Fukuyama congenital muscular dystrophy (FCMD) is a rare,
autosomal
An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosomes ...
recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
form of
muscular dystrophy
Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily af ...
(weakness and breakdown of muscular tissue) mainly described in
Japan but also identified in Turkish and Ashkenazi Jewish patients;
fifteen cases were first described on 1960 by Dr.
Yukio Fukuyama.
FCMD mainly affects the
brain
The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...
,
eyes
Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and c ...
, and
muscles
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, in particular, the disorder affects development of the
skeletal muscles
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
leading to weakness and deformed appearances, and brain development is blunted affecting cognitive functioning as well as social skills.
In 1995, the disorder was linked to mutations in a
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
coding for the protein
fukutin
Fukutin is a eukaryotic protein necessary for the maintenance of muscle integrity, cortical histogenesis, and normal ocular development. Mutations in the fukutin gene have been shown to result in Fukuyama congenital muscular dystrophy (FCMD) c ...
(the ''FCMD'' gene). Fukuyama congenital muscular dystrophy is the second most prevalent form of muscular dystrophy in Japan. One out of every 90 people in Japan is a heterozygous carrier.
Symptoms and signs
In terms of the signs/symptoms of Fukuyama congenital muscular dystrophy it is characterized by a decrease in
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
tone as well as an impairment in brain and eye development. Initial symptoms of FCMD present in early infancy as decreased ability to feed. Marked differences in facial appearance occur due to decreased muscle tone. Further characteristics include:
[
* ]Seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
* Delay in development
* Cardiac
The heart is a muscular organ found in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon di ...
issues
* Swallowing difficulty
* Neurological
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
problems
Fukuyama congenital muscular dystrophy also affects the nervous system and various associated parts. FCMD affects normal development of the brain producing a broadly smooth, bumpy shaped cortex named cobblestone lissencephaly
Lissencephaly (, meaning "smooth brain") is a set of rare brain disorders whereby the whole or parts of the surface of the brain appear smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation resulting in ...
as well as various other malformations, notably micropolygyria
Micropolygyria is a neuronal migration disorder, a developmental anomaly of the brain characterized by development of numerous small convolutions ( microgyri), causing intellectual disability and/or other neurological disorders. It is present in a ...
. Children also experience delayed myelination in the brain.
Cause
The cause of Fukuyama congenital muscular dystrophy is rooted in the FKTN gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
, located at human chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins ar ...
9q31, codes for the protein fukutin
Fukutin is a eukaryotic protein necessary for the maintenance of muscle integrity, cortical histogenesis, and normal ocular development. Mutations in the fukutin gene have been shown to result in Fukuyama congenital muscular dystrophy (FCMD) c ...
. Mutations in this gene, and therefore the fukutin protein, are the cause of FCMD. The disease is inherited in an autosomal recessive manner.[
This means the defective gene responsible for the disorder is located on an autosome (chromosome 9 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both ]carry
Carry or carrying may refer to:
People
* Carry (name)
Finance
* Carried interest (or carry), the share of profits in an investment fund paid to the fund manager
* Carry (investment), a financial term: the carry of an asset is the gain or cost of ...
one copy of the defective gene but usually do not experience any signs or symptoms of the disorder.
Two mutations have been identified. The first and most common is an SVA retrotransposal insertion in the 3'-untranslated region. The second is a deep-intronic point mutation c.647+2084G>T. This second mutation has only been found to date in the presence of the first mutation.[Kobayashi K, Kato R, Kondo-Iida E, Taniguchi-Ikeda M, Osawa M, Saito K, Toda T (2017) Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan. J Hum Genet doi: 10.1038/jhg.2017.71]
Pathophysiology
The mechanism of this sub-type of muscular dystrophy consists of a mutation in the FKTN gene which results in a malformed fukutin protein. It is thought that fukutin modifies the alpha-dystroglycan protein, which is important in anchoring cells to certain molecules, specifically including some proteins. Alpha-dystroglycan in skeletal muscles helps to prevent the breakdown of muscle fibers through stabilization and protection. Alpha-dystroglycan also helps brain development by assisting in the migration of neurons. Most frequently, FKTN is mutated in such a way that creates a shortage of fukutin
Fukutin is a eukaryotic protein necessary for the maintenance of muscle integrity, cortical histogenesis, and normal ocular development. Mutations in the fukutin gene have been shown to result in Fukuyama congenital muscular dystrophy (FCMD) c ...
in the cell, which in turn creates problems during formation of alpha-dystroglycan leading to less stabilization of muscle cells.[ Use of the destabilized muscle fibers over time causes them to break down and a gradual decline in muscle tone and atrophy of muscle fibers occurs. The decline in cerebral fukutin causes neuronal cells to continue moving beyond their intended destination. Additionally, oxidative stress has some effect on ]astrocytes
Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...
(as well as, neurons
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
) when fukutin is subdued.
Diagnosis
In terms of diagnosis of Fukuyama congenital muscular dystrophy, serum creatine kinase concentration and muscle biopsies
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a di ...
can be obtained to help determine if the individual has FMCD. FKTN molecular genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
is used to determine a mutation in the FKTN gene after a serum creatine kinase concentration, muscle biopsies, and/or MRI imaging have presented abnormalities indicative of FCMD, the presence of the symptoms indicates Fukuyama congenital muscular dystrophy. The available genetic test include:
* Linkage analysis
* Deletion
Deletion or delete may refer to:
Computing
* File deletion, a way of removing a file from a computer's file system
* Code cleanup, a way of removing unnecessary variables, data structures, cookies, and temporary files in a programming language
* ...
analysis
* Sequence analysis - exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
* Sequence analysis - entire coding region
Treatment
Currently this sub-type of muscular dystrophy has no cure and no ''definitive'' treatment exists. Treatment offers preventative tactics to delay muscle breakdown and increase life expectancy. Stretching and physical therapy can increase mobility. Treatment also includes correcting skeletal abnormalities through orthopedic surgery and other orthopedic techniques. Antiepileptic medication is administered to help prevent seizures. ACE inhibitor
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease in blood volum ...
s and beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...
s help treat heart conditions, and respiratory assistance is more than likely needed at some point for the affected individual.[
]
Prognosis
Fukuyama congenital muscular dystrophy has a poor prognosis. Most children with FCMD reach a maximum mobility at sitting upright and sliding. Due to the compounded effects of continually worsening heart problems, impaired mental
Mental may refer to:
* of or relating to the mind
Films
* ''Mental'' (2012 film), an Australian comedy-drama
* ''Mental'' (2016 film), a Bangladeshi romantic-action movie
* ''Mental'', a 2008 documentary by Kazuhiro Soda
* ''Mental'', a 2014 Od ...
development, problems swallowing
Swallowing, sometimes called deglutition in scientific contexts, is the process in the human or animal body that allows for a substance to pass from the mouth, to the pharynx, and into the esophagus, while shutting the epiglottis. Swallowing ...
and additional complications, children with FCMD rarely live through adolescence, the disorder proves fatal by age 20.
See also
* Congenital muscular dystrophy
Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges fr ...
* Muscular dystrophy
Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily af ...
References
Further reading
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External links
{{Medicine
Muscular dystrophy
Rare diseases