Andermann syndrome

Overview

Andermann syndrome is a rare, inherited neurodegenerative disorder characterized by a combination of agenesis or hypoplasia of the corpus callosum (partial or complete absence of the structure that connects the two brain hemispheres) and a progressive peripheral neuropathy that leads to severe muscle weakness and wasting. The condition typically presents in infancy or early childhood and worsens over time, often leading to significant physical and intellectual disability.

It was first described in French-Canadian populations, particularly in Quebec, where it is more common due to a founder effect. The disorder is also known as agenesis of the corpus callosum with peripheral neuropathy (ACCPN).

Causes

Andermann syndrome is caused by mutations in the SLC12A6 gene, which encodes the KCC3 protein (a potassium-chloride cotransporter important for nerve cell function and volume regulation). These mutations result in defective nerve signaling and abnormal development of the central and peripheral nervous systems.

The syndrome follows an autosomal recessive inheritance pattern, meaning an affected individual must inherit two mutated copies of the gene—one from each parent.

Symptoms

Symptoms typically begin in early infancy or childhood and progressively worsen. Common features of Andermann syndrome include:

Neurological and Motor Symptoms:

• Progressive muscle weakness and wasting (peripheral neuropathy)

• Hypotonia (low muscle tone) in infancy

• Loss of deep tendon reflexes

• Motor delays and difficulty walking

• Eventual wheelchair dependence (often in early adolescence)

Central Nervous System Abnormalities:

• Complete or partial agenesis of the corpus callosum

• Intellectual disability (mild to moderate)

• Seizures in some individuals

• Developmental delay

Other Features:

• Facial dysmorphism (e.g., prominent forehead, wide-set eyes)

• Spinal deformities (e.g., scoliosis)

• Joint contractures in severe cases

Diagnosis

Diagnosis of Andermann syndrome involves clinical evaluation, neurological testing, imaging studies, and genetic confirmation. Key diagnostic steps include:

• Neurological examination: To assess muscle strength, reflexes, and motor function

• Brain MRI: Reveals agenesis or thinning of the corpus callosum

• Nerve conduction studies (EMG/NCV): Show demyelinating and axonal peripheral neuropathy

• Genetic testing: Confirms biallelic pathogenic variants in the SLC12A6 gene

• Family history: Especially relevant in populations with higher carrier rates

Treatment

There is no cure for Andermann syndrome, and treatment is supportive and focused on improving quality of life and managing symptoms. Management strategies include:

Physical and Occupational Therapy:

• To maintain mobility, prevent contractures, and improve coordination

Assistive Devices:

• Braces, walkers, or wheelchairs to support mobility

Speech and Developmental Therapy:

• Support for communication and cognitive development

Medical Management:

• Anti-seizure medications if seizures are present

• Regular monitoring of scoliosis and orthopedic complications

Genetic Counseling:

• Essential for affected families and those at risk of being carriers

Prognosis

The prognosis for individuals with Andermann syndrome is generally poor due to the progressive nature of the disease. Most individuals become wheelchair-dependent in childhood or early adolescence, and life expectancy may be reduced, often due to complications like respiratory infections or severe scoliosis. However, supportive care and assistive technologies can significantly improve comfort and function.

Early diagnosis and intervention are crucial in maximizing developmental outcomes and providing families with guidance and support for long-term care.