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Condition report · Metabolic

P5CS Deficiency (ALDH18A1-Related)

Whole genome sequencing reads the ALDH18A1 gene for inherited changes that cause P5CS deficiency, a rare metabolic condition with loose, wrinkled skin, eye problems and developmental delay.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

A rare inherited metabolic condition in which the body makes too little proline and related amino acids, causing loose skin, eye problems, developmental delay or leg stiffness. It is caused by changes in the ALDH18A1 gene.

P5CS deficiency is a rare inherited metabolic condition in which the body makes too little proline and related amino acids. Features span a spectrum and can include loose, wrinkled skin, a prematurely aged appearance, cloudy corneas or lens changes, loose joints and developmental delay. Leg stiffness can also occur, and some people have intellectual disability.

The condition is caused by changes in the ALDH18A1 gene. It makes the enzyme P5CS, which is needed to produce proline and ornithine and works inside the mitochondria, the energy-producing parts of cells. Blood tests may show low levels of ornithine, citrulline or arginine.

It can be inherited in two ways. Some people inherit a change from each parent, in an autosomal recessive pattern, while others have one changed copy, often arising new, in an autosomal dominant pattern. Care includes eye assessment and surgery for clouding when needed, physiotherapy, spasticity management, developmental support and follow-up of amino acid levels.

The condition we analyse

P5CS Deficiency

P5CS deficiency is caused by changes in ALDH18A1, which makes the enzyme P5CS needed to produce proline and ornithine. It can be inherited in an autosomal recessive way (changes in both copies) or in an autosomal dominant way, where a single changed copy, often arising de novo, interferes with the enzyme.

Signs and symptoms

Features range across a spectrum. Features can include loose, wrinkled skin (cutis laxa), a progeroid (prematurely aged) appearance, cloudy corneas or lens opacities, loose joints, developmental delay and intellectual disability. Lower limb spasticity (stiffness) can also occur. Blood tests may show low ornithine, citrulline or arginine.

What a diagnosis changes

Care includes eye assessment and surgery for clouding when needed, physiotherapy and spasticity management, developmental support, and metabolic follow-up of amino acid levels. Genetic counselling is recommended because both recessive and dominant inheritance occur; testing parents helps clarify recurrence risk.

Genes analysed

Also known as

delta1-pyrroline-5-carboxylate synthetase deficiency

Includes 6 related subtypes ↓
  • ALDH18A1-related de Barsy syndrome
  • autosomal dominant complex spastic paraplegia type 9B
  • autosomal dominant spastic paraplegia type 9
  • autosomal recessive complex spastic paraplegia type 9B
  • cutis laxa, autosomal dominant 3
  • hereditary spastic paraplegia 9A
MONDO:0100126Sources: [1][2]

Why whole genome sequencing

P5CS deficiency can follow either a recessive or a dominant pattern, so the genetic result shapes the advice for relatives. Whole genome sequencing reads ALDH18A1 in the same test.

Two inheritance patterns need different advice

In the recessive form, each child of two carriers has a 1 in 4 chance of being affected. Where a dominant change is not found in either parent, the estimated recurrence risk to siblings is about 1%, because of the possibility of mosaicism in a parent's reproductive cells.

Eye and metabolic checks guide care

Eye assessment is needed, with surgery for clouding when required. Arginine supplementation has been described in a limited number of people with low amino acid levels, but any benefit is not yet confirmed.

References

  1. Fischer-Zirnsak B, Callewaert BL, Gardeitchik T, Kornak U, 2026. Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects. GeneReviews
  2. ALDH18A1 gene. MedlinePlus Genetics

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