PYCR1-Related De Barsy Syndrome

Disease-characteristics research report — evidence reviewed through 18 October 2026

Executive summary

PYCR1-related De Barsy syndrome is the severe end of the phenotypic spectrum of biallelic PYCR1-related autosomal-recessive cutis laxa, historically called autosomal-recessive cutis laxa type IIIB (ARCL3B). Core manifestations are congenital loose, thin, translucent or wrinkled skin; a triangular/progeroid facial appearance; pre- and postnatal growth deficiency; hypotonia and developmental delay; joint laxity or contractures; osteopenia; and variably cataract, corneal clouding, movement disorder, seizures, or corpus-callosum abnormalities. The boundary between ARCL2B and ARCL3B is not biologically sharp: many authorities now treat them as one PYCR1-related ARCL spectrum, reserving “De Barsy syndrome” for severe cases, particularly those with ocular and neurologic involvement. [4][38][61]

The disease is caused by germline biallelic loss-of-function or function-reducing variants in PYCR1, encoding mitochondrial pyrroline-5-carboxylate reductase 1. PYCR1 catalyzes the final NAD(P)H-dependent step of de novo proline synthesis. Patient fibroblasts exhibit altered mitochondrial morphology, reduced membrane potential, and increased oxidative-stress-induced apoptosis; vertebrate models show dermal or epidermal abnormalities and apoptosis. These findings support a mechanism combining disturbed proline/redox metabolism, mitochondrial stress, loss of connective-tissue cells, and impaired extracellular-matrix maintenance. [17][19][33]

There is no disease-modifying therapy and no validated drug, gene, RNA, or cell therapy. Care is multidisciplinary and symptomatic. Amino-acid supplementation has only case-report-level evidence, without established clinical benefit. [172][175]

1. Disease information

1.1 Definition and scope

PYCR1-related De Barsy syndrome is a congenital Mendelian neurocutaneous and connective-tissue disorder caused by biallelic pathogenic variants in PYCR1. It belongs to the mitochondrial proline-synthesis disorders and the autosomal-recessive cutis laxa group. The classic De Barsy phenotype comprises progeroid facies, cutis laxa, growth restriction, intellectual/developmental disability, movement abnormalities, and ocular opacities. [35][39]

A major nosologic issue is that identical or overlapping PYCR1 genotypes have been diagnosed as:

• De Barsy syndrome;
• ARCL type 2B;
• ARCL type 3B;
• wrinkly-skin syndrome;
• geroderma osteodysplasticum-like disease; or
• a nonspecific progeroid cutis laxa syndrome.

A 2013 cohort included 33 individuals from 27 families whose original diagnoses spanned those categories, supporting one continuous PYCR1-related spectrum rather than sharply distinct disorders. [106]

1.2 Identifiers

The ICD mappings are not disease-specific and vary among legacy resources: older documents also use Q87.7 or Q87.8. The curated Orphanet listing currently supplies Q87.0 and ICD-11 LD28.2. [1][2][152][153][155]

1.3 Synonyms

Common names include:

• PYCR1-related De Barsy syndrome;
• De Barsy syndrome B;
• autosomal-recessive cutis laxa type IIIB / ARCL3B;
• PYCR1 deficiency;
• pyrroline-5-carboxylate reductase 1 deficiency;
• cutis laxa–corneal clouding–intellectual disability syndrome;
• progeroid syndrome of De Barsy;
• De Barsy–Moens–Dierckx syndrome.

Related but not completely interchangeable: PYCR1-related ARCL2B, wrinkly-skin syndrome, and geroderma osteodysplasticum-like phenotype. [151][153][163]

1.4 Evidence granularity

This report is an aggregated disease-level synthesis, not an EHR-derived individual-patient record. Evidence includes:

• small human case series and case reports;
• the 33-person genotype–phenotype cohort;
• curated resources such as OMIM, Orphanet, ClinVar and GeneReviews;
• patient-derived fibroblast and transfected-cell experiments;
• zebrafish, Xenopus and mouse models.

