Fukuyama congenital muscular dystrophy is an inherited condition that predominantly affects the muscles, brain, and eyes. Congenital muscular dystrophies are a group of genetic conditions that cause muscle weakness and wasting (atrophy) beginning very early in life.

Fukuyama congenital muscular dystrophy affects the skeletal muscles, which are muscles the body uses for movement. The first signs of the disorder appear in early infancy and include a weak cry, poor feeding, and weak muscle tone (hypotonia). Weakness of the facial muscles often leads to a distinctive facial appearance including droopy eyelids (ptosis) and an open mouth. In childhood, muscle weakness and joint deformities (contractures) restrict movement and interfere with the development of motor skills such as sitting, standing, and walking.

Fukuyama congenital muscular dystrophy also impairs brain development. People with this condition have a brain abnormality called cobblestone lissencephaly, in which the surface of the brain develops a bumpy, irregular appearance (like that of cobblestones). These changes in the structure of the brain lead to significantly delayed development of speech and motor skills and moderate to severe intellectual disability. Social skills are less severely impaired. Most children with Fukuyama congenital muscular dystrophy are never able to stand or walk, although some can sit without support and slide across the floor in a seated position. More than half of all affected children also experience seizures.

Other signs and symptoms of Fukuyama congenital muscular dystrophy include impaired vision, other eye abnormalities, and slowly progressive heart problems after age 10. As the disease progresses, affected people may develop swallowing difficulties that can lead to a bacterial lung infection called aspiration pneumonia. Because of the serious medical problems associated with Fukuyama congenital muscular dystrophy, most people with the disorder live only into late childhood or adolescence.

Fukuyama congenital muscular dystrophy is caused by mutations in the FKTN gene. This gene provides instructions for making a protein called fukutin. Although the exact function of fukutin is unclear, researchers predict that it may chemically modify a protein called alpha (α)-dystroglycan. This protein anchors cells to the lattice of proteins and other molecules (the extracellular matrix) that surrounds them. In skeletal muscles, α-dystroglycan helps stabilize and protect muscle fibers. In the brain, this protein helps direct the movement (migration) of nerve cells (neurons) during early development.

The most common mutation in the FKTN gene reduces the amount of fukutin produced within cells. A shortage of fukutin likely prevents the normal modification of α-dystroglycan, which disrupts that protein's normal function. Without functional α-dystroglycan to stabilize muscle cells, muscle fibers become damaged as they repeatedly contract and relax with use. The damaged fibers weaken and die over time, leading to progressive weakness and atrophy of the skeletal muscles.

Defective α-dystroglycan also affects the migration of neurons during the early development of the brain. Instead of stopping when they reach their intended destinations, some neurons migrate past the surface of the brain into the fluid-filled space that surrounds it. Researchers believe that this problem with neuronal migration causes cobblestone lissencephaly in children with Fukuyama congenital muscular dystrophy. Less is known about the effects of FKTN mutations in other parts of the body.

Because Fukuyama congenital muscular dystrophy involves a malfunction of α-dystroglycan, this condition is described as a dystroglycanopathy.

Normal Function

The FKTN gene (formerly known as FCMD) provides instructions for making a protein called fukutin. This protein is present in many of the body's tissues but is particularly abundant in heart (cardiac) muscle, the brain, and the muscles used for movement (skeletal muscles). Within cells, fukutin is found in a specialized structure called the Golgi apparatus, where newly produced proteins are modified.

The fukutin protein is involved in a protein modification process called glycosylation. Through this chemical process, sugar molecules are added to certain proteins. In particular, the fukutin protein adds a molecule called ribitol 5-phosphate to the chain of sugars attached to a protein called alpha (α)-dystroglycan. Glycosylation is critical for the normal function of α-dystroglycan.

The α-dystroglycan protein helps anchor the structural framework inside each cell (cytoskeleton) to the lattice of proteins and other molecules outside the cell (extracellular matrix). In skeletal muscles, glycosylated α-dystroglycan helps stabilize and protect muscle fibers. In the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development.

