What Is Fukuyama Type Congenital Muscular Dystrophy?

Overview

Fukuyama Congenital Muscular Dystrophy (FCMD) is a rare genetic disorder associated with a mutation in the Fukutin (FKTN) gene at position 9q31-33 on chromosome 9. This causes muscle weakness and significant learning difficulties due to brain structure and muscle abnormalities. Predominantly found in Japan, FCMD ranks second in childhood muscular dystrophy cases, with 0.7-1.2 cases per 100,000 children.¹ 

While most common in Japan, isolated cases do exist globally. Named after Japanese neurologist Professor Yukio Fukuyama, who discovered it in 1960, FCMD is now recognised as an independent subtype of progressive muscular dystrophy (MD).² Children with FCMD need lifelong care as symptoms progress, and although a diagnosis can be difficult to process as a family, learning about key symptoms is vital for optimal care. Close collaboration with experienced medical teams, including neurologists and geneticists, is crucial for tailored guidance based on the child’s condition.

Causes

FCMD is an inherited disorder resulting from a mutation in the FKTN gene. If both parents carry this mutation without symptoms, there's a 25% chance of their child having FCMD and a 50% chance of being an asymptomatic carrier. FCMD, therefore, follows an autosomal recessive inheritance pattern.³

Mutation in the Fukutin (FKTN) gene

FKTN is a gene on chromosome 9 (9q31-33) that codes for a protein responsible for maintaining healthy muscle structure and function. Different mutations in FKTN lead to a spectrum of FCMD severity, spanning mild to severe muscular dystrophy, sometimes coupled with brain abnormalities.

Role of Fukutin (FKTN) in Muscle and brain development

FCMD is known as the α-Dystroglycan-related (α-DG) form of muscular dystrophy. The protein α-DG is needed to help cells adhere to each other.  Research has shown that FKTN proteins are vital for α-DG proteins to carry out a process known as glycosylation — the process by which sugars are added to proteins after production to define their function. This process is crucial for coordinated muscle function and brain structure development.^REF

Muscle development

Proper glycosylation is vital for muscle growth and upkeep. Mutations in FKTN cause faulty FKTN proteins to be produced. These faulty proteins then can’t help α-DG proteins from being able to carry out glycosylation reactions, leading to their loss. α-DG is essential in connecting muscle foundations, known as the basal lamina, to the cytoskeleton connective tissue that offers structural support and is directly involved with muscle contraction. This disruption in the interaction of the basal lamina and cytoskeleton weakens muscles and causes FCMD’s progressive weakness due to compromised muscle structure and function.

Brain development

Glycosylation is required for healthy brain development. In FCMD and brain conditions from FKTN mutations, faulty glycosylation of α-DG disrupts cell movement and the formation of neural connections, causing structural brain issues, learning difficulties and epilepsy.⁴

Clinical presentation

From birth, typically before 9 months, children with FCMD show early signs like motor, feeding, and speaking delays due to weak muscles and abnormal brain development. Progressively, muscle wasting and joint stiffness occur. The severity of symptoms will vary based on the specific mutation:

• Mild: Some muscle strength remains; a few may stand or walk with help. Mild cognitive issues and muscle weakness. Moderate muscle weakness, delayed motor milestones, and some cognitive impairment. Mobility and independent tasks may be hard.
• Severe: Profound muscle weakness, trouble controlling head or sitting without support, breathing and swallowing issues, severe developmental delays, learning difficulties.^2,5

Symptoms might overlap, and not all listed effects may show as FCMD advances. As patients age, these experiences can change.

