PIGA-CDG is a congenital disorder of glycosylation. It is also known as phosphatidylinositol glycan class A protein deficiency and multiple congenital anomalies-hypotonia-seizures syndrome 2, or MCAHS2. Throughout this page, we will refer to the condition as PIGA or PIGA-CDG.
PIGA-CDG is an extremely rare, X-linked genetic disorder caused by a pathogenic change in the PIGA gene. This gene provides instructions for making an essential part of the enzyme complex responsible for the first stage of glycosylphosphatidylinositol, or GPI, anchor production.
GPI anchors allow many important proteins to attach to the surface of cells. When the body cannot produce these anchors correctly, the function of many proteins can be disrupted. This can affect several parts of the body, particularly the brain and nervous system.
Symptoms
The symptoms of PIGA-CDG vary considerably between individuals. Some children are severely affected from birth, while others have an intermediate or milder form of the condition. Not every child will experience every symptom, and some children may develop symptoms that have not previously been associated with PIGA-CDG.
Possible symptoms include:
- Global developmental delay
- Intellectual disability
- Developmental regression
- Early-onset seizures and epilepsy
- Infantile spasms
- Myoclonic, tonic or focal seizures
- Epilepsy that is difficult to control with medication
- Hypotonia, meaning reduced muscle tone
- Hypertonia, meaning increased muscle tone
- Dystonia, chorea or other involuntary movements
- Cortical visual impairment
- Delayed myelination and other abnormalities visible on MRI scans
- Difficulties swallowing
- Aspiration of food, drink or saliva into the lungs
- Slow gastrointestinal motility
- Constipation and other digestive problems
- Sleep difficulties
- Respiratory complications
- Distinctive facial features
- Congenital abnormalities affecting other parts of the body
The range and severity of PIGA-related conditions are now understood to be much broader than first thought. A review published in March 2026 examined 107 previously reported individuals and added five newly described patients, bringing the published total to 112. The true number of diagnosed individuals is likely to be higher because not every diagnosis is published in medical literature.
Rex, Spain’s first PIGA-CDG patient
Rex was Spain’s first known patient to be diagnosed with PIGA-CDG and the first case to be formally documented and published in the country. This was confirmed by his geneticist, Alba Gabaldon-Albero.
Rex’s case was published on 18 June 2024 by researchers and clinicians from the Instituto de Investigación Sanitaria La Fe and Hospital Universitario y Politécnico La Fe in Valencia.
The paper documented a previously unreported PIGA variant and provided functional evidence that the variant disrupted GPI-anchor production. Clinical photographs of Rex were included in Figure 1 of the published paper.
The research also produced an important finding relating to X-chromosome inactivation. Before Rex’s case, it was generally expected that female carriers of a disease-causing PIGA variant would have highly skewed X-chromosome inactivation. Testing showed that Rex’s mother had a non-skewed, or random, pattern of X-chromosome inactivation.
Further testing using flow cytometry identified reduced expression of the GPI-anchored protein CD16. This helped confirm that the PIGA variant was pathogenic, despite the unexpected X-inactivation result. The researchers recommended considering similar flow-cytometry testing when investigating uncertain PIGA variants.
You can read the full La Fe paper here:
Diagnosis
PIGA-CDG is usually diagnosed through genetic testing. Testing may be carried out as part of an epilepsy or neurodevelopmental gene panel, through whole-exome sequencing, or through whole-genome sequencing.
When a PIGA variant is identified, further testing may be required to determine whether it is responsible for the patient’s symptoms.
Flow cytometry can be used to examine GPI-anchored proteins on the surface of certain white blood cells, particularly granulocytes and neutrophils. Proteins and markers that may be examined include CD16, CD24, CD157 and FLAER.
Reduced expression of these markers can provide functional evidence that GPI-anchor production has been disrupted. However, flow-cytometry results should be considered alongside the person’s symptoms, genetic results and other clinical findings.
Inheritance
PIGA is located on the X chromosome, which means PIGA-CDG follows an X-linked pattern of inheritance.
The disorder has overwhelmingly been reported in males. Males have one X chromosome, so a disease-causing PIGA variant on that chromosome can directly affect them.