Only 114 individuals with biallelic PYCR1 variants had been collated in the 2026 GeneReviews synthesis; therefore, frequency estimates remain vulnerable to referral, ascertainment and publication bias. [61]

2. Etiology

2.1 Causal factor

The primary cause is biallelic germline pathogenic or likely pathogenic PYCR1 variation, inherited in an autosomal-recessive manner. The established molecular mechanism is predominantly loss of function, including absent protein after truncating variants and instability or reduced catalytic activity from missense variants. The gene–disease relationship is classified as definitive. [41][79][222]

No infectious, toxic, nutritional or lifestyle cause has been demonstrated.

2.2 Genetic risk factors

Disease risk requires two affected alleles, typically:

• homozygosity for one pathogenic allele, often in consanguineous families;
• compound heterozygosity for two pathogenic alleles;
• rarely, a whole-gene or intragenic deletion paired with another pathogenic allele.

Reported variant classes include missense, nonsense, frameshift, canonical splice-site, small insertion/deletion and whole-gene deletion variants. Most variants in the 2013 cohort clustered in exons 4–6; missense substitutions of conserved residues were most frequent, followed by splice variants and a nonsense variant. [106]

Representative variants—not a complete ClinVar catalogue—include:

[81][85][197][200][202]

The 2024 p.Ala187Thr study measured activity of 8.12±0.64 nmol/min/mg in mutant cells versus 17.78±0.62 in wild-type cells, P<0.01, providing functional evidence of impaired enzyme activity (PMID 39172257, published 22 August 2024). [33]

2.3 Susceptibility and modifier factors

• Consanguinity increases the probability that both parents carry the same rare pathogenic allele; it does not alter the molecular mechanism.
• A French-Acadian founder context has been reported for p.Arg266Gln in Maritime Canadian families, but no global founder mutation dominates.
• Variants in the first coding exon or first two exons have been associated with lower average severity and absent or mild intellectual disability, possibly because of alternative translation or residual function.
• Whole-gene deletion has been reported with the cutis-laxa phenotype but without intellectual disability, emphasizing imperfect genotype–phenotype correlation. [61][106][213]

No validated modifier gene, protective allele, polygenic-risk score, anticipation phenomenon or established germline-mosaicism rate is known.

2.4 Environmental and protective factors

No environmental exposure has been shown to cause or prevent the disorder. Oxidative stress is mechanistically relevant at the cellular level: PYCR1-deficient fibroblasts are unusually vulnerable to hydrogen peroxide and related oxidative challenges. This does not establish ordinary environmental oxidants as epidemiologic causes. Avoidance of smoking, excessive ultraviolet exposure, prolonged fasting and unnecessary high-injury activities is precautionary rather than primary prevention. [19][61]

There is no demonstrated protective diet or supplement. Proline, citrulline, arginine, antioxidant or vitamin-C therapy remains unproven.

3. Phenotypes

3.1 Frequency caveat

The best consolidated percentages encompass mitochondrial proline-synthesis disorders collectively, not exclusively molecularly confirmed ARCL3B. They are therefore useful estimates but should not be treated as precise PYCR1-specific penetrance figures. [61]

3.2 Core phenotype matrix

Frequencies and course derive from the 2026 aggregate synthesis and must be applied cautiously to PYCR1-related De Barsy syndrome. [61]

Important natural-history points

• Skin wrinkling is present at birth but may become less conspicuous with age.
• Thin/translucent skin and reduced subcutaneous fat may become more conspicuous.
• Motor and speech delay vary from mild to profound, but neurodevelopmental regression has not been a characteristic finding.
• Growth deficiency may partially improve with age.
• Brain MRI can be normal despite profound developmental disability. [61][66]

In a 2024 Chinese child homozygous for p.Ala187Thr, birth weight was 1,400 g; at 33 months he could not sit or hold an object independently, and his estimated developmental age was 1.5 months, despite a normal MRI. This demonstrates the severe end of expressivity but is a single case, not a typical outcome (PMID 39172257). [33]

3.3 Quality of life

No disease-specific EQ-5D, SF-36, PROMIS or validated caregiver-burden studies were located. Anticipated major burdens arise from developmental disability, impaired mobility, feeding problems, visual impairment, seizures, orthopedic deformity and need for long-term therapies. Cosmetic differences and the “prematurely aged” appearance may also affect psychosocial well-being. These impacts are clinically plausible but not quantified by formal PYCR1-specific quality-of-life research.