Physical symptoms

• Muscle weakness, atrophy
• Hypotonia – reduced muscle tone, difficulty in maintaining posture
• Contractures – stiff hips/ joints, beginning around age 3 (hips/ knees), progress to elbows, spine, arms and wrists by ages 5–6
• Facial myopathy – drooping facial musclesEnlarged calves, forearms

Cognitive and neurological symptoms

• Intellectual disabilities
• Seizures – onset within 1–3 years
• Visual impairments

The progressive nature of symptoms

The progressive nature of FCMD carries a challenging outlook, as many children often don't reach 20 years. Symptoms that worsen with age and need careful monitoring include:

• Heart issues: FCMD can damage the heart muscle, sometimes leading to fatal complications.
• Breathing difficulties: Breathing muscles can be affected, making independent breathing challenging.
• Swallowing issues: Muscles controlling swallowing might be affected, leading to the risk of food or liquid entering the lungs and causing serious respiratory infections.^6,7

Clinical evaluation and diagnosis

To diagnose FCMD, specialised investigations follow a clinical diagnosis of symptom observation, including muscle biopsy, MRI neuroimaging, and FKTN molecular genetic testing. Healthcare providers differ in prioritising FKTN genetic tests; a definite diagnosis might follow molecular analysis after a muscle biopsy.

Muscle biopsy

Biopsies usually involve a small piece of affected skeletal muscle tissue suitable for diagnosis. The sample is then looked at to see if there are any signs of muscular dystrophy and FDMD-specific signs. When looking at a muscle biopsy, healthcare experts look out for:

• Muscle tissue issues, like degeneration, atrophy, or unusual fibre size
• Complete absence, near absence, or reduced levels of α-DG in muscle fibres detected through immunohistology or immunolabelling tests^7,8

Brain imaging (MRI)

Brain imaging helps identify FCMD-related structural abnormalities during brain development. Although not commonly used in diagnosis, MRI detects brain malformations, assesses the extent to which the brain is involved in diagnosis and can guide treatment. It pinpoints concerns needing specialised attention and enhances treatment plans.

In FCMD, structural changes are observed across the front, side, and back areas of the brain (frontotemporal space and cerebellum). These regions manage higher-order functions like decision-making, understanding language, movement coordination and muscle control. FCMD may cause disorganised and malformed functions in these areas, affecting individuals’ lives.

Distinctive brain anomalies in FCMD

• Cobblestone Lissencephaly: The cortex (outer layer of the brain) shows abnormal folds, creating a bumpy appearance on MRI scans
• Focal Pachygyria: Specific areas of abnormality, in contrast to diffuse cobblestone lissencephaly
• Cysts
• White matter abnormalities
• Hypoplasia
• Eye abnormalities: Examples are retinal detachment, cataracts, and vision issues⁷

Genetic testing

looks for specific FKTN gene mutations through blood tests in people with symptoms of FCMD as well as those that have a relative found to have the condition or be carriers of an FKTN mutation. Testing methods can vary depending on patient ancestry or FCMD diagnostic certainty.

• Single-gene testing: Common for patients of Japanese, Korean, or Chinese ancestry, it tests for a single ancestral FKTN mutation
• Multigene panel: When clinical FCMD diagnosis is unclear, a multigene panel can identify FKTN and other dystrophy-related gene mutations⁶

Differential diagnosis from other muscular dystrophies

FCMD is recognised as an α-DG subtype of progressive muscular dystrophy. Identifying FKTN gene mutations enables specialised care and rules out other cases like:

• Duchenne Muscular Dystrophy (DMD)
• Becker Muscular Dystrophy (BMD)
• Limb-Girdle Muscular Dystrophies (LGMD)
• Congenital Muscular Dystrophies
• Emery-Dreifuss Muscular Dystrophy (EDMD)

Notably, most FCMD patients with muscle, eye, and brain abnormalities would be diagnosed outside of Japan as having Muscle-eye-brain disease (MEB). Hence, the global term “MEB/FCMD syndrome” is increasingly used.⁹ This unified term reflects the condition's international recognition.

Management and treatment

Currently, there’s no cure for FCMD, so families and healthcare teams focus on symptom management. Early diagnosis, ongoing medical attention, strategic care as FCMD advances, and supportive interventions are vital in improving patients’ quality of life and facilitating long-term care planning, ensuring the best possible journey for them.

