👪

Inheritance

1

Autosomal Recessive HP:0000007

Biallelic PYCR1 pathogenic variants, homozygous or compound heterozygous, cause the disorder. Heterozygous parents and sibs are asymptomatic; when both parents are heterozygous each sib has a 25% chance of being affected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:41570168 SUPPORT Other

"If both parents are known to be heterozygous for a pathogenic variant, each sib of an individual with PYCR1- or ALDH18A1-related ARCL has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier. Heterozygous sibs of..."

GeneReviews states recessive recurrence risks for PYCR1-related ARCL and that heterozygous sibs are asymptomatic.

PMID:22052856 SUPPORT Human clinical

"Mutation analysis of PYCR1 revealed compound heterozygous PYCR1 mutations, including a p.P115fsX7 null mutation allele and a second allele with two missense mutations in cis: p.G248E and p.G297R."

A de Barsy syndrome patient carries biallelic (compound heterozygous) PYCR1 variants.

◆

Subtypes

1

Autosomal Recessive Cutis Laxa Type 2B MONDO:0013051

The ARCL2B label covers PYCR1-related patients described as having cutis laxa of variable severity, intrauterine growth restriction, congenital hip dislocation, joint hyperlaxity, wrinkling of the dorsum of the hands and feet and progeroid facial features, with frequent hypotonia and developmental delay. It overlaps clinically and genetically with de Barsy syndrome (ARCL3B); the same PYCR1 genotypes have received either diagnosis.

Show evidence (2 references)

PMID:24035636 SUPPORT Human clinical

"Here we describe 33 patients with PYCR1-related ARCL from 27 families with initial diagnoses varying between wrinkly skin syndrome, gerodermia osteodysplastica, De Barsy syndrome or more severe progeria syndromes."

One PYCR1 cohort includes patients first diagnosed as de Barsy syndrome and as other ARCL entities, supporting modelling ARCL2B and ARCL3B as one PYCR1-related spectrum.

ORPHA:357064 SUPPORT Other

"A rare, hereditary, developmental defect with connective tissue involvement characterized by cutis laxa of variable severity, in utero growth restriction, congenital hip dislocation and joint hyperlaxity, wrinkling of the skin, in particular the dorsum of hands and feet, and progeroid facial features."

Orphanet definition of the ARCL2B branch of the spectrum.

⚙

Pathophysiology

6

Biallelic PYCR1 Loss of Function

Biallelic PYCR1 variants reduce the amount or catalytic activity of mitochondrial pyrroline-5-carboxylate reductase 1. A null allele with a second missense allele lowered PYCR1 mRNA and protein in patient skin fibroblasts, and a homozygous missense allele lowered protein abundance and reductase activity in transfected cells.

PYCR1 hgnc:9721 ↓ DECREASED

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

pyrroline-5-carboxylate reductase activity GO:0004735 ↓ DECREASED

Downstream

Impaired Mitochondrial Proline Biosynthesis PYCR1 performs the final reduction of pyrroline-5-carboxylate to proline, so its loss is expected to reduce de novo proline synthesis.

Mitochondrial Morphology and Membrane Potential Defect Fibroblasts from affected individuals show altered mitochondria. Whether this follows from proline shortage, altered NAD(P)H redox balance, or another PYCR1 function is unresolved.

Neurodevelopmental Impairment PYCR1 loss is associated with hypotonia, psychomotor delay and variable intellectual disability; the neural mechanism is unknown, and severity tracks the location of the variant.

Intrauterine growth retardation Prenatal growth restriction is a hallmark of PYCR1 deficiency; the mechanism is unknown.

Postnatal growth retardation Postnatal growth deficiency accompanies PYCR1 deficiency; the mechanism is unknown.

Strabismus Strabismus occurs in about a third of evaluated patients; the mechanism is unknown.

Cataract Lens opacity occurs in a minority of patients; the mechanism is unknown.

Glaucoma Glaucoma has been reported in individual patients; the mechanism is unknown.

Osteopenia Reduced bone mineralization occurs in PYCR1 deficiency; the bone mechanism is unknown.

Wormian bones Wormian bones are reported in PYCR1 deficiency; the mechanism is unknown.

Large fontanelles An open or large fontanel is reported in PYCR1 deficiency; the mechanism is unknown.

Adducted thumb Adducted thumbs are reported in PYCR1 deficiency; the mechanism is unknown.

Aortic root dilatation Aortic root dilatation was reported in one de Barsy patient; the mechanism is unknown.

Show evidence (2 references)

PMID:22052856 SUPPORT Human clinical

"The effect of mutation results in a reduction of PYCR1 mRNA expression and PYCR1 protein expression in skin fibroblasts from the patient."

Patient fibroblasts from a de Barsy syndrome case show reduced PYCR1 expression.

PMID:39172257 SUPPORT In vitro / ex vivo

"Mutagenesis and enzyme assay study revealed decreased activity of the mutant protein in vitro, indicating that this mutation impairs PYCR1 function."

A patient missense allele reduces PYCR1 catalytic activity.

Impaired Mitochondrial Proline Biosynthesis

Reduced conversion of pyrroline-5-carboxylate to proline in mitochondria. In mouse the paralogue Pycr2 can supply proline when Pycr1 is lost, so the size of the systemic proline deficit in patients is uncertain.

L-proline biosynthetic process GO:0055129 ↓ DECREASED

Animal models

pycr1 knockout zebrafish Zebrafish recapitulates Adult knockout fish have reduced proline content.

Downstream

Progeroid Skin and Connective-Tissue Changes Elastin is a proline-rich protein abundant in the most affected tissues, so reduced local proline supply is the proposed link to the connective-tissue phenotype. This remains a hypothesis.

Show evidence (2 references)

PMID:31091804 SUPPORT Model organism

"Biochemical assays showed that adult pycr1 KO fish have significantly reduced proline and extracellular matrix contents"

Loss of pycr1 lowers proline content in a vertebrate model.

PMID:33734376 SUPPORT Model organism

"Thus, Pycr1 and -2 have redundant functions in proline biosynthesis, and their loss makes proline a semi-essential amino acid."

Mouse genetics place PYCR1 in proline biosynthesis and show paralogue redundancy that limits the deficit when PYCR1 alone is lost.

Mitochondrial Morphology and Membrane Potential Defect

PYCR1-deficient patient fibroblasts show altered mitochondrial morphology and reduced membrane potential, and skin biopsies show abnormal mitochondria and cristae.

skin fibroblast CL:0002620

mitochondrion organization GO:0007005 ⚠ ABNORMAL

Downstream

Increased Oxidative-Stress-Induced Apoptosis Mitochondrially compromised PYCR1-deficient cells are hypersensitive to oxidative stress and undergo more apoptosis.

Show evidence (2 references)

PMID:19648921 SUPPORT In vitro / ex vivo

"Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals."

Direct observation of the mitochondrial defect in patient fibroblasts.

PMID:21487760 SUPPORT Human clinical

"Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size."

Patient skin biopsies show abnormal mitochondrial and cristae morphology.

Increased Oxidative-Stress-Induced Apoptosis

PYCR1-deficient fibroblasts undergo more apoptosis when challenged with oxidative stress. Silencing PYCR1 with PYCR2 in normal fibroblasts reproduces the oxidative-stress hypersensitivity, and pycr1 knockdown or knockout vertebrates show marked apoptosis.

skin fibroblast CL:0002620

intrinsic apoptotic signaling pathway in response to oxidative stress GO:0008631 ↑ INCREASED

Animal models

pycr1 knockout zebrafish Zebrafish partially recapitulates Reproduces increased apoptosis and reduced antioxidant capacity in vivo.

pycr1 morpholino knockdown Xenopus and zebrafish embryos Xenopus partially recapitulates Reproduces increased apoptosis with skin hypoplasia in embryos.

Downstream

Progeroid Skin and Connective-Tissue Changes Loss of skin cells by apoptosis is the proposed route to cutaneous hypoplasia; in pycr1 knockdown frog and fish embryos epidermal hypoplasia accompanies a large rise in apoptosis.

Show evidence (3 references)

PMID:19648921 SUPPORT In vitro / ex vivo

"Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals."

Patient fibroblasts show increased oxidative-stress-induced apoptosis.

PMID:26733354 SUPPORT INDIRECT In vitro / ex vivo

"Silencing of both PYCR1 and PYCR2 by expressing short hairpin RNAs induced defects in cell proliferation, partial fragmentation of the mitochondrial network, and hypersensitivity to oxidative stress in hTERT-immortalized human foreskin fibroblasts (HFF-hTERT)."

Combined PYCR1/PYCR2 knockdown in normal fibroblasts reproduces the mitochondrial fragmentation and oxidative-stress sensitivity; it is a double knockdown, not the patient genotype.

PMID:31091804 SUPPORT Model organism

"Marked apoptosis and senescence were detected in pycr1 KO zebrafish"

pycr1 knockout zebrafish show marked apoptosis.

Progeroid Skin and Connective-Tissue Changes

Skin of affected individuals shows smaller and fragmented elastic fibres and irregular collagen fibrils, with loss of subcutaneous fat. These connective-tissue changes underlie the lax, thin, wrinkled skin and the prematurely aged appearance, and joint laxity is part of the same connective-tissue phenotype.

skin fibroblast CL:0002620

Animal models

Pycr1 null mouse Mouse fails to recapitulate The single Pycr1 knockout does not reproduce the human skin phenotype.

Downstream

Cutis laxa Elastic-fibre and collagen changes in the dermis are the tissue substrate of lax skin.

Thin skin Dermal and subcutaneous connective-tissue loss presents as thin skin.

Excessive wrinkled skin Lax dermis wrinkles, most visibly on the dorsum of the hands and feet.

Prominent superficial veins Thin skin with little subcutaneous fat leaves superficial veins visible.

Lipodystrophy Loss of subcutaneous adipose tissue is part of the progeroid tissue phenotype.

Prematurely aged appearance The skin and fat changes produce the progeroid appearance.

Triangular face Facial lipoatrophy and thin skin contribute to the triangular progeroid face.

Joint hypermobility Joint laxity accompanies the connective-tissue phenotype; the periarticular mechanism is not studied.

Congenital hip dislocation Hip dislocation is attributed to connective-tissue laxity; the mechanism is not studied.

Hernia Hernias are attributed to connective-tissue weakness of the abdominal wall; the mechanism is not studied in PYCR1 disease.

Pes planus Flat feet are attributed to ligamentous laxity; the mechanism is not studied in PYCR1 disease.

Blue sclerae Blue sclerae are taken to reflect thin scleral connective tissue; scleral histology has not been reported in PYCR1 disease.

Corneal opacity A corneal button from a PYCR1 patient showed loss of the stromal lamellar architecture, a connective-tissue defect of the cornea.

Show evidence (2 references)

PMID:21487760 SUPPORT Human clinical

"Light- and electron microscopy investigations of skin biopsies showed smaller and fragmented elastic fibres, abnormal morphology of the mitochondria and their cristae, and slightly abnormal collagen fibril diameters with irregular outline and variable size."

Patient skin biopsies show the elastic-fibre and collagen-fibril abnormalities.

PMID:19648921 SUPPORT Human clinical

"Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues."

The founding study frames the disease as progeroid connective-tissue change.

Neurodevelopmental Impairment

PYCR1 deficiency impairs neurodevelopment, with hypotonia, psychomotor delay, variable intellectual disability, movement disorder and corpus-callosum dysgenesis. Neural mechanisms have not been studied in patient tissue. Patients with variants in the first two exons have milder or absent intellectual disability.

Downstream

Global developmental delay

Intellectual disability

Hypotonia

Microcephaly

Seizure

Abnormal corpus callosum morphology

Athetosis

Dystonia

Spasticity

Show evidence (1 reference)

PMID:24035636 SUPPORT Human clinical

"Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects."

Psychomotor retardation and hypotonia are core features in the PYCR1 cohort.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

32

Cardiovascular 2

Prominent superficial veins VERY_FREQUENT HP:0001015

Show evidence (3 references)

PMID:21487760 SUPPORT Human clinical

"Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints."

Visible veins over the chest in PYCR1-deficient patients.

PMID:28294978 SUPPORT Human clinical

"ARCL2B infants have very thin skin, visible veins over thorax and clenched hands, but these symptoms improve considerably as the patient grows older"

Visible veins over the thorax in ARCL2B infants.

PMID:28294978 SUPPORT Human clinical

"Visible veins on the chest | NE | NE | 0/2 | 46/53 | 87%"

Visible veins on the chest 46/53 (87%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Aortic root dilatation Aortic root aneurysm HP:0002616

Show evidence (1 reference)

PMID:22052856 SUPPORT Human clinical

"The exceptional observation of congenital glaucoma, aortic root dilatation, and idiopathic hypertrophic pyloric stenosis in this patient widened the range of symptoms that have been noted in DBS."

Aortic root dilatation in a compound-heterozygous PYCR1 de Barsy patient.

Eye 5

Blue sclerae FREQUENT HP:0000592

Show evidence (2 references)

PMID:19576563 SUPPORT Human clinical

"Craniofacial dysmorphism included microcephaly, broad and prominent forehead, prominent ears, blue sclerae, and sagging cheeks."

Blue sclerae in the eastern Canadian PYCR1 (p.Arg266Gln) ARCL2 families.

PMID:28294978 SUPPORT Human clinical

"Blue sclera | 2/4 | 50% | 1/2 | 23/48 | 48%"

Blue sclera 23/48 (48%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Strabismus FREQUENT HP:0000486

Show evidence (2 references)

PMID:23963297 SUPPORT Human clinical

"Patients 2–8 had corneal clouding and/or cataract; patients 4, 7, 9, 10, 12, 13, 14 and 15 had strabismus"

Strabismus in a neurometabolic cutis-laxa cohort that includes PYCR1 patients 4 and 7 (patients 3, 4, 6 and 7 carried PYCR1 mutations).

PMID:28294978 SUPPORT Human clinical

"Strabismus | 21/48 | 44% | 1/2 | 17/48 | 35%"

Strabismus 17/48 (35%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Corneal opacity OCCASIONAL HP:0007957

Show evidence (4 references)

PMID:24035636 SUPPORT Human clinical

"Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value."

Corneal clouding is rare but predictive in the PYCR1 cohort.

PMID:36524384 SUPPORT Human clinical

"A 2 year-old child presented to the pediatric ophthalmology outpatients with bilateral congenital corneal opacification"

Bilateral congenital corneal opacification in a homozygous PYCR1 patient.

PMID:28294978 SUPPORT Human clinical

"Cataract/corneal clouding | 1/38 | 3% | 0/2 | 13/88 | 15%"

Cataract/corneal clouding 13/88 (15%). The row combines both lesions, so the figure is an upper bound for either alone. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Cataract OCCASIONAL HP:0000518

Show evidence (4 references)

PMID:24035636 SUPPORT Human clinical

"Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value."

Cataract is rare but predictive in the PYCR1 cohort.

PMID:28294978 SUPPORT Human clinical

"Though not seen in all patients with cutis laxa IIB, wormian bones, athetoid movements, lipodystrophy, cataracts and corneal clouding are highly specific for ARCL2B."

Cataract is a specific though inconstant ARCL2B feature.

PMID:28294978 SUPPORT Human clinical

"Cataract/corneal clouding | 1/38 | 3% | 0/2 | 13/88 | 15%"

Cataract/corneal clouding 13/88 (15%). The row combines both lesions, so the figure is an upper bound for either alone. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Glaucoma HP:0000501

Show evidence (2 references)

PMID:22052856 SUPPORT Human clinical

"The exceptional observation of congenital glaucoma, aortic root dilatation, and idiopathic hypertrophic pyloric stenosis in this patient widened the range of symptoms that have been noted in DBS."

Congenital glaucoma in a compound-heterozygous PYCR1 de Barsy patient.

PMID:36524384 SUPPORT Human clinical

"a left eye trabeculectomy for medically uncontrolled angle-closure glaucoma was performed"

Angle-closure glaucoma in a homozygous PYCR1 de Barsy patient.

