The clinical presentation of PD9 is complex. Symptom onset is subacute, often unilateral and generally occurs in adolescence [1]. Najim al-Din and colleagues described their young patients to present with a "mask-like face" [2]. The former resulted from muscle rigidity, one of the major symptoms of parkinsonism. Frequent falls, slowness, rigidity and decreasing performance in school were the presenting symptoms in affected members of a Chilean family [3]. Similar to other forms of Parkinson's disease, PD9 is also associated with tremor and postural instability, although intention tremor may be absent. Affected individuals also show pyramidal signs that are triggered by corticospinal tract disease. Spasticity and Babinski-like abnormal plantar reflexes are most commonly observed [4].

Additionally, vertical supranuclear gaze palsy, saccadic pursuit, and dementia are characteristic features of PD9 [1] [3]. The assessment of eye movements and cognitive performance is important to recognize these symptoms and to distinguish PD9 from other forms of Parkinson's disease that may manifest as a so-called pallido-pyramidal or Parkinsonian-pyramidal syndrome. These include, but are not limited to, autosomal recessive juvenile Parkinson's disease not related to ATP13A2 mutations [4] [5]. In PD9 patients, cognitive decline may be recognized early in the course of the disease [5].

• Falling

  The predominant initial motor symptoms include rigidity and painful cramps which may be followed by tremor, bradykinesia, gait complaints and falls. [orpha.net]

  As dopamine levels continue to fall, symptoms gradually become more severe. [medicalnewstoday.com]

  No difference between arms was noted in falls (Falls Efficacy Scale: -1.91 points, 95% CI -4.76 to 0.94, P = 0.19) or patient-rated quality of life (PDQ-39 Summary Index: -0.38 points, 95% CI -2.58 to 1.81, P = 0.73). [cochrane.org]

• Fatigue

  Fatigue. Many people with Parkinson's disease lose energy and experience fatigue, especially later in the day. The cause isn't always known. Pain. [mayoclinic.org]

  [from OMIM] From HPO Fatigue MedGen UID: 41971 •Concept ID: C0015672 • Sign or Symptom A subjective feeling of tiredness characterized by a lack of energy and motivation. [ncbi.nlm.nih.gov]

  Malfunctioning AV node cells tend to progressively fatigue until they fail to conduct an impulse. This is different to cells of the His-Purkinje system which tend to fail suddenly and unexpectedly (i.e. producing a Mobitz II block). [m.blog.naver.com]

  FATIGUE AND SLEEP DISTURBANCE Fatigue is present in one-third of patients with Parkinson disease at diagnosis, and is associated with severity of illness. [aafp.org]

  Symptoms of second- and third-degree heart block include fainting, dizziness, fatigue, shortness of breath and chest pain. In third-degree heart block, the symptoms reflect the severity of the slow heart rate. [my.clevelandclinic.org]

• Abnormal Eye Movement

  Abstract: Kufor-Rakeb syndrome (KRS)/PARK9 presents with autosomal recessive young onset Parkinson’s disease (YOPD), spastic paraparesis, abnormal eye movements and facial myokymia. [content.iospress.com]

  Abstract Kufor-Rakeb syndrome (KRS)/PARK9 presents with autosomal recessive young onset Parkinson's disease (YOPD), spastic paraparesis, abnormal eye movements and facial myokymia. [pubmed.ncbi.nlm.nih.gov]

  Kufor-Rakeb syndrome is a NBIA disorder that is characterized by juvenile parkinsonism, progressive cognitive decline, abnormal eye movements and involuntary jerking of the facial and finger muscles. [nbiacure.org]

• Mask-like Facies

  Symptoms List: Kufor-Rakeb Syndrome Symptoms and clinical features may include: 3 Clinical Features of Kufor-Rakeb Syndrome : Autosomal recessive inheritance Mask-like facies Anosmia Torticollis Slow saccadic eye movements Supranuclear gaze palsy Aggressive [familydiagnosis.com]

  Clinical Synopsis: INHERITANCE: Autosomal recessive HEAD AND NECK: [Face]; Mask-like facies; [Eyes]; Supranuclear gaze palsy; Oculogyric dystonic spasms NEUROLOGIC: [Central nervous system]; Parkinsonism; Hypokinesia; Akinesia; Mask-like facies; Rigidity [genome.jp]