Physical therapy

Physiotherapy for patients with muscular dystrophy aims to uphold independence and mobility as conditions worsen. Through exercises and stretches, physiotherapists will collaborate with families to craft plans that aim to slow disease progression and maintain:

• Muscle function
• Range of motion
• Mobility
• Flexibility

Occupational therapy

Occupational therapy enhances life for non-mobile FCMD patients, introducing tools like motorised wheelchairs to boost independence and daily activity skills.¹⁰

Respiratory support

Given FCMD's impact on respiratory muscles, consistent respiratory function assessment is crucial for patients above 10 years. Since cognitive issues and sleep problems can mask respiratory signs, vigilant monitoring is vital. Individual clinical evaluation guides the choice of necessary respiratory support:

Non-invasive

• Breathing Exercises
• Non-invasive pressure ventilation (NPPV)
• Management of respiratory infections
• Cough Assist device

Invasive

• Invasive Ventilation (TIC)
• Tracheostomy¹¹

Medications for symptom management

Tailored medication plans are pivotal for FCMD patients. They offer relief and prevent secondary health issues or complications. Medications address:

• Pain and muscle stiffness – corticosteroids like prednisone
• Heart complications – angiotensin receptor blockers, beta-blockers, or aldosterone antagonists
• Seizures – antiepileptic drugs like clonazepam, phenytoin or valproic acid

Multidisciplinary approaches to care are essential in treating FCMD. This can be achieved by collaborating with experienced medical teams specialising in neuromuscular disorders. As medication effectiveness varies, tailoring treatment plans to specific symptoms and needs will ensure comprehensive care.

Current research and future directions

Over the past 50 years, FCMD's complexity is reflected in its absence of a cure. However, ongoing clinical trials, a clear grasp of its genetic basis and inheritance pattern, along with researchers' dedication, offer hope. Notably, Mariko et al. achieved groundbreaking success by restoring FKTN gene function in animal and human models, elevating α-DG levels in organ-like cells and restoring organisation in muscular and brain structures.¹² Another study led by Murakami et al. demonstrated potential through steroid therapy, showing promise in restoring motor function and delaying disease progression for mild-severe FCMD patients.¹³ These efforts spotlight the evolving landscape of FCMD research and the optimism surrounding potential breakthroughs.

Patient and family support

For families dealing with conditions like FCMD, a strong support network in which to raise visibility and support for rare disorders whilst fostering connections with other families and sharing knowledge is pivotal in offering comfort and empowerment, ensuring that families and patients don’t feel alone. Support networks grant autonomy and allow for the enhancement of care decisions whilst equipping families with the right language to engage healthcare professionals effectively. For caregivers of those with FCMD, using support networks is crucial in maintaining their own and their child’s well-being, as FCMD can elevate the risk of accompanying disorders like depression, anxiety, and obsessive-compulsive disorders.

Charities such as the Muscle Help Foundation, Muscular Dystrophy Association, Pain UK and Muscular Dystrophy UK are on hand to offer help, support and advice for those that have FCMD, are carriers of mutations linked with the condition as well as family members of those affected.

Genetic counselling

There is no known way to prevent FCMD in someone born with a genetic mutation responsible for the disease. If FMCD runs in your family, it is recommended that at-risk couples consult a genetic counsellor to assess their risk if they plan to have children.

Summary

Fukuyama Congenital Muscular Dystrophy (FCMD) is a genetic disorder marked by an FKTN mutation that hinders healthy muscle and brain development. Individuals with FCMD experience motor, feeding, and speaking delays, later progressing to muscle wasting and joint stiffness and a significantly reduced life span. Early diagnosis, regular medical assessments, rehabilitation therapies, adaptive devices, and a strong support network also play critical roles in addressing the challenges posed by FCMD. In the realm of progressive diseases, where times’ impact is profound, every moment is invaluable for families navigating the challenges of FCMD.