Head and Neck 4

Triangular face HP:0000325

Show evidence (3 references)

PMID:24035636 SUPPORT Human clinical

"Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects."

A triangular facial gestalt is a distinctive hallmark in the PYCR1 cohort.

PMID:21487760 SUPPORT Human clinical

"All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose."

Triangular face in all six PYCR1-deficient patients.

PMID:41570168 SUPPORT Other

"These disorders are characterized by thin, translucent skin with wrinkles (especially on the hands and feet); typical facial characteristics including a triangular face with a progeroid appearance, a broad forehead (prominent-appearing neurocranium due to small viscerocranium), convex nasal..."

Triangular face with pointed chin. GeneReviews statement pooled across PYCR1- and ALDH18A1-related disease, so it is supporting rather than PYCR1-specific.

Microcephaly FREQUENT HP:0000252

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"The neurological findings common to ARCL2A and ARCL2B patients are intellectual disability, hypotonia, psychomotor retardation, microcephaly, and seizures."

Microcephaly is listed among neurological findings of ARCL2B.

PMID:28294978 SUPPORT Human clinical

"Microcephaly | 33/47 | 70% | 0/2 | 32/49 | 65%"

Microcephaly 32/49 (65%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Wormian bones FREQUENT HP:0002645

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"Though not seen in all patients with cutis laxa IIB, wormian bones, athetoid movements, lipodystrophy, cataracts and corneal clouding are highly specific for ARCL2B."

Wormian bones are a specific though inconstant ARCL2B feature.

PMID:28294978 SUPPORT Human clinical

"Wormian bonses | NE | NE | 0/2 | 20/32 | 63%"

Wormian bones 20/32 (63%); the source row label is misspelled "Wormian bonses". ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Large fontanelles FREQUENT HP:0000239

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"Short stature and open fontanel are common findings in cutis laxa types 2A and 2B, but occur less frequently in GO"

Open fontanel is common in ARCL2B.

PMID:28294978 SUPPORT Human clinical

"Persistent open Fontanel | 53/58 | 91% | 1/1 | 30/40 | 75%"

Persistent open fontanel 30/40 (75%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Integument 4

Cutis laxa HP:0000973

Show evidence (3 references)

PMID:36524384 SUPPORT Human clinical

"dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint"

Homozygous PYCR1 de Barsy patient with loose wrinkled skin.

PMID:39172257 SUPPORT Human clinical

"The patient displayed characteristic symptoms of ARCL2B, which were consistent with previous reports, including wrinkled and/or sagging skin, distinct facial dysmorphism, hyperlaxity of joints, growth retardation, hypotonia, and psychomotor developmental delay."

Homozygous PYCR1 patient with wrinkled and sagging skin.

PMID:28294978 SUPPORT Human clinical

"ARCL2B is characterized by intra-uterine growth retardation, cutis laxa, wrinkling of skin, particularly of dorsum of hands and feet, visible veins on the chest, congenital hip dislocation, hyperextensible joints, and adducted thumbs."

Cutis laxa is part of the characteristic ARCL2B presentation.

Thin skin HP:0000963

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"ARCL2B infants have very thin skin, visible veins over thorax and clenched hands, but these symptoms improve considerably as the patient grows older"

Thin skin in PYCR1-related ARCL2B infants, improving with age.

PMID:41570168 SUPPORT Other

"These disorders are characterized by thin, translucent skin with wrinkles (especially on the hands and feet); typical facial characteristics including a triangular face with a progeroid appearance, a broad forehead (prominent-appearing neurocranium due to small viscerocranium), convex nasal..."

Thin, translucent skin. GeneReviews statement pooled across PYCR1- and ALDH18A1-related disease, so it is supporting rather than PYCR1-specific.

Excessive wrinkled skin VERY_FREQUENT HP:0007392

Show evidence (4 references)

PMID:21487760 SUPPORT Human clinical

"Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints."

PYCR1-deficient patients have wrinkling over the dorsum of the hands and feet.

PMID:28294978 SUPPORT Human clinical

"ARCL2B is characterized by intra-uterine growth retardation, cutis laxa, wrinkling of skin, particularly of dorsum of hands and feet, visible veins on the chest, congenital hip dislocation, hyperextensible joints, and adducted thumbs."

Wrinkling of the dorsum of the hands and feet characterizes ARCL2B.

PMID:28294978 SUPPORT Human clinical

"Wrinkled skin | 60/60 | 100% | 2/2 | 93/93 | 100%"

Wrinkled skin 93/93 (100%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Prematurely aged appearance VERY_FREQUENT HP:0007495

Show evidence (3 references)

PMID:36524384 SUPPORT Human clinical

"dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint"

Progeroid appearance in a homozygous PYCR1 de Barsy patient.

PMID:28294978 SUPPORT Human clinical

"Aged Appearance | 25/25 | 100% | 2/2 | 89/87 | 98%"

Aged appearance reported at 98%; the printed count 89/87 has a numerator larger than its denominator, so the frequency rests on the stated percentage. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

PMID:41570168 SUPPORT Other

"These disorders are characterized by thin, translucent skin with wrinkles (especially on the hands and feet); typical facial characteristics including a triangular face with a progeroid appearance, a broad forehead (prominent-appearing neurocranium due to small viscerocranium), convex nasal..."

Triangular face with a progeroid appearance. GeneReviews statement pooled across PYCR1- and ALDH18A1-related disease, so it is supporting rather than PYCR1-specific.

Limbs 3

Congenital hip dislocation FREQUENT HP:0001374

Show evidence (4 references)

PMID:36524384 SUPPORT Human clinical

"dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint"

Congenital hip dislocation in a homozygous PYCR1 de Barsy patient.

PMID:28294978 SUPPORT Human clinical

"ARCL2B is characterized by intra-uterine growth retardation, cutis laxa, wrinkling of skin, particularly of dorsum of hands and feet, visible veins on the chest, congenital hip dislocation, hyperextensible joints, and adducted thumbs."

Congenital hip dislocation is part of the ARCL2B presentation.

PMID:28294978 SUPPORT Human clinical

"Congenital hip dislocation | 9/15 | 60% | 1/2 | 53/86 | 62%"

Congenital hip dislocation 53/86 (62%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Adducted thumb FREQUENT HP:0001181

Show evidence (3 references)

PMID:28294978 SUPPORT Human clinical

"ARCL2B is characterized by intra-uterine growth retardation, cutis laxa, wrinkling of skin, particularly of dorsum of hands and feet, visible veins on the chest, congenital hip dislocation, hyperextensible joints, and adducted thumbs."

Adducted thumbs are part of the ARCL2B presentation.

PMID:28294978 SUPPORT Human clinical

"Adducted thumbs | 0/5 | 0% | 0/2 | 28/45 | 62%"

Adducted thumbs 28/45 (62%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

PMID:41570168 SUPPORT Other

"Additional features can include joint laxity, congenital hypotonia, progressive increased lower limb reflexes/spasticity, congenital hip dislocation, adducted thumbs, corneal clouding, and lens opacities."

Adducted thumbs. GeneReviews statement pooled across PYCR1- and ALDH18A1-related disease, so it is supporting rather than PYCR1-specific.

Pes planus FREQUENT HP:0001763

Show evidence (1 reference)

PMID:28294978 SUPPORT Human clinical

"Flat feet | 1/3 | 33% | 1/2 | 5/7 | 71%"

Flat feet 5/7 (71%), from only seven evaluated cases. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Musculoskeletal 6

Lipodystrophy HP:0009125

Show evidence (2 references)

PMID:21487760 SUPPORT Human clinical

"All patients have distinct facial features comprising triangular face, loss of adipose tissue and thin pointed nose."

Loss of adipose tissue in all six PYCR1-deficient patients.

PMID:28294978 SUPPORT Human clinical

"The adult ARCL2B patient, however, is not particularly short but usually has a low weight and exhibits lipodystrophy"

Adult ARCL2B patients exhibit lipodystrophy.

Hypotonia FREQUENT HP:0001252

Show evidence (4 references)

PMID:24035636 SUPPORT Human clinical

"Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects."

Hypotonia is a distinctive hallmark in the PYCR1 cohort.

PMID:36524384 SUPPORT Human clinical

"dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint"

Muscular hypotonia in a homozygous PYCR1 de Barsy patient.

PMID:28294978 SUPPORT Human clinical

"Hypotonia | 29/35 | 83% | 2/2 | 33/46 | 72%"

Hypotonia 33/46 (72%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Spasticity HP:0001257

Show evidence (2 references)

PMID:23963297 SUPPORT Human clinical

"Several CL syndromes are presenting with muscle hypotonia (ATP6V0A2 and PYCR1 defects), spasticity (PYCR1 and ALDH18A1 defects), dystonic, athetoid movements (ALDH18A1 and PYCR1 defect) or epilepsy (ALDH18A1 and ATP6V0A2 defects)."

Spasticity is listed as a presenting feature of PYCR1 defects.

PMID:41570168 SUPPORT Other

"Additional features can include joint laxity, congenital hypotonia, progressive increased lower limb reflexes/spasticity, congenital hip dislocation, adducted thumbs, corneal clouding, and lens opacities."

Progressive increased lower limb reflexes and spasticity. GeneReviews statement pooled across PYCR1- and ALDH18A1-related disease, so it is supporting rather than PYCR1-specific.

Joint hypermobility VERY_FREQUENT HP:0001382

Show evidence (4 references)

PMID:21487760 SUPPORT Human clinical

"Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints."

Hyperextensible joints in PYCR1-deficient patients.

PMID:36524384 SUPPORT Human clinical

"dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint"

Multiple hyperextensible joints in a homozygous PYCR1 de Barsy patient.

PMID:28294978 SUPPORT Human clinical

"Hyperextensibility of joints | 40/46 | 87% | 2/2 | 75/79 | 95%"

Hyperextensibility of joints 75/79 (95%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Osteopenia FREQUENT HP:0000938

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"While patients with ARCL2B may manifest osteopenia, osteopenia that is severe enough to cause pathologic fractures is more characteristic of GO."

ARCL2B patients may have osteopenia, rarely severe enough to fracture.

PMID:28294978 SUPPORT Human clinical

"Osteopenia | NE | NE | 1/2 | 38/52 | 73%"

Osteopenia 38/52 (73%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Hernia FREQUENT HP:0100790

Show evidence (1 reference)

PMID:28294978 SUPPORT Human clinical

"Hernia | 17/36 | 47% | 1/2 | 33/84 | 39%"

Hernia 33/84 (39%); the row does not state inguinal or umbilical, so the general hernia term is bound. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Nervous System 6

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:24035636 SUPPORT Human clinical

"Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects."

Psychomotor retardation is a distinctive hallmark in the PYCR1 cohort.

PMID:39172257 SUPPORT Human clinical

"The patient has typical clinical findings consistent with ARCL2B and extremely severe developmental delays."

A homozygous p.Ala187Thr patient had extremely severe developmental delay.

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (4 references)

PMID:21487760 SUPPORT Human clinical

"Three of the patients from a large consanguineous family do not have mental retardation, while the remaining three patients from three unrelated families have mental and developmental delay."

Intellectual disability is present in some PYCR1-deficient patients and absent in others.

PMID:28294978 SUPPORT Human clinical

"Patients with GO have normal mentation, whereas the majority of the patients with ARCL2A and ARCL2B have variable degrees of intellectual disability."

Most ARCL2B patients have variable intellectual disability.

PMID:28294978 SUPPORT Human clinical

"Intellectual Disability | 45/58 | 78% | 2/2 | 86/92 | 93%"

Intellectual disability 86/92 (93%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

Seizure OCCASIONAL HP:0001250

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"The neurological findings common to ARCL2A and ARCL2B patients are intellectual disability, hypotonia, psychomotor retardation, microcephaly, and seizures."

Seizures are listed among neurological findings of ARCL2B.

PMID:28294978 SUPPORT Human clinical

"Seizures | 13/53 | 25% | 0/2 | 14/62 | 23%"

Seizures 14/62 (23%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Abnormal corpus callosum morphology FREQUENT HP:0001273

Show evidence (2 references)

PMID:23963297 SUPPORT Human clinical

"An important observation is the common presence of corpus callosum dysgenesis or corpus callosum agenesis (CCA) in patients with PYCR1 mutations."

Corpus-callosum dysgenesis or agenesis is common in PYCR1 patients in this cohort.

PMID:28294978 SUPPORT Human clinical

"Corpus Callosum Dysgenesis | 2/20 | 10% | NE | 26/53 | 49%"

Corpus callosum dysgenesis 26/53 (49%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Athetosis OCCASIONAL HP:0002305

Show evidence (2 references)

PMID:24035636 SUPPORT Human clinical

"Corneal clouding or cataracts, athetoid movements, and finger contractures were rather rare features, but had a high predictive value."

Athetoid movements are rare but predictive in the PYCR1 cohort.

PMID:28294978 SUPPORT Human clinical

"Athetoid/Dystonic Movements | 1/15 | 6% | 0/2 | 17/85 | 20%"

Athetoid/dystonic movements 17/85 (20%). The row combines athetosis and dystonia, so the figure is an upper bound for either alone. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Dystonia OCCASIONAL HP:0001332

Show evidence (2 references)

PMID:23963297 SUPPORT Human clinical

"Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects."

Dystonic posturing discriminated PYCR1 (and ALDH18A1) defects in a neurometabolic cutis-laxa cohort.

PMID:28294978 SUPPORT Human clinical

"Athetoid/Dystonic Movements | 1/15 | 6% | 0/2 | 17/85 | 20%"

Athetoid/dystonic movements 17/85 (20%). The row combines athetosis and dystonia, so the figure is an upper bound for either alone. ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

Growth 2

Intrauterine growth retardation VERY_FREQUENT HP:0001511

Show evidence (3 references)

PMID:24035636 SUPPORT Human clinical

"Intrauterine growth retardation, a characteristic triangular facial gestalt, psychomotor retardation, and hypotonia were the most relevant distinctive hallmarks of ARCL due to proline de novo synthesis defects."

IUGR is a distinctive hallmark in the 33-patient PYCR1 cohort.

PMID:28294978 SUPPORT Human clinical

"Intra-Uterine Growth Retardation | 7/17 | 41% | 2/2 | 78/83 | 94%"

Intrauterine growth retardation 78/83 (94%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

PMID:41570168 SUPPORT Other

"These disorders are characterized by thin, translucent skin with wrinkles (especially on the hands and feet); typical facial characteristics including a triangular face with a progeroid appearance, a broad forehead (prominent-appearing neurocranium due to small viscerocranium), convex nasal..."

Prenatal growth deficiency. GeneReviews statement pooled across PYCR1- and ALDH18A1-related disease, so it is supporting rather than PYCR1-specific.

Postnatal growth retardation FREQUENT HP:0008897

Show evidence (4 references)

PMID:21487760 SUPPORT Human clinical

"Additional features are short stature, wrinkling over dorsum of hand and feet, visible veins over the chest and hyperextensible joints."

Short stature in PYCR1-deficient patients.

PMID:36524384 SUPPORT Human clinical

"dysmorphic facial features, including loose wrinkled skin, progeroid appearance, delayed milestones, short stature, multiple hyper-extensible joints, muscular hypotonia, pectus excavatum and congenital dislocation of the hip joint"

Short stature in a homozygous PYCR1 de Barsy patient.

PMID:28294978 SUPPORT Human clinical

"Postnatal Growth Delay | 10/24 | 42% | 0/2 | 43/64 | 67%"

Postnatal growth delay 43/64 (67%). ARCL2B (PYCR1) literature aggregate in Table 2 of this review: the fourth and fifth values are the positive/evaluated count and percentage across published ARCL2B cases (the first three are ARCL2A); these cases may overlap other cited reports.

+ 1 more reference

🧬

Genetic Associations

1

PYCR1 (Causative)

Gene: PYCR1 hgnc:9721 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:19648921 SUPPORT Human clinical

"Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1."

