Titin Related Myopathy with Ophthalmoplegia. A Novel Phenotype. (2023)


Titin is the largest known protein which is encoded by the TTN gene (MIM:188840).

In both cardiac and skeletal muscles, titin plays a critical role in sarcomere assembly during muscle development. It also generates passive tension and structural integrity. [1] Titinopathies present with a wide spectrum of clinical phenotypes. Autosomal recessive TTN mutations cause childhood to adult-onset distal titinopathy (MIM: 600334), Limb girdle muscle dystrophy (LGMD)R10 (MM: 608807), Childhood-Juvenile onset Emery-Dreifuss like myopathy and congenital myopathy. On the other hand, autosomal dominant TTN mutations give rise to tibial muscular dystrophy (TMD) (MIM:600334), Hereditary myopathy with early respiratory failure (HMERF) (MIM: 603689), and dilated cardiomyopathy (MIM: 604145). [2] Emily C Oates et al 2018 [2], suggested the term congenital titinopathy be adopted for a disorder that presents with early-onset myopathy with fatal cardiomyopathy, centronuclear myopathy, core myopathy with heart diseases, and arthrogryposis multiplex congenita with myopathy.

With the significant advance in genetic testing, the clinical spectrum of titinopathies has been expanding, adding more clinical phenotypes and features for titinopathies. Notwithstanding, titinopathies have never been reported to manifest with ophthalmoplegia, here we report the first case in the literature of congenital titinopathy with ophthalmoplegia, hence widening the spectrum of the disorder.

Section snippets

Case Report

Our proband is a 19-year-old male patient followed for congenital myopathy manifesting with facial diplegia, ptosis, complete ophthalmoplegia, muscle weakness, osteopenia, scoliosis, and obstructive sleep apnea. Written informed consent was obtained from the family.

He was born to a 33-year-old G7P1A6 mother following an uneventful pregnancy in terms of infections, hypertension, diabetes, or trauma. His mother noted decreased fetal movements, there was also oligohydramnios, which may have been


Congenital titinopathies are a group of disorders caused by autosomal recessive mutations in the TTN gene which has the longest coding sequence (>100kb) of any human gene. [1] As a consequence, mutations in the TTN gene have been reported to cause a wide spectrum of disorders with emerging cases of TTN-related congenital myopathy. [3], [4], [5] Emily C Oates et al 2018, reported a large cohort of patients with congenital titinopathy. None of the 27 patients presented with ophthalmoplegia, this

Uncited References


Declaration of Competing Interest

We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.

We know of no conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. As Corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.


We would like to thank the patient and his parents for agreeing to participate in this study so the expanding knowledge of this disorder can be published to others. Also we would like to thank Dr Emily C Oates who is an expert in Titin related disorders for the generous efforts in reviewing the patient and his investigations.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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What is titin related myopathy? ›

Titin abnormalities can cause a wide spectrum of muscle disorders called “Titinopathy”. These disorders may be also called a “myopathy” or a “dystrophy” including limb-girdle muscular dystrophy (LGMD) and tibial muscular dystrophy.

What causes titin muscular dystrophy? ›

The late-onset autosomal dominant tibial muscular dystrophy (TMD) is caused by mutations in the last exon (364), which cause a posttranslational pathological cleavage of a larger portion of the C-terminal titin protein.

What diseases are caused by titin protein? ›

Titin gene mutations as a cause of cardiomyopathies

Cardiomyopathies are diseases that cause primary abnormalities in the heart muscle [57]. The most common type is dilated cardiomyopathy (DCM) with a prevalence of up to ~1:250 [57,99]. DCM is characterized by left ventricular dilation and systolic dysfunction [57].

What is TTN gene mutation? ›

Mutations in titin were found to cause familial restrictive cardiomyopathy. the hereditary myopathy with early respiratory failure due to mutations in the TTN gene be nosologically classified as myofibrillar myopathy-titinopathy.

Can you live a long life with myopathy? ›

For dermatomyositis, polymyositis, and necrotizing myopathy, the progression of the disease is more complicated and harder to predict. More than 95 percent of those with DM, PM, and NM are still alive more than five years after diagnosis.

What are the symptoms of Titinopathy? ›

The most common symptoms of recessive titinopathy are muscle weakness and breathing difficulties. Some affected individuals also develop heart problems.

What disease is too much protein in the brain? ›

Toxic buildups of proteins are a key hallmark of most forms of dementia, including Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia. These buildups are formed when the proteins misfold and form large clumps that are thought to be toxic to brain cells.

What brain disease is caused by protein? ›

Creutzfeldt-Jakob disease (CJD) is caused by an abnormal infectious protein in the brain called a prion. Proteins are molecules made up of amino acids that help the cells in our body function. They begin as a string of amino acids that then fold themselves into a 3-dimensional shape.

How many people in the world have titin gene mutation? ›

This condition is known as dilated cardiomyopathy, and it affects about 1 in 250 people worldwide. It was previously thought that the titin mutation would not affect people carrying the mutated gene, so long as it wasn't expressed.

Is titin muscular dystrophy fatal? ›

Muscular dystrophies are not always fatal. While some types of muscular dystrophy can shorten a person's life expectancy, people with other forms of the disease live full, average-length lives.

Is a TTN gene mutation rare? ›

Mutations in the TTN gene are considered as the most frequent cause of inherited DCM and cover 10–30% of the cases.

What does titin do in muscles? ›

Titin has long been recognized as a mechanical protein in muscle cells that has a main function as a molecular spring in the contractile units, the sarcomeres. Recent work suggests that the titin spring contributes to muscle contraction in a more active manner than previously thought.

What is the most common cause of death in muscular dystrophy? ›

End stage cardio-respiratory failure is the most common cause of death in DMD. Young unexpected deaths do still occur. Vigilance is needed for nutritional, respiratory and cardiac failure at any age.

What does myopathy mean in medical terms? ›

Myopathy is derived from the Greek words “myo” for muscle, and “pathy” for suffering which means muscle disease. The most common signs and symptoms of myopathies include weakness, stiffness, cramps, and spasms.

What is the life expectancy of someone with muscular dystrophy? ›

The average lifespan for Duchenne muscular dystrophy is 18 to 25 years. With early treatment, it can reach 30 years. But recent technological advances have made it possible to improve treatment. As a result, people living with the disease live better and longer.

What organs does myopathy affect? ›

Mitochondrial myopathy is caused by a defect in the mitochondria, which are the energy-producing part of cells. These conditions have muscle weakness, but also a variety of other symptoms, as mitochondrial disorders typically affect other organ systems like your heart, brain and gastrointestinal tract.

Does myopathy affect the brain? ›

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD) is a condition that can affect the muscles, bones, and brain.

What does myopathy feel like? ›

Cramping, stiffness, and soreness can also occur. Some myopathies can affect muscles in the hands or feet, or facial and eye muscles. In some cases, the problem can affect the heart and breathing muscles.

What is the rarest muscular disease? ›

Disease Overview

Duchenne muscular dystrophy (DMD) is a rare muscle disorder but it is one of the most frequent genetic conditions affecting approximately 1 in 3,500 male births worldwide. It is usually recognized between three and six years of age.

Are you born with myopathy? ›

Congenital myopathy is a term for any genetic muscle disorder that is typically noticed at birth and includes weakness and lack of muscle tone. Some congenital myopathies may not show symptoms until infancy or childhood.

Is there a cure for myopathies? ›

No, there is not a cure for myopathy itself. However, it can be treated to improve symptoms. If myopathy is related to an illness, like a virus or electrolyte imbalance, the muscle symptoms will improve when the underlying condition resolves. Immunosuppressants can help relieve symptoms of certain types of myopathy.

Will drinking water reduce protein in blood? ›

No, drinking more water won't treat proteinuria. Drinking more water will make you pee more, so there may be less protein every time you pee, but it won't stop your kidneys from leaking protein.

How do you flush excess protein from your body? ›

How To Remove Excess Protein From The Body
  1. Reduce the amount of protein you eat.
  2. Reduce the amount of salt you eat, which may lower blood pressure.
  3. Increase the amount of fiber you eat, which may lower cholesterol and regulate blood sugar.
  4. Engage in regular physical activity.
  5. Regularly check your blood sugar.
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How can I reduce tau protein in my brain naturally? ›

A 2013 study from UC Santa Barbara implicated that cinnamon might be able to prevent the build up of tau protein tangles in the brains of people with Alzheimer's. Researchers extracted two chemicals from cinnamon — cinnamaldehyde and epicatechin — and used them to treat lab-created cells as part of the experiment.

What are 5 diseases caused by protein? ›

Protein misfolding is believed to be the primary cause of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, cystic fibrosis, Gaucher's disease and many other degenerative and neurodegenerative disorders.

What are symptoms of protein in the brain? ›

These symptoms include: Drowsiness. Headache (usually in a certain part of the head) Nervous system changes that may start suddenly, including confusion, delirium, double vision, decreased vision, sensation changes, speech problems, weakness, or paralysis.

What are the symptoms of lack of protein in the brain? ›

Protein deficiencies slow down development and lower cognitive function. A lack of proteins depletes the chemicals in the brain that control mood, appetite, and energy levels. Protein deficiencies have also been linked to depression, anxiety, ADHD, epilepsy, and a certain type of autism.

What is the most known human mutation? ›

In fact, the G-T mutation is the single most common mutation in human DNA. It occurs about once in every 10,000 to 100,000 base pairs -- which doesn't sound like a lot, until you consider that the human genome contains 3 billion base pairs.

What is the rarest human mutation ever? ›

KAT6A syndrome is an extremely rare genetic neurodevelopmental disorder in which there is a variation (mutation) in the KAT6A gene.

What is the rarest genetic mutation in the world? ›

The Rarest of the Rare
  • Hutchinson-Gilford Progeria Syndrome (HGPS) Frequency: Occurs in 1 in 4 million newborns worldwide. ...
  • Alkaptonuria. Frequency: Occurs in 1 in 250,000 -1,000,000 live births. ...
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  • Ogden syndrome. ...
  • KAT6A syndrome.
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What is the most fatal muscular dystrophy? ›

Yes, Duchenne muscular dystrophy is ultimately fatal. Most people with the condition die from lung or heart issues caused by it.

