What is Congenital Titinopathy?

What is Congenital Titinopathy?

Congenital Titinopathy is a prenatal or infant onset genetic disorder (disease causing variants of TTN gene) caused by recessive TTN gene leading to production, structural and functional changes of the Titin protein thereby impacting the way muscles contract and relax.

Titin is the largest elastic filamentous protein in the human body located in the sarcomeres of the muscles cells (spanning 50% of the sarcomeres) and provides structure, stability and flexibility to cardiac and skeletal muscles. In case of Titinopathy the TTN gene mutation alters the production and the way titin works in the body, thereby potentially causing muscle weakness, mobility issues, low muscle tone, cardiac and respiratory issues to name a few.

Congenital Titinopathy Types

Everyone of us has 2 copies of the TTN genes, one we inherit from the mother and the other from the father. Based on whether one copy of the TTN gene or both carry the disease causing variants Titinopathy is categorized into 2 types:

1. Dominant Titinopathy: A single copy of the disease causing gene variant is enough to cause the disorder. The gene variant can be inherited from either parent or could be a result of mutation in the baby (de novo)

2. Recessive Titinopathy: Two copies of the disease causing variant of TTN gene is inherited, one from each parent to cause the disorder. Congenital Titinopathy falls under this category. There are different types of Congenital Titinopathy, to name a few:

   1. Autosomal recessive centronuclear myopathy

   2. Congenital myopathy with fatal cardiomyopathy

   3. Autosomal recessive tibial muscular dystrophy

   4. Titin related limb girdle muscular dystrophy R10

   5. Early onset myopathy with fatal cardiomyopathy

   6. Emery Dreifuss like muscular dystrophy

   7. Autosomal recessive arthrogryposis

      
      

Congenital Titinopathy Causes

Mutations in the TTN gene responsible for encoding (instructions to) the Titin protein, affects the production, structure, stability and function of the muscles across the body causing several types of cardiac and musculoskeletal diseases.

The exact cause of why these gene mutations happen is not well understood, however many researchers believe certain risk factors can increase the chances of gene mutations in parents that could be passed down to future generations.

• Use of recreational drugs, alcohol, smoking

• Exposure to certain harmful chemicals, environmental factors like radiation, x-rays that can alter the DNA

• Viral Infections, where the viral DNA integrates into the hosts causing mutations

• Errors in DNA replication during cell division

Congenital Titinopathy Symptoms

Based on the type and severity of the disorder there are many symptoms that may be evident immediately after birth or could show as the child grows or much later in life at adulthood.

• Muscle weakness that can affect different parts of the body

• Weakness in the head (weak facial muscles, difficulty to hold expression), neck, limbs and trunk of the baby (hypotonia)

• Developmental delays

• Bone and Joint changes or stiffness (contractures)

• Spinal changes causing scoliosis, side curvature of spine

• Changes in the shape of the chest

• Feeding difficulties - sucking, chewing and swallowing

• Breathing difficulties

• Heart enlargement, failure, difficulty in pumping blood

• Swelling in the legs

• Fatigue or palpitations

• Increased falls, Tipping over

• Weight gain

• Difficulty in breathing while asleep

• Movement difficulties

Congenital Titinopathy Diagnosis

There are different tests through which a doctor can diagnose or confirm Titinopathy both during pregnancy and after birth.

• During Pregnancy: A doctor would look for anomalies using an ultrasound scan, presence of contractures, abnormal features, less to lack of movements during pregnancy could point to Titinopathy, but there could be many other reasons as well for these symptoms so the doctor would probe more with other tests to confirm the diagnosis. In most cases the diagnosis happens after birth.

• Genetic Testing: In case of fetus, as these are invasive tests so done only if the doctor feels something is not right. The doctor will ask for amniocentesis (drawing out using a needle and testing the amniotic fluid) or using chorionic villus sampling test (tests the cells of placenta) to confirm the diagnosis. After birth, the baby's blood is tested to look for disease causing variant of TTN gene.

• Physical Examination: Right after birth the doctor performs a thorough physical examination to look for any anomalies like low muscle tone, weakness, difficulty breathing, troubled or less movements, among others.

• Ultrasound: Is used both prenatally and after birth of the baby to look functioning of the body - heart, lungs, muscles, etc.

• Muscle Imaging Studies: Studying the impact of the disorder on the muscles using ultrasound, CT scan (computed tomography) and MRI (Magnetic Resonance Imaging ) to help assess the muscle mass, quality, functioning and muscle cross sectional area in detail.

• Sleep Study: Painless test that uses sensors attached to the baby to measure breathing and functioning of the heart, lungs.

• ECG or Electrocardiogram: It uses multiple sensors attached to your child's chest to measure electrical activity that comes up as a graph, doctors look for any cardiac anomalies associated with Titinopathy using ECG.

Congenital Titinopathy Treatment

Although there is no cure or specific treatment or medication for Congenital Titinopathy, the healthcare provider can support management of the symptoms with physical therapy based on severity, help with breathing (specialists), and cardiac complications to an extent. Your child may need to see different specialist throughout their life based on the severity and the part of the body Titinopathy affects.

Congenital Titinopathy Life Expectancy

Life expectancy depends a lot on the type and severity of congenital titinopathy, with quite a wide range of possibilities. In some cases the disease remains moderate even at advanced age while some need life long support. Given the plethora of symptoms that varies from patient to patient, body parts it affects and the manifestations from mild to severe it is very difficult to predict the life expectancy. In cases where the symptoms are mild and remain stable over the years, it is possible with physical therapy and medical support to lead close to normal life.