Phosphoglycerate dehydrogenase deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Phosphoglycerate dehydrogenase deficiency is a condition characterized by an unusually small head size (microcephaly); impaired development of physical reactions, movements, and speech (psychomotor retardation); and recurrent seizures (epilepsy). Different types of phosphoglycerate dehydrogenase deficiency have been described; they are distinguished by their severity and the age at which symptoms first begin. Most affected individuals have the infantile form, which is the most severe form, and are affected from infancy. Symptoms of the juvenile and adult types appear later in life; these types are very rare.

In phosphoglycerate dehydrogenase deficiency there is a progressive loss of brain cells leading to a loss of brain tissue (brain atrophy), specifically affecting the fatty tissue known as myelin that surrounds nerve cells (hypomyelination). Frequently, the tissue that connects the two halves of the brain (corpus callosum) is small and thin, and the fluid-filled cavities (ventricles) near the center of the brain are enlarged. Because development of the brain is disrupted, the head does not grow at the same rate as the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Poor brain growth leads to an inability to achieve many developmental milestones such as sitting unsupported and speaking. Many affected infants also have difficulty feeding.

The seizures in phosphoglycerate dehydrogenase deficiency can vary in type. Recurrent muscle contractions called infantile spasms are typical early in the disorder. Without early treatment, seizures may progress to tonic-clonic seizures, which involve a loss of consciousness, muscle rigidity, and convulsions; myoclonic seizures, which involve rapid, uncontrolled muscle jerks; or drop attacks, which are sudden episodes of weak muscle tone.

Individuals with the infantile form of phosphoglycerate dehydrogenase deficiency develop many of the features described above. Individuals with the juvenile form typically have epilepsy as well as mild developmental delay and intellectual disability. Only one case of the adult form has been reported; signs and symptoms began in mid-adulthood and included mild intellectual disability; difficulty coordinating movements (ataxia); and numbness, tingling, and pain in the arms and legs (sensory neuropathy).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the PHGDH gene cause phosphoglycerate dehydrogenase deficiency. The PHGDH gene provides instructions for making the parts (subunits) that make up the phosphoglycerate dehydrogenase enzyme. Four PHGDH subunits combine to form the enzyme. This enzyme is involved in the production of the protein building block (amino acid) serine. Specifically, the enzyme converts a substance called 3-phosphoglycerate to 3-phosphohydroxypyruvate in the first step in serine production. Serine is necessary for the development and function of the brain and spinal cord (central nervous system). Serine is a part of chemical messengers called neurotransmitters that transmit signals in the nervous system. Proteins that form cell membranes and myelin also contain serine. Serine can be obtained from the diet, but brain cells must produce their own serine because dietary serine cannot cross the protective barrier that allows only certain substances to pass between blood vessels and the brain (the blood-brain barrier).

PHGDH gene mutations result in the production of an enzyme with decreased function. As a result, less 3-phosphoglycerate is converted into 3-phosphohydroxypyruvate than normal and serine production is stalled at the first step. The lack of serine likely prevents the production of proteins and neurotransmitters in the brain and impairs the formation of normal cells and myelin. These disruptions in normal brain development lead to the signs and symptoms of phosphoglycerate dehydrogenase deficiency.

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

This condition is likely a rare disorder, but its prevalence is unknown. At least 15 cases have been described in the scientific literature.

Which doctor should you see?

The suggested department for discussing Phosphoglycerate dehydrogenase deficiency 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

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

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.