sequencing with RNA splicing analysis was used to diagnose SPG9B and characterize intronic splice variants; splicing prediction and RNA assays were emphasized as informative. (chen2021novelcompoundmissense pages 1-2)
  • Large HSP screening approach (2015): ALDH18A1 evaluated across 530 HSP patients (435 WES; 95 panel). (coutelier2015alterationofornithine pages 5-5)
  • 2023 real‑world cohort (South Africa; 61 probands total): after initial targeted tests, remaining cases underwent WES or WGS; among 29 HSP probands, 48% were solved genetically, with ALDH18A1 represented among solved genes (single case). Variant curation used internal African‑ancestry control genomes (n=537) and ClinGen SVI guidance. (mahungu2023themutationalprofile pages 1-2)

10.4 Differential diagnosis

Within “neurometabolic cutis laxa,” strong overlap exists early in life; diagnostic discrimination can depend on metabolic testing and imaging. In a 26‑child cohort referred for suspected ARCL, mutations were found in 16 children (14 probands), and corpus callosum dysgenesis/dystonic posturing were associated with PYCR1 and ALDH18A1. (gardeitchik2014clinicalandbiochemical pages 1-2)

11. Outcomes / prognosis

  • The ALDH18A1 spectrum ranges from severe early neurocutaneous disease (including growth restriction and multisystem involvement) to later‑onset spastic paraplegia. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • HSP broadly does not reduce lifespan, but impairs quality of life. (awuah2024hereditaryspasticparaplegia pages 1-2)
  • No ALDH18A1‑specific survival curves, life expectancy estimates, or validated prognostic biomarkers were present in the retrieved sources.

12. Treatment

12.1 Metabolic interventions (evidence and rationale)

  • Early ARCL3A cases included paradoxical hyperammonemia “alleviated by protein,” suggesting dietary intake can modulate metabolic phenotype. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)
  • A 2020 review cites literature describing a “novel therapy with arginine” (full primary report not retrievable here), consistent with the pathway logic of replenishing urea‑cycle amino acids. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 18-22)

12.2 Supportive management

Disease‑specific management guidelines were not present in the retrieved corpus. For HSP broadly, there is “no disease‑modifying treatment,” implying management is symptomatic/supportive. (awuah2024hereditaryspasticparaplegia pages 1-2)

12.3 Experimental directions

A review of amino‑acid synthesis deficiencies summarizes attempted and hypothesized treatments in P5CS deficiency, including L‑glutamine escalation (minimal clinical change despite biochemical/EEG improvement) and potential therapeutic interest in nicotinamide due to NAD rescue in cellular models. (koning2017aminoacidsynthesis pages 6-7)

12.4 Clinical trials

A ClinicalTrials.gov search for ALDH18A1/P5CS did not surface any clearly ALDH18A1‑specific interventional trials in the retrieved set; returned trials were unrelated. (clinical‑trial tool output; no trial context IDs were provided for ALDH18A1‑specific disease trials).

Suggested MAXO terms (examples): - Amino acid supplementation therapy (arginine/proline/ornithine) (conceptual; limited primary evidence in retrieved texts) (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 18-22) - Physical therapy / rehabilitation therapy for spasticity (general HSP supportive care; not ALDH18A1‑specific in evidence) (awuah2024hereditaryspasticparaplegia pages 1-2)

13. Prevention

Primary prevention is not available (genetic disorder). Secondary/tertiary prevention centers on: - Early molecular diagnosis enabling anticipatory care and family counseling (fischerzirnsak2015recurrentdenovo pages 1-2) - Genetic counseling given de novo dominant cases and recessive inheritance patterns (fischerzirnsak2015recurrentdenovo pages 1-2, marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5)

14. Other species / natural disease

No naturally occurring veterinary ALDH18A1‑related analogs were identified in the retrieved sources.

