COACH Syndrome

What Causes COACH Syndrome?

COACH syndrome is caused by abnormal changes in a gene (mutations) that impair the development of specific cell structures. Scientists have identified mutations in a gene called the TMEM67 gene that appear to be responsible for most cases of CS. A combination of multiple gene mutations may account for the variability of symptoms in CS cases.

The gene mutation associated with COACH syndrome affects the development of microscopic hair-like structures on the surface of cells called primary cilia. Primary cilia are vital in the function of sensory cells, and they also play a role in communication pathways between nerve cells. Researchers believe that cilia abnormalities are responsible for the brain defects in CS, but they don’t yet know precisely how the disorder develops.

Many scientists believe that COACH syndrome is a type of Joubert syndrome, but the gene mutations that cause CS seem distinct from those that cause other kinds of JS. At least one study has found that TMEM67 mutations are present in most CS cases but are present in very few cases of JS without liver disease.

Is COACH Syndrome Hereditary?

COACH syndrome is an inherited disorder. Most cases are inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the mutated gene, one from each parent, for the disorder to develop. However, the parents in these cases carry just one copy of the mutation, so they typically do not show any symptoms of CS themselves.

Parents who have a child with CS have a 25 percent chance of having another affected child with each pregnancy.

How Is COACH Syndrome Detected?

COACH syndrome is often diagnosed late in childhood or adolescence after the disorder’s neurological symptoms are apparent. However, the disorder’s liver-related symptoms may be severe and life-threatening even when neurological symptoms are relatively mild.

Diagnosis of CS and other types of Joubert syndrome may be possible using ultrasound before birth, but prenatal detection of the condition is rare. Ultrasound imaging does not always show the brain malformation characteristic of CS, and some of the developmental features may be similar to those of other disorders, such as Dandy-Walker syndrome.

How Is COACH Syndrome Diagnosed?

Doctors can diagnose CS if a child suffers from congenital liver disease and imaging scans show the condition’s distinctive brain malformations. Other neurological symptoms that can suggest the presence of CS include:

• Weak muscle tone in infants
• Coordination and movement problems in older children
• Developmental delays
• Intellectual impairment

When doctors suspect CS, they will usually conduct a magnetic resonance imaging (MRI) scan to look for brain malformations. In CS, a structure in the back of the brain called the cerebellar vermis is underdeveloped or missing entirely. Abnormalities in the brain stem are also common.

Genetic testing can detect the gene mutations responsible for many cases of CS.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is COACH Syndrome Treated?

COACH syndrome has no cure. Standard treatment for the disorder includes therapies intended to reduce the impact of developmental delays, manage symptoms, and prevent complications. Commonly used therapies include:

• Treatment of complications of liver disease
• Physical therapy
• Occupational therapy
• Speech therapy
• Infant stimulation (providing babies with sensory-stimulating activities and surroundings)

Treatment of CS also includes ongoing monitoring for the development of complications such as kidney disease and vision impairments.

How Does COACH Syndrome Progress?

Children with CS exhibit a wide range of symptoms and complications. Some children have only mild symptoms and experience only slight developmental delays. However, in other cases, developmental and intellectual impairments are severe. Factors that influence the severity of symptoms include:

• Which gene mutations cause the disorder.
• The degree of malformation in the cerebellar vermis.
• The involvement of other vital organs.

CS can be fatal in childhood or later in life. Fibrosis of the liver can cause high blood pressure in the portal vein (portal hypertension), which can lead to fatal bleeding in the esophagus or other parts of the gastrointestinal system. Kidney failure is also a potential complication of the disorder.

How Is COACH Syndrome Prevented?

There is no known way to prevent COACH syndrome. Parents with a family history of the disorder or who have had another child with CS are advised to consult a genetic counselor to assess their risk if they plan to have another child.