4. Genetic and molecular information

4.1 Gene and protein

[91][94][95]

4.2 Variant interpretation

• Disease-associated variants are germline, not somatic.
• Classification should use ACMG/AMP criteria and current ClinVar evidence.
• A VUS, or one pathogenic variant plus one VUS, does not establish the diagnosis.
• Population frequency must be checked per variant in gnomAD; causal alleles are generally absent or exceptionally rare. No single global disease-allele frequency or reliable carrier-frequency estimate is available.
• The principal mechanism is loss of function or reduced function, not established gain of function or dominant-negative action. [61][222]

The p.Ala187Thr allele illustrates a function-reducing missense mechanism: altered hydrogen-bonding was predicted, exogenous protein abundance was reduced, and catalytic activity fell by approximately 54% in transfected HEK293T cells. [33]

4.3 Modifier, epigenetic and structural-genomic evidence

• No validated modifier genes have been established.
• No disease-specific DNA-methylation signature, histone alteration or chromatin biomarker has been validated.
• Large chromosomal abnormalities are not typical; rare intragenic or whole-gene deletions may occur.
• CMA can detect a sufficiently large deletion but is not a first-line standalone test.
• There is no recurrent aneuploidy, translocation or inversion defining the disease.

5. Environmental information

There are no causal toxins, occupational exposures, pollutants, infections, smoking patterns, alcohol exposures or exercise behaviors known to produce PYCR1-related De Barsy syndrome.

Potentially relevant modifiers are largely precautionary:

• smoking may accelerate general elastic-fiber damage;
• excessive sun exposure may aggravate cutis-laxa skin;
• prolonged fasting may be undesirable in a mitochondrial/metabolic disorder;
• contact sports may increase injury risk in persons with joint laxity, osteopenia or cervical instability.

These recommendations are extrapolations from phenotype and mechanism, not proven gene–environment interactions. [61]

No bacterium, virus, fungus or parasite causes or transmits the disease; it is not contagious or zoonotic.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

1. Biallelic pathogenic PYCR1 variants lead to absent, unstable, misfolded or catalytically impaired mitochondrial PYCR1 protein.
2. Reduced PYCR1 activity leads to impaired conversion of Δ¹-pyrroline-5-carboxylate to L-proline and reduced oxidation of NAD(P)H to NAD(P)+.
3. This metabolic/redox disturbance leads to altered mitochondrial morphology and reduced mitochondrial membrane potential; a direct causal sequence is supported in patient fibroblasts, although the relative contribution of proline shortage versus redox imbalance remains unresolved.
4. Mitochondrial dysfunction leads to increased susceptibility to oxidative-stress-induced apoptosis.
5. Increased apoptosis and impaired survival of dermal/connective-tissue cells lead to dermal thinning and defective maintenance of collagen- and elastin-rich extracellular matrix; the precise collagen/elastin biochemical linkage is partly inferred.
6. Dermal and extracellular-matrix loss results in thin, translucent, lax and wrinkled skin, visible veins, reduced subcutaneous tissue and progeroid appearance.
7. The same proline/redox and cell-survival disturbance in bone, cartilage and periarticular connective tissue leads to osteopenia, delayed fontanel closure, Wormian bones, joint laxity, hip dislocation and contractures; parts of this tissue-level sequence remain inferred.
8. Branch A—neural development: mitochondrial stress and increased vulnerability of neural cells lead to, or are inferred to contribute to, hypotonia, developmental disability, movement abnormalities, seizures and variable corpus-callosum/gyral abnormalities.
9. Branch B—ocular connective tissue: impaired development or maintenance of corneal and lens structures leads to cataract, corneal clouding, blue sclerae and visual impairment.
10. Combined skin, skeletal, neurologic and ocular abnormalities result in the recognizable PYCR1-related De Barsy/ARCL phenotype.

