NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University 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.
Kufor Rakeb syndrome (KRS), also known as Parkinson’s disease 9, is a very rare form of inherited juvenile-onset Parkinson’s disease. 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 (cerebral atrophy) 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.
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 only 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.
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.
For most individuals, symptoms will begin to appear between 10 and 20 years of age. KRS is a neurodegenerative disorder, so the severity of symptoms tends to progress with time. Symptoms varies depending on the individual and can be divided in two major categories: symptoms that affect movement (motor symptoms) and those that do not (non-motor symptoms).
Motor symptoms can be further subdivided into typical Parkinson’s disease symptoms (parkinsonism) and symptoms that are not typically associated with Parkinson’s disease. The four main features of parkinsonism are slowed movements (bradykinesia), tremor, rigidity, and postural instability. Other symptoms present in KRS include partial or total paralysis of the legs (paraplegia), inability to move the eyes upward (supranuclear upgaze palsy), loss of coordination of movements (ataxia), muscle stiffness (spasticity), involuntary muscle contractions resulting in abnormal postures (dystonia), involuntary movements (dyskinesia), and increased reflexes (hyperreflexia). This can lead to imbalance and falls in affected individuals. A feature typical of KRS is small, involuntary muscle contractions of the fingers, face, and passage at the back of the mouth leading to the pharynx (facial-faucial-finger mini-myoclonus). Patients can also have difficulty articulating (dysarthria) or swallowing (dysphagia).
Intellectual disability and learning difficulties can be the first symptoms to appear, and are among the most common non-motor symptoms. A large proportion of patients will also develop dementia. Other non-motor symptoms include severe anxiety, reduced or absent smell (hyposmia or anosmia), panic attacks, as well as visual and auditory hallucinations. Non-motor symptoms usually greatly impact the quality of life of affected individuals.
Kufor Rakeb syndrome is an autosomal recessive disorder caused by changes (mutations) in the ATP13A2 gene. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one working gene and one non-working gene for the disease, 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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. 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 syndrome 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 syndrome.
Some patients also have iron accumulation in a deep brain structure called the basal ganglia (in the caudate and putamen, specifically). The mechanism by which iron accumulation occurs in the brain is not fully understood yet.
Kufor Rakeb syndrome is considered an ultra-rare disorder. Fewer than 50 individuals have been reported in the literature. Because KRS is a rare and complex disease, it is possibly underdiagnosed and the real prevalence of the disease is therefore hard to estimate. As it is the case for all autosomal recessive disorders, children of parents who are blood relatives are at an increased risk of developing the disease, as they are more likely to receive the same copy of a disease-causing (pathogenic) mutation from each parent.
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 individuals that 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 screening allows the identification of disease-causing (pathogenic) changes (mutations) in the ATP13A2 gene and can lead to a definitive diagnosis.
As 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. 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 services should be offered to affected families.
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