The founding gene-discovery study identifies PYCR1 mutations in ARCL kindreds.

PMID:24035636 SUPPORT Human clinical

"In our cohort we identified 20 different PYCR1 mutations of which seven were novel. Most of the mutations accumulated in exons 4 to 6. Missense alterations of highly conserved residues were most frequent followed by splice site changes and a single nonsense mutation."

Describes the PYCR1 allelic spectrum in the largest cohort.

PMID:24035636 SUPPORT Human clinical

"Analysis of genotype-phenotype correlation revealed that patients with mutations in the first two exons had lower average clinical scores and absent or only mild intellectual disability."

Supports the stated genotype-severity correlation.

Variants (2)

c.797G>A (p.Arg266Gln)

Homozygous missense variant at the last nucleotide of exon 6 found in ARCL2 families from an eastern Canadian subpopulation isolate. It causes skipping of exon 6, deleting the reductase functional domain and shifting the downstream reading frame.

Show evidence (1 reference)

PMID:19576563 SUPPORT Human clinical

"Skipping of the associated exon was confirmed in RNA from blood lymphocytes of affected homozygotes and heterozygous mutation carriers. Exon skipping leads to deletion of the reductase functional domain-coding region and an obligatory downstream frameshift."

Patient RNA shows the splice consequence of the founder allele.

c.559G>A (p.Ala187Thr)

Homozygous missense variant in a Chinese child with severe developmental delay. In transfected HEK293T cells the mutant protein was less abundant and had about half the wild-type reductase activity.

Show evidence (1 reference)

PMID:39172257 SUPPORT In vitro / ex vivo

"The in vitro assay showed significantly decreased 3,4-dehydro-L-proline dehydrogenase activity in Mut cells compared with WT cells (17.78 ± 0.62 vs. 8.12 ± 0.64 nmol/min/mg protein"

Transfected-cell enzyme assay showing reduced activity of the p.Ala187Thr protein.

💊

Medical Actions

5

Physical Therapy

Action: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Supportive physical therapy for motor delay and lower-limb spasticity. GeneReviews also lists contact sports, prolonged fasting, smoking and sunbathing among circumstances to avoid for this disorder group.

Show evidence (2 references)

PMID:41570168 SUPPORT Other

"physical therapy for motor delays and spastic diplegia"

GeneReviews management recommendation for the proline-synthesis cutis-laxa disorders, including PYCR1-related ARCL.

PMID:41570168 SUPPORT Other

"Agents/circumstances to avoid: Contact sports; prolonged fasting; activities requiring hyperbaric pressure; aesthetic surgical intervention; activities with high acceleration or that increase the risk for seizures; smoking; sunbathing."

GeneReviews list of circumstances to avoid for the disorder group.

Speech and Swallowing Therapy

Action: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Prelingual speech therapy to support swallowing and speech development.

Show evidence (1 reference)

PMID:41570168 SUPPORT Other

"Prelingual speech therapy to improve swallowing and speech development"

GeneReviews management recommendation for the disorder group.

Penetrating Keratoplasty

Action: Penetrating Keratoplasty NCIT:C222070

Platform: Surgery

Corneal transplantation for vision-limiting congenital corneal opacity, reported in a homozygous PYCR1 de Barsy patient who underwent bilateral sequential penetrating keratoplasty followed by amblyopia therapy.

Show evidence (2 references)

PMID:36524384 SUPPORT Human clinical

"Ophthalmic management in the form of bilateral sequential penetrating keratoplasties and a left eye trabeculectomy for medically uncontrolled angle-closure glaucoma was performed."

Case-level report of keratoplasty for corneal opacity in PYCR1 disease.

PMID:41570168 SUPPORT Other

"correction of diffraction abnormalities and possible surgical correction in those with impaired vision due to clouding"

GeneReviews recommends possible surgical correction of vision-impairing corneal clouding. The recommendation is pooled across PYCR1- and ALDH18A1-related disease.

Orthopedic Management

Orthopedic treatment of hip dislocation, scoliosis and joint contractures. No NCIT clinical-action term in the treatment enum names orthopedic care that is not necessarily surgical, so no term is bound.

Show evidence (1 reference)

PMID:41570168 SUPPORT Other

"treatment of hip dislocation, scoliosis, and joint contractures per orthopedist"

GeneReviews management recommendation, pooled across PYCR1- and ALDH18A1-related disease.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling on autosomal recessive recurrence risk, carrier testing of relatives once the familial variants are known, and prenatal or preimplantation genetic testing.

Show evidence (1 reference)

PMID:41570168 SUPPORT Other

"Carrier testing for at-risk relatives requires prior identification of the PYCR1 or ALDH18A1 pathogenic variants in the family."

GeneReviews counseling recommendation naming PYCR1.

🔬

Diagnosis

3

Molecular Genetic Confirmation

Diagnosis rests on compatible clinical findings with identification of biallelic pathogenic PYCR1 variants. Clinical features overlap with ALDH18A1-related ARCL, ATP6V0A2-related ARCL2A and geroderma osteodysplastica, so molecular testing is needed to assign the gene.

molecular genetic testing NCIT:C19770

Results: Biallelic pathogenic or likely pathogenic PYCR1 variants.

Show evidence (1 reference)

PMID:41570168 SUPPORT Other

"The diagnosis of a neurocutaneous disorder due a to mitochondrial proline synthesis defect can be established in a proband with characteristic clinical findings and identification of biallelic ALDH18A1 or PYCR1 pathogenic variants"

GeneReviews diagnostic criterion for PYCR1-related ARCL.

Annual Anterior Chamber Examination

Surveillance: yearly anterior-chamber evaluation for corneal clouding and cataract.

anterior chamber eye examination NCIT:C38060

Show evidence (1 reference)

PMID:41570168 SUPPORT Other

"anterior chamber evaluation to assess for corneal clouding and cataract annually"

GeneReviews surveillance recommendation, pooled across PYCR1- and ALDH18A1-related disease.

Echocardiographic Surveillance

Surveillance: echocardiogram every three years, more often when findings are abnormal. Aortic root dilatation has been reported in a PYCR1 de Barsy patient, whose authors recommended cardiovascular survey.

echocardiography NCIT:C16525

Show evidence (2 references)

PMID:41570168 SUPPORT Other

"echocardiogram every three years or more frequently in those with abnormal findings"

GeneReviews surveillance recommendation, pooled across PYCR1- and ALDH18A1-related disease.

PMID:22052856 SUPPORT Human clinical

"The findings presented here suggest a mutation screening of PYCR1 and cardiovascular survey in patients with DBS."

After finding aortic root dilatation in a PYCR1 de Barsy patient, the authors recommend cardiovascular survey.

📊

Prevalence

2

Worldwide

Cases/families reported in the literature Ultra-rare

A 2024 report counted approximately 70 published individuals with PYCR1 variants since the gene was identified in 2009. This is a literature count with no population denominator, not a prevalence estimate.

Show evidence (1 reference)

PMID:39172257 SUPPORT BACKGROUND Human clinical

"approximately 70 cases carrying PYCR1 mutations have been reported, with about 84% of mutations in exons 4 to 6"

The introduction of a single-case report summarises the size of the published PYCR1 case literature.

Worldwide

Point prevalence <1 in 1,000,000 ARCL2B

Orphanet worldwide point-prevalence class for ARCL2B is <1 / 1 000 000.

Show evidence (1 reference)

ORPHA:357064 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence"

Orphanet epidemiology row for ARCL2B.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from PYCR1-Related De Barsy Syndrome:

Autosomal recessive cutis laxa type 2A MONDO:0018163

Overlapping Features ATP6V0A2-related cutis laxa shares neonatal skin laxity, hypotonia and developmental delay. It has abnormal glycosylation and cobblestone brain malformation, where PYCR1 disease has normal biochemistry and callosal dysgenesis.

Distinguishing Features

Abnormal glycosylation biochemistry supports ARCL2A; it is uninformative for PYCR1 disease.
Cobblestone cortical dysgenesis on MRI favours ARCL2A; corpus-callosum dysgenesis or agenesis favours PYCR1 disease.

Show evidence (2 references)

PMID:28294978 SUPPORT Human clinical

"Brain MRI imaging would be expected to differentiate between ARCL2A and ARCL2B based on the presence of cobblestone dysgenesis in ARCL2A compared to dysgenesis or agenesis of corpus callosum in cutis laxa IIB"

Distinguishes ARCL2A and PYCR1-related ARCL2B by brain imaging.

PMID:28294978 SUPPORT Human clinical

"Biochemical analysis is good for identification of ARCL2A patients but it cannot be used for identification of ARCL2B and GO cases."

Biochemical testing identifies ARCL2A but not PYCR1 disease.

Geroderma osteodysplastica Not Yet Curated MONDO:0009271

Overlapping Features GORAB-related geroderma osteodysplastica shares wrinkled skin on the dorsum of the hands and feet and osteopenia; some PYCR1 families were first diagnosed with it.

Distinguishing Features

Severe osteopenia with pathologic fractures and normal intellect favour geroderma osteodysplastica.
Intellectual disability favours PYCR1 disease.

Show evidence (2 references)

PMID:21204221 SUPPORT Human clinical

"While the patients with GORAB mutations have severe osteopenia, the patients with PYCR1 mutations have severe mental retardation."

Contrasts the bone and cognitive phenotypes of the two disorders.

PMID:28294978 SUPPORT Human clinical

"Patients with GO have normal mentation, whereas the majority of the patients with ARCL2A and ARCL2B have variable degrees of intellectual disability."

Normal cognition favours geroderma osteodysplastica over PYCR1 disease.

🐁

Animal Models

3

pycr1 knockout zebrafish

Stable pycr1 knockout zebrafish are viable but show apoptosis and senescence from the embryo or larva stage, reduced proline and extracellular matrix content, a progeroid phenotype from 4 months and about 50% mortality by 6 months.

Species

Zebrafish

Genotype

pycr1 homozygous 2-bp deletion in exon 4 (knockout)

Publication

PMID:31091804

Pathograph links

Increased Oxidative-Stress-Induced Apoptosis partially recapitulates fidelity: moderate observes: cellular Reproduces increased apoptosis and reduced antioxidant capacity in vivo.

Limitations: Fish skin, lifespan and paralogue complement differ from human; the ageing and behavioural phenotypes have no direct human counterpart in the congenital disorder.

Show evidence (1 reference)

PMID:31091804 SUPPORT Model organism

"Marked apoptosis and senescence were detected in pycr1 KO zebrafish"

The knockout shows the apoptosis node in vivo.

Impaired Mitochondrial Proline Biosynthesis recapitulates fidelity: moderate observes: organism Adult knockout fish have reduced proline content.

Show evidence (1 reference)

PMID:31091804 SUPPORT Model organism

"Biochemical assays showed that adult pycr1 KO fish have significantly reduced proline and extracellular matrix contents"

Measured proline reduction in the knockout.

pycr1 morpholino knockdown Xenopus and zebrafish embryos

Knockdown of the PYCR1 orthologues in Xenopus and zebrafish embryos caused epidermal hypoplasia and blistering with a large increase in apoptosis.

Species

Xenopus

Genotype

morpholino knockdown of the PYCR1 orthologues

Publication

PMID:19648921

Pathograph links

Increased Oxidative-Stress-Induced Apoptosis partially recapitulates fidelity: low observes: tissue Reproduces increased apoptosis with skin hypoplasia in embryos.

Limitations: Transient embryonic knockdown with morpholino-specific caveats; the affected layer is epidermis, while the human lesion is dermal and connective-tissue.

Show evidence (1 reference)

PMID:19648921 SUPPORT Model organism

"Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis."

The knockdown embryos show apoptosis with skin hypoplasia.

Pycr1 null mouse

A Pycr1 null allele produced no integument or cutis-laxa-related phenotype, while Pycr1;Pycr2 double mutants were sub-viable, indicating that the two paralogues are largely redundant in mouse.

Species

Mouse

Genotype

Pycr1 null allele (homozygous)

Publication

PMID:33734376

Pathograph links

Progeroid Skin and Connective-Tissue Changes fails to recapitulate fidelity: low observes: organism The single Pycr1 knockout does not reproduce the human skin phenotype.

Limitations: Mouse Pycr2 compensates for loss of Pycr1 in proline synthesis, so the single knockout does not reproduce the human connective-tissue phenotype.

Show evidence (2 references)

PMID:33734376 SUPPORT Model organism

"A null allele of Pycr1 did not show integument or CL-related phenotypes."

Direct report that the Pycr1 null mouse lacks the cutis-laxa phenotype.