Health Conditions Related to Genetic Changes

Fukuyama congenital muscular dystrophy

At least 18 mutations in the FKTN gene have been found to cause Fukuyama congenital muscular dystrophy, a condition that causes skeletal muscle weakness and brain and eye abnormalities. This form of congenital muscular dystrophy is seen almost exclusively in Japan.

Virtually everyone with this condition has at least one copy of the same mutation, an insertion of about 3,000 extra DNA building blocks (3 kilobases [kb]) in the FKTN gene. This insertion occurs in a part of the gene known as the 3' untranslated region, which helps regulate the gene's activity. Researchers believe that the 3-kb insertion reduces the amount of fukutin protein that is produced from the gene.

A shortage of fukutin prevents the normal glycosylation of α-dystroglycan. As a result, α-dystroglycan can no longer effectively anchor cells to the proteins and other molecules that surround them. Without functional α-dystroglycan to stabilize the muscle fibers, they become damaged as they repeatedly contract and relax with use. The damaged fibers weaken and die over time, which affects the development, structure, and function of skeletal muscles in people with Fukuyama congenital muscular dystrophy.

Defective α-dystroglycan also affects the migration of neurons during the early development of the brain. Instead of stopping when they reach their intended destinations, some neurons migrate past the surface of the brain into the fluid-filled space that surrounds it. Researchers believe that this problem with neuronal migration causes a brain abnormality called cobblestone lissencephaly, in which the surface of the brain lacks the normal folds and grooves and instead appears bumpy and irregular. Less is known about the effects of FKTN mutations in other parts of the body.

Limb-girdle muscular dystrophy

MedlinePlus Genetics provides information about Limb-girdle muscular dystrophy

Walker-Warburg syndrome

At least 11 FKTN gene mutations have been identified in people with Walker-Warburg syndrome, the most severe form of congenital muscular dystrophy. This condition is found in populations worldwide. Like Fukuyama congenital muscular dystrophy (described above), Walker-Warburg syndrome is associated with skeletal muscle weakness and eye and brain abnormalities, including cobblestone lissencephaly. However, individuals with Walker-Warburg syndrome have more severe brain and eye abnormalities and live only into infancy or early childhood. The FKTN gene mutations associated with this condition prevent the production of any functional fukutin protein, which leads to the severe muscle, eye, and brain problems that develop in Walker-Warburg syndrome.

Other disorders

Mutations in the FKTN gene cause other disorders that affect skeletal muscles and the heart. Unlike Fukuyama congenital muscular dystrophy (described above), which is mostly limited to the Japanese population, these conditions have been described in several populations worldwide.

Several people with a heart condition called dilated cardiomyopathy have been found to have mutations in the FKTN gene. This condition weakens and enlarges the heart, preventing it from pumping blood efficiently. When dilated cardiomyopathy is associated with FKTN gene mutations, it is known as type 1X (DCM1X). In addition to heart problems, some people with DCM1X have experienced mild skeletal muscle weakness beginning in adulthood.

Changes in the FKTN gene that reduce but do not eliminate the production of fukutin lead to the somewhat less severe medical problems seen in DCM1X and limb-girdle muscular dystrophy (linked above).

Other Names for This Gene

• CMD1X
• FCMD
• FKTN_HUMAN
• Fukuyama type congenital muscular dystrophy protein
• LGMD2M
• MGC126857
• MGC134944
• MGC134945
• MGC138243

Genomic Location

• Low muscle tone (hypotonia)
• Poor feeding
• Weak cry
• Speech delay
• Intellectual disability
• Seizures
• Vision problems
• Swallowing difficulty (dysphagia)
• Heart muscle damage (cardiomyopathy)
• Difficulty breathing

• Orthopedist
• Neurologist
• Pulmonologist
• Physical therapist
• Speech pathologist
• Cardiologist
• Ophthalmologist

Fukuyama congenital muscular dystrophy is seen almost exclusively in Japan, where it is the second most common form of childhood muscular dystrophy (after Duchenne muscular dystrophy). Fukuyama congenital muscular dystrophy has an estimated incidence of 2 to 4 per 100,000 Japanese infants.