This very rare NBIA disorder named for the village in Jordan where it was first described in 1994. The responsible altered gene ATP13A2 (also called PARK9) was identified in 2006. Few affected families in the U.S., Italy, South America, the Middle East and Asia are diagnosed.
It is characterized by juvenile parkinsonism, progressive cognitive decline, abnormal eye movements and involuntary jerking of the facial and finger muscles. It has been suggested that only a portion of cases may have iron accumulation; it may develop late in disease course, or it may only be associated with more severe mutations.
Typically start to appear around adolescence (age 10-19), but can appear during young adulthood. Brain CT and MRI may show diffuse moderate cerebral and cerebellar atrophy. Iron accumulation in the basal ganglia affecting the putamen and caudate is present in some, but not all individuals.
Juvenile Parkinsonism (symptoms similar to Parkinson’s disease) begins in childhood.
- Bradykinesia (slow movement)
- Rigidity (stiffness)
- Tremors (shaking), chin and tongue tremors, arm tremors not typically seen
Oculogyric dystonic spasms (rotating of the eye balls into a fixed position, usually upward)
Involuntary jerking of facial and finger muscles.
Pyramidal tract signs (motor pathway between brain and spine)
- Hyperreflexia (overactive reflexes)
- Spasticity (stiff or rigid muscles)
- Paresis (weakness of voluntary movement)
- Babinski sign (Plantar reflex), when the sole of the foot is rubbed with a blunt object, the big toe flexes upwards
Facial-faucial-finger myoclonus (quick, jerking of the facial and finger muscles)
Supranuclear gaze palsy (inability to look in a particular direction because of brain impairment)
Cognitive (mental) decline, More research is needed to determine the level of impairment, Can lead to dementia
Response to dopaminergic treatment has been noted, followed by the early development of dyskinesias (diminished voluntary movements and the presence of involuntary movements).
MRI findings for Kufor-Rakeb
Hypointensity on T2 MRI (dark patches) in the globus pallidus, putamen, and caudate. The dark patches indicate iron accumulation. Only some individuals may have iron accumulation. It may develop late in the disease course. It may only be associated with more severe cases
Generalized cerebral and cerebellar atrophy (decrease in cerebellum and overall brain size), possible progressive atrophy of the Brain
Genetic testing gene changes through sequence analysis of the ATP13A2 gene can confirm the Kufor-Rakeb diagnosis
There is no standard treatment for Kufor-Rakeb. A team of medical professionals recommends treatments based on current symptoms.
The evaluations of the extent of the disease is done by
- Neurologic examination for dystonia, rigidity, and spasticity, and/or parkinsonism
- Ophthalmologic assessment for evidence of eye movement abnormalities
- Assessment for physical therapy, occupational therapy, and/or speech therapy
- Medical genetics consultation
The symptoms of parkinsonism can be treated with the same medications used in Parkinson’s disease.
Long-term surveillance for Kufor-Rakeb s
Medication for spasticity, dystonia, and/or parkinsonism
Nutrition monitoring of height and weight in children. swallowing evaluation and regular dietary assessments, assure adequate nutrition, prevent aspiration, gastrostomy tube placement (as needed)
Monitoring of individuals receiving dopaminergic drugs for parkinsonism adverse neuropsychiatric effects, psychiatric symptoms, worsening of parkinsonism
Routine eye exams
The symptoms of Kufor-Rakeb typically progress at a slow rate.
The average lifespan varies for individuals with Kufor-Rakeb, but due to improvements in medical care, more affected individuals are now living into adulthood.
ATP13A2 (also called PARK9) is the only gene known to cause Kufor-Rakeb. This gene is highly expressed in the brain and neurones and encodes for an enzyme called ATPase13A2, which is responsible for transporting cations (positively charged atoms or molecules). This protein is a part of the ATPase protein family. The role of ATPases is to accelerate (catalyze) the decomposition (hydrolysis) of ATP (the energy currency of the cell) into ADP. This process allows energy to be utilized for other chemical reactions in the body. ATP13A2 is involved in maintaining constant levels (homeostasis) of zinc and manganese inside the cell.
Mutations in the ATP13A2 gene lead to the production of a dysfunctional protein, which leads to dysregulation (dyshomeostasis) of zinc and manganese levels in the cell. This in turn leads to dysfunction in the mitochondria (responsible for energy production in the cell) and lysosomes (responsible for waste degradation in the cell), which are dependent on zinc homeostasis. Cells of patients with ATP13A2 mutations causing Kufor Rakeb therefore have impaired energy production and waste accumulation, notably of a protein called alpha-synuclein. This ultimately leads to neuronal degeneration and is thought to be responsible for the symptoms of Kufor Rakeb.
Kufor-Rakeb is inherited in an autosomal recessive manner. “Autosomal” refers to the fact that the ATP13A2 gene is located on chromosome 1, which is one of the autosomes (chromosome pairs 1-22). Since the sex chromosomes are not involved, males and females are equally likely to inherit a mutation located in the autosomes. “Recessive” refers to the fact that a mutation must be present in both copies of the ATP13A2 gene for a person to have Kufor-Rakeb. If an individual has only one DCAF17 mutation, then they are called a “carrier” for Kufor-Rakeb and have not health problems related to the mutation. two Kufor-Rakeb. If two Kufor-Rakeb carriers have a child together, then there is a 25% chance that they will both pass on their recessive ATP13A2 gene mutations and have a child affected with Kufor-Rakeb, a 50% chance that a child will be a carrier like his/her parents and a 25% chance that the child will not have Kufor-Rakeb or be a carrier.
There is 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.