Last updated:
9/26/2024
Years published: 2019, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Etienne Leveille, MD, Yale School of Medicine, and Allison Gregory, MS, CGC and Susan J. Hayflick, MD, Hayflick Laboratory, Department of Molecular & Medical Genetics, Oregon Health & Science University, for the preparation of this report.
Summary
Kufor Rakeb syndrome (KRS), also known as Parkinson’s disease 9, is a very rare form of Parkinson’s disease that has a juvenile onset and is inherited.
Typical (idiopathic) Parkinson’s disease usually affects people aged 60 or over, but individuals affected by KRS will usually start to develop symptoms before 20 years of age.
Depending on the individual, symptoms can include typical Parkinson’s disease symptoms (parkinsonism) such as slowed movements (bradykinesia), rigidity,and tremor, as well as other symptoms that are not typically associated with Parkinson’s disease, including partial or complete paralysis of the legs (paraplegia), inability to move the eyes upward (supranuclear upgaze palsy) and loss of coordination of movements (ataxia). Affected individuals also have brain atrophy (damaged cerebral tissue with loss of the brain cells known as neurons) and sometimes have an accumulation of iron in a region of the brain known as the basal ganglia. For this reason, Kufor Rakeb syndrome is part of a group of diseases called neurodegeneration with brain iron accumulation (NBIA).
People living with Kufor Rakeb syndrome also experience symptoms that don’t affect movement (non-motor symptoms), including anxiety, learning difficulties, visual and auditory hallucinations and dementia.
Kufor Rakeb syndrome is caused by changes (variants) in the ATP13A2 gene. Inheritance is autosomal recessive.
Treatment of Kufor Rakeb syndrome is similar to treatment of typical Parkinson’s disease and is mainly composed of a combination of two medications called levodopa (L-DOPA) and carbidopa. Other medications, such as dopamine agonists, can also be prescribed. Medication is used to control the symptoms of the disease (symptomatic treatment), not to cure it. Benefits of medication are mostly for motor symptoms and have no significant effect on non-motor symptoms of KRS.
Introduction
Kufor Rakeb syndrome was first identified in 1994 in five individuals from a large family living in a Jordanian town called Kufr Rakeb, hence the name of the disease. The gene that is altered in KRS was identified in 2006. Since that time, early detection of the disease and screening of family members is possible with genetic testing. A timely and accurate diagnosis is crucial for patients, as their symptoms can be managed with medication.
Kufor-Rakeb Syndrome (KRS) is a rare neurodegenerative disorder that typically begins to show symptoms between the ages of 10 and 20. The disease worsens over time and symptoms are categorized into motor and non-motor symptoms. Both types of symptoms can vary from person to person, and the progression of the disease may differ depending on the specific gene variant.
Motor Symptoms
Motor symptoms are divided into those resembling Parkinson’s disease (parkinsonism) and those not typically seen in Parkinson’s.
Non-Motor Symptoms
Non-motor symptoms are often among the earliest signs and can have a significant impact on the quality of life.
In most patients, brain MRI reveals cerebral and cerebellar atrophy (brain shrinkage due to the loss of brain cells or a loss in the number of connections between brain cells), sometimes with evidence of iron accumulation in the brain structure known as basal ganglia. This can be seen as “T2 hypointensities” in certain imaging techniques. However, not all the affected people may show these signs early in the disease.
Initially, the disease tends to progress rapidly and then slows down over time.
Early diagnosis and tracking of symptoms are important, as the course of the disease can vary significantly depending on the underlying gene variant.
Kufor Rakeb syndrome is caused by changes (variants) in the ATP13A2 gene.
The ATP13A2 gene produces a protein highly expressed in the brain and neurons called ATP13A2 that is 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.
There are different kinds of variants that cause Kufor-Raket syndrome, such as frameshift variants, missense variants and nonsense variants. Missense variants cause the ATP13A2 protein to misfold and be retained and degraded.
A frameshift variant in a gene refers to the insertion or deletion of nucleotide bases in numbers that are not multiples of three. This is important because a cell reads a gene’s code in groups of three bases when making a protein. Each of these “triplet codons” corresponds to one of 20 different amino acids used to build a protein. If a variant disrupts this normal reading frame, then the entire gene sequence following the genetic variant will be incorrectly read. This can result in the addition of the wrong amino acids to the protein and/or the creation of a codon that stops the protein from growing longer. A missense variant is a DNA change that results in different amino acids being encoded at a particular position in the resulting protein. Some missense variants alter the function of the resulting protein.
Therefore, all ATP13A2 variants cause a loss of function in the protein, which leads to dysregulation of zinc and manganese levels in the cell. This dysregulation impairs the function of mitochondria and lysosomes, which are responsible for energy production and waste degradation, respectively.
Cells of patients with ATP13A2 variants causing Kufor Rakeb syndrome 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 syndrome.
Some patients also have iron accumulation in a deep brain structure called the basal ganglia (involved with motor control). The mechanism by which iron accumulation occurs in the brain is not fully understood yet.
Inheritance is autosomal recessive. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Fewer than 50 individuals have been reported in the medical literature with Kufor Rakeb syndrome. Because KRS is a rare and complex disease, it is possibly underdiagnosed, and the real prevalence of the disease is difficult to estimate.
A diagnosis of Kufor Rakeb syndrome requires an extensive patient history, as well as a complete physical and neurological examination. KRS can be suspected in people who start to develop atypical parkinsonism (typical symptoms of Parkinson’s disease in addition to other features such as dystonia, muscle stiffness and rapid progression) between 10 and 20 years of age. MRI imaging will also show brain atrophy (cerebral atrophy) and possibly accumulation of iron in a brain structure called the basal ganglia (in the caudate and putamen, specifically). Genetic testing can identify the disease-causing variants in the ATP13A2 gene and can lead to a definitive diagnosis.
There is no cure for Kufor Rakeb syndrome. Therapy is focused on the management of symptoms and improvement of quality of life of affected individuals.
As it is the case for typical (idiopathic) Parkinson’s disease, a combination of levodopa and carbidopa is usually prescribed. The goal of this medication is to alleviate motor symptoms by increasing the concentration of dopamine in the nervous system. Dopamine receptor agonists can also be used. Trihexylphenidyl and amantadine might also be prescribed, especially in cases where dopaminergic medication is not effective or tolerated. Botulinum toxin (Botox) can be used to treat dystonia.
Bilateral globus pallidi deep brain stimulation may be useful in some people, but the long-term follow-up is yet unknown.
Physical, occupational and/or speech therapy can also be useful interventions. Treatment options for non-motor symptoms are more limited.
Individuals living with Kufor Rakeb syndrome might also require a walking aid or a wheelchair. Special education might be indicated, as intellectual disability and learning difficulties are common in KRS. The help of caregivers or health professionals might also be necessary to perform activities of daily living, depending on the severity of the disease.
Genetic counselling is recommended for affected families.
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JOURNAL ARTICLES
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INTERNET
Gregory A, Hayflick S. Neurodegeneration with Brain Iron Accumulation Disorders Overview. 2013 Feb 28 [Updated 2019 Oct 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK121988/ Accessed Sept 26, 2024.
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