FLNA Gene Mutation: Associated Disorders and Symptoms

The FLNA gene provides the blueprint for a protein called filamin A. This protein contributes to the structure, movement, and communication of cells, influencing the development of nearly every system in the body. When a mutation occurs in the FLNA gene, the instructions for making filamin A are altered.

This can disrupt cellular activities, leading to health conditions affecting the brain, skeleton, and heart. The specific health issue depends on how the mutation affects the protein’s function.

The Role of the FLNA Gene

The FLNA gene produces the filamin A protein, which is integral to the cellular cytoskeleton. The cytoskeleton is the cell’s internal scaffolding, providing structural support and maintaining shape. Filamin A interacts with actin to form a branching network of filaments, a structure that allows cells to be both stable and flexible enough to move.

Filamin A also links the actin cytoskeleton to proteins in the cell membrane. This connection is necessary for cell adhesion, where cells attach to one another, and cell migration, the movement of cells during development. These processes are required for the formation of tissues and organs.

Filamin A’s functions are especially apparent in the development of the nervous, cardiovascular, and skeletal systems. In the brain, the protein guides neurons to their final destination for proper brain structure. It also contributes to tissue formation in the heart and blood vessels and is involved in bone development.

Associated Genetic Disorders

FLNA gene mutations lead to a spectrum of disorders with overlapping features. These are categorized by how the mutation alters the filamin A protein. A “loss-of-function” mutation means the protein is less effective or absent, while a “gain-of-function” mutation means its activity is abnormally increased.

Periventricular Nodular Heterotopia (PNH) results from a loss of filamin A function. In this disorder of brain development, neurons fail to migrate properly in the cerebral cortex, forming clumps of nerve cells near the brain’s ventricles. Individuals with PNH may experience seizures, which can begin in their teenage years.

Gain-of-function mutations are associated with the Otopalatodigital (OPD) spectrum disorders, a group of conditions affecting skeletal development. Common features include hearing loss, cleft palate, and abnormalities of the fingers and toes. The disorders vary in severity and include:

• Otopalatodigital syndrome type 1 (OPD1)
• Otopalatodigital syndrome type 2 (OPD2)
• Melnick-Needles syndrome
• Frontometaphyseal dysplasia

OPD1 is the mildest of these conditions, characterized by distinct facial features, hearing loss, and abnormalities of the hands and feet. OPD2 is more severe, with significant skeletal issues and underdeveloped ribs that can cause breathing problems. Melnick-Needles syndrome shares features with OPD2, while Frontometaphyseal dysplasia involves prominent brow ridges and underdeveloped muscles. FLNA mutations are also linked to heart valve diseases and joint hypermobility.

Inheritance and Manifestation

FLNA-related disorders are inherited in an X-linked dominant pattern. The gene is on the X chromosome, and only one copy of the mutated gene is needed to cause the disorder. This has different implications for males (XY) and females (XX).

The manifestation of these disorders differs between sexes. Females have a second, normal copy of the FLNA gene on their other X chromosome, which compensates for the mutated one and results in milder symptoms. For example, females with PNH may only experience seizures with otherwise normal cognitive function.

Males have only a single X chromosome and no backup copy of the gene, leading to more severe effects. For many FLNA conditions, like severe OPD spectrum disorders or PNH, the mutation is often lethal in males before or shortly after birth. A male may survive if the mutation is less severe or if they have mosaicism, where the mutation is present in only some cells.

An affected father passes the mutated gene to all of his daughters but none of his sons. An affected mother has a 50% chance of passing the mutated X chromosome to each of her children, regardless of sex.

Diagnosis and Management

Diagnosis of an FLNA-related disorder begins with a clinical evaluation of symptoms and family history. If a condition like PNH or an OPD spectrum disorder is suspected from physical features or imaging, it is confirmed with molecular genetic testing. This test analyzes a blood sample to identify a pathogenic variant in the FLNA gene.

There is no cure for the underlying genetic mutation, so management focuses on supportive care tailored to an individual’s symptoms. This approach requires a multidisciplinary team of specialists to address the various ways the condition can manifest.

For instance, a neurologist manages seizures from PNH with anti-seizure medications, while a cardiologist monitors heart issues like valve problems. Orthopedic specialists and physical therapists address skeletal abnormalities, and audiologists manage hearing loss. Regular surveillance for potential heart, lung, and joint issues is part of ongoing care.