Females have two X chromosomes and may carry a PIGA variant without displaying symptoms. This is partly because cells normally deactivate one of their two X chromosomes. However, Rex’s case demonstrated that the relationship between PIGA variants and X-chromosome inactivation can be more complicated than previously believed.
PIGA-CDG has been identified in families throughout the world. There is no evidence that it is limited to a particular country, geographical area or ethnic background.
Families affected by PIGA-CDG should be offered advice from a qualified genetic counsellor or clinical genetics team regarding inheritance, carrier testing and the likelihood of the condition affecting future children.
Treatment
There is currently no approved treatment that corrects the underlying genetic cause of PIGA-CDG.
Medical care is tailored to each individual and focuses on treating symptoms, reducing complications and maintaining comfort and quality of life. Treatment may include:
- Anti-seizure medication
- Rescue medication for prolonged seizures
- Respiratory monitoring and support
- Physiotherapy
- Management of muscle tone and movement disorders
- Treatment for gastrointestinal problems
- Nutritional support
- Speech and language therapy
- Swallowing assessments
- Management of sleep difficulties
- Visual support
- Occupational therapy
- Supportive and palliative care
Some children require a nasogastric tube or gastrostomy feeding tube because swallowing difficulties and reduced muscle control can increase the risk of aspiration. Feeding support may also be needed when a child cannot safely consume enough food or fluid by mouth.
Epilepsy can sometimes be controlled with anti-seizure medication. However, many people with PIGA-CDG experience drug-resistant epilepsy, meaning that seizures continue despite treatment with appropriate medication.
Gene therapy research
Gene-replacement therapy for PIGA-CDG is currently being investigated in preclinical research.
A peer-reviewed mouse study published in 2024 found that AAV-based gene replacement improved some effects of PIGA deficiency and extended survival in treated mice. The study also identified safety concerns associated with the particular vector and promoter used, demonstrating that more research is required before this approach could be considered for people.
A separate PIGA-specific study released as a preprint in December 2025 tested an AAV9-based treatment in a mouse model. Researchers reported improvements in survival, structural brain abnormalities, neurological impairment and levels of GPI-anchored proteins following treatment.
These findings are encouraging, but the treatment remains experimental. It has been studied in mice and has not been approved as a treatment for children or adults with PIGA-CDG.
Prognosis
The prognosis for someone with PIGA-CDG varies greatly and depends on the specific genetic variant, the severity of their symptoms, the organs affected and the medical complications they experience.
Some individuals have a milder form of the condition with developmental difficulties and epilepsy that can be managed. Others experience profound developmental impairment, treatment-resistant seizures, swallowing difficulties, recurrent respiratory infections and serious complications affecting multiple parts of the body.
PIGA-CDG is associated with an increased risk of premature death, particularly in its most severe forms. A study of 88 individuals found that respiratory failure was the most frequently identified cause of death. However, people with PIGA-related conditions have also survived into adolescence and adulthood, including individuals reported to have lived into their forties.
Because the condition varies so widely, published statistics cannot predict the outcome for an individual child. Prognosis and care should always be discussed with the child’s medical team.
Research articles and further information
Rex’s La Fe paper
Published by Genes on 18 June 2024.
Latest published case review
Developmental and epileptic encephalopathies with germline PIGA variants in five Chinese children
Published by Frontiers in Genetics in March 2026. This review brought the number of published individuals described by the authors to 112.
Major PIGA patient review
Lessons learned from 40 novel PIGA patients and a review of the literature
Published by Epilepsia in 2020.
Mortality research
Deciphering the premature mortality in PIGA-CDG: An untold story
Published by Epilepsy Research in 2021.
Peer-reviewed gene-therapy research
AAV-based gene therapy ameliorated CNS-specific GPI defect in mouse models
Published by Molecular Therapy: Methods & Clinical Development in 2024.
PIGA-specific gene-replacement preprint
Gene replacement therapy for Piga GPI-anchor deficiency in the developing nervous system
Released as a preprint in December 2025. This research has not yet been established as a treatment in humans.
General PIGA-CDG information
PIGA-CDG information from the Frontiers in Congenital Disorders of Glycosylation Consortium
Medical disclaimer
This information is provided for general awareness and education. It is not intended to replace advice, diagnosis or treatment from a qualified medical professional. Anyone concerned about PIGA-CDG should speak with a clinical geneticist, paediatric neurologist or another appropriate healthcare professional.