  Leg muscle stiffness MedGen UID: 870176 •Concept ID: C4024610 • Sign or Symptom Mask-like facies MedGen UID: 140860 •Concept ID: C0424448 • Finding A lack of facial expression often with staring eyes and a slightly open mouth. [ncbi.nlm.nih.gov]

  facies Expressionless face Lack of facial expression Mask-like facial appearance [ more ] 0000298 Paraparesis Partial paralysis of legs 0002385 Parkinsonism with favorable response to dopaminergic medication 0002548 Postural instability Balance impairment [rarediseases.info.nih.gov]

• Postural Instability

  […] thereof) is used to rate the degree of postural instability. [ncbi.nlm.nih.gov]

  instability Akinesia Hypokinesia Paraparesis Anarthria Parkinsonism with favorable response to dopaminergic medication ... ... [familydiagnosis.com]

  Keywords: Parkinson’s disease, postural control, postural instability, retropulsion test, falls INTRODUCTION OF THE CLINICAL DILEMMA Postural instability is a common and disabling feature of Parkinson’s disease (PD), contributing to recurrent falls and [journalofparkinsonsdisease.com]

  She also had postural instability (Video S2). Krs103‐iv‐10 This 33‐year‐old woman with normal birth history and psychomotor development presented balance problems and difficulties walking and speaking at age 12. [onlinelibrary.wiley.com]

  instability) In addition to movement-related (“motor”) symptoms, Parkinson’s symptoms may be unrelated to movement (“non-motor”). [parkinson.org]

• Hyperreflexia

  Kufor-Rakeb Syndrome : Autosomal recessive inheritance Mask-like facies Anosmia Torticollis Slow saccadic eye movements Supranuclear gaze palsy Aggressive behavior Psychotic episodes Dementia Hallucinations Seizures Spasticity Parkinsonism Myoclonus Hyperreflexia [familydiagnosis.com]

  Hyperreflexia MedGen UID: 57738 •Concept ID: C0151889 • Finding Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles. [ncbi.nlm.nih.gov]

  Showing of 61 | Medical Terms Other Names Learn More: HPO ID 80%-99% of people have these symptoms Babinski sign 0003487 Dementia Dementia, progressive Progressive dementia [ more ] 0000726 Hyperreflexia in upper limbs 0007350 Parkinsonism 0001300 Rigidity [rarediseases.info.nih.gov]

• Babinski Sign

  DTRs were increased without Babinski sign. Gait was mildly spastic with impaired tandem gait (Video S3). Brain MRI was normal (Fig. 1B). [onlinelibrary.wiley.com]

  If the Babinski sign is present it can indicate damage to the corticospinal tract. [ncbi.nlm.nih.gov]

  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 [nbiacure.org]

  The deep tendon reflexes were all brisk, and the Babinski sign and palmomental reflex were present bilaterally. Cerebellar signs and tremor were absent. [link.springer.com]

• Myokymia

  Abstract: Kufor-Rakeb syndrome (KRS)/PARK9 presents with autosomal recessive young onset Parkinson’s disease (YOPD), spastic paraparesis, abnormal eye movements and facial myokymia. [content.iospress.com]

  Abstract Kufor-Rakeb syndrome (KRS)/PARK9 presents with autosomal recessive young onset Parkinson's disease (YOPD), spastic paraparesis, abnormal eye movements and facial myokymia. [pubmed.ncbi.nlm.nih.gov]

First and foremost, the diagnosis of PD9 requires a thorough anamnesis. Young age at symptom onset and familial clustering are valuable hints on this hereditary neurodegenerative disease and thus, it is essential to assess the patient's medical and family history [6]. It may be necessary to carry out a genealogical analysis to recognize the autosomal recessive pattern of inheritance characteristic of PD9.

