CLPB deficiency

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

CLPB deficiency is a rare disorder characterized by neurological problems and a shortage of infection-fighting white blood cells (neutropenia). Signs and symptoms of the condition develop by early childhood, and their severity varies widely among affected individuals.

In the most severely affected individuals, features of CLPB deficiency are apparent in infancy and sometimes at birth. Affected babies have serious neurological problems, which can include an exaggerated startle reaction (hyperekplexia) to unexpected stimuli such as loud noises, reduced movement, muscle tone that is either decreased (hypotonia) or increased (hypertonia), swallowing problems, difficulty breathing, and recurrent seizures (epilepsy). These babies may also have movement abnormalities, such as difficulty coordinating movements (ataxia), involuntary tensing of the muscles (dystonia), or uncontrolled movements of the body (dyskinesia). In addition, these babies have recurrent, life-threatening infections due to severe neutropenia. Affected individuals are at risk of developing a blood cell disorder called myelodysplastic syndrome or a form of blood cancer called leukemia. Because of their severe health problems, affected infants usually live only a few weeks or months.

Moderately affected individuals have neurological problems similar to those described above, although they are less severe. They include hypotonia, muscle stiffness (spasticity), and movement abnormalities. Other features of moderate CLPB deficiency include epilepsy and mild to severe intellectual disability. Neutropenia in these individuals can lead to recurrent infections, although they are not life-threatening.

Mildly affected individuals have no neurological problems, and although they have neutropenia, it does not increase the risk of infections. Some people with mild CLPB deficiency develop deposits of calcium in the kidneys (nephrocalcinosis) or kidney (renal) cysts.

Many people with mild, moderate, or severe CLPB deficiency have clouding of the lenses of the eyes (cataracts) from birth (congenital) or beginning in infancy.

CLPB deficiency is associated with increased levels of a substance called 3-methylglutaconic acid in the urine (3-methylglutaconic aciduria). This abnormality, which provides a clue to the diagnosis, does not appear to cause any health problems.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

CLPB deficiency is caused by mutations in the CLPB gene, which provides instructions for making a protein whose function is unknown. Based on its similarity to a protein in other organisms, the CLPB protein is thought to help unfold misfolded proteins so they can be refolded correctly. If not fixed, misfolded proteins cannot function properly and may be damaging to cells.

CLPB gene mutations likely reduce or eliminate the amount of functional CLPB protein. The severity of the condition is thought to be related to the amount of functional protein remaining: severe CLPB deficiency is likely caused by a complete absence of CLPB protein, while moderate and mild CLPB deficiency result when some functional CLPB protein is produced. Researchers are unsure how reduction or absence of this protein leads to the signs and symptoms of CLPB 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

CLPB deficiency is a rare disorder; the prevalence is not known. At least 26 cases have been reported in the medical literature.

Which doctor should you see?

The suggested department for discussing CLPB 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

The material gathered for this draft does not provide a complete condition-specific treatment pathway for CLPB deficiency. 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.