The foundational human-cell and vertebrate study stated directly: “Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals.” It further reported that PYCR1 knockdown in zebrafish and Xenopus caused epidermal hypoplasia, blistering and markedly increased apoptosis (PMID 19648921, published online 2 August 2009). [17][107]

6.2 Pathway and biochemical detail

PYCR1 is downstream of ALDH18A1/P5CS in mitochondrial de novo proline synthesis:

Glutamate → glutamate semialdehyde/P5C → L-proline

PYCR1 catalyzes the second step and consumes NADH or NADPH. Suggested annotations include:

• GO:0006561 — proline biosynthetic process;
• GO:0004657 — pyrroline-5-carboxylate reductase activity;
• GO:0005739 — mitochondrion;
• GO:0005759 — mitochondrial matrix;
• GO:0034599 — cellular response to oxidative stress;
• GO:0008631 — intrinsic apoptotic signaling in response to oxidative stress;
• GO:0043066 — negative regulation of apoptotic process;
• GO:0043062 — extracellular structure organization;
• GO:0030199 — collagen fibril organization.

The affected metabolites/substrates include L-proline (CHEBI:17203), Δ¹-pyrroline-5-carboxylate, NADH, NADPH, NAD+ and NADP+. [91][105]

Plasma or urine proline, ornithine, citrulline and arginine may be low, but normal values are common. Thus amino-acid analysis is supportive, not diagnostic. [61][218]

6.3 Cellular and tissue mechanisms

Demonstrated in human fibroblasts:

• fragmented/altered mitochondrial network;
• reduced mitochondrial membrane potential;
• increased apoptosis after oxidative stress;
• reduced PYCR1 enzyme activity for at least some missense variants.

Supported or inferred at tissue level:

• reduced dermal thickness;
• reduced or fragmented elastic fibers;
• disturbed extracellular-matrix organization;
• reduced collagen abundance in experimental models.

Neurometabolic cutis-laxa biopsies have shown decreased, irregular, short, thick and fragmented elastic fibers and generalized ECM disorganization, although these findings are not unique to PYCR1 deficiency. [184]

Suggested cell types:

• dermal fibroblast — CL:0000057;
• keratinocyte — CL:0000312;
• neuron — CL:0000540;
• oligodendrocyte — CL:0000128, only indirectly implicated;
• osteoblast — CL:0000062;
• chondrocyte — CL:0000138;
• lens epithelial cell and corneal stromal keratocyte, appropriate ocular cell concepts where available.

6.4 Immune and epigenetic mechanisms

No primary immunodeficiency, autoimmunity or disease-driving inflammatory pathway is established. Secondary inflammatory responses to tissue stress have not been sufficiently characterized.

No reproducible disease-specific epigenomic, single-cell, spatial-transcriptomic, proteomic, lipidomic or multi-omic signature has entered clinical use. Much PYCR1 omics work concerns cancer metabolism and should not be extrapolated to congenital PYCR1 loss-of-function disease.

6.5 Recent mechanistic research, 2023–2024

A 2023 study/preprint reported five pathogenic PYCR1 alleles and a constitutive Pycr1-null mouse. Mutant mice had dermal thinning and fewer collagen fibers but relatively normal overall development, apparently because mouse Pycr2 can compensate more effectively than human PYCR2 in cutaneous fibroblasts. The authors proposed that a Pycr1/Pycr2 double knockout may better reproduce the full human phenotype. [124][126]

The 2024 p.Ala187Thr study provided variant-specific evidence of reduced protein expression and enzyme activity and quantitatively documented an extremely severe developmental trajectory (PMID 39172257). Its abstract concludes: “Our findings confirmed abnormal enzymatic activity and neurodevelopmental trajectory of this PYCR1 mutation.” [33]

7. Anatomical structures affected

Disease distribution is generally bilateral and systemic; no consistent lateralization is known. A unilateral manifestation such as isolated limb anomaly should be recorded separately rather than treated as characteristic.

