Autosomal recessive primary microcephaly

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive primary microcephaly is characterized by an unusually small head size (microcephaly) that is noticeable at birth or soon after. Affected infants typically have intellectual disabilities, which can range from mild to severe.

Autosomal recessive primary microcephaly is defined by an unusually small head circumference. Head circumference is the distance around the widest part of the head, measured by placing a measuring tape above the eyebrows and ears and around the back of the head. Infants with autosomal recessive primary microcephaly also have a brain that is smaller than usual. Although the head and brain grow throughout childhood and adolescence, they continue to be smaller than normal in affected individuals.

The smaller brain size contributes to the intellectual disabilities seen in people with autosomal recessive primary microcephaly. Delayed speech and language development are common. Some affected individuals have other brain abnormalities, which can include malformations of the outer surface of the brain (cerebral cortex). These cortical malformations may also contribute to the intellectual disabilities seen in affected individuals.

A few additional features have been associated with autosomal recessive primary microcephaly. These include seizures, behavioral issues, and problems with balance and coordination (ataxia). The development of motor skills, such as sitting, standing, and walking, may also be delayed.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in more than 20 different genes can cause autosomal recessive primary microcephaly. The signs and symptoms that are seen in affected individuals may vary depending on the particular gene involved. Pathogenic variants in the ASPM gene are the most common cause of autosomal recessive primary microcephaly, accounting for 25 to 50 percent of all cases. Pathogenic variants in the WDR62 gene are the second most common cause. The remaining genes are each responsible for a small percentage of cases.

The ASPM and WDR62 genes provide instructions for making proteins that are involved in cell division. These proteins appear to be particularly important for the division of cells in the developing brain. The pathogenic variants in the ASPM and WDR62 genes that cause autosomal recessive primary microcephaly lead to the production of abnormal proteins. These proteins affect the cells of the developing brain, impairing their ability to divide. As a result, affected infants have fewer nerve cells (neurons) than normal and are born with unusually small brains. The smaller brain size contributes to the smaller head size and the intellectual disabilities seen in affected individuals.

Many of the other genes that are associated with autosomal recessive primary microcephaly are also thought to play important roles in early brain development, particularly in determining brain size. Studies suggest that the proteins that are produced from many of these genes help regulate cell division in the developing brain.

Some people with autosomal recessive primary microcephaly do not have one of the pathogenic variants that are known to cause this condition. In these individuals, the cause of the condition 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 must have a pathogenic variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Autosomal recessive primary microcephaly occurs in approximately 1 in 30,000 to 1 in 250,000 newborns. The condition is more common in parts of Asia and the Middle East, where as many as 1 in 10,000 newborns may be affected. More than 300 families with autosomal recessive primary microcephaly have been reported 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.

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.

Gray matter heterotopia · Very frequent (99-80%)

Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.

Growth delay · Very frequent (99-80%)

A deficiency or slowing down of growth pre- and postnatally.

Intellectual disability, severe · Very frequent (99-80%)

Severe intellectual disability (ID) is defined as a type of ID characterized by severely sub-average adaptive functioning and intellectual functioning, with an intelligence quotient (IQ) the range of 20-34.

Microcephaly · Very frequent (99-80%)

Head circumference below 2 standard deviations below the mean for age and gender.

Short stature · Very frequent (99-80%)

A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).

Sloping forehead · Very frequent (99-80%)

Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.

Thin upper lip vermilion · Very frequent (99-80%)

Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).

Other findings in the same source

From: Orphanet

Additional reported features include Upslanted palpebral fissure (Very frequent (99-80%)); Abnormal cortical bone morphology (Frequent (79-30%)); Agenesis of corpus callosum (Frequent (79-30%)); Hyperreflexia (Frequent (79-30%)); Hypoplasia of the frontal lobes (Frequent (79-30%)); Pachygyria (Frequent (79-30%)); Unilateral renal agenesis (Frequent (79-30%)); Ventriculomegaly (Frequent (79-30%)); Vesicoureteral reflux (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Autosomal recessive primary microcephaly 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 Autosomal recessive primary microcephaly. 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.