X-linked periventricular heterotopia

Alternate names

Heterotopia periventricular X-linked dominant; Periventricular nodular heterotopia 1; Heterotopia familial nodular; Nodular heterotopia bilateral periventricular; NHBP; Bilateral periventricular nodular heterotopia; BPNH; PVNH1

Definition

X-linked periventricular heterotopia or FLNA-related periventricular nodular heterotopia is a genetic disorder in which nerve cells in the brain do not migrate properly during early fetal development (a neuronal migration disorder).

Cause

• X-linked periventricular heterotopia is caused by mutations in the FLNA gene.
• This gene provides instructions for making the protein filamin A, which helps build the network of protein that gives structure to cells and allows them to change shape and move (cytoskeleton).

Gene mutations

• Certain mutations in the FLNA gene result in an impaired filamin A protein that cannot perform this function, leading to a disruption of the normal migration patterns of neurons during brain development.

Inheritance

X-linked dominant inheritance

• Inheritance of X-linked periventricular heterotopia is X-linked dominant. This means that the gene responsible for the condition is located on the X chromosome, and having only one mutated copy of the gene is enough to cause the condition.
• Because males have only one X chromosome (and one Y chromosome) and females have two X chromosomes, X-linked dominant conditions affect males and females differently. Both males and females can have an X-linked dominant condition. However, because males don't have a second, working copy of the gene (as females do), they usually have more severe disease than females.
• In rare cases, males with FLNA mutations survive to adulthood and father children. If a father has the mutated X-linked gene:
• all of his daughters will inherit the mutated gene (they will all receive his X chromosome)
• none of his sons will inherit the mutated gene (they only inherit his Y chromosome)
• If a mother has the mutated X-linked gene, each of her children (both male and female) has a 50% chance to inherit the mutated gene.
• In about 50 percent of cases of X-linked periventricular heterotopia, an affected person inherits the mutation from a mother who is also affected. Other cases may result from new mutations in the gene (de novo). These cases occur in people with no history of the disorder in their family.

Signs and symptoms

It is characterized by the presence of clumps of neurons near the brain's ventricles. Most people with this disorder are female, as it can be lethal in males. Symptoms typically begin with seizures in the teenage years. Intelligence is usually normal, but mild intellectual disability (including difficulty with reading and spelling) may occur. People with this condition also appear to be at increased risk for stroke and other vascular or coagulation (clotting) problems. Some people also have hyperflexible joints and vascular anomalies, which also occur in Ehlers-Danlos syndrome (EDS).

Other signs and symptoms may include:

• Heart problems (patent ductus arteriosus, dilatation and rupture of the thoracic aorta, atrial and ventricular septal defects, weakness of the cardiac valves)
• Congenital strabismus
• Shortened fingers and toes
• Hyperflexible joints
• Pulmonary (lung) disease
• Skin that is very elastic
• Males with this condition often have much more severe symptoms than females. IN many cases, males with this condition do not survive to birth.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormal bleeding(Bleeding tendency)
• Gastroesophageal reflux(Acid reflux)
• Hernia
• Pyloric stenosis
• Scoliosis

30%-79% of people have these symptoms

• Abnormal heart valve morphology
• Aortic regurgitation
• Focal-onset seizure(Seizure affecting one half of brain)
• Joint hypermobility(Double-Jointed)
• Patent ductus arteriosus
• Periventricular heterotopia
• Thin skin

5%-29% of people have these symptoms

• Aortic aneurysm(Bulge in wall of large artery that carries blood away from heart)
• Patellar dislocation(Dislocated kneecap)
• Shoulder dislocation

Diagnosis

The diagnosis of FLNA-related PVNH is established by the identification of:[1].

• Characteristic head MRI findings; and
• Heterozygous pathogenic variants in FLNA in females or hemizygous pathogenic variants in FLNA in males.

Treatment

• Although there is no cure for X-linked periventricular heterotopia, there may be ways to manage the signs and symptoms in each individual.
• Seizures are typically treated with antiepileptic medications.
• Given the risk for aortic or carotid dissection (leaking of blood into the artery wall), individuals with this condition may be advised to keep blood pressure within the normal range.
• Additionally, it is recommended that individuals with X-linked periventricular heterotopia undergo carotid and abdominal ultrasound surveillance studies for aortic and carotid dissection and echocardiograms to monitor valvular abnormalities.

NIH genetic and rare disease info

• NIH info on X-linked periventricular heterotopia

X-linked periventricular heterotopia is a rare disease.

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