8. Temporal development

8.1 Onset

• Prenatal: intrauterine growth restriction is common.
• Congenital/neonatal: cutis laxa, wrinkled skin, low weight/length, hypotonia, large fontanel, hip dislocation, adducted thumbs or clubfoot may be apparent.
• Infancy: feeding difficulty, poor growth and developmental delay become evident.
• Childhood: speech/motor disability, movement disorder, spasticity, scoliosis, osteopenia, cataract or corneal clouding may become clearer.

The onset is developmental and chronic rather than acute or episodic. [61]

8.2 Course

There is no formal staging system. A practical course model is:

1. Prenatal/neonatal phase: growth restriction and congenital connective-tissue phenotype.
2. Infancy/early childhood: emerging neurodevelopmental and feeding problems.
3. Later childhood/adolescence: orthopedic complications, mobility limitations and ocular disease may dominate.
4. Adulthood: data are sparse; disease is lifelong, with some skin wrinkling and growth parameters becoming less striking.

Regression and spontaneous remission are not typical. Skin appearance changes with age, but the genetic disease does not resolve. No critical therapeutic window has been established, although early visual, developmental, nutritional and orthopedic intervention is clinically important.

9. Inheritance and population

9.1 Inheritance

• Mode: autosomal recessive — HP:0000007.
• If both parents are heterozygous, each pregnancy has a 25% affected, 50% carrier and 25% non-carrier/unaffected probability.
• Heterozygous carriers are generally asymptomatic.
• Penetrance for convincingly pathogenic biallelic genotypes appears high, but formal age-specific estimates are unavailable.
• Expressivity is markedly variable.
• Genetic anticipation is not expected.
• Parental mosaicism, uniparental isodisomy or a hidden deletion can theoretically explain unusual segregation, but no disease-specific mosaicism frequency is known. [61]

9.2 Epidemiology

• Estimated prevalence: unknown, probably below 1 per 1,000,000.
• Incidence per 100,000 person-years: not established.
• Reported molecularly confirmed PYCR1 cases collated by 2026: 114.
• No consistent sex bias is expected for an autosomal-recessive condition.
• Cases occur worldwide, with no established ethnic preponderance.
• Consanguinity is common in published families because it increases homozygosity for rare alleles, but affected children also occur in non-consanguineous families.
• Reliable global carrier frequency is unavailable. [61]

A French-Acadian cluster involving p.Arg266Gln is evidence of a local founder effect, not globally elevated prevalence. [213]

10. Diagnostics

10.1 Diagnostic approach

Diagnosis requires compatible clinical findings plus biallelic pathogenic or likely pathogenic PYCR1 variants in trans.

Recommended workflow

1. Recognize congenital cutis laxa/progeroid facies with growth and neurodevelopmental abnormalities.
2. Obtain serum and urine amino-acid profiles, while recognizing that results may be normal.
3. Perform a cutis-laxa/connective-tissue/neurodevelopmental multigene panel or trio exome/genome sequencing.
4. Confirm variants and parental phase by Sanger or equivalent testing.
5. Add exon-level deletion/duplication analysis if sequencing identifies only one allele.
6. Undertake phenotype-directed baseline investigations.

Sequence analysis is estimated to detect about 98% of known PYCR1 pathogenic variants, with deletion/duplication analysis contributing approximately 2%. PYCR1 accounts for about 80.5% of reported mitochondrial proline-synthesis neurocutaneous disorders, not 80.5% of all cutis laxa. [61]

10.2 Clinical tests

The 2011 compound-heterozygous case broadened the phenotype to include congenital glaucoma, aortic-root dilation and hypertrophic pyloric stenosis, but these should be regarded as uncommon associations rather than defining criteria (PMID 22052856). [81]

10.3 Genetic-testing modalities

• Multigene panel: appropriate first-line test where a cutis-laxa phenotype is recognizable. Include at least PYCR1, ALDH18A1, ATP6V0A2, ATP6V1A, ATP6V1E1, GORAB, FBLN5, EFEMP2, LTBP4, LOX, EMILIN1, SLC25A24, LTBP1 and relevant progeroid genes.
• WES: highly useful because most known variants are coding or splice-proximal and phenotypic overlap is extensive.
• WGS: useful after negative panel/WES, particularly for structural, deep intronic or regulatory variants.
• Single-gene sequencing: reasonable in a highly characteristic familial phenotype or for cascade testing.
• CMA: low yield as an isolated test; can identify large deletions or an alternative genomic diagnosis.
• Karyotype/FISH: not routinely indicated.
• Mitochondrial-DNA testing: not indicated unless a separate mtDNA disorder is suspected.
• Repeat-expansion testing: not applicable.
• RNA sequencing: potentially useful to resolve a suspected splice variant, but not routine.
• Proteomics/metabolomics/epigenomics/liquid biopsy: research only.

