Kufor-Rakeb

Kufor-Rakeb Syndrome, also known as Parkinson’s Disease 9 (PARK9), is an ultra-rare form of NBIA inherited in an autosomal-recessive manner. It is characterized by juvenile-onset parkinsonism and dementia.

Kufor-Rakeb is named for the village in Jordan where it was first described in 1994. In 2006, a mutation in the ATP13A2 gene was deemed responsible. Fewer than 50 affected individuals have been diagnosed with Kufor-Rakeb. They live in the US, Italy, South America, the Middle East and Asia.

Clinical Diagnosis

Brain CT and MRI scans may show diffuse, or widespread, moderate cerebral, cerebellar and brain stem atrophy. Iron accumulation in the basal ganglia affecting the putamen and caudate is present in some, but not all, individuals.

Disease onset is usually in adolescence. Parkinsonism is caused by the degeneration of nerve cells in the brain and is characterized by tremors and shaking; slow movements; stiffness in the arms, legs or trunk; instability while standing; and freezing of gait.

Key Clinical Manifestations:

Parkinsonism
Dementia (progressive cognitive decline)
Supranuclear gaze palsy (inability to look in a particular direction because of cerebral impairment)
Facial-faucial-finger myoclonus (involuntary jerking of the facial and finger muscles)
Visual hallucinations
Oculogyric dystonic spasms (involuntary intermittent or sustained deviation of the eyes in a usually upward direction)

Symptom onset often leads to genetic testing to search for a diagnosis. Because Kufor-Rakeb is so rare and not often suspected, it is often diagnosed with Whole Exome Sequencing (WES), which looks at all the protein coding regions of the genome. Whole Genome Sequencing (WGS) is becoming more common. It looks at the entire genome and is the most extensive test available at this time.

Genetics

Kufor-Rakeb is caused by a mutation in the ATP13A2 gene and is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier.

Recessive diseases only occur when both parents are carriers for the same condition and pass their changed genes on to their child. Statistically, there is a one in four chance that two carriers would have an affected child. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation. Carrier testing for relatives and prenatal testing for at-risk pregnancies are suggested if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

When disease-causing mutations are identified in a family, prenatal diagnosis for pregnancies can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation. Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families.

Treatments

There is no cure for Kufor-Rakeb syndrome, but treatments are available to manage symptoms. As symptom severity and complexity varies widely, management should be tailored to the individual. Individuals will benefit from routine follow up by a neurologist for medication management and interval assessment of motor and cognitive functioning.

Treatment of Kufor-Rakeb syndrome often resembles treatment of typical Parkinson’s disease. Commonly, two medications, levodopa (L-DOPA) and carbidopa, are combined.

Other therapies also may benefit individuals with Kufor-Rakeb Syndrome. Physical therapy often is recommended to address gross motor dysfunction, maximize mobility and reduce risk of later onset orthopedic complications. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function, such as feeding, grooming and dressing. Feeding therapy by an occupational or speech therapist is recommended for affected individuals who have difficulty feeding due to poor oral motor control.