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Joubert syndrome (TMEM67)
This condition affects how the brain develops, leading to a range of physical and developmental challenges. It is caused by changes in the TMEM67 gene and typically affects individuals from birth.
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Overview
Joubert syndrome (TMEM67) is a type of ciliopathy, a group of disorders caused by issues with cilia, which are tiny, hair-like structures found on the surface of cells. These structures play a vital role in cell communication and development across many organs [PMID:27038379]. In Joubert syndrome, the main feature is a distinctive brain malformation called the 'molar tooth sign', visible on brain imaging, which affects the cerebellum and brainstem [PMID:18987192].
Individuals with Joubert syndrome (TMEM67) can experience a variety of symptoms, which vary in type and severity. These often include developmental delays, problems with muscle coordination (ataxia), and specific breathing patterns. The condition is considered rare, with its exact prevalence not well established.
Symptoms & clinical features
The symptoms of Joubert syndrome (TMEM67) typically become apparent during infancy. Key features often include hypotonia (reduced muscle tone), developmental delays affecting motor skills such as sitting and walking, and difficulties with speech. Eye movement abnormalities, such as oculomotor apraxia, where moving the eyes voluntarily is difficult, can also be present.
Characteristic breathing patterns are another common feature in newborns, involving episodes of rapid breathing followed by pauses [PMID:18987192]. In some individuals, additional features can include kidney disease, liver fibrosis, and retinal degeneration, which can affect vision. The specific combination and severity of symptoms can differ significantly between affected individuals.
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Affected organs
Joubert syndrome primarily affects the brain, specifically the cerebellum and brainstem, which are crucial for coordination, balance, and vital functions like breathing. The distinctive 'molar tooth sign' seen on brain MRI scans is a hallmark of the condition.
Beyond the central nervous system, other organs can also be involved. The kidneys may be affected, leading to kidney disease. The liver can develop fibrosis, impacting its function. Additionally, the eyes may show retinal degeneration, potentially leading to vision impairment, and occasionally, skeletal abnormalities or polydactyly (extra fingers or toes) can occur.
Risks & severity
The severity of Joubert syndrome (TMEM67) can range from mild to severe, even within the same family. The condition presents from birth, with symptoms often becoming noticeable in early infancy. Developmental milestones, such as walking and talking, are typically delayed. The long-term outlook depends on the specific organs affected and the severity of their involvement.
Kidney and liver complications can progress over time, and regular monitoring is important to manage these aspects. Retinal degeneration can lead to progressive vision loss. The condition is not progressive in terms of brain malformation itself, but the developmental impact can vary significantly.
Genetic causes
Joubert syndrome (TMEM67) is caused by pathogenic variants in the TMEM67 gene. This gene provides instructions for making a protein called meckelin. Meckelin is located in the primary cilia, which are small, finger-like projections on the surface of cells that play a crucial role in cell signalling and development [PMID:27038379].
When the TMEM67 gene has pathogenic changes, the meckelin protein may not function correctly or might be absent. This disrupts the normal development and function of primary cilia, particularly in the brain, kidneys, and liver. The impaired ciliary function leads to the characteristic features of Joubert syndrome, including the brain malformation and involvement of other organs [PMID:22095393].
- TMEM67 transmembrane protein 67
Inheritance pattern
Joubert syndrome (TMEM67) is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the TMEM67 gene - one from each parent - to develop the condition.
Parents who each carry one altered copy of the TMEM67 gene are known as carriers. Carriers typically do not show symptoms of the condition. For each pregnancy, if both parents are carriers, there is a 25% chance their child will inherit two altered copies and develop Joubert syndrome, a 50% chance their child will be a carrier like them, and a 25% chance their child will inherit two unaffected copies of the gene.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of Joubert syndrome (TMEM67) is typically based on clinical features combined with imaging findings. Magnetic Resonance Imaging (MRI) of the brain is crucial for identifying the 'molar tooth sign' - a distinctive malformation of the brainstem and cerebellum characteristic of Joubert syndrome [PMID:18987192].
Genetic testing confirms the diagnosis by identifying pathogenic variants in the TMEM67 gene. In the UK, genetic testing for Joubert syndrome is available through the NHS Genomic Medicine Service (GMS) pathways, often initiated following a referral from a paediatrician or neurologist. The relevant NHS Genomic Test Directory R-code for Joubert syndrome is R141. A clinical genetics service can arrange for this testing and provide genetic counselling.
Management & lifestyle
The management of Joubert syndrome (TMEM67) is supportive and multidisciplinary, addressing the specific symptoms and organ involvement in each individual. Management plans are individualised and developed by a team of specialists, which may include paediatricians, neurologists, nephrologists, hepatologists, ophthalmologists, and physiotherapists.
Interventions often include early physiotherapy, occupational therapy, and speech and language therapy to support developmental progress. Regular monitoring of kidney and liver function is important, and vision assessments are crucial for detecting and managing retinal degeneration. Genetic counsellors can provide information and support to families regarding the genetic aspects of the condition and its inheritance patterns.
UK care pathway
In the UK, individuals suspected of having Joubert syndrome would typically be referred to a paediatrician or neurologist. If clinical signs and brain imaging suggest Joubert syndrome, a referral to a clinical genetics service would follow. These services can coordinate genetic testing through the NHS Genomic Medicine Service, using the appropriate R-code (e.g., R141 for Joubert syndrome) to confirm the diagnosis.
Genetic counsellors within these services play a vital role in explaining the genetic basis of the condition, inheritance patterns, and implications for family members. They also help families navigate the available support services and coordinate care with other specialist teams.
Frequently asked questions
What is the 'molar tooth sign'?
The 'molar tooth sign' is a distinctive appearance of the brainstem and cerebellum on an MRI scan. It is a key diagnostic feature of Joubert syndrome, named because it resembles a molar tooth.
Can Joubert syndrome be prevented?
Joubert syndrome is a genetic condition, so it cannot be prevented. If you have a family history of Joubert syndrome, genetic counselling can provide information about the risks for future pregnancies and reproductive options.
How does Joubert syndrome affect daily life?
The impact on daily life varies significantly. Some individuals may have milder developmental delays and fewer complications, while others may experience more significant physical and cognitive challenges requiring extensive support and therapies throughout their lives.
Is there a cure for Joubert syndrome?
Currently, there is no cure for Joubert syndrome. Management focuses on treating symptoms, supporting development through therapies, and monitoring for potential complications such as kidney or liver disease.
What support is available for families affected by Joubert syndrome?
Families can access support through their clinical genetics service, patient support groups, and charities dedicated to rare diseases or ciliopathies. These resources can offer information, connect families with similar experiences, and help navigate care.