+ 1 more reference

{ }

Source YAML

click to show

name: PYCR1-Related De Barsy Syndrome
creation_date: "2026-10-18T00:00:00Z"
category: Mendelian
description: >-
  Autosomal recessive neurocutaneous connective-tissue disorder caused by
  biallelic pathogenic variants in PYCR1, which encodes mitochondrial
  pyrroline-5-carboxylate reductase 1, the enzyme for the final step of de novo
  proline synthesis. Affected individuals have congenital lax, thin and wrinkled
  skin (most marked on the dorsum of the hands and feet) with visible veins, a
  triangular progeroid face, intrauterine and postnatal growth deficiency,
  hypotonia, psychomotor delay and variable intellectual disability, joint
  hypermobility and congenital hip dislocation, and in a subset corneal
  clouding, cataract, athetoid or dystonic movements, and corpus-callosum
  dysgenesis. The historical labels de Barsy syndrome (cutis laxa, autosomal
  recessive, type IIIB) and autosomal recessive cutis laxa type 2B describe
  overlapping parts of one PYCR1-related spectrum. Patient fibroblasts show
  altered mitochondrial morphology and membrane potential and increased
  apoptosis under oxidative stress.
disease_term:
  preferred_term: PYCR1-related de Barsy syndrome
  term:
    id: MONDO:0013755
    label: PYCR1-related de Barsy syndrome
synonyms:
- ARCL3B
- Cutis laxa, autosomal recessive, type IIIB
- PYCR1 deficiency
- Pyrroline-5-carboxylate reductase 1 deficiency
- De Barsy syndrome caused by mutation in PYCR1
- PYCR1-related autosomal recessive cutis laxa
parents:
- Cutis Laxa
- Inborn Error of Amino Acid Metabolism
notes: >-
  Lump/split decision. The entry is bound to MONDO:0013755 (PYCR1-related de
  Barsy syndrome, OMIM 614438, ARCL3B), the term the curation stub named, and
  carries autosomal recessive cutis laxa type 2B (MONDO:0013051, OMIM 612940,
  ARCL2B) as a has_subtypes row rather than as a second disorder entry. The
  basis is the 33-patient PYCR1 cohort (PMID:24035636), whose patients carried
  initial diagnoses ranging across wrinkly skin syndrome, gerodermia
  osteodysplastica, de Barsy syndrome and progeria and were analysed as one
  PYCR1-related ARCL spectrum with genotype-dependent severity, and the
  GeneReviews chapter (PMID:41570168), which treats PYCR1-related ARCL as one
  disorder. MONDO places the two terms as siblings (ARCL3B under de Barsy
  syndrome and inherited cutis laxa; ARCL2B under autosomal recessive cutis
  laxa type 2), so no mappings.mondo_mappings row is asserted: neither
  exactMatch nor narrowMatch describes ARCL2B relative to the bound term. The
  structure mirrors ALDH18A1_De_Barsy_Spectrum, the P5CS counterpart one step
  upstream in the same pathway. No dismech mechanism module was a genuine fit:
  mitochondrial_dysfunction is scoped to age-associated bioenergetic decline,
  and no elastic-fibre or cutis-laxa module exists. The GeneReviews chapter
  pools PYCR1- and ALDH18A1-related disease, so its abstract is cited only for
  statements it makes about PYCR1 or about the group as a whole, and
  PYCR1-specific primary reports are preferred for phenotypes.
has_subtypes:
- name: ARCL2B
  display_name: Autosomal Recessive Cutis Laxa Type 2B
  subtype_term:
    preferred_term: autosomal recessive cutis laxa type 2B
    term:
      id: MONDO:0013051
      label: autosomal recessive cutis laxa type 2B
  description: >-
    The ARCL2B label covers PYCR1-related patients described as having cutis
    laxa of variable severity, intrauterine growth restriction, congenital hip
    dislocation, joint hyperlaxity, wrinkling of the dorsum of the hands and
    feet and progeroid facial features, with frequent hypotonia and
    developmental delay. It overlaps clinically and genetically with de Barsy
    syndrome (ARCL3B); the same PYCR1 genotypes have received either diagnosis.
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe 33 patients with PYCR1-related ARCL from 27 families with
      initial diagnoses varying between wrinkly skin syndrome, gerodermia
      osteodysplastica, De Barsy syndrome or more severe progeria syndromes.
    explanation: >-
      One PYCR1 cohort includes patients first diagnosed as de Barsy syndrome
      and as other ARCL entities, supporting modelling ARCL2B and ARCL3B as one
      PYCR1-related spectrum.
  - reference: ORPHA:357064
    reference_title: Autosomal recessive cutis laxa type 2B
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare, hereditary, developmental defect with connective tissue
      involvement characterized by cutis laxa of variable severity, in utero
      growth restriction, congenital hip dislocation and joint hyperlaxity,
      wrinkling of the skin, in particular the dorsum of hands and feet, and
      progeroid facial features.
    explanation: Orphanet definition of the ARCL2B branch of the spectrum.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PYCR1 pathogenic variants, homozygous or compound heterozygous,
    cause the disorder. Heterozygous parents and sibs are asymptomatic; when
    both parents are heterozygous each sib has a 25% chance of being affected.
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If both parents are known to be heterozygous for a pathogenic variant,
      each sib of an individual with PYCR1- or ALDH18A1-related ARCL has at
      conception a 25% chance of being affected, a 50% chance of being
      heterozygous, and a 25% chance of being unaffected and not a carrier.
      Heterozygous sibs of a proband with PYCR1-related ARCL are asymptomatic.
    explanation: >-
      GeneReviews states recessive recurrence risks for PYCR1-related ARCL and
      that heterozygous sibs are asymptomatic.
  - reference: PMID:22052856
    reference_title: Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation analysis of PYCR1 revealed compound heterozygous PYCR1
      mutations, including a p.P115fsX7 null mutation allele and a second
      allele with two missense mutations in cis: p.G248E and p.G297R.
    explanation: A de Barsy syndrome patient carries biallelic (compound heterozygous) PYCR1 variants.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2024 report counted approximately 70 published individuals with PYCR1
    variants since the gene was identified in 2009. This is a literature count
    with no population denominator, not a prevalence estimate.
  evidence:
  - reference: PMID:39172257
    reference_title: Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      approximately 70 cases carrying PYCR1 mutations have been reported, with
      about 84% of mutations in exons 4 to 6
    explanation: >-
      The introduction of a single-case report summarises the size of the
      published PYCR1 case literature.
- population: Worldwide
  subtype: ARCL2B
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class for ARCL2B is <1 / 1 000 000.
  evidence:
  - reference: ORPHA:357064
    reference_title: Autosomal recessive cutis laxa type 2B
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence"
    explanation: Orphanet epidemiology row for ARCL2B.
genetic:
- name: PYCR1
  gene_term:
    preferred_term: PYCR1
    term:
      id: hgnc:9721
      label: PYCR1
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    PYCR1 (17q25.3) encodes mitochondrial pyrroline-5-carboxylate reductase 1,
    which reduces delta-1-pyrroline-5-carboxylate to proline with oxidation of
    NAD(P)H. Reported disease alleles include missense, splice-site, nonsense,
    frameshift and whole-gene deletion variants; most cluster in exons 4 to 6.
    Missense alleles reduce protein abundance or catalytic activity, and some
    are predicted to interfere with PYCR1 multimerization. Patients with
    variants in the first two exons had lower average clinical scores and
    absent or mild intellectual disability, but the correlation is imperfect.
  evidence:
  - reference: PMID:19648921
    reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygosity mapping in several kindreds with ARCL identified a candidate
      region on chromosome 17q25. By high-throughput sequencing of the entire
      candidate region, we detected disease-causing mutations in the gene PYCR1.
    explanation: The founding gene-discovery study identifies PYCR1 mutations in ARCL kindreds.
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our cohort we identified 20 different PYCR1 mutations of which seven
      were novel. Most of the mutations accumulated in exons 4 to 6. Missense
      alterations of highly conserved residues were most frequent followed by
      splice site changes and a single nonsense mutation.
    explanation: Describes the PYCR1 allelic spectrum in the largest cohort.
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of genotype-phenotype correlation revealed that patients with
      mutations in the first two exons had lower average clinical scores and
      absent or only mild intellectual disability.
    explanation: Supports the stated genotype-severity correlation.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_ca242cd8-1f57-4c7b-ba97-5ec0c97b425b-2020-05-21T191607.864Z
    subtype: ARCL2B
    notes: >-
      ClinGen classified PYCR1 for autosomal recessive cutis laxa type 2B
      (MONDO:0013051), the has_subtypes row of this entry. No ClinGen record
      names MONDO:0013755 itself.
    evidence:
    - reference: CGGV:assertion_ca242cd8-1f57-4c7b-ba97-5ec0c97b425b-2020-05-21T191607.864Z
      reference_title: PYCR1 / autosomal recessive cutis laxa type 2B (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PYCR1 | HGNC:9721 | autosomal recessive cutis laxa type 2B | MONDO:0013051 | AR | Definitive"
      explanation: ClinGen classifies the PYCR1-ARCL2B relationship as definitive with autosomal recessive inheritance.
  variants:
  - name: c.797G>A (p.Arg266Gln)
    description: >-
      Homozygous missense variant at the last nucleotide of exon 6 found in
      ARCL2 families from an eastern Canadian subpopulation isolate. It causes
      skipping of exon 6, deleting the reductase functional domain and shifting
      the downstream reading frame.
    evidence:
    - reference: PMID:19576563
      reference_title: Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skipping of the associated exon was confirmed in RNA from blood
        lymphocytes of affected homozygotes and heterozygous mutation carriers.
        Exon skipping leads to deletion of the reductase functional
        domain-coding region and an obligatory downstream frameshift.
      explanation: Patient RNA shows the splice consequence of the founder allele.
  - name: c.559G>A (p.Ala187Thr)
    description: >-
      Homozygous missense variant in a Chinese child with severe developmental
      delay. In transfected HEK293T cells the mutant protein was less abundant
      and had about half the wild-type reductase activity.
    evidence:
    - reference: PMID:39172257
      reference_title: Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The in vitro assay showed significantly decreased
        3,4-dehydro-L-proline dehydrogenase activity in Mut cells compared with
        WT cells (17.78 ± 0.62 vs. 8.12 ± 0.64 nmol/min/mg protein
      explanation: Transfected-cell enzyme assay showing reduced activity of the p.Ala187Thr protein.
pathophysiology:
- name: Biallelic PYCR1 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic PYCR1 variants reduce the amount or catalytic activity of
    mitochondrial pyrroline-5-carboxylate reductase 1. A null allele with a
    second missense allele lowered PYCR1 mRNA and protein in patient skin
    fibroblasts, and a homozygous missense allele lowered protein abundance and
    reductase activity in transfected cells.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: PYCR1
    modifier: DECREASED
    term:
      id: hgnc:9721
      label: PYCR1
  molecular_functions:
  - preferred_term: pyrroline-5-carboxylate reductase activity
    modifier: DECREASED
    term:
      id: GO:0004735
      label: pyrroline-5-carboxylate reductase activity
  evidence:
  - reference: PMID:22052856
    reference_title: Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The effect of mutation results in a reduction of PYCR1 mRNA expression and
      PYCR1 protein expression in skin fibroblasts from the patient.
    explanation: Patient fibroblasts from a de Barsy syndrome case show reduced PYCR1 expression.
  - reference: PMID:39172257
    reference_title: Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutagenesis and enzyme assay study revealed decreased activity of the
      mutant protein in vitro, indicating that this mutation impairs PYCR1
      function.
    explanation: A patient missense allele reduces PYCR1 catalytic activity.
  downstream:
  - target: Impaired Mitochondrial Proline Biosynthesis
    description: >-
      PYCR1 performs the final reduction of pyrroline-5-carboxylate to proline,
      so its loss is expected to reduce de novo proline synthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19576563
      reference_title: Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Similarly, loss of PYCR1 activity in our patients would be expected to
        reduce proline biosynthesis.
      explanation: >-
        The authors infer reduced proline synthesis from loss of PYCR1
        activity in their patients; it is an expectation, not a measurement.
    - reference: PMID:31091804
      reference_title: Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Biochemical assays showed that adult pycr1 KO fish have significantly
        reduced proline and extracellular matrix contents
      explanation: pycr1 knockout zebrafish have measurably reduced proline.
  - target: Mitochondrial Morphology and Membrane Potential Defect
    description: >-
      Fibroblasts from affected individuals show altered mitochondria. Whether
      this follows from proline shortage, altered NAD(P)H redox balance, or
      another PYCR1 function is unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19648921
      reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Altered mitochondrial morphology, membrane potential and increased
        apoptosis rate upon oxidative stress were evident in fibroblasts from
        affected individuals.
      explanation: Patient fibroblasts carrying PYCR1 mutations show the mitochondrial defect.
  - target: Neurodevelopmental Impairment
    description: >-
      PYCR1 loss is associated with hypotonia, psychomotor delay and variable
      intellectual disability; the neural mechanism is unknown, and severity
      tracks the location of the variant.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24035636
      reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Analysis of genotype-phenotype correlation revealed that patients with
        mutations in the first two exons had lower average clinical scores and
        absent or only mild intellectual disability.
      explanation: Neurodevelopmental severity varies with PYCR1 genotype, linking the lesion to the neural phenotype.
  - target: Intrauterine growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Prenatal growth restriction is a hallmark of PYCR1 deficiency; the mechanism is unknown.
  - target: Postnatal growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Postnatal growth deficiency accompanies PYCR1 deficiency; the mechanism is unknown.
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Strabismus occurs in about a third of evaluated patients; the mechanism is unknown.
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lens opacity occurs in a minority of patients; the mechanism is unknown.
  - target: Glaucoma
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Glaucoma has been reported in individual patients; the mechanism is unknown.
  - target: Osteopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced bone mineralization occurs in PYCR1 deficiency; the bone mechanism is unknown.
  - target: Wormian bones
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Wormian bones are reported in PYCR1 deficiency; the mechanism is unknown.
  - target: Large fontanelles
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: An open or large fontanel is reported in PYCR1 deficiency; the mechanism is unknown.
  - target: Adducted thumb
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Adducted thumbs are reported in PYCR1 deficiency; the mechanism is unknown.
  - target: Aortic root dilatation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Aortic root dilatation was reported in one de Barsy patient; the mechanism is unknown.
- name: Impaired Mitochondrial Proline Biosynthesis
  biological_scale: MOLECULAR
  description: >-
    Reduced conversion of pyrroline-5-carboxylate to proline in mitochondria.
    In mouse the paralogue Pycr2 can supply proline when Pycr1 is lost, so the
    size of the systemic proline deficit in patients is uncertain.
  biological_processes:
  - preferred_term: L-proline biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0055129
      label: L-proline biosynthetic process
  evidence:
  - reference: PMID:31091804
    reference_title: Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Biochemical assays showed that adult pycr1 KO fish have significantly
      reduced proline and extracellular matrix contents
    explanation: Loss of pycr1 lowers proline content in a vertebrate model.
  - reference: PMID:33734376
    reference_title: Genetic analysis of Pycr1 and Pycr2 in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, Pycr1 and -2 have redundant functions in proline biosynthesis, and
      their loss makes proline a semi-essential amino acid.
    explanation: >-
      Mouse genetics place PYCR1 in proline biosynthesis and show paralogue
      redundancy that limits the deficit when PYCR1 alone is lost.
  downstream:
  - target: Progeroid Skin and Connective-Tissue Changes
    description: >-
      Elastin is a proline-rich protein abundant in the most affected tissues,
      so reduced local proline supply is the proposed link to the
      connective-tissue phenotype. This remains a hypothesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33734376
      reference_title: Genetic analysis of Pycr1 and Pycr2 in mice.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        is most logically associated with the demand for the proline-rich
        protein elastin in the affected tissues.
      explanation: >-
        In the authors' discussion the subject of this sentence is the cutis
        laxa phenotype of PYCR1 mutations (the cached full text runs the gene
        name into its neighbouring words, so the quote starts at the verb).
        It proposes elastin's proline demand as the link between PYCR1 loss
        and cutis laxa; it is argument, not a measurement.
    - reference: PMID:31091804
      reference_title: Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Biochemical assays showed that adult pycr1 KO fish have significantly
        reduced proline and extracellular matrix contents
      explanation: >-
        Reduced proline and reduced extracellular matrix co-occur in pycr1
        knockout zebrafish; co-occurrence does not show that one causes the other.
- name: Mitochondrial Morphology and Membrane Potential Defect
  biological_scale: CELLULAR
  description: >-
    PYCR1-deficient patient fibroblasts show altered mitochondrial morphology
    and reduced membrane potential, and skin biopsies show abnormal
    mitochondria and cristae.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: mitochondrion organization
    modifier: ABNORMAL
    term:
      id: GO:0007005
      label: mitochondrion organization
  evidence:
  - reference: PMID:19648921
    reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Altered mitochondrial morphology, membrane potential and increased
      apoptosis rate upon oxidative stress were evident in fibroblasts from
      affected individuals.
    explanation: Direct observation of the mitochondrial defect in patient fibroblasts.
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Light- and electron microscopy investigations of skin biopsies showed
      smaller and fragmented elastic fibres, abnormal morphology of the
      mitochondria and their cristae, and slightly abnormal collagen fibril
      diameters with irregular outline and variable size.
    explanation: Patient skin biopsies show abnormal mitochondrial and cristae morphology.
  downstream:
  - target: Increased Oxidative-Stress-Induced Apoptosis
    description: >-
      Mitochondrially compromised PYCR1-deficient cells are hypersensitive to
      oxidative stress and undergo more apoptosis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19648921
      reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Altered mitochondrial morphology, membrane potential and increased
        apoptosis rate upon oxidative stress were evident in fibroblasts from
        affected individuals.
      explanation: >-
        Patient fibroblasts show the mitochondrial defect together with
        increased apoptosis under oxidative stress. The two are observed in the
        same cells; the sentence does not show that one causes the other.
- name: Increased Oxidative-Stress-Induced Apoptosis
  biological_scale: CELLULAR
  description: >-
    PYCR1-deficient fibroblasts undergo more apoptosis when challenged with
    oxidative stress. Silencing PYCR1 with PYCR2 in normal fibroblasts
    reproduces the oxidative-stress hypersensitivity, and pycr1 knockdown or
    knockout vertebrates show marked apoptosis.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway in response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0008631
      label: intrinsic apoptotic signaling pathway in response to oxidative stress
  evidence:
  - reference: PMID:19648921
    reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Altered mitochondrial morphology, membrane potential and increased
      apoptosis rate upon oxidative stress were evident in fibroblasts from
      affected individuals.
    explanation: Patient fibroblasts show increased oxidative-stress-induced apoptosis.
  - reference: PMID:26733354
    reference_title: PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Silencing of both PYCR1 and PYCR2 by expressing short hairpin RNAs
      induced defects in cell proliferation, partial fragmentation of the
      mitochondrial network, and hypersensitivity to oxidative stress in
      hTERT-immortalized human foreskin fibroblasts (HFF-hTERT).
    explanation: >-
      Combined PYCR1/PYCR2 knockdown in normal fibroblasts reproduces the
      mitochondrial fragmentation and oxidative-stress sensitivity; it is a
      double knockdown, not the patient genotype.
  - reference: PMID:31091804
    reference_title: Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Marked apoptosis and senescence were detected in pycr1 KO zebrafish
    explanation: pycr1 knockout zebrafish show marked apoptosis.
  downstream:
  - target: Progeroid Skin and Connective-Tissue Changes
    description: >-
      Loss of skin cells by apoptosis is the proposed route to cutaneous
      hypoplasia; in pycr1 knockdown frog and fish embryos epidermal hypoplasia
      accompanies a large rise in apoptosis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19648921
      reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Knockdown of the orthologous genes in Xenopus and zebrafish led to
        epidermal hypoplasia and blistering that was accompanied by a massive
        increase of apoptosis.
      explanation: >-
        In knockdown embryos, apoptosis accompanies epidermal hypoplasia. The
        model is epidermal and embryonic, so the link to human dermal changes
        is an inference.
- name: Progeroid Skin and Connective-Tissue Changes
  biological_scale: TISSUE
  description: >-
    Skin of affected individuals shows smaller and fragmented elastic fibres
    and irregular collagen fibrils, with loss of subcutaneous fat. These
    connective-tissue changes underlie the lax, thin, wrinkled skin and the
    prematurely aged appearance, and joint laxity is part of the same
    connective-tissue phenotype.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Light- and electron microscopy investigations of skin biopsies showed
      smaller and fragmented elastic fibres, abnormal morphology of the
      mitochondria and their cristae, and slightly abnormal collagen fibril
      diameters with irregular outline and variable size.
    explanation: Patient skin biopsies show the elastic-fibre and collagen-fibril abnormalities.
  - reference: PMID:19648921
    reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings link mutations in PYCR1 to altered mitochondrial function
      and progeroid changes in connective tissues.
    explanation: The founding study frames the disease as progeroid connective-tissue change.
  downstream:
  - target: Cutis laxa
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Elastic-fibre and collagen changes in the dermis are the tissue substrate of lax skin.