15. Model organisms

The retrieved sources did not include specific ALDH18A1 animal models. The 2023 functional study used patient fibroblasts and an ALDH18A1‑null human embryonic kidney cell system expressing variant P5CS for mechanistic validation. (colonna2023functionalassessmentof pages 1-1)

Expert opinion / analysis (synthesis across authoritative sources)

1) Nosology: Multiple expert sources argue ALDH18A1 disorders should be conceptualized as a single P5CS deficiency continuum, with “essentially different spectra of ALDH18A1 mutations” producing dominant/recessive and neurocutaneous/motor presentations but sharing decreased P5CS function. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5) 2) Diagnostics: ALDH18A1 is unusual among HSP genes in having a plausible trait biomarker (low urea‑cycle amino acids/proline) and functional confirmation tests in fibroblasts; therefore adding plasma amino‑acid chromatography can be rational in the diagnostic work‑up, especially when genetic results are uncertain. (coutelier2015alterationofornithine pages 1-2) 3) Current research direction: The 2023 multi‑omics study shifts the field from single‑metabolite thinking to system‑level metabolic and redox pathway disruption (glutathione/putrescine), suggesting new biomarker candidates and therapeutic hypotheses (antioxidant/NAD‑related interventions) that need clinical validation. (colonna2023functionalassessmentof pages 1-1, koning2017aminoacidsynthesis pages 6-7)

Key figure/table evidence

A key table summarizing frequency of clinical findings in the eight‑person Arg138 de novo cohort is available and should be consulted for structured phenotyping. (fischerzirnsak2015recurrentdenovo media 44a36465)

Limitations of this report (evidence gaps)

  • Orphanet/ICD‑10/ICD‑11/MeSH identifiers and ALDH18A1‑specific prevalence/incidence were not retrievable via the provided tools in this run.
  • The primary 2012 “novel therapy with arginine” study was not obtainable, so arginine treatment details (dose/outcomes) cannot be stated beyond citation‑level mention in a review. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 18-22)
  • No ALDH18A1‑specific interventional clinical trials were identified in the retrieved ClinicalTrials.gov results.

References

  1. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 1-5): Clara Marco‐Marín, Juan M. Escamilla‐Honrubia, José L. Llácer, Marco Seri, Emanuele Panza, and Vicente Rubio. Δ1‐pyrroline‐5‐carboxylate synthetase deficiency: an emergent multifaceted urea cycle‐related disorder. Journal of Inherited Metabolic Disease, 43:657-670, Feb 2020. URL: https://doi.org/10.1002/jimd.12220, doi:10.1002/jimd.12220. This article has 33 citations and is from a peer-reviewed journal.

  2. (colonna2023functionalassessmentof pages 1-1): Maxwell B Colonna, Tonya Moss, Sneha Mokashi, Sujata Srikanth, Julie R Jones, Jackson R Foley, Cindy Skinner, Angie Lichty, Anthony Kocur, Tim Wood, Tracy Murray Stewart, Robert A Casero Jr., Heather Flanagan-Steet, Arthur S Edison, Michael J Lyons, and Richard Steet. Functional assessment of homozygous aldh18a1 variants reveals alterations in amino acid and antioxidant metabolism. Human molecular genetics, 32:732-744, Sep 2023. URL: https://doi.org/10.1093/hmg/ddac226, doi:10.1093/hmg/ddac226. This article has 20 citations and is from a domain leading peer-reviewed journal.

  3. (kalmar2021tremorasan pages 1-2): Tibor Kalmár, Zoltán Maróti, Alíz Zimmermann, and László Sztriha. Tremor as an early sign of hereditary spastic paraplegia due to mutations in aldh18a1. Brain and Development, 43:144-151, Jan 2021. URL: https://doi.org/10.1016/j.braindev.2020.07.015, doi:10.1016/j.braindev.2020.07.015. This article has 10 citations and is from a peer-reviewed journal.

