Kufor-Rakeb Syndrome, also known as Parkinson’s Disease 9 (PARK9), is an ultra-rare disease that is 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. This is a very rare NBIA disorder, with fewer than 50 affected individuals diagnosed in the US, Italy, South America, the Middle East and Asia.
Brain CT and MRI may show diffuse 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, slowness of movement, stiffness in the arms, legs or trunk, instability while standing, and freezing of gait.
Key Clinical Manifestations:
- Dementia (progressive cognitive decline)
- Supranuclear gaze palsy (inability to look in a particular direction as a result 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)
The onset of the above-mentioned symptoms often leads to genetic testing in order to search for a diagnosis. Since Kufor-Rakeb is a very rare disease 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, as this test looks at the entire genome and is the most extensive test available at this time.
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 then pass their changed genes onto 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 at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.
If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. 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 in which the disease-causing mutations have been identified.
Though there is no cure for Kufor-Rakeb syndrome, various types of treatments and therapies exist 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 is often similar to treatment of typical Parkinson’s disease and is mainly composed of a combination of two medications called levodopa (L-DOPA) and carbidopa.
Various therapies also can benefit individuals with Kufor-Rakeb Syndrome. In order to address gross motor dysfunction, physical therapy is recommended to 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.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies as they become available.
Following is a list of relevant published research articles. Other free access articles can be found at Pub Med Central.
2018 - Action Myoclonus and Seizure in Kufor-Rakeb Syndrome
2012 - Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis | Human Molecular Genetics | Oxford Academic
2011 - Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein
2006 - Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase