Mabry syndrome is a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms.

People with Mabry syndrome have intellectual disability that is often moderate to severe. They typically have little to no speech development and are delayed in the development of motor skills (such as sitting, crawling, and walking). Many affected individuals have low muscle tone (hypotonia) and develop recurrent seizures (epilepsy) in early childhood. Seizures are usually the generalized tonic-clonic type, which involve muscle rigidity, convulsions, and loss of consciousness.

Individuals with Mabry syndrome have distinctive facial features that include wide-set eyes (hypertelorism), long openings of the eyelids (long palpebral fissures), a nose with a broad bridge and a rounded tip, downturned corners of the mouth, and a thin upper lip. These facial features usually become less pronounced over time.

Hyperphosphatasia begins within the first year of life in people with Mabry syndrome. There are many different types of alkaline phosphatase found in tissues; the type that is increased in Mabry syndrome is called the tissue non-specific type and is found throughout the body. In affected individuals, alkaline phosphatase levels in the blood are usually increased by one to two times the normal amount, but can be up to 20 times higher than normal. The elevated enzyme levels remain relatively stable over a person's lifetime. Hyperphosphatasia appears to cause no negative health effects, but this finding can help health professionals diagnose Mabry syndrome.

Another common feature of Mabry syndrome is shortened bones at the ends of fingers (brachytelephalangy), which can be seen on x-ray imaging. Underdeveloped fingernails (nail hypoplasia) may also occur. Sometimes, individuals with Mabry syndrome have abnormalities of the digestive system, including narrowing or blockage of the anus (anal stenosis or anal atresia) or Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. Rarely, affected individuals experience hearing loss.

The signs and symptoms of Mabry syndrome vary among affected individuals. Those who are least severely affected have only intellectual disability and hyperphosphatasia, without distinctive facial features or the other health problems listed above.

Mutations in the PIGV, PIGO, or PGAP2 gene cause Mabry syndrome. These genes are all involved in the production (synthesis) of a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. This molecule is synthesized in a series of steps. It then attaches (binds) to various proteins and binds them to the outer surface of the cell membrane, ensuring that they are available when needed. Alkaline phosphatase is an example of a protein that is bound to the cell membrane by a GPI anchor.

The proteins produced from the PIGV and PIGO genes are involved in piecing together the GPI anchor. After the complete GPI anchor is attached to a protein, the protein produced from the PGAP2 gene adjusts the anchor to enhance the anchor's ability to bind to the cell membrane.

Mutations in the PIGV, PIGO, or PGAP2 gene result in the production of an incomplete GPI anchor that cannot attach to proteins or to cell membranes. Proteins lacking a functional GPI anchor cannot bind to the cell membrane and are instead released from the cell. The release of non-GPI anchored alkaline phosphatase elevates the amount of this protein in the blood, causing hyperphosphatasia in people with Mabry syndrome. It is unclear how gene mutations lead to the other features of Mabry syndrome, but these signs and symptoms are likely due to a lack of proper GPI anchoring of proteins.

PIGV gene mutations are the most frequent cause of Mabry syndrome, accounting for approximately half of all cases. Mutations in the PIGO and PGAP2 genes are responsible for a small proportion of Mabry syndrome. The remaining affected individuals do not have an identified mutation in any of these three genes; the cause of the condition in these individuals is unknown.

Normal Function

The PGAP2 gene provides instructions for making a protein that modifies a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. The GPI anchor attaches (binds) to various proteins and then binds them to the outer surface of the cell membrane, ensuring that they are available when needed. The GPI anchor is made up of many different pieces and is assembled in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. The anchor is then transferred to a different cell structure called the Golgi apparatus, which modifies newly produced enzymes and other proteins. In the Golgi apparatus, the PGAP2 protein assists in attaching a molecule called a saturated fatty acid to the anchor. This saturated fatty acid is likely needed to help transport and attach the anchor to the fat-rich cell membrane.

Health Conditions Related to Genetic Changes

Mabry syndrome

At least five PGAP2 gene mutations have been found to cause Mabry syndrome. The features of Mabry syndrome include intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms. These mutations change single protein building blocks (amino acids) in the PGAP2 protein and probably reduce the activity of the protein. As a result, the PGAP2 protein cannot efficiently modify the GPI anchor, likely impairing the anchor's ability to attach itself and its associated protein to the cell membrane. GPI anchor-associated proteins that cannot attach to the cell membrane are released from the cell.