  - target: Thin skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Dermal and subcutaneous connective-tissue loss presents as thin skin.
  - target: Excessive wrinkled skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Lax dermis wrinkles, most visibly on the dorsum of the hands and feet.
  - target: Prominent superficial veins
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Thin skin with little subcutaneous fat leaves superficial veins visible.
  - target: Lipodystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of subcutaneous adipose tissue is part of the progeroid tissue phenotype.
  - target: Prematurely aged appearance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The skin and fat changes produce the progeroid appearance.
    evidence:
    - reference: PMID:19648921
      reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our findings link mutations in PYCR1 to altered mitochondrial function
        and progeroid changes in connective tissues.
      explanation: Links the PYCR1 connective-tissue change to the progeroid phenotype.
  - target: Triangular face
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Facial lipoatrophy and thin skin contribute to the triangular progeroid face.
  - target: Joint hypermobility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Joint laxity accompanies the connective-tissue phenotype; the periarticular mechanism is not studied.
  - target: Congenital hip dislocation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hip dislocation is attributed to connective-tissue laxity; the mechanism is not studied.
  - target: Hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hernias are attributed to connective-tissue weakness of the abdominal wall; the mechanism is not studied in PYCR1 disease.
  - target: Pes planus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Flat feet are attributed to ligamentous laxity; the mechanism is not studied in PYCR1 disease.
  - target: Blue sclerae
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Blue sclerae are taken to reflect thin scleral connective tissue; scleral histology has not been reported in PYCR1 disease.
  - target: Corneal opacity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A corneal button from a PYCR1 patient showed loss of the stromal lamellar
      architecture, a connective-tissue defect of the cornea.
    evidence:
    - reference: PMID:36524384
      reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathology of the corneal button revealed loss of the bowman's
        layer which was replaced by a fibrous pannus while the stroma showed
        loss of stromal lamellar architecture with anterior and mid stroma
        showing vascularization.
      explanation: >-
        Corneal histology in one homozygous PYCR1 patient shows stromal
        connective-tissue disorganisation underlying the opacity.
- name: Neurodevelopmental Impairment
  biological_scale: ORGANISM
  description: >-
    PYCR1 deficiency impairs neurodevelopment, with hypotonia, psychomotor
    delay, variable intellectual disability, movement disorder and
    corpus-callosum dysgenesis. Neural mechanisms have not been studied in
    patient tissue. Patients with variants in the first two exons have milder
    or absent intellectual disability.
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine growth retardation, a characteristic triangular facial
      gestalt, psychomotor retardation, and hypotonia were the most relevant
      distinctive hallmarks of ARCL due to proline de novo synthesis defects.
    explanation: Psychomotor retardation and hypotonia are core features in the PYCR1 cohort.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal corpus callosum morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Athetosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Dermatological
  name: Cutis laxa
  description: >-
    Congenital lax, inelastic and sagging skin, the defining cutaneous sign.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features, including loose wrinkled skin, progeroid
      appearance, delayed milestones, short stature, multiple hyper-extensible
      joints, muscular hypotonia, pectus excavatum and congenital dislocation
      of the hip joint
    explanation: >-
      Homozygous PYCR1 de Barsy patient with loose wrinkled skin.
  - reference: PMID:39172257
    reference_title: Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient displayed characteristic symptoms of ARCL2B, which were
      consistent with previous reports, including wrinkled and/or sagging
      skin, distinct facial dysmorphism, hyperlaxity of joints, growth
      retardation, hypotonia, and psychomotor developmental delay.
    explanation: >-
      Homozygous PYCR1 patient with wrinkled and sagging skin.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARCL2B is characterized by intra-uterine growth retardation, cutis laxa,
      wrinkling of skin, particularly of dorsum of hands and feet, visible
      veins on the chest, congenital hip dislocation, hyperextensible joints,
      and adducted thumbs.
    explanation: >-
      Cutis laxa is part of the characteristic ARCL2B presentation.
- category: Dermatological
  name: Thin skin
  description: >-
    Very thin, translucent skin in infancy that improves with age.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARCL2B infants have very thin skin, visible veins over thorax and
      clenched hands, but these symptoms improve considerably as the patient
      grows older
    explanation: >-
      Thin skin in PYCR1-related ARCL2B infants, improving with age.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Thin, translucent skin. GeneReviews statement pooled across PYCR1- and
      ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Dermatological
  name: Excessive wrinkled skin
  description: >-
    Wrinkling most marked on the dorsum of the hands and feet.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Excessive wrinkled skin
    term:
      id: HP:0007392
      label: Excessive wrinkled skin
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features are short stature, wrinkling over dorsum of hand and
      feet, visible veins over the chest and hyperextensible joints.
    explanation: >-
      PYCR1-deficient patients have wrinkling over the dorsum of the hands and
      feet.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARCL2B is characterized by intra-uterine growth retardation, cutis laxa,
      wrinkling of skin, particularly of dorsum of hands and feet, visible
      veins on the chest, congenital hip dislocation, hyperextensible joints,
      and adducted thumbs.
    explanation: >-
      Wrinkling of the dorsum of the hands and feet characterizes ARCL2B.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wrinkled skin | 60/60 | 100% | 2/2 | 93/93 | 100%
    explanation: >-
      Wrinkled skin 93/93 (100%). ARCL2B (PYCR1) literature aggregate in Table
      2 of this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Wrinkled skin, especially on the hands and feet. GeneReviews statement
      pooled across PYCR1- and ALDH18A1-related disease, so it is supporting
      rather than PYCR1-specific.
- category: Dermatological
  name: Prominent superficial veins
  description: >-
    Visible veins over the chest and thorax, most evident in infancy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Visible veins
    term:
      id: HP:0001015
      label: Prominent superficial veins
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features are short stature, wrinkling over dorsum of hand and
      feet, visible veins over the chest and hyperextensible joints.
    explanation: >-
      Visible veins over the chest in PYCR1-deficient patients.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARCL2B infants have very thin skin, visible veins over thorax and
      clenched hands, but these symptoms improve considerably as the patient
      grows older
    explanation: >-
      Visible veins over the thorax in ARCL2B infants.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visible veins on the chest | NE | NE | 0/2 | 46/53 | 87%
    explanation: >-
      Visible veins on the chest 46/53 (87%). ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
- category: Dermatological
  name: Lipodystrophy
  description: >-
    Loss of subcutaneous adipose tissue, persisting into adulthood.
  phenotype_term:
    preferred_term: Lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have distinct facial features comprising triangular face,
      loss of adipose tissue and thin pointed nose.
    explanation: >-
      Loss of adipose tissue in all six PYCR1-deficient patients.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The adult ARCL2B patient, however, is not particularly short but usually
      has a low weight and exhibits lipodystrophy
    explanation: >-
      Adult ARCL2B patients exhibit lipodystrophy.
- category: Craniofacial
  name: Prematurely aged appearance
  description: >-
    Progeroid appearance from birth or early childhood.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Progeroid appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features, including loose wrinkled skin, progeroid
      appearance, delayed milestones, short stature, multiple hyper-extensible
      joints, muscular hypotonia, pectus excavatum and congenital dislocation
      of the hip joint
    explanation: >-
      Progeroid appearance in a homozygous PYCR1 de Barsy patient.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aged Appearance | 25/25 | 100% | 2/2 | 89/87 | 98%
    explanation: >-
      Aged appearance reported at 98%; the printed count 89/87 has a numerator
      larger than its denominator, so the frequency rests on the stated
      percentage. ARCL2B (PYCR1) literature aggregate in Table 2 of this
      review: the fourth and fifth values are the positive/evaluated count and
      percentage across published ARCL2B cases (the first three are ARCL2A);
      these cases may overlap other cited reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Triangular face with a progeroid appearance. GeneReviews statement
      pooled across PYCR1- and ALDH18A1-related disease, so it is supporting
      rather than PYCR1-specific.
- category: Craniofacial
  name: Triangular face
  description: >-
    Triangular face with a pointed chin in childhood; in adults the face
    becomes long with a prominent chin.
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine growth retardation, a characteristic triangular facial
      gestalt, psychomotor retardation, and hypotonia were the most relevant
      distinctive hallmarks of ARCL due to proline de novo synthesis defects.
    explanation: >-
      A triangular facial gestalt is a distinctive hallmark in the PYCR1
      cohort.
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients have distinct facial features comprising triangular face,
      loss of adipose tissue and thin pointed nose.
    explanation: >-
      Triangular face in all six PYCR1-deficient patients.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Triangular face with pointed chin. GeneReviews statement pooled across
      PYCR1- and ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Growth
  name: Intrauterine growth retardation
  description: >-
    Prenatal growth restriction with low birth weight.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine growth retardation, a characteristic triangular facial
      gestalt, psychomotor retardation, and hypotonia were the most relevant
      distinctive hallmarks of ARCL due to proline de novo synthesis defects.
    explanation: >-
      IUGR is a distinctive hallmark in the 33-patient PYCR1 cohort.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intra-Uterine Growth Retardation | 7/17 | 41% | 2/2 | 78/83 | 94%
    explanation: >-
      Intrauterine growth retardation 78/83 (94%). ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Prenatal growth deficiency. GeneReviews statement pooled across PYCR1-
      and ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Growth
  name: Postnatal growth retardation
  description: >-
    Postnatal growth deficiency with short stature in childhood; adults may be
    less markedly short but remain underweight.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features are short stature, wrinkling over dorsum of hand and
      feet, visible veins over the chest and hyperextensible joints.
    explanation: >-
      Short stature in PYCR1-deficient patients.
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features, including loose wrinkled skin, progeroid
      appearance, delayed milestones, short stature, multiple hyper-extensible
      joints, muscular hypotonia, pectus excavatum and congenital dislocation
      of the hip joint
    explanation: >-
      Short stature in a homozygous PYCR1 de Barsy patient.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatal Growth Delay | 10/24 | 42% | 0/2 | 43/64 | 67%
    explanation: >-
      Postnatal growth delay 43/64 (67%). ARCL2B (PYCR1) literature aggregate
      in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Postnatal growth deficiency. GeneReviews statement pooled across PYCR1-
      and ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Neurological
  name: Global developmental delay
  description: >-
    Psychomotor delay ranging from mild to extremely severe.
  phenotype_term:
    preferred_term: Psychomotor delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine growth retardation, a characteristic triangular facial
      gestalt, psychomotor retardation, and hypotonia were the most relevant
      distinctive hallmarks of ARCL due to proline de novo synthesis defects.
    explanation: >-
      Psychomotor retardation is a distinctive hallmark in the PYCR1 cohort.
  - reference: PMID:39172257
    reference_title: Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has typical clinical findings consistent with ARCL2B and
      extremely severe developmental delays.
    explanation: >-
      A homozygous p.Ala187Thr patient had extremely severe developmental
      delay.
- category: Neurological
  name: Intellectual disability
  description: >-
    Variable intellectual disability; absent or mild in some genotypes,
    including first-two-exon variants and a whole-gene deletion family.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of the patients from a large consanguineous family do not have
      mental retardation, while the remaining three patients from three
      unrelated families have mental and developmental delay.
    explanation: >-
      Intellectual disability is present in some PYCR1-deficient patients and
      absent in others.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with GO have normal mentation, whereas the majority of the
      patients with ARCL2A and ARCL2B have variable degrees of intellectual
      disability.
    explanation: >-
      Most ARCL2B patients have variable intellectual disability.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual Disability | 45/58 | 78% | 2/2 | 86/92 | 93%
    explanation: >-
      Intellectual disability 86/92 (93%). ARCL2B (PYCR1) literature aggregate
      in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These disorders are characterized by thin, translucent skin with
      wrinkles (especially on the hands and feet); typical facial
      characteristics including a triangular face with a progeroid appearance,
      a broad forehead (prominent-appearing neurocranium due to small
      viscerocranium), convex nasal ridge, full or sagging cheeks, and pointed
      chin; moderate-to-severe intellectual disability or mild intellectual
      disability with additional neurodiverse phenotypes including autism
      spectrum disorder or attention-deficit/hyperactivity disorder; and pre-
      and postnatal growth deficiency.
    explanation: >-
      Moderate-to-severe or mild intellectual disability. GeneReviews
      statement pooled across PYCR1- and ALDH18A1-related disease, so it is
      supporting rather than PYCR1-specific.
- category: Neurological
  name: Hypotonia
  description: >-
    Congenital muscular hypotonia.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrauterine growth retardation, a characteristic triangular facial
      gestalt, psychomotor retardation, and hypotonia were the most relevant
      distinctive hallmarks of ARCL due to proline de novo synthesis defects.
    explanation: >-
      Hypotonia is a distinctive hallmark in the PYCR1 cohort.
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features, including loose wrinkled skin, progeroid
      appearance, delayed milestones, short stature, multiple hyper-extensible
      joints, muscular hypotonia, pectus excavatum and congenital dislocation
      of the hip joint
    explanation: >-
      Muscular hypotonia in a homozygous PYCR1 de Barsy patient.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypotonia | 29/35 | 83% | 2/2 | 33/46 | 72%
    explanation: >-
      Hypotonia 33/46 (72%). ARCL2B (PYCR1) literature aggregate in Table 2 of
      this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Congenital hypotonia. GeneReviews statement pooled across PYCR1- and
      ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Neurological
  name: Microcephaly
  description: >-
    Microcephaly is reported in ARCL2B.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological findings common to ARCL2A and ARCL2B patients are
      intellectual disability, hypotonia, psychomotor retardation,
      microcephaly, and seizures.
    explanation: >-
      Microcephaly is listed among neurological findings of ARCL2B.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly | 33/47 | 70% | 0/2 | 32/49 | 65%
    explanation: >-
      Microcephaly 32/49 (65%). ARCL2B (PYCR1) literature aggregate in Table 2
      of this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
- category: Neurological
  name: Seizure
  description: >-
    Seizures are reported in a minority of patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological findings common to ARCL2A and ARCL2B patients are
      intellectual disability, hypotonia, psychomotor retardation,
      microcephaly, and seizures.
    explanation: >-
      Seizures are listed among neurological findings of ARCL2B.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures | 13/53 | 25% | 0/2 | 14/62 | 23%
    explanation: >-
      Seizures 14/62 (23%). ARCL2B (PYCR1) literature aggregate in Table 2 of
      this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
- category: Neurological
  name: Abnormal corpus callosum morphology
  description: >-
    Corpus-callosum dysgenesis or agenesis on brain imaging.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Corpus callosum dysgenesis
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:23963297
    reference_title: Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An important observation is the common presence of corpus callosum
      dysgenesis or corpus callosum agenesis (CCA) in patients with PYCR1
      mutations.
    explanation: >-
      Corpus-callosum dysgenesis or agenesis is common in PYCR1 patients in
      this cohort.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corpus Callosum Dysgenesis | 2/20 | 10% | NE | 26/53 | 49%
    explanation: >-
      Corpus callosum dysgenesis 26/53 (49%). ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
- category: Neurological
  name: Athetosis
  description: >-
    Athetoid movements; uncommon but highly predictive of PYCR1-related ARCL.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Athetoid movements
    term:
      id: HP:0002305
      label: Athetosis
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corneal clouding or cataracts, athetoid movements, and finger
      contractures were rather rare features, but had a high predictive value.
    explanation: >-
      Athetoid movements are rare but predictive in the PYCR1 cohort.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Athetoid/Dystonic Movements | 1/15 | 6% | 0/2 | 17/85 | 20%
    explanation: >-
      Athetoid/dystonic movements 17/85 (20%). The row combines athetosis and
      dystonia, so the figure is an upper bound for either alone. ARCL2B
      (PYCR1) literature aggregate in Table 2 of this review: the fourth and
      fifth values are the positive/evaluated count and percentage across
      published ARCL2B cases (the first three are ARCL2A); these cases may
      overlap other cited reports.
- category: Neurological
  name: Dystonia
  description: >-
    Dystonic posturing, which discriminated PYCR1 and ALDH18A1 defects from
    other cutis-laxa genes.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dystonic posturing
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:23963297
    reference_title: Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects.
    explanation: >-
      Dystonic posturing discriminated PYCR1 (and ALDH18A1) defects in a
      neurometabolic cutis-laxa cohort.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Athetoid/Dystonic Movements | 1/15 | 6% | 0/2 | 17/85 | 20%
    explanation: >-
      Athetoid/dystonic movements 17/85 (20%). The row combines athetosis and
      dystonia, so the figure is an upper bound for either alone. ARCL2B
      (PYCR1) literature aggregate in Table 2 of this review: the fourth and
      fifth values are the positive/evaluated count and percentage across
      published ARCL2B cases (the first three are ARCL2A); these cases may
      overlap other cited reports.
- category: Neurological
  name: Spasticity
  description: >-
    Spasticity with increased lower-limb reflexes, which can be progressive.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:23963297
    reference_title: Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several CL syndromes are presenting with muscle hypotonia (ATP6V0A2 and
      PYCR1 defects), spasticity (PYCR1 and ALDH18A1 defects), dystonic,
      athetoid movements (ALDH18A1 and PYCR1 defect) or epilepsy (ALDH18A1 and
      ATP6V0A2 defects).
    explanation: >-
      Spasticity is listed as a presenting feature of PYCR1 defects.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Progressive increased lower limb reflexes and spasticity. GeneReviews
      statement pooled across PYCR1- and ALDH18A1-related disease, so it is
      supporting rather than PYCR1-specific.
- category: Musculoskeletal
  name: Joint hypermobility
  description: >-
    Hyperextensible joints in infancy and childhood; milder or absent in
    adults.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:21487760
    reference_title: "Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features are short stature, wrinkling over dorsum of hand and
      feet, visible veins over the chest and hyperextensible joints.
    explanation: >-
      Hyperextensible joints in PYCR1-deficient patients.
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features, including loose wrinkled skin, progeroid
      appearance, delayed milestones, short stature, multiple hyper-extensible
      joints, muscular hypotonia, pectus excavatum and congenital dislocation
      of the hip joint
    explanation: >-
      Multiple hyperextensible joints in a homozygous PYCR1 de Barsy patient.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperextensibility of joints | 40/46 | 87% | 2/2 | 75/79 | 95%
    explanation: >-
      Hyperextensibility of joints 75/79 (95%). ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Joint laxity. GeneReviews statement pooled across PYCR1- and
      ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Musculoskeletal
  name: Congenital hip dislocation
  description: >-
    Congenital dislocation of the hip.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congenital hip dislocation
    term:
      id: HP:0001374
      label: Congenital hip dislocation
  evidence:
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysmorphic facial features, including loose wrinkled skin, progeroid
      appearance, delayed milestones, short stature, multiple hyper-extensible
      joints, muscular hypotonia, pectus excavatum and congenital dislocation
      of the hip joint
    explanation: >-
      Congenital hip dislocation in a homozygous PYCR1 de Barsy patient.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARCL2B is characterized by intra-uterine growth retardation, cutis laxa,
      wrinkling of skin, particularly of dorsum of hands and feet, visible
      veins on the chest, congenital hip dislocation, hyperextensible joints,
      and adducted thumbs.
    explanation: >-
      Congenital hip dislocation is part of the ARCL2B presentation.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital hip dislocation | 9/15 | 60% | 1/2 | 53/86 | 62%
    explanation: >-
      Congenital hip dislocation 53/86 (62%). ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Congenital hip dislocation. GeneReviews statement pooled across PYCR1-