COACH Syndrome Caregiver Tips

• Learn everything you can about the disorder. CS is rare, and it’s not well known even to some medical professionals. You’ll be able to be an active part of your child’s medical team if you know as much as possible about their condition.
• Be an advocate for your child. It’s likely that teachers and other important people in your child’s life will not know how to best deal with your child’s challenges. Be educated and be prepared to speak up on behalf of your child.
• Find a community. The Joubert Syndrome & Related Disorders Foundation (JSRDF) maintains a directory of resources to help you find local and online support groups for families living with JS.

COACH Syndrome Brain Science

COACH syndrome can be diagnosed when an MRI scan shows abnormal development in specific parts of the brain in conjunction with liver disease. The distinctive features of the disorder include:

• An underdeveloped (hypoplastic) or completely missing cerebellar vermis, a structure that divides the two halves of the cerebellum
• Thickened and incorrectly oriented superior cerebellar peduncles, structures that connect the cerebellum to the midbrain
• Malformation of the brainstem

These malformations show up on an MRI scan as an easily recognizable pattern referred to as a “molar tooth sign,” so-called because it looks like the cross-section of a tooth.

Although a molar tooth sign can indicate JS, it can also be present in the case of other disorders such as Senior-Loken syndrome, Varadi-Papp syndrome, Cogan’s syndrome, and Malta syndrome.

COACH Syndrome Research

Title:  UAB HRFD Core Center: Core A: The Hepato/Renal Fibrocystic Diseases Translational Resource

Stage: Recruiting

Principal Investigator: Lisa Guay-Woodford, MD

Children’s National Health System

Washington, DC

In 2005, The University of Alabama at Birmingham (UAB) established an NIDDK-funded, interdisciplinary center of excellence in PKD-related research, with specific emphasis on recessive PKD. In the previous Core Center award period, UAB developed a Core Resource to capture clinical and mutational data for ARPKD patients (“Core A: ARPKD Clinical and Genetic Resource,” NCT00575705). However, studies in the last several years have demonstrated that ARPKD and other single-gene disorders characterized by renal cystic disease and extra-renal phenotypes share numerous pathogenic features. In the current competitively- renewed Center, UAB has expanded this Core resource to include other hepato/renal fibrocystic diseases.

Title: The Effect of a Dietary Supplement Rich in Nitric Oxide in Patients Diagnosed With Primary Ciliary Dyskinesia

Stage: Recruiting

Principal investigator:  Ricardo A. Mosquera, MD

The University of Texas Health Science Center, Houston

Houston, TX

The purpose of this study is to determine the effect of a dietary supplement rich in nitric oxide (NO) on nasal nitric oxide and fractional exhaled nitric oxide (FeNO), on ciliary beat frequency assessed by high-speed digital video microscopy, and on lung function assessed by spirometry, in normal patients and patients with primary ciliary dyskinesia (PCD).

Title: Inherited Retinal Degenerative Disease Registry (MRTR)

Stage: Recruiting

Principal investigator:  Todd Durham, PhD

Foundation Fighting Blindness

Columbia, MD

The My Retina Tracker® Registry is sponsored by the Foundation Fighting Blindness and is for people affected by one of the rare inherited retinal degenerative diseases studied by the Foundation. It is a patient-initiated registry accessible via a secure online portal at www.MyRetinaTracker.org. Affected individuals who register are guided to create a profile that captures their perspective on their retinal disease and its progress; family history; genetic testing results; preventive measures; general health, and interest in participating in research studies. The participants may also choose to ask their clinician to add clinical measurements and results at each clinical visit. Participants are urged to update the information regularly to create longitudinal records of their disease, from their perspective, and their clinical progress. The overall goals of the Registry are: to better understand the diversity within the inherited retinal degenerative diseases; to understand the prevalence of the different diseases and gene variants; to assist in the establishment of genotype-phenotype relationships; to help understand the natural history of the diseases; to help accelerate research and development of clinical trials for treatments; and to provide a tool to investigators that can assist with recruitment for research studies and clinical trials.