X-linked periventricular heterotopia

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). 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).^[1][2][3]

X-linked periventricular heterotopia is caused by mutations in the FLNA gene and is inherited in an X-linked dominant manner.^[3][4] Treatment depends on the symptoms in each person and typically includes anti-seizure medications.^[3][5]

EDS with periventricular heterotopia, previously considered a variant of EDS, is now considered to be the same as X-linked periventricular heterotopia type 1 (PVNH1) and is not included as an EDS subtype under the 2017 classification of EDS.

The signs and symptoms of X-linked periventricular heterotopia usually begin in the teenage years with seizures. Although intelligence is usually normal, some may have mild intellectual disability, including difficulties with reading and spelling (dyslexia). There additionally may be a greater risk for cardiovascular disease, stroke, and other vascular or coagulation (blood clotting) problems.^[3][4] 

Other signs and symptoms may include:^[3][5]

• 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

Less commonly, people with X-linked periventricular heterotopia may have other brain findings, gastrointestinal symptoms, and musculoskeletal symptoms similar to those seen in Ehlers-Danlos syndrome.^[3][4][5]

Males with this condition often have much more severe symptoms than females. IN many cases, males with this condition do not survive to birth.^[3][4]

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). 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.^[4]

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.^[6] 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.^[4][6]

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.^[3] 

You can find relevant articles on X-linked periventricular heterotopia through PubMed, a searchable database of biomedical journal articles. Although not all of the articles are available for free online, most articles listed in PubMed have a summary available. To obtain the full article, contact a medical/university library or your local library for interlibrary loan. You can also order articles online through the publisher’s Web site. Using "X-linked periventricular heterotopia" as your search term should help you locate articles. Use the advanced search feature to narrow your search results. Click here to view a search.
http://www.ncbi.nlm.nih.gov/PubMed

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