      and ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Musculoskeletal
  name: Adducted thumb
  description: >-
    Adducted thumbs.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Adducted thumb
    term:
      id: HP:0001181
      label: Adducted thumb
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ARCL2B is characterized by intra-uterine growth retardation, cutis laxa,
      wrinkling of skin, particularly of dorsum of hands and feet, visible
      veins on the chest, congenital hip dislocation, hyperextensible joints,
      and adducted thumbs.
    explanation: >-
      Adducted thumbs are part of the ARCL2B presentation.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adducted thumbs | 0/5 | 0% | 0/2 | 28/45 | 62%
    explanation: >-
      Adducted thumbs 28/45 (62%). ARCL2B (PYCR1) literature aggregate in
      Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Adducted thumbs. GeneReviews statement pooled across PYCR1- and
      ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Musculoskeletal
  name: Osteopenia
  description: >-
    Osteopenia, usually without pathologic fractures.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While patients with ARCL2B may manifest osteopenia, osteopenia that is
      severe enough to cause pathologic fractures is more characteristic of
      GO.
    explanation: >-
      ARCL2B patients may have osteopenia, rarely severe enough to fracture.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteopenia | NE | NE | 1/2 | 38/52 | 73%
    explanation: >-
      Osteopenia 38/52 (73%). ARCL2B (PYCR1) literature aggregate in Table 2
      of this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
- category: Musculoskeletal
  name: Wormian bones
  description: >-
    Wormian bones of the skull.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Though not seen in all patients with cutis laxa IIB, wormian bones,
      athetoid movements, lipodystrophy, cataracts and corneal clouding are
      highly specific for ARCL2B.
    explanation: >-
      Wormian bones are a specific though inconstant ARCL2B feature.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Wormian bonses | NE | NE | 0/2 | 20/32 | 63%
    explanation: >-
      Wormian bones 20/32 (63%); the source row label is misspelled "Wormian
      bonses". ARCL2B (PYCR1) literature aggregate in Table 2 of this review:
      the fourth and fifth values are the positive/evaluated count and
      percentage across published ARCL2B cases (the first three are ARCL2A);
      these cases may overlap other cited reports.
- category: Musculoskeletal
  name: Pes planus
  description: >-
    Flat feet, reported in a small number of evaluated ARCL2B cases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Flat feet
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Flat feet | 1/3 | 33% | 1/2 | 5/7 | 71%
    explanation: >-
      Flat feet 5/7 (71%), from only seven evaluated cases. ARCL2B (PYCR1)
      literature aggregate in Table 2 of this review: the fourth and fifth
      values are the positive/evaluated count and percentage across published
      ARCL2B cases (the first three are ARCL2A); these cases may overlap other
      cited reports.
- category: Musculoskeletal
  name: Hernia
  description: >-
    Hernia, not further specified by site in the source table.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hernia
    term:
      id: HP:0100790
      label: Hernia
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hernia | 17/36 | 47% | 1/2 | 33/84 | 39%
    explanation: >-
      Hernia 33/84 (39%); the row does not state inguinal or umbilical, so the
      general hernia term is bound. ARCL2B (PYCR1) literature aggregate in
      Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
- category: Craniofacial
  name: Large fontanelles
  description: >-
    Persistent open or large anterior fontanel in infancy.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Open fontanel
    term:
      id: HP:0000239
      label: Large fontanelles
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature and open fontanel are common findings in cutis laxa types
      2A and 2B, but occur less frequently in GO
    explanation: >-
      Open fontanel is common in ARCL2B.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistent open Fontanel | 53/58 | 91% | 1/1 | 30/40 | 75%
    explanation: >-
      Persistent open fontanel 30/40 (75%). ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
- category: Ophthalmological
  name: Blue sclerae
  description: >-
    Blue sclerae.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:19576563
    reference_title: Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Craniofacial dysmorphism included microcephaly, broad and prominent
      forehead, prominent ears, blue sclerae, and sagging cheeks.
    explanation: >-
      Blue sclerae in the eastern Canadian PYCR1 (p.Arg266Gln) ARCL2 families.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Blue sclera | 2/4 | 50% | 1/2 | 23/48 | 48%
    explanation: >-
      Blue sclera 23/48 (48%). ARCL2B (PYCR1) literature aggregate in Table 2
      of this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
- category: Ophthalmological
  name: Strabismus
  description: >-
    Strabismus.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:23963297
    reference_title: Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients 2–8 had corneal clouding and/or cataract; patients 4, 7, 9, 10,
      12, 13, 14 and 15 had strabismus
    explanation: >-
      Strabismus in a neurometabolic cutis-laxa cohort that includes PYCR1
      patients 4 and 7 (patients 3, 4, 6 and 7 carried PYCR1 mutations).
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strabismus | 21/48 | 44% | 1/2 | 17/48 | 35%
    explanation: >-
      Strabismus 17/48 (35%). ARCL2B (PYCR1) literature aggregate in Table 2
      of this review: the fourth and fifth values are the positive/evaluated
      count and percentage across published ARCL2B cases (the first three are
      ARCL2A); these cases may overlap other cited reports.
- category: Ophthalmological
  name: Corneal opacity
  description: >-
    Corneal clouding, sometimes bilateral and congenital; uncommon overall but
    highly predictive.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Corneal clouding
    term:
      id: HP:0007957
      label: Corneal opacity
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corneal clouding or cataracts, athetoid movements, and finger
      contractures were rather rare features, but had a high predictive value.
    explanation: >-
      Corneal clouding is rare but predictive in the PYCR1 cohort.
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 2 year-old child presented to the pediatric ophthalmology outpatients
      with bilateral congenital corneal opacification
    explanation: >-
      Bilateral congenital corneal opacification in a homozygous PYCR1
      patient.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cataract/corneal clouding | 1/38 | 3% | 0/2 | 13/88 | 15%
    explanation: >-
      Cataract/corneal clouding 13/88 (15%). The row combines both lesions, so
      the figure is an upper bound for either alone. ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Corneal clouding. GeneReviews statement pooled across PYCR1- and
      ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Ophthalmological
  name: Cataract
  description: >-
    Lens opacity in a minority of patients.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:24035636
    reference_title: Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corneal clouding or cataracts, athetoid movements, and finger
      contractures were rather rare features, but had a high predictive value.
    explanation: >-
      Cataract is rare but predictive in the PYCR1 cohort.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Though not seen in all patients with cutis laxa IIB, wormian bones,
      athetoid movements, lipodystrophy, cataracts and corneal clouding are
      highly specific for ARCL2B.
    explanation: >-
      Cataract is a specific though inconstant ARCL2B feature.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cataract/corneal clouding | 1/38 | 3% | 0/2 | 13/88 | 15%
    explanation: >-
      Cataract/corneal clouding 13/88 (15%). The row combines both lesions, so
      the figure is an upper bound for either alone. ARCL2B (PYCR1) literature
      aggregate in Table 2 of this review: the fourth and fifth values are the
      positive/evaluated count and percentage across published ARCL2B cases
      (the first three are ARCL2A); these cases may overlap other cited
      reports.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Additional features can include joint laxity, congenital hypotonia,
      progressive increased lower limb reflexes/spasticity, congenital hip
      dislocation, adducted thumbs, corneal clouding, and lens opacities.
    explanation: >-
      Lens opacities. GeneReviews statement pooled across PYCR1- and
      ALDH18A1-related disease, so it is supporting rather than
      PYCR1-specific.
- category: Ophthalmological
  name: Glaucoma
  description: >-
    Glaucoma in individual patients: congenital glaucoma in one
    compound-heterozygous de Barsy patient and medically uncontrolled
    angle-closure glaucoma in a homozygous patient with corneal opacification.
  phenotype_term:
    preferred_term: Glaucoma
    term:
      id: HP:0000501
      label: Glaucoma
  evidence:
  - reference: PMID:22052856
    reference_title: Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The exceptional observation of congenital glaucoma, aortic root
      dilatation, and idiopathic hypertrophic pyloric stenosis in this patient
      widened the range of symptoms that have been noted in DBS.
    explanation: >-
      Congenital glaucoma in a compound-heterozygous PYCR1 de Barsy patient.
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a left eye trabeculectomy for medically uncontrolled angle-closure
      glaucoma was performed
    explanation: >-
      Angle-closure glaucoma in a homozygous PYCR1 de Barsy patient.
- category: Cardiovascular
  name: Aortic root dilatation
  description: >-
    Aortic root dilatation reported in one compound-heterozygous de Barsy
    patient; the authors recommend cardiovascular survey.
  phenotype_term:
    preferred_term: Aortic root dilatation
    term:
      id: HP:0002616
      label: Aortic root aneurysm
  evidence:
  - reference: PMID:22052856
    reference_title: Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The exceptional observation of congenital glaucoma, aortic root
      dilatation, and idiopathic hypertrophic pyloric stenosis in this patient
      widened the range of symptoms that have been noted in DBS.
    explanation: >-
      Aortic root dilatation in a compound-heterozygous PYCR1 de Barsy
      patient.
diagnosis:
- name: Molecular Genetic Confirmation
  description: >-
    Diagnosis rests on compatible clinical findings with identification of
    biallelic pathogenic PYCR1 variants. Clinical features overlap with
    ALDH18A1-related ARCL, ATP6V0A2-related ARCL2A and geroderma
    osteodysplastica, so molecular testing is needed to assign the gene.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic pathogenic or likely pathogenic PYCR1 variants.
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of a neurocutaneous disorder due a to mitochondrial proline
      synthesis defect can be established in a proband with characteristic
      clinical findings and identification of biallelic ALDH18A1 or PYCR1
      pathogenic variants
    explanation: GeneReviews diagnostic criterion for PYCR1-related ARCL.
- name: Annual Anterior Chamber Examination
  description: >-
    Surveillance: yearly anterior-chamber evaluation for corneal clouding and
    cataract.
  diagnosis_term:
    preferred_term: anterior chamber eye examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: anterior chamber evaluation to assess for corneal clouding and cataract annually
    explanation: >-
      GeneReviews surveillance recommendation, pooled across PYCR1- and
      ALDH18A1-related disease.
- name: Echocardiographic Surveillance
  description: >-
    Surveillance: echocardiogram every three years, more often when findings
    are abnormal. Aortic root dilatation has been reported in a PYCR1 de Barsy
    patient, whose authors recommended cardiovascular survey.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: echocardiogram every three years or more frequently in those with abnormal findings
    explanation: >-
      GeneReviews surveillance recommendation, pooled across PYCR1- and
      ALDH18A1-related disease.
  - reference: PMID:22052856
    reference_title: Compound heterozygous mutations in PYCR1 further expand the phenotypic spectrum of De Barsy syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The findings presented here suggest a mutation screening of PYCR1 and
      cardiovascular survey in patients with DBS.
    explanation: >-
      After finding aortic root dilatation in a PYCR1 de Barsy patient, the
      authors recommend cardiovascular survey.
differential_diagnoses:
- name: ALDH18A1-related de Barsy syndrome
  disease_term:
    preferred_term: ALDH18A1-related de Barsy syndrome
    term:
      id: MONDO:0009053
      label: ALDH18A1-related de Barsy syndrome
  description: >-
    Biallelic ALDH18A1 (P5CS) deficiency, one step upstream in the same
    mitochondrial proline-synthesis pathway, produces an overlapping
    neurocutaneous progeroid cutis-laxa phenotype. GeneReviews covers both in
    one chapter.
  distinguishing_features:
  - Molecular testing distinguishes PYCR1 from ALDH18A1 disease; dystonic posturing and corpus-callosum dysgenesis are shared and do not discriminate between them.
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neurocutaneous disorders due to mitochondrial proline synthesis defects
      comprise PYCR1-related autosomal recessive cutis laxa (ARCL),
      ALDH18A1-related ARCL, and ALDH18A1-related autosomal dominant cutis laxa
      (ADCL).
    explanation: GeneReviews groups PYCR1- and ALDH18A1-related ARCL as overlapping disorders of one pathway.
  - reference: PMID:23963297
    reference_title: Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects.
    explanation: The same neurological sign points to both proline-synthesis genes, so it cannot separate them.
- name: Autosomal recessive cutis laxa type 2A
  disease_term:
    preferred_term: autosomal recessive cutis laxa type 2A
    term:
      id: MONDO:0018163
      label: autosomal recessive cutis laxa type 2A
  description: >-
    ATP6V0A2-related cutis laxa shares neonatal skin laxity, hypotonia and
    developmental delay. It has abnormal glycosylation and cobblestone brain
    malformation, where PYCR1 disease has normal biochemistry and callosal
    dysgenesis.
  distinguishing_features:
  - Abnormal glycosylation biochemistry supports ARCL2A; it is uninformative for PYCR1 disease.
  - Cobblestone cortical dysgenesis on MRI favours ARCL2A; corpus-callosum dysgenesis or agenesis favours PYCR1 disease.
  evidence:
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI imaging would be expected to differentiate between ARCL2A and
      ARCL2B based on the presence of cobblestone dysgenesis in ARCL2A compared
      to dysgenesis or agenesis of corpus callosum in cutis laxa IIB
    explanation: Distinguishes ARCL2A and PYCR1-related ARCL2B by brain imaging.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical analysis is good for identification of ARCL2A patients but it
      cannot be used for identification of ARCL2B and GO cases.
    explanation: Biochemical testing identifies ARCL2A but not PYCR1 disease.
- name: Geroderma osteodysplastica
  disease_term:
    preferred_term: geroderma osteodysplastica
    term:
      id: MONDO:0009271
      label: geroderma osteodysplastica
  description: >-
    GORAB-related geroderma osteodysplastica shares wrinkled skin on the dorsum
    of the hands and feet and osteopenia; some PYCR1 families were first
    diagnosed with it.
  distinguishing_features:
  - Severe osteopenia with pathologic fractures and normal intellect favour geroderma osteodysplastica.
  - Intellectual disability favours PYCR1 disease.
  evidence:
  - reference: PMID:21204221
    reference_title: The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While the patients with GORAB mutations have severe osteopenia, the
      patients with PYCR1 mutations have severe mental retardation.
    explanation: Contrasts the bone and cognitive phenotypes of the two disorders.
  - reference: PMID:28294978
    reference_title: "Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with GO have normal mentation, whereas the majority of the
      patients with ARCL2A and ARCL2B have variable degrees of intellectual
      disability.
    explanation: Normal cognition favours geroderma osteodysplastica over PYCR1 disease.
treatments:
- name: Physical Therapy
  description: >-
    Supportive physical therapy for motor delay and lower-limb spasticity.
    GeneReviews also lists contact sports, prolonged fasting, smoking and
    sunbathing among circumstances to avoid for this disorder group.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: physical therapy for motor delays and spastic diplegia
    explanation: GeneReviews management recommendation for the proline-synthesis cutis-laxa disorders, including PYCR1-related ARCL.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Agents/circumstances to avoid: Contact sports; prolonged fasting;
      activities requiring hyperbaric pressure; aesthetic surgical
      intervention; activities with high acceleration or that increase the risk
      for seizures; smoking; sunbathing.
    explanation: GeneReviews list of circumstances to avoid for the disorder group.
- name: Speech and Swallowing Therapy
  description: Prelingual speech therapy to support swallowing and speech development.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Prelingual speech therapy to improve swallowing and speech development
    explanation: GeneReviews management recommendation for the disorder group.
- name: Penetrating Keratoplasty
  description: >-
    Corneal transplantation for vision-limiting congenital corneal opacity,
    reported in a homozygous PYCR1 de Barsy patient who underwent bilateral
    sequential penetrating keratoplasty followed by amblyopia therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Penetrating Keratoplasty
    term:
      id: NCIT:C222070
      label: Penetrating Keratoplasty
  evidence:
  - reference: PMID:36524384
    reference_title: Progeroid syndrome of De Barsy - a case report and review of ophthalmic literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmic management in the form of bilateral sequential penetrating
      keratoplasties and a left eye trabeculectomy for medically uncontrolled
      angle-closure glaucoma was performed.
    explanation: Case-level report of keratoplasty for corneal opacity in PYCR1 disease.
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      correction of diffraction abnormalities and possible surgical correction
      in those with impaired vision due to clouding
    explanation: >-
      GeneReviews recommends possible surgical correction of vision-impairing
      corneal clouding. The recommendation is pooled across PYCR1- and
      ALDH18A1-related disease.
- name: Orthopedic Management
  description: >-
    Orthopedic treatment of hip dislocation, scoliosis and joint contractures.
    No NCIT clinical-action term in the treatment enum names orthopedic care
    that is not necessarily surgical, so no term is bound.
  treatment_term:
    preferred_term: orthopedic management of hip dislocation, scoliosis and joint contractures
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: treatment of hip dislocation, scoliosis, and joint contractures per orthopedist
    explanation: >-
      GeneReviews management recommendation, pooled across PYCR1- and
      ALDH18A1-related disease.
- name: Genetic Counseling
  description: >-
    Counseling on autosomal recessive recurrence risk, carrier testing of
    relatives once the familial variants are known, and prenatal or
    preimplantation genetic testing.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41570168
    reference_title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Carrier testing for at-risk relatives requires prior identification of
      the PYCR1 or ALDH18A1 pathogenic variants in the family.
    explanation: GeneReviews counseling recommendation naming PYCR1.
animal_models:
- name: pycr1 knockout zebrafish
  species: Zebrafish
  genotype: pycr1 homozygous 2-bp deletion in exon 4 (knockout)
  publication: PMID:31091804
  description: >-
    Stable pycr1 knockout zebrafish are viable but show apoptosis and
    senescence from the embryo or larva stage, reduced proline and
    extracellular matrix content, a progeroid phenotype from 4 months and about
    50% mortality by 6 months.
  modeled_mechanisms:
  - target: Increased Oxidative-Stress-Induced Apoptosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reproduces increased apoptosis and reduced antioxidant capacity in vivo.
    limitations: >-
      Fish skin, lifespan and paralogue complement differ from human; the
      ageing and behavioural phenotypes have no direct human counterpart in
      the congenital disorder.
    evidence:
    - reference: PMID:31091804
      reference_title: Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Marked apoptosis and senescence were detected in pycr1 KO zebrafish
      explanation: The knockout shows the apoptosis node in vivo.
  - target: Impaired Mitochondrial Proline Biosynthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Adult knockout fish have reduced proline content.
    evidence:
    - reference: PMID:31091804
      reference_title: Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Biochemical assays showed that adult pycr1 KO fish have significantly
        reduced proline and extracellular matrix contents
      explanation: Measured proline reduction in the knockout.
- name: pycr1 morpholino knockdown Xenopus and zebrafish embryos
  species: Xenopus
  genotype: morpholino knockdown of the PYCR1 orthologues
  publication: PMID:19648921
  description: >-
    Knockdown of the PYCR1 orthologues in Xenopus and zebrafish embryos caused
    epidermal hypoplasia and blistering with a large increase in apoptosis.
  modeled_mechanisms:
  - target: Increased Oxidative-Stress-Induced Apoptosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Reproduces increased apoptosis with skin hypoplasia in embryos.
    limitations: >-
      Transient embryonic knockdown with morpholino-specific caveats; the
      affected layer is epidermis, while the human lesion is dermal and
      connective-tissue.
    evidence:
    - reference: PMID:19648921
      reference_title: Mutations in PYCR1 cause cutis laxa with progeroid features.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Knockdown of the orthologous genes in Xenopus and zebrafish led to
        epidermal hypoplasia and blistering that was accompanied by a massive
        increase of apoptosis.
      explanation: The knockdown embryos show apoptosis with skin hypoplasia.
- name: Pycr1 null mouse
  species: Mouse
  genotype: Pycr1 null allele (homozygous)
  publication: PMID:33734376
  description: >-
    A Pycr1 null allele produced no integument or cutis-laxa-related phenotype,
    while Pycr1;Pycr2 double mutants were sub-viable, indicating that the two
    paralogues are largely redundant in mouse.
  modeled_mechanisms:
  - target: Progeroid Skin and Connective-Tissue Changes
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: The single Pycr1 knockout does not reproduce the human skin phenotype.
    limitations: >-
      Mouse Pycr2 compensates for loss of Pycr1 in proline synthesis, so the
      single knockout does not reproduce the human connective-tissue
      phenotype.
    evidence:
    - reference: PMID:33734376
      reference_title: Genetic analysis of Pycr1 and Pycr2 in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: A null allele of Pycr1 did not show integument or CL-related phenotypes.
      explanation: Direct report that the Pycr1 null mouse lacks the cutis-laxa phenotype.
    - reference: PMID:33734376
      reference_title: Genetic analysis of Pycr1 and Pycr2 in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In mice, Pycr1; Pycr2 double mutants were sub-viable and unhealthy
        compared to either single mutant, indicating the genes are largely
        functionally redundant.
      explanation: Paralogue redundancy explains the failure of the single knockout.
references:
- reference: PMID:41570168
  title: Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:41570168

Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: PYCR1-Related De Barsy Syndrome · 2026-10-18T06:03:45Z · View source

Created the PYCR1-related de Barsy syndrome entry (MONDO:0013755) from the stub, with ARCL2B (MONDO:0013051) as a has_subtypes row. Deep research: one Perplexity sonar-deep-research report, run with --param reasoning_effort=low because default-effort requests were dropped by the network after about five minutes. Report validation: 15/15 references resolved, 0 unresolved, 8 on topic, 0 off topic, 7 undecided; term validation 58/63 resolved, 1 obsolete (GO:0006561, not used; GO:0055129 bound instead), 4 unverifiable (ORPHA, MGI prefixes), needs_review set. just preflight-dr PASS (PYCR1 74 mentions). The report's numbered in-text citations do not correspond to its citation sidecar, so claims were anchored to PubMed records found by DOI lookup and targeted esearch rather than to the report's bracket numbers. Not used: PMID:22411858 and PMID:21834030 (cache body empty), PMID:29148179 (de Barsy anaesthesia series without genotyping), PMID:21431621 and PMID:32518230 (general reviews), the eLife 2023 Pycr1 mouse preprint (not fetched; mouse evidence taken from PMID:33734376). GeneReviews chapter PMID:41570168 (Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects) tagged; it pools PYCR1 and ALDH18A1 disease, so PYCR1-specific primary reports were preferred for phenotypes and the chapter was cited for inheritance, diagnosis and management. Lump/split: PYCR1 ARCL2B and ARCL3B treated as one spectrum per the 33-patient cohort PMID:24035636 and GeneReviews; no mondo_mappings row because MONDO places the two as siblings. ClinGen Definitive (PYCR1/ARCL2B) recorded on the genetic row with subtype ARCL2B. No module conformance (no fitting module). No grouping edit: no cutis-laxa grouping exists and the ALDH18A1 entries are not members of any. Validation: just validate, validate-terms, count-verified-snippets (94/94), check-entity-refs, check-causal-targets, check-duplicate-keys, check-block-scalar-comments, connectivity 28/28, check-genereviews --online TAGGED, validate-disorders; whole-KB check-snippet-length, check-title-snippets, check-snippet-grading (one divergence on a PMID:19648921 conclusion sentence fixed by grading it HUMAN_CLINICAL in both places), check-retired-support-prose, check-coarse-phenotypes, check-reference-titles and check-qualifier-terms pass.

Perplexity ▸

PYCR1-Related De Barsy Syndrome

sonar-deep-research 54 citations 2026-10-18T05:45:09.942851

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

Resource	Identifier/name	Qualification
MONDO	MONDO:0013755, PYCR1-related De Barsy syndrome	Target concept
OMIM disease	614438, Cutis laxa, autosomal recessive, type IIIB	De Barsy/ARCL3B
OMIM overlapping disease	612940, Cutis laxa, autosomal recessive, type IIB	Same PYCR1 spectrum, generally less severe
OMIM gene	179035, PYCR1	Gene entry
Orphanet	ORPHA:293633, PYCR1-related De Barsy syndrome	Gene-defined subtype
Broader Orphanet concept	ORPHA:2962, De Barsy syndrome	Includes genetically heterogeneous DBS
MeSH	C535990, De Barsy syndrome	Supplementary concept
SNOMED CT	1295488006	PYCR1-related De Barsy syndrome / ARCL3B
MedGen	C3280799	PYCR1-related De Barsy syndrome
ICD-10	Q87.0 in current Orphanet/SNOMED mapping	Congenital malformation syndromes predominantly affecting facial appearance
ICD-11	LD28.2	Syndromes with multiple structural anomalies, not elsewhere classified

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:

Variant, transcript NM_006907.4	Type	Evidence/status
c.356G>A, p.Arg119His	Missense	ClinVar pathogenic
c.355C>G, p.Arg119Gly	Missense	Pathogenic; foundational reports
c.616G>T, p.Gly206Trp	Missense	ClinVar pathogenic
c.797G>A, p.Arg266Gln	Missense	Pathogenic; reported in two French-Acadian Canadian families
c.540+1G>T	Canonical splice	ClinVar likely pathogenic
c.11del, p.Gly4fs	Frameshift	Pathogenic
c.345del, p.Arg116fs / historically p.Pro115fsTer7	Frameshift	De Barsy case; germline
c.743G>A, p.Gly248Glu	Missense	De Barsy case, in trans with frameshift
c.559G>A, p.Ala187Thr	Missense	Homozygous 2024 case; absent from gnomAD/1000 Genomes/dbSNP in that report; reduced protein and enzymatic activity