10.4 Differential diagnosis

[61]

There are no universally adopted disease-specific clinical criteria; molecular confirmation is the standard.

10.5 Screening

• Not included in routine newborn biochemical screening.
• Newborn evaluation is indicated when there is an affected sibling or known familial genotype.
• Carrier and cascade testing should be offered after familial variants are identified.
• Prenatal diagnosis and preimplantation genetic testing are technically feasible.
• Population-wide carrier screening is not currently standard.

11. Outcome and prognosis

No valid 5- or 10-year survival rate, mortality rate or median life expectancy has been established. Available data do not support applying the high early mortality of severe pulmonary ARCL1 disorders to PYCR1-related ARCL.

Likely long-term morbidity includes:

• intellectual and developmental disability;
• impaired speech, mobility and self-care;
• joint instability or contractures;
• scoliosis and hip disease;
• osteopenia and occasional fracture;
• feeding and growth problems;
• cataract or corneal-clouding-associated visual impairment;
• seizures or movement disorder in some individuals.

Developmental improvement may occur with therapy, but full recovery from the genetic neurodevelopmental phenotype is not expected. Regression is not usual. Wrinkling and growth deficiency can become less prominent, which is phenotypic evolution rather than remission. [61]

No validated prognostic biomarker exists. Potential prognostic indicators include:

• variant location/residual enzyme function;
• degree of early developmental impairment;
• ocular involvement;
• congenital orthopedic burden;
• seizures or spasticity;
• nutritional status.

Variant-specific prediction remains unreliable: the same p.Ala187Thr allele was associated with mild intellectual disability in one compound-heterozygous individual and extremely severe delay in a homozygous child. [33]

12. Treatment

12.1 Current standard

There is no approved disease-modifying therapy. Management is individualized and multidisciplinary. No PYCR1-specific treatment-response rates or controlled adverse-event data are available. [169][172]

The limited literature explicitly states that supplementation evidence is confined to case reports and that clinical benefit remains unconfirmed. [172][175]

12.2 Surveillance

A reasonable schedule based on the current GeneReviews framework is:

• neurologic examination every six months initially, then annually;
• developmental/educational review every six months initially, then annually;
• growth and nutrition at each visit;
• orthopedic review every six months through infancy, then annually;
• annual anterior-chamber and lens examination;
• EEG as clinically indicated;
• echocardiography approximately every three years, more often if abnormal;
• brain MRI/MR angiography approximately every ten years or sooner for new neurologic findings;
• pulmonary function testing every three years from about age eight, where feasible. [63]

Some vascular surveillance recommendations are precautionary extrapolations across mitochondrial proline-synthesis disorders because intracranial arterial tortuosity has not been adequately evaluated in PYCR1 disease.

12.3 Experimental therapy

No confirmed active interventional trial, gene therapy, CRISPR therapy, RNA therapy, cell therapy, targeted small molecule or immunotherapy specific to PYCR1-related De Barsy syndrome was identified.

Proposed research directions—not clinical recommendations—include:

• restoration of PYCR1 expression;
• augmentation of compensatory PYCR2;
• mitochondrial/redox-targeted antioxidants;
• proline-pathway supplementation;
• prevention of stress-induced apoptosis;
• cell-specific gene replacement.

Proline or antioxidant rescue remains speculative; normal systemic proline in many patients and incomplete animal-model recapitulation argue against assuming that simple supplementation will correct disease. [180][218]

12.4 Anaesthesia and procedures

Before surgery, assess:

• difficult airway from craniofacial anatomy;
• joint and cervical-spine instability;
• ocular vulnerability;
• nutritional status;
• respiratory and cardiovascular involvement;
• skin fragility and pressure-point protection.