  4. (chen2021novelcompoundmissense pages 1-2): Yi-Jun Chen, Zai-Qiang Zhang, Meng-Wen Wang, Yu-Sen Qiu, Ru-Ying Yuan, En-Lin Dong, Zhe Zhao, Hai-Tao Zhou, Ning Wang, Wan-Jin Chen, and Xiang Lin. Novel compound missense and intronic splicing mutation in aldh18a1 causes autosomal recessive spastic paraplegia. Frontiers in Neurology, May 2021. URL: https://doi.org/10.3389/fneur.2021.627531, doi:10.3389/fneur.2021.627531. This article has 7 citations and is from a peer-reviewed journal.

  5. (gardeitchik2014clinicalandbiochemical pages 1-2): Thatjana Gardeitchik, Miski Mohamed, Björn Fischer, Martin Lammens, Dirk Lefeber, Baiba Lace, Michael Parker, Ki-Joong Kim, Bing C Lim, Johannes Häberle, Livia Garavelli, Sujatha Jagadeesh, Ariana Kariminejad, Deanna Guerra, Michel Leão, Riikka Keski-Filppula, Han Brunner, Leo Nijtmans, Bert van den Heuvel, Ron Wevers, Uwe Kornak, and Eva Morava. Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa. European Journal of Human Genetics, 22:888-895, Aug 2014. URL: https://doi.org/10.1038/ejhg.2013.154, doi:10.1038/ejhg.2013.154. This article has 67 citations and is from a domain leading peer-reviewed journal.

  6. (OpenTargets Search: -ALDH18A1): Open Targets Query (-ALDH18A1, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  7. (fischerzirnsak2015recurrentdenovo pages 1-2): Björn Fischer-Zirnsak, Nathalie Escande-Beillard, Jaya Ganesh, Yu Xuan Tan, Mohammed Al Bughaili, Angela E. Lin, Inderneel Sahai, Paulina Bahena, Sara L. Reichert, Abigail Loh, Graham D. Wright, Jaron Liu, Elisa Rahikkala, Eniko K. Pivnick, Asim F. Choudhri, Ulrike Krüger, Tomasz Zemojtel, Conny van Ravenswaaij-Arts, Roya Mostafavi, Irene Stolte-Dijkstra, Sofie Symoens, Leila Pajunen, Lihadh Al-Gazali, David Meierhofer, Peter N. Robinson, Stefan Mundlos, Camilo E. Villarroel, Peter Byers, Amira Masri, Stephen P. Robertson, Ulrike Schwarze, Bert Callewaert, Bruno Reversade, and Uwe Kornak. Recurrent de novo mutations affecting residue arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa. American journal of human genetics, 97 3:483-92, Sep 2015. URL: https://doi.org/10.1016/j.ajhg.2015.08.001, doi:10.1016/j.ajhg.2015.08.001. This article has 93 citations and is from a highest quality peer-reviewed journal.

  8. (fischerzirnsak2015recurrentdenovo media 44a36465): Björn Fischer-Zirnsak, Nathalie Escande-Beillard, Jaya Ganesh, Yu Xuan Tan, Mohammed Al Bughaili, Angela E. Lin, Inderneel Sahai, Paulina Bahena, Sara L. Reichert, Abigail Loh, Graham D. Wright, Jaron Liu, Elisa Rahikkala, Eniko K. Pivnick, Asim F. Choudhri, Ulrike Krüger, Tomasz Zemojtel, Conny van Ravenswaaij-Arts, Roya Mostafavi, Irene Stolte-Dijkstra, Sofie Symoens, Leila Pajunen, Lihadh Al-Gazali, David Meierhofer, Peter N. Robinson, Stefan Mundlos, Camilo E. Villarroel, Peter Byers, Amira Masri, Stephen P. Robertson, Ulrike Schwarze, Bert Callewaert, Bruno Reversade, and Uwe Kornak. Recurrent de novo mutations affecting residue arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa. American journal of human genetics, 97 3:483-92, Sep 2015. URL: https://doi.org/10.1016/j.ajhg.2015.08.001, doi:10.1016/j.ajhg.2015.08.001. This article has 93 citations and is from a highest quality peer-reviewed journal.

