What it means, how it manifests itself, what research progress has been made…

CLIFAHDD syndrome is a rare disease. The abbreviation stands for “Congenital Contractures of the Limbs and Face, Hypotonia and Developmental Delay” (CLIFAHDD; OMIM #616266). CLIFAHDD is caused by a single de novo autosomal dominant mutation in the NALCN gene, which is believed to cause an increase in function in the NALCN channel. The mutation is usually acquired randomly and is not inherited from the parents.

The syndrome is characterized by developmental and neurological symptoms, including global neurological developmental delay, joint contractures, low muscle tone (hypotonia), facial anomalies and sleep apnea.

The main features of the syndrome are:

• Global neurodevelopmental delay/intellectual disabilities: Individuals with CLIFAHDD have developmental delays, particularly in motor skills, language, feeding and cognitive abilities. The degree of delay varies among affected individuals. Individuals with CLIFAHDD have intellectual disabilities that range from mild to moderate.
• Joint contractures and abnormalities (“arthrogryposis”): Individuals with CLIFAHDD may have various joint disorders. These may affect the upper extremities (such as ulnar deviation, thumb adduction, finger splay) or the lower extremities (such as clubfoot or hip dysplasia). These often require bracing and specialized orthopedic treatment to treat and may affect mobility and overall function.
• Hypotonia: Hypotonia refers to reduced muscle tone, resulting in low muscle strength. This may contribute to motor developmental delays and mobility difficulties. Some children may experience hypertonia.
• Abnormal breathing and sleep apnea: The NALCN channel is involved in normal breathing rhythms – mutations affect these breathing patterns. Children with CLIFAHDD may have irregular breathing patterns that may require oxygen and other forms of respiratory support. In addition, children may develop pauses in breathing, especially during sleep (sleep apnea).
• Distinctive facial features: Distinctive facial features may include a high forehead, arched eyebrows, flat nasal bridge, short nose and downturned mouth.
• Constipation: Many individuals experience constipation that requires treatment.
• Other neurological conditions: Individuals with CLIFAHDD are at increased risk of seizures, hyperkinetic movement disorders (such as dystonia, ataxia) and visual disturbances.
• Increased salivation: This can be treated with medication or injections (Botox) if needed.

What treatment options are available?

Supporting and treating people with CLIFAHDD syndrome requires a holistic approach involving different specialties. It is incredibly important to consider the individual medical, developmental and educational needs of those affected. Key therapy approaches include:

• Physical therapy: To improve motor skills and joint mobility. Physical therapy helps prevent contractures and improve muscle strength.
• Speech therapy: To promote language and communication skills. Speech therapy can help overcome language and communication barriers often associated with CLIFAHDD.
• Occupational therapy: To support daily living skills and improve fine motor skills. Occupational therapy helps patients to manage everyday tasks independently and improve quality of life.
• Genetic counseling: For affected families to understand the genetic basis of the syndrome. This counseling includes information about the inheritance patterns, risk for future children and possible therapeutic options.

In addition, regular medical examinations may be required to monitor and treat accompanying health problems such as sleep apnea and other symptoms.

What is research currently working on?

Die laufende Forschung konzentriert sich darauf, das VOngoing research is focused on deepening the understanding of the syndrome and developing potential treatment strategies:

• Molecular studies: Investigating the specific genetic mutations in the NALCN gene that cause CLIFAHDD. These studies aim to clarify the exact effects of the mutations on NALCN channel function.
• Functional analyses: Analyzing how the mutations affect NALCN channel function and the neuronal network. This research helps to understand the pathophysiological mechanisms of the syndrome.
• Therapeutic developments: Testing new therapeutic approaches that target the specific dysfunctions of the NALCN channel. These include potential pharmacological treatments that could modulate channel activity, as well as developing gene therapies to correct the underlying genetic defects.
• Interdisciplinary research: Collaboration between geneticists, neurologists, therapists and other professionals to develop and test comprehensive treatment strategies.

Advances in research offer hope for new therapeutic options and improve our understanding of CLIFAHDD. The goal is to develop effective treatment strategies that can significantly improve patients’ quality of life.