No PYCR1-specific pharmacogenomic guidance exists in PharmGKB/CPIC terms.

13. Prevention

13.1 Primary prevention

The phenotype cannot be prevented through vaccination, diet, lifestyle or avoidance of infection. Reproductive prevention options after identifying familial variants include:

• carrier testing of relatives;
• partner testing;
• preimplantation genetic testing for monogenic disease;
• chorionic-villus or amniotic-fluid prenatal diagnosis;
• donor gametes or other informed reproductive choices.

Genetic counseling should communicate the 25% recurrence risk per pregnancy when both parents are carriers. [61]

13.2 Secondary prevention

There is no population newborn-screening program. In an at-risk neonate:

• perform targeted familial-variant testing promptly;
• evaluate feeding, growth, hips, eyes, development and tone;
• begin early intervention before fixed contractures or preventable visual loss develops.

13.3 Tertiary prevention

Measures include:

• early developmental therapy;
• hip and scoliosis surveillance;
• maintenance of mobility and range of motion;
• treatment of cataract/corneal opacity before irreversible visual deprivation;
• seizure recognition and treatment;
• pressure-injury and skin protection;
• assessment of bone density and nutritional deficiencies;
• avoidance of smoking, excessive sun exposure, high-impact/contact sports where unsafe and prolonged fasting.

No vaccine, antimicrobial prophylaxis or public-health environmental intervention is disease-specific.

14. Other species and natural disease

No well-established naturally occurring PYCR1-related De Barsy syndrome was identified in companion animals, livestock or wildlife. Accordingly:

• there is no recognized affected breed;
• no Vertebrate Breed Ontology term is applicable;
• there is no zoonotic or cross-species transmission.

Relevant orthologues include:

Mouse, rat and human have one stringent PYCR1 orthologue, whereas zebrafish have two related orthologues/paralogues. [137][138]

15. Model organisms

The original model-organism abstract reports: “Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis.” (PMID 19648921). [107]

The stable zebrafish knockout was viable but developed a progeroid phenotype from four months and reached approximately 50% mortality by six months (PMID 31091804, published 14 May 2019). [123][125]

Mouse results are model-dependent. A 2021 KOMP study found no overt integumentary or cutis-laxa phenotype, whereas the more recent model detected dermal thinning and reduced collagen. Together these indicate partial rather than complete recapitulation and likely species-specific PYCR2 compensation. [130][126]

Recommended resources include MGI/IMPC/KOMP for mouse alleles, ZFIN for pycr1a, and patient-derived fibroblast repositories where consent permits.

Evidence highlights and exact abstract quotations

Knowledge gaps and curation cautions

1. ARCL2B versus ARCL3B: these should be cross-referenced as a spectrum, not treated as completely independent molecular disorders.
2. Phenotype frequencies: most percentages combine PYCR1 and ALDH18A1 disorders; annotate them as pooled estimates.
3. Epidemiology: no population-based incidence or robust prevalence data exist.
4. Prognosis: life expectancy and long-term adult natural history are unknown.
5. Mechanism: mitochondrial oxidative-stress susceptibility is demonstrated, but whether deficient proline supply, altered NAD(P)H redox balance, apoptosis or another PYCR1 function is dominant remains unresolved.
6. Treatment: no controlled therapeutic trial or validated disease-modifying intervention exists.
7. Omics: disease-specific single-cell, spatial, proteomic, lipidomic and epigenomic datasets are lacking.
8. Animal models: current models only partially reproduce human disease, especially the neurologic and ocular phenotype.
9. Ontology practice: retain MONDO:0013755 for gene-defined PYCR1-related De Barsy syndrome, while linking OMIM 614438, ARCL3B, ARCL2B/OMIM 612940 and the broader PYCR1-related ARCL spectrum.

Reference Validation

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Term Validation

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Obsolete terms

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• GO:0006561 (obsolete proline biosynthetic process) (1 mention) - replaced by GO:0055129

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