  9. (mahungu2023themutationalprofile pages 1-2): Amokelani C. Mahungu, Elizabeth Steyn, Niki Floudiotis, Lindsay A. Wilson, Jana Vandrovcova, Mary M. Reilly, Christopher J. Record, Michael Benatar, Gang Wu, Sharika Raga, Jo M. Wilmshurst, Kireshnee Naidu, Michael Hanna, Melissa Nel, and Jeannine M. Heckmann. The mutational profile in a south african cohort with inherited neuropathies and spastic paraplegia. Frontiers in Neurology, Aug 2023. URL: https://doi.org/10.3389/fneur.2023.1239725, doi:10.3389/fneur.2023.1239725. This article has 14 citations and is from a peer-reviewed journal.

  10. (coutelier2015alterationofornithine pages 1-2): Marie Coutelier, Cyril Goizet, Alexandra Durr, Florence Habarou, Sara Morais, Alexandre Dionne-Laporte, Feifei Tao, Juliette Konop, Marion Stoll, Perrine Charles, Maxime Jacoupy, Raphaël Matusiak, Isabel Alonso, Chantal Tallaksen, Mathilde Mairey, Marina Kennerson, Marion Gaussen, Rebecca Schule, Maxime Janin, Fanny Morice-Picard, Christelle M. Durand, Christel Depienne, Patrick Calvas, Paula Coutinho, Jean-Marie Saudubray, Guy Rouleau, Alexis Brice, Garth Nicholson, Frédéric Darios, José L. Loureiro, Stephan Zuchner, Chris Ottolenghi, Fanny Mochel, and Giovanni Stevanin. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain : a journal of neurology, 138 Pt 8:2191-205, Aug 2015. URL: https://doi.org/10.1093/brain/awv143, doi:10.1093/brain/awv143. This article has 114 citations.

  11. (colonna2023functionalassessmentof pages 1-2): Maxwell B Colonna, Tonya Moss, Sneha Mokashi, Sujata Srikanth, Julie R Jones, Jackson R Foley, Cindy Skinner, Angie Lichty, Anthony Kocur, Tim Wood, Tracy Murray Stewart, Robert A Casero Jr., Heather Flanagan-Steet, Arthur S Edison, Michael J Lyons, and Richard Steet. Functional assessment of homozygous aldh18a1 variants reveals alterations in amino acid and antioxidant metabolism. Human molecular genetics, 32:732-744, Sep 2023. URL: https://doi.org/10.1093/hmg/ddac226, doi:10.1093/hmg/ddac226. This article has 20 citations and is from a domain leading peer-reviewed journal.

  12. (panza2016aldh18a1genemutations pages 8-8): Emanuele Panza, Juan M. Escamilla-Honrubia, Clara Marco-Marín, Nadine Gougeard, Giuseppe De Michele, Vincenzo Brescia Morra, Rocco Liguori, Leonardo Salviati, Maria Alice Donati, Roberto Cusano, Tommaso Pippucci, Roberto Ravazzolo, Andrea H. Németh, Sarah Smithson, Sally Davies, Jane A. Hurst, Domenico Bordo, Vicente Rubio, and Marco Seri. Aldh18a1 gene mutations cause dominant spastic paraplegia spg9: loss of function effect and plausibility of a dominant negative mechanism. Brain : a journal of neurology, 139 Pt 1:e3, Aug 2016. URL: https://doi.org/10.1093/brain/awv247, doi:10.1093/brain/awv247. This article has 61 citations.

  13. (lugli2022autosomalrecessivecutis pages 6-6): Licia Lugli, Francesca Cavalleri, Emma Bertucci, Björn Fischer-Zirnsak, Giulia Cinelli, Viola Trevisani, Cecilia Rossi, Marika Riva, Lorenzo Iughetti, and Alberto Berardi. Autosomal recessive cutis laxa type iiia: report of a patient with severe phenotype and review of the literature. European Journal of Medical Genetics, 65:104568, Sep 2022. URL: https://doi.org/10.1016/j.ejmg.2022.104568, doi:10.1016/j.ejmg.2022.104568. This article has 6 citations and is from a peer-reviewed journal.

