Mabry syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Elevated circulating alkaline phosphatase concentration · Very frequent (99-80%)

Abnormally increased serum levels of alkaline phosphatase activity.

Floppy infant · Very frequent (99-80%)

Floppiness/hypotonia is defined as reduced resistance to passive movement of joints. Physical examination of floppy/hypotonic infants shows head lag, lack of shoulder and elbow muscle contraction on traction response, inability to tighten the shoulder girdle muscles (or slipping through) when held under the axillae, scarf sign (when the arm is pulled to the opposite side, the arm wraps around the neck with the elbow crossing midline), hyperdorsiflexion of the feet, easy apposition of the thumb against the forearm, feet touching the cheek with ease and without discomfort, frog leg position, and inverted U sign on ventral suspension (head, arms, and legs hanging down without elbow or knee flexion and the trunk rounded in a dome shape).

Global developmental delay · Very frequent (99-80%)

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

Hypertelorism · Very frequent (99-80%)

Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).

Seizure · Very frequent (99-80%)

A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

Shortening of all distal phalanges of the fingers · Very frequent (99-80%)

Hypoplasia of all of the distal phalanx of finger.

Abnormal facial shape · Frequent (79-30%)

An abnormal morphology (form) of the face or its components.

Bilateral tonic-clonic seizure · Frequent (79-30%)

A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.

Other findings in the same source

From: Orphanet

Additional reported features include Downturned corners of mouth (Frequent (79-30%)); Growth delay (Frequent (79-30%)); Intellectual disability (Frequent (79-30%)); Long palpebral fissure (Frequent (79-30%)); Tented upper lip vermilion (Frequent (79-30%)); Wide nasal bridge (Frequent (79-30%)); Abnormal parietal bone morphology (Occasional (29-5%)); Aganglionic megacolon (Occasional (29-5%)); Anteriorly placed anus (Occasional (29-5%)); Ataxia (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Mabry syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Mabry syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.