[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

Phenotype and suggested HPO term	Type	Onset/course	Approximate frequency or strength of association	Functional/QOL impact
Cutis laxa — HP:0000973	Physical sign	Congenital; wrinkles may lessen with age while translucency/lipoatrophy becomes more evident	100% in pooled proline-synthesis cohort	Cosmetic difference, bruising/wound and pressure-injury concerns
Thin/translucent skin — HP:0000963	Sign	Congenital/lifelong	90% pooled	Visible veins, skin fragility
Progeroid appearance — HP:0007495	Sign	Congenital/early childhood	Dysmorphic/progeroid features 95% pooled	Psychosocial and cosmetic impact
Triangular face — HP:0000325	Sign	Congenital; pointed chin becomes more evident with age	Characteristic	Diagnostic clue
Intrauterine growth restriction — HP:0001511	Sign	Prenatal	96% pooled	Low birth weight/length
Postnatal growth retardation — HP:0008897	Sign	Infancy/childhood; may improve somewhat	85% pooled	Nutritional and mobility effects
Microcephaly — HP:0000252	Sign	Congenital or progressive relative microcephaly	68% pooled; generally mild in PYCR1	Correlates variably with neurodevelopment
Global developmental delay — HP:0001263	Neurodevelopmental	Infancy; chronic, usually non-regressive	98% pooled; usually milder in PYCR1 than ALDH18A1-ARCL	Major educational, communication and self-care burden
Intellectual disability — HP:0001249	Behavioral/cognitive	Childhood	Variable, mild to severe	Lifelong assistance may be needed
Hypotonia — HP:0001252	Sign	Often congenital	93% pooled; moderate truncal hypotonia in PYCR1	Delayed sitting/walking, feeding problems
Hyperreflexia — HP:0001347 / lower-limb spasticity — HP:0002061	Sign	May emerge/progress	Mild peripheral spasticity in PYCR1	Gait and contracture burden
Athetoid/dystonic movements — HP:0002305/HP:0001332	Sign	Childhood; variable	Athetoid movement 26% pooled; uncommon but predictive	Impairs motor control
Seizures — HP:0001250	Sign	Variable pediatric onset	Occasional in PYCR1 ARCL	Safety and medication burden
Corpus-callosum dysgenesis — HP:0001273	Imaging abnormality	Congenital	55% pooled, but mild/variable in PYCR1	Variable developmental significance
Joint hypermobility — HP:0001382	Sign	Congenital	98% pooled	Instability, delayed motor skills
Adducted thumb — HP:0001181 / contractures — HP:0001371	Sign	Congenital	Adducted thumbs/clubfoot 67% pooled	Hand function and mobility limitations
Congenital hip dislocation — HP:0001374	Sign	Congenital	53% pooled	Orthopedic treatment/surgery
Osteopenia — HP:0000938	Imaging/sign	Childhood onward	74% pooled	Fracture risk, though spontaneous fractures are uncommon
Wormian bones — HP:0002645	Imaging sign	Congenital/childhood	49% pooled	Usually diagnostic rather than symptomatic
Large/delayed-closing fontanel — HP:0000239/HP:0001476	Sign	Infancy	37% pooled	Monitoring/protection
Hernia — HP:0000023, HP:0001537	Sign	Congenital/childhood	46% pooled	Possible surgical correction
Cataract — HP:0000518	Ocular sign	Congenital or early childhood	58% pooled; generally mild/less frequent in PYCR1	Visual impairment
Strabismus — HP:0000486	Ocular sign	Childhood	40% pooled	Amblyopia risk
Blue sclerae — HP:0000592	Sign	Congenital	35% pooled	Usually limited direct impairment
Corneal opacity/clouding — HP:0007957	Ocular sign	May be congenital	20% pooled; less frequent in PYCR1 than ALDH18A1 disease	Potential severe visual loss
Sparse hair — HP:0008070	Sign	Early childhood	Recurrent, exact PYCR1 frequency unavailable	Cosmetic impact
Feeding difficulty — HP:0011968	Symptom	Infancy	Recurrent, unquantified	Malnutrition/poor growth
Cryptorchidism — HP:0000028	Sign	Congenital, males	Occasional	Surgical/endocrine implications

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

Attribute	Value
Gene	PYCR1, pyrroline-5-carboxylate reductase 1
HGNC	HGNC:9721
NCBI Gene	5831
OMIM gene	179035
Ensembl	ENSG00000183010
Chromosomal locus	17q25.3
UniProt	P32322
Protein	Mitochondrial pyrroline-5-carboxylate reductase 1
Approximate protein size	319 amino acids, 33.4 kDa
Normal reaction	P5C + NAD(P)H → L-proline + NAD(P)+
Main localization	Mitochondrion, especially mitochondrial matrix
Oligomeric state	Homopolymeric enzyme

[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

Biallelic pathogenic PYCR1 variants lead to absent, unstable, misfolded or catalytically impaired mitochondrial PYCR1 protein.
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)+.
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.
Mitochondrial dysfunction leads to increased susceptibility to oxidative-stress-induced apoptosis.
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.
Dermal and extracellular-matrix loss results in thin, translucent, lax and wrinkled skin, visible veins, reduced subcutaneous tissue and progeroid appearance.
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.
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.
Branch B—ocular connective tissue: impaired development or maintenance of corneal and lens structures leads to cataract, corneal clouding, blue sclerae and visual impairment.
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

Level	Structure/system	Suggested ontology annotation
Organ	Skin, especially hands, feet, face, trunk and extremities	UBERON:0002097, skin of body
Tissue	Dermis, subcutaneous tissue, elastic-fiber/collagen ECM	UBERON:0002067, dermis; adipose tissue concepts
Skeleton	Skull/fontanelles, hips, vertebral column, hands and feet	UBERON skull, hip joint, vertebral column
Nervous system	Brain, corpus callosum, corticospinal/motor system	UBERON:0000955, brain; UBERON:0002336, corpus callosum
Eye	Cornea, lens and sclera	UBERON:0000964, cornea; UBERON:0000965, lens; UBERON:0001775, sclera
Cardiovascular	Usually not primary; occasional aortic-root dilation or other findings require individual evaluation	Heart/aorta terms
Subcellular	Mitochondrion/mitochondrial matrix	GO:0005739, GO:0005759
Molecular structure	Collagen- and elastin-containing extracellular matrix	GO:0031012, extracellular matrix

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:

Prenatal/neonatal phase: growth restriction and congenital connective-tissue phenotype.
Infancy/early childhood: emerging neurodevelopmental and feeding problems.
Later childhood/adolescence: orthopedic complications, mobility limitations and ocular disease may dominate.
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

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

Test	Purpose/findings
Physical and dermatologic examination	Distribution and severity of cutis laxa, translucency, bruising and pressure-injury risk
Growth measurements	Weight, length/height and head circumference
Serum/urine amino acids	Proline, ornithine, citrulline and arginine may be low or normal
Developmental/neuropsychological assessment	Quantifies motor, language, adaptive and cognitive impairment
Brain MRI	May show thin/dysgenetic corpus callosum, cerebral atrophy or abnormal gyration; may be normal
EEG	If seizures or suspicious events occur
Hip ultrasound/radiographs	Congenital hip dislocation
Skeletal survey/targeted radiographs	Osteopenia, Wormian bones, scoliosis, contractures
Flexion–extension cervical radiographs	Consider instability where clinically indicated
Full ophthalmologic/anterior-segment examination	Cataract, corneal clouding, strabismus and refractive error
Echocardiography	Baseline/periodic evaluation; occasional aortic or cardiac involvement
Pulmonary function testing	Older cooperative children, particularly if respiratory symptoms
Skin biopsy with elastic stain/electron microscopy	Can demonstrate reduced/fragmented elastic fibers but is nonspecific and usually unnecessary after molecular diagnosis

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

Disorder/gene	Distinguishing considerations
ALDH18A1-related ARCL/De Barsy	Often more severe developmental impairment, metabolic amino-acid abnormalities and corneal disease; substantial overlap
ATP6V0A2/ATP6V1A/ATP6V1E1-related cutis laxa	Abnormal transferrin glycosylation, large fontanel and characteristic brain/cortical findings
GORAB-related geroderma osteodysplasticum	Recurrent fractures, little CNS involvement, usually no IUGR
FBLN5/LTBP4-related ARCL	Severe pulmonary emphysema, diaphragmatic hernia or visceral diverticula; cognition usually normal
EFEMP2/LOX/EMILIN1 disorders	Arterial tortuosity, aneurysm/dissection or marfanoid features
Hutchinson–Gilford progeria, LMNA	Progressive atherosclerosis, alopecia and characteristic skeletal changes rather than congenital cutis laxa
Wiedemann–Rautenstrauch syndrome, POLR3A	Neonatal progeroid appearance and natal teeth
Fontaine progeroid syndrome, SLC25A24	Craniosynostosis and hypertrichosis
Nestor–Guillermo progeria, BANF1	Severe mandibular hypoplasia
SOPH syndrome, NBAS	Pelger–Huët anomaly, elevated liver enzymes and optic atrophy
Menkes/occipital-horn syndrome, ATP7A	Abnormal copper metabolism, pili torti and X-linked inheritance

[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]

Intervention	Indication/purpose	Evidence	Suggested NCIT concept
Physical therapy	Hypotonia, delayed motor skills, hypermobility, spasticity, contractures	Expert consensus/supportive	Physical Therapy
Occupational therapy	Hand function, adaptive skills, activities of daily living	Expert consensus	Occupational Therapy
Speech/language and feeding therapy	Speech delay, dysphagia and communication	Expert consensus	Speech Therapy
Nutritional support	Feeding difficulty, malnutrition, poor growth	Supportive	Nutritional Support
Standard antiseizure medication	Epilepsy	Treat as other epilepsies; no genotype-specific drug	Anticonvulsant Therapy
Orthoses/mobility devices	Contractures, gait impairment, long-distance mobility	Supportive	Assistive Device
Orthopedic intervention	Hip dislocation, scoliosis, clubfoot, severe contracture	Case-specific	Orthopedic Surgery
Cataract/corneal surgery	Vision-limiting opacity	Case-specific	Cataract Surgery / Corneal Transplantation
Hernia repair	Symptomatic inguinal/umbilical hernia	Standard surgical practice	Hernia Repair
Calcium/vitamin D management	Documented deficiency or osteopenia	General bone-health practice; not disease-modifying	Calcium Supplementation / Vitamin D Supplementation
Arginine supplementation	Low ornithine/citrulline/arginine	Case reports only; benefit unconfirmed	Arginine Supplementation
Citrulline/proline replacement	Biochemical deficiency	Case reports only; benefit unconfirmed	Amino Acid Supplementation
Blood-pressure/cardiology care	Individual vascular/cardiac abnormality	Precautionary/standard care	Antihypertensive Therapy

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:

Species	NCBI taxonomy	Orthologue/resource	Natural disease
Human, Homo sapiens	9606	PYCR1, NCBI Gene 5831	Yes
Mouse, Mus musculus	10090	Pycr1, MGI:2384795	Experimental knockout; no established natural homologous disease
Zebrafish, Danio rerio	7955	pycr1a, NCBI Gene 393799; also pycr1b paralogue	Experimental model only
Frog, Xenopus spp.	Species-dependent	pycr1 orthologue	Morpholino/knockdown model only

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

15. Model organisms

Model	Manipulation	Phenotype recapitulated	Limitations and applications
Patient dermal fibroblasts	Endogenous biallelic pathogenic variants	Altered mitochondrial morphology, reduced membrane potential, oxidative-stress hypersensitivity and increased apoptosis	Most directly disease-relevant cellular model, but lacks whole-organism development
HEK293T cells	Overexpression of p.Ala187Thr	Reduced PYCR1 abundance and approximately 54% lower enzyme activity	Artificial overexpression and non-dermal cell context; useful for variant functional testing
Zebrafish embryo	pycr1 knockdown	Epidermal hypoplasia, blistering and increased apoptosis	Morpholino-specific limitations
Zebrafish pycr1a knockout	TALEN-generated 2-bp frameshift	Progeroid appearance from about four months, behavioral abnormalities, increased senescence/apoptosis and approximately 50% mortality near six months	Fish skin and lifespan differ from humans; valuable for aging and drug-screen research
Xenopus embryo	Orthologue knockdown	Epidermal hypoplasia, blistering and marked apoptosis	Transient developmental model
Mouse Pycr1 knockout, KOMP line	Null allele	Male impaired glucose tolerance and reduced triglycerides; no overt cutis laxa phenotype	Poor human-phenotype recapitulation, likely Pycr2 compensation
Mouse constitutive Pycr1 knockout, 2023 model	Near-complete loss of Pycr1	Dermal thinning and fewer collagen fibers	Epidermis and overall phenotype comparatively normal; may require Pycr1/Pycr2 double knockout

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

Evidence type	Publication	Key quotation/finding
Human genetics + patient fibroblasts + vertebrate knockdown	Reversade et al., Nature Genetics, published online 2 August 2009, PMID 19648921, DOI: https://doi.org/10.1038/ng.413	“Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals.” [17]
Human genotype–phenotype cohort	Dimopoulou et al., Molecular Genetics and Metabolism, November 2013, PMID 24035636, DOI: https://doi.org/10.1016/j.ymgme.2013.08.009	“Here we describe 33 patients with PYCR1-related ARCL from 27 families…” Twenty mutations were identified, seven novel; first-two-exon variants were associated with lower severity. [106][115]
Human De Barsy case	Lin et al., American Journal of Medical Genetics A, December 2011, PMID 22052856, DOI: https://doi.org/10.1002/ajmg.a.34326	Compound heterozygous frameshift/missense alleles expanded the clinical spectrum to congenital glaucoma, aortic-root dilation and pyloric stenosis. [81]
Variant assay + longitudinal child assessment	2024 study, published 22 August 2024, PMID 39172257, DOI: https://doi.org/10.1007/s00438-024-02173-y	“Mutagenesis and enzyme assay study revealed decreased activity of the mutant protein in vitro, indicating that this mutation impairs PYCR1 function.” [33]
Stable zebrafish model	Liang et al., Cells, published 14 May 2019, PMID 31091804	pycr1-deficient fish developed premature-aging and behavioral phenotypes and approximately 50% mortality near six months. [123][125]
Recent skin-aging/mouse work	PYCR1 Levels Track with Premature and Chronological Skin Aging, 2023	Pycr1 loss caused dermal thinning and reduced collagen, but the mouse remained otherwise relatively normal, indicating incomplete phenocopy. [124][126]

Knowledge gaps and curation cautions

ARCL2B versus ARCL3B: these should be cross-referenced as a spectrum, not treated as completely independent molecular disorders.
Phenotype frequencies: most percentages combine PYCR1 and ALDH18A1 disorders; annotate them as pooled estimates.
Epidemiology: no population-based incidence or robust prevalence data exist.
Prognosis: life expectancy and long-term adult natural history are unknown.
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.
Treatment: no controlled therapeutic trial or validated disease-modifying intervention exists.
Omics: disease-specific single-cell, spatial, proteomic, lipidomic and epigenomic datasets are lacking.
Animal models: current models only partially reproduce human disease, especially the neurologic and ocular phenotype.
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

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	8
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	63
Resolved	58
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	4

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

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

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

58 of 63 terms resolved to a current term; the rest could not be looked up either way.

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

PYCR1-Related De Barsy Syndrome

Executive summary

1. Disease information

1.1 Definition and scope

1.2 Identifiers

1.3 Synonyms

1.4 Evidence granularity

2. Etiology

2.1 Causal factor

2.2 Genetic risk factors

2.3 Susceptibility and modifier factors

2.4 Environmental and protective factors

3. Phenotypes

3.1 Frequency caveat

3.2 Core phenotype matrix

Important natural-history points

3.3 Quality of life

4. Genetic and molecular information

4.1 Gene and protein

4.2 Variant interpretation

4.3 Modifier, epigenetic and structural-genomic evidence

5. Environmental information

6. Mechanism and pathophysiology

6.1 Ordered causal chain

6.2 Pathway and biochemical detail

6.3 Cellular and tissue mechanisms

6.4 Immune and epigenetic mechanisms

6.5 Recent mechanistic research, 2023–2024

7. Anatomical structures affected

8. Temporal development

8.1 Onset

8.2 Course

9. Inheritance and population

9.1 Inheritance

9.2 Epidemiology

10. Diagnostics

10.1 Diagnostic approach

Recommended workflow

10.2 Clinical tests

10.3 Genetic-testing modalities

10.4 Differential diagnosis

10.5 Screening

11. Outcome and prognosis

12. Treatment

12.1 Current standard

12.2 Surveillance

12.3 Experimental therapy

12.4 Anaesthesia and procedures

13. Prevention

13.1 Primary prevention

13.2 Secondary prevention

13.3 Tertiary prevention

14. Other species and natural disease

15. Model organisms

Evidence highlights and exact abstract quotations

Knowledge gaps and curation cautions

Reference Validation

Term Validation

Obsolete terms

Prefixes with no resolver