  14. (fischerzirnsak2026neurocutaneousdisordersduea pages 20-22): B Fischer-Zirnsak and BL Callewaert. Neurocutaneous disorders due to mitochondrial proline synthesis defects. Unknown journal, 2026.

  15. (awuah2024hereditaryspasticparaplegia pages 1-2): Wireko Andrew Awuah, Joecelyn Kirani Tan, Anastasiia D Shkodina, Tomas Ferreira, Favour Tope Adebusoye, Adele Mazzoleni, Jack Wellington, Lian David, Ellie Chilcott, Helen Huang, Toufik Abdul-Rahman, Vallabh Shet, Oday Atallah, Jacob Kalmanovich, Riaz Jiffry, Divine Elizabeth Madhu, Kateryna Sikora, Oleksii Kmyta, and Mykhailo Yu Delva. Hereditary spastic paraplegia: novel insights into the pathogenesis and management. SAGE Open Medicine, Dec 2024. URL: https://doi.org/10.1177/20503121231221941, doi:10.1177/20503121231221941. This article has 29 citations.

  16. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 5-9): Clara Marco‐Marín, Juan M. Escamilla‐Honrubia, José L. Llácer, Marco Seri, Emanuele Panza, and Vicente Rubio. Δ1‐pyrroline‐5‐carboxylate synthetase deficiency: an emergent multifaceted urea cycle‐related disorder. Journal of Inherited Metabolic Disease, 43:657-670, Feb 2020. URL: https://doi.org/10.1002/jimd.12220, doi:10.1002/jimd.12220. This article has 33 citations and is from a peer-reviewed journal.

  17. (coutelier2015alterationofornithine pages 5-5): Marie Coutelier, Cyril Goizet, Alexandra Durr, Florence Habarou, Sara Morais, Alexandre Dionne-Laporte, Feifei Tao, Juliette Konop, Marion Stoll, Perrine Charles, Maxime Jacoupy, Raphaël Matusiak, Isabel Alonso, Chantal Tallaksen, Mathilde Mairey, Marina Kennerson, Marion Gaussen, Rebecca Schule, Maxime Janin, Fanny Morice-Picard, Christelle M. Durand, Christel Depienne, Patrick Calvas, Paula Coutinho, Jean-Marie Saudubray, Guy Rouleau, Alexis Brice, Garth Nicholson, Frédéric Darios, José L. Loureiro, Stephan Zuchner, Chris Ottolenghi, Fanny Mochel, and Giovanni Stevanin. Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain : a journal of neurology, 138 Pt 8:2191-205, Aug 2015. URL: https://doi.org/10.1093/brain/awv143, doi:10.1093/brain/awv143. This article has 114 citations.

  18. (marco‐marin2020δ1‐pyrroline‐5‐carboxylatesynthetasedeficiency pages 18-22): Clara Marco‐Marín, Juan M. Escamilla‐Honrubia, José L. Llácer, Marco Seri, Emanuele Panza, and Vicente Rubio. Δ1‐pyrroline‐5‐carboxylate synthetase deficiency: an emergent multifaceted urea cycle‐related disorder. Journal of Inherited Metabolic Disease, 43:657-670, Feb 2020. URL: https://doi.org/10.1002/jimd.12220, doi:10.1002/jimd.12220. This article has 33 citations and is from a peer-reviewed journal.

  19. (koning2017aminoacidsynthesis pages 6-7): T. J. de Koning. Amino acid synthesis deficiencies. Journal of Inherited Metabolic Disease, 40:609-620, Jun 2017. URL: https://doi.org/10.1007/s10545-017-0063-1, doi:10.1007/s10545-017-0063-1. This article has 87 citations and is from a peer-reviewed journal.