Kufor–Rakeb syndrome

Overview

Kufor–Rakeb syndrome is a rare, inherited neurodegenerative disorder that primarily affects movement and cognition. It is considered a form of juvenile-onset parkinsonism and belongs to a broader group of diseases known as hereditary parkinsonian syndromes. The condition is named after the town of Kufor-Rakeb in Jordan, where it was first described. It typically begins in adolescence or early adulthood and progresses over time, leading to a combination of motor symptoms, cognitive decline, and other neurological features.

Causes

Kufor–Rakeb syndrome is caused by mutations in the ATP13A2 gene, which encodes a protein that is believed to play a role in lysosomal function and metal ion transport, particularly in neurons. The gene mutation leads to the accumulation of toxic substances in cells, contributing to neurodegeneration. The condition is inherited in an autosomal recessive pattern, meaning a person must inherit two copies of the mutated gene, one from each parent to develop the disorder.

Symptoms

Symptoms of Kufor–Rakeb syndrome usually begin in early adolescence and progress over time. Common clinical features include:

• Parkinsonism: Bradykinesia (slowness of movement), rigidity, tremor, and postural instability

• Dystonia: Involuntary muscle contractions that cause twisting and repetitive movements

• Spasticity: Increased muscle tone and stiffness, often affecting the legs

• Supranuclear gaze palsy: Difficulty moving the eyes, particularly vertically

• Cognitive decline: Progressive loss of intellectual and executive function

• Dysarthria: Slurred or slow speech

• Swallowing difficulties (dysphagia)

• Occasional psychiatric symptoms, such as mood changes or psychosis

The symptoms tend to worsen with age, and patients eventually become severely disabled without treatment.

Diagnosis

Diagnosis of Kufor–Rakeb syndrome is based on a combination of clinical evaluation, neuroimaging, and genetic testing. Key diagnostic steps include:

• Neurological examination: To assess motor function, eye movements, and cognitive status

• Brain MRI: May show signs of brain atrophy or iron accumulation in the basal ganglia

• Genetic testing: Identification of biallelic mutations in the ATP13A2 gene confirms the diagnosis

• Family history: A detailed pedigree can help identify inheritance patterns in consanguineous families

Early diagnosis is critical for initiating treatment and planning supportive care.

Treatment

There is currently no cure for Kufor–Rakeb syndrome, but treatment focuses on managing symptoms and improving quality of life. Therapeutic strategies include:

• Levodopa or dopaminergic agents: May provide temporary relief of parkinsonian symptoms, although effectiveness tends to diminish over time

• Muscle relaxants and antispasmodics: To manage spasticity and dystonia

• Physical therapy: To maintain mobility, balance, and muscle strength

• Speech therapy: To address dysarthria and swallowing difficulties

• Psychological support: For mood and behavioral symptoms, if present

• Multidisciplinary care: Involving neurologists, physiotherapists, and genetic counselors

Prognosis

The prognosis for Kufor–Rakeb syndrome varies but is generally poor due to the progressive nature of the disease. Most individuals experience worsening motor and cognitive symptoms over time, eventually requiring assistance with daily activities. Life expectancy may be shortened, especially in severe cases with early onset. However, with supportive therapy and symptomatic management, some patients can maintain function and quality of life for an extended period. Ongoing research into gene therapies and neuroprotective treatments holds hope for the future.