An enzyme called alkaline phosphatase is normally attached to the cell membrane by a GPI anchor. However, when the anchor is impaired, alkaline phosphatase is released from the cell. This abnormal release of alkaline phosphatase is responsible for the hyperphosphatasia in Mabry syndrome. It is unclear how PGAP2 gene mutations lead to the other features of Mabry syndrome, but these signs and symptoms are likely due to a lack of proper GPI anchoring of proteins to cell membranes.

Other Names for This Gene

• cell wall biogenesis 43 N-terminal homolog
• CWH43-N
• FGF receptor activating protein 1
• FGF receptor-activating protein 1
• FRAG1
• PGAP2_HUMAN
• post-GPI attachment to proteins factor 2

Genomic Location

Normal Function

The PIGO gene provides instructions for making one part of an enzyme called GPI ethanolamine phosphate transfer 3 (GPI-ET3). The other part of the GPI-ET3 enzyme is produced from a gene called PIGF. The GPI-ET3 enzyme is involved in a series of steps that produce a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. Specifically, this enzyme adds a molecule of ethanolamine phosphate to the end of the forming GPI anchor. This step takes place in the endoplasmic reticulum, which is a structure involved in protein processing and transport within cells. The complete GPI anchor attaches (binds) to various proteins in the endoplasmic reticulum; this process requires the ethanolamine phosphate at the end of the anchor. After the anchor and protein are bound, the anchor attaches itself to the outer surface of the cell membrane, ensuring that the protein will be available when it is needed.

Health Conditions Related to Genetic Changes

Mabry syndrome

At least three mutations in the PIGO gene have been found to cause Mabry syndrome, a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms. These mutations change single protein building blocks (amino acids) in the GPI-ET3 enzyme. The altered protein is less able to add ethanolamine phosphate to the end of GPI anchors. The incomplete GPI anchor cannot attach to proteins; without the anchor, the proteins cannot bind to the cell membrane and are released from the cell.

An enzyme called alkaline phosphatase is normally attached to the cell membrane by a GPI anchor. However, when the anchor is impaired, alkaline phosphatase is released from the cell. This abnormal release of alkaline phosphatase is responsible for the hyperphosphatasia in Mabry syndrome. It is unclear how PIGO gene mutations lead to the other features of Mabry syndrome, but these signs and symptoms are likely due to a lack of proper GPI anchoring of proteins to cell membranes.

Other Names for This Gene

• FLJ00135
• GPI ethanolamine phosphate transferase 3
• phosphatidylinositol glycan anchor biosynthesis, class O
• phosphatidylinositol-glycan biosynthesis class O protein
• PIG-O
• PIGO_HUMAN

Genomic Location

Normal Function

The PIGV gene provides instructions for making an enzyme called GPI mannosyltransferase 2. This enzyme takes part in a series of steps that produce a molecule called a glycosylphosphosphatidylinositol (GPI) anchor. Specifically, GPI mannosyltransferase 2 adds the second of three molecules of a complex sugar called mannose to the GPI anchor. This step takes place in the endoplasmic reticulum, which is a structure involved in protein processing and transport within cells. The complete GPI anchor attaches (binds) to various proteins in the endoplasmic reticulum. After the anchor and protein are bound, the anchor attaches itself to the outer surface of the cell membrane, ensuring that the protein will be available when it is needed.

Health Conditions Related to Genetic Changes

Mabry syndrome

At least 14 mutations in the PIGV gene have been found to cause Mabry syndrome, a condition characterized by intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood (hyperphosphatasia), and other signs and symptoms. These mutations change single protein building blocks (amino acids) in the GPI mannosyltransferase 2 enzyme. The altered protein is less able to add mannose to the forming GPI anchor. The incomplete GPI anchor cannot attach to proteins; without the anchor, the proteins cannot bind to the cell membrane and are released from the cell.

An enzyme called alkaline phosphatase is normally attached to a GPI anchor. However, when the anchor is impaired, alkaline phosphatase cannot be anchored to the cell membrane. Instead, alkaline phosphatase is released from the cell. This abnormal release of alkaline phosphatase is responsible for the hyperphosphatasia in Mabry syndrome. It is unclear how PIGV gene mutations lead to the other features of Mabry syndrome, but these signs and symptoms are likely due to a lack of proper GPI anchoring of proteins to cell membranes.

Other Names for This Gene

• dol-P-Man dependent GPI mannosyltransferase
• FLJ20477
• GPI mannosyltransferase 2
• GPI mannosyltransferase II
• GPI-MT-II
• HPMRS1
• phosphatidylinositol glycan anchor biosynthesis, class V
• PIG-V
• PIGV_HUMAN

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Mabry syndrome is likely a rare condition, but its prevalence is unknown. More than 20 cases have been described in the scientific literature.