Who is the longest survivor of muscular dystrophy? ›

Tom Sulfaro has outlived all predictions for patients with Duchenne Muscular Dystrophy by decades and is believed to be the oldest survivor with the disease.

What is the most severe muscular dystrophy? ›

Duchenne MD (DMD)

DMD is the most common and severe form of MD among children, and it accounts for approximately half of MD cases. DMD occurs mostly in boys, usually between 3 and 5 years of age, and progresses rapidly.

Is there a genetic test for TTN? ›

Diagnostic testing of this gene is recommended to identify a potential genetic basis for a condition. This type of testing can inform prognosis and clinical care for a symptomatic patient or be used to screen unaffected patients (including family members) for increased genetic risk for the condition.

How big is the TTN gene? ›

Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa).

What is a very rare genetic disorder? ›

Fabry disease is a rare genetic disorder that can affect many parts of the body and lead to many different types of symptom.

What does titin stand for? ›

Titin /ˈtaɪtɪn/ (contraction for Titan protein) (also called connectin) is a protein that in humans is encoded by the TTN gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for the passive elasticity of muscle.

What are some fun facts about titin? ›

Though still microscopically small, titin is gigantic compared to other proteins. Comprised of more than 30,000 amino acids, the supersize protein is made from super-repeated structures. The amino acid super-repeats of titin are like tick marks on a yardstick, measuring out uniform sections of the thick filament.

What is the technical name for titin? ›

isoleucine is the chemical name for the protein of “titin” also known as “connectin.” The largest known protein that consists of 26, 926 amino acids is made up of 189, 819 letters and can take about three hours to pronounce.

What are the symptoms of idiopathic myopathy? ›

The primary symptom of idiopathic inflammatory myopathy is muscle weakness, which develops gradually over a period of weeks to months or even years. Other symptoms include joint pain and general tiredness (fatigue).

How serious is myopathy? ›

The morbidity and mortality of myopathies is related to the etiology of the condition, severity of disease, and the presence of comorbid conditions. Severe weakness may lead to respiratory failure and death.

What is the survival of myopathy? ›

Kaplan–Meier analysis revealed that the 3-year, 5-year, and 10-year survival rates for SSc patients with myopathy were 97.7%, 95.1%, and 81.4% respectively, compared with those of patients without myopathy, which were 98.8%, 97.8%, and 94.1%, respectively, (P = .

What are two disorders that cause myopathy? ›

Myopathies can stem from systemic diseases including thyroid disorders, lupus, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, amyloidosis, or another critical illness.
  • Symptoms of Myopathy. ...
  • Causes of Myopathy. ...
  • Treatments for Myopathy.

What is the life expectancy of someone with idiopathic inflammatory myopathy? ›

A total of 69.8% (109/156 cases) of the patients died within 6 months after diagnosis.

What does myopathy pain feel like? ›

The most common signs and symptoms of myopathies include weakness, stiffness, cramps, and spasms. Myopathies are a heterogeneous group of disorders primarily affecting the skeletal muscle structure, metabolism, or channel function. They usually present with muscle weakness interfering in daily life activities.

Is myopathy considered a disability? ›

A myopathy is essentially a medical term used to describe a condition that affects the muscles. The result is often inflammation in the muscles, which make them weak. This causes a slew of issues, which is why the Social Security Administration (SSA) lists some myopathies in their Blue Book of disabilities.

What kind of doctor treats myopathy? ›

Patients with dermatomyositis, polymyositis, or necrotizing myopathy are usually treated by rheumatologists. Those with dermatomyositis may also work with a dermatologist.

Is myopathy terminal? ›

Clinically, muscular dystrophies are typically progressive, because the muscles' ability to regenerate is eventually lost, leading to progressive weakness, often leading to use of a wheelchair, and eventually death, usually related to respiratory weakness.

What is the mortality rate for myopathy? ›

Cumulative survival from diagnosis has been estimated at 74.9% at 5 years and 62.5% at 10 years. Pulmonary involvement represented the main cause of death.

What drugs can cause myopathy? ›

  • Recreational drugs. Alcohol. Cocaine.
  • Lipid-lowering medications.
  • Antiinflammatory and immunosuppressive agents. Chloroquine/hydroxychloroquine. Glucocorticoids. Colchicine.
  • Antipsychotic medications.
  • Antinucleoside analogues.
  • Chemotherapeutic agents.
  • Others.
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What is the best treatment for myopathy? ›

Physical therapy, supportive devices such as braces, and sometimes surgery may also be used as treatment tools. Treatment of metabolic, toxic and endocrine-related myopathy generally focuses on the underlying cause of the condition. Medication or surgery may be used to address the symptoms.

What is myopathy of the eye? ›

An ocular myopathy is a degenerative disorder of extra-ocular muscles with the primary site of the lesion in the striated eye muscle cell itself.

Can myopathy affect the heart? ›

Myopathies are frequently not confined to the skeletal muscles but also involve other organs or tissues. One of the most frequently affected organ in addition to the skeletal muscle is the heart (cardiac involvement, CI).


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