PD9 is diagnosed clinically [7], although additional diagnostic tools are frequently employed to support the tentative diagnosis and to rule out differential diagnoses: Magnetic resonance imaging may reveal atrophy of the globus pallidus and the pyramids but doesn't generally demonstrate specific nigrostriatal anomalies. In later stages of the disease, generalized cerebral atrophy becomes visible [2] [3]. In rare cases, brain images reveal iron deposition in the basal ganglia. Reduced fluorodopa uptake has been described as the main finding in positron emission tomography of patients suffering from Parkinson's disease, and has been found at least in an East-Asian PD9 patient [7]. Results obtained by means of electroencephalography may be in agreement with diffuse encephalopathy and cognitive decline [3].

In the context of a positive family history, the presence of parkinsonism, pyramidal signs, supranuclear gaze palsy and/or dementia warrants the diagnosis of PD9 or Kufor-Rakeb syndrome. It is important to note that these symptoms are not necessarily presented in their entirety by an individual patient. Symptoms not presented by the patient at hand can be observed in other members of the affected family, though. Still, it is highly recommended to complement clinical and imaging studies with genetic analyses in order to dispel any remaining doubts. Furthermore, precise knowledge regarding the underlying mutation largely facilitates genetic counseling and prenatal diagnoses.

• Diffuse Encephalopathy

  Results obtained by means of electroencephalography may be in agreement with diffuse encephalopathy and cognitive decline. [symptoma.com]

Affected individuals are treated symptomatically. PD9-associated parkinsonism is levodopa-responsive and patients have been reported to experience substantial improvements of extrapyramidal function within two days after the initiation of dopamine replacement [2]. However, the efficacy of levodopa may decline as soon as six months into therapy, and levodopa-induced dyskinesias, facial-faucial-finger minimyoclonus, moculogyric dystonia, and visual hallucinations are likely to occur after long-term treatment [1] [3] [4] [5] [8]. In order to increase treatment efficacy, levodopa may be combined with other drugs commonly used to alleviate symptoms related to Parkinson's disease: Patients may benefit from the administration of anticholinergics, COMT inhibitors, MAO-B inhibitors, and NMDA receptor antagonists.

Pyramidal signs can't be improved by dopamine replacement therapy. Treatment of patients suffering from spasticity still poses a major challenge, with botulinum toxin injections possibly providing relief from focal complaints [5].

PD9 patients should also be offered physical therapy and psychological support.

PD9 follows a progressive course. Both slow and rapid progression have been described and thus, patients may survive over decades maintaining an acceptable quality of life or become unable to manage their everyday life within months [5]. Dys- or anarthria and the inability to use hands, arms, and legs are major factors of disability in patients suffering from advanced-stage PD9. Death is often due to aspiration pneumonia. With regard to the Chilean kindred affected by PD9, the mean duration of the disease was 29 years [3].

About 10-20% of patients diagnosed with Parkinson's disease have a positive family history of this neurodegenerative disorder [9]. However, familial accumulation of Parkinson's disease may be due to distinct mechanisms: On the one hand, predisposing sequence anomalies may trigger the disease in the presence of unfavorable environmental factors. On the other hand, pathogenic mutations alone may be sufficient to provoke neurodegeneration. The latter applies to monogenic forms of Parkinson's disease, which are caused by germline mutations and which often manifest earlier than the sporadic disease. Linkage studies may provide valuable information as to the genes involved in etiology and pathogenesis of the disease in individual families, and such a study has been carried out to identify the trigger of PD9. In this study, PD9 has been linked to chromosomal locus 1p36, which has subsequently been designated PARK9 [1] [10].

The ATP13A2 gene is located at 1p36 and has later been identified as the trigger of PD9 [11]. This gene encodes for a lysosomal P-type ATPase mainly expressed by neurons [4]. The enzyme is required for the maintenance of neuronal integrity, possibly by sustaining intracellular ion homeostasis, lysosomal and/or mitochondrial function. The mutated enzyme doesn't locate to the lysosomal membrane but is retained in the endoplasmatic reticulum and degraded by the proteasome [11]. To date, several missense mutations, insertions, deletions, and splice-site mutations have been described in the ATP13A2 gene [9].

Sporadic Parkinson's disease is the second most common neurodegenerative disorder, second only to Alzheimer disease. The annual incidence of Parkinson's disease ranges between 10 and 20 per 100,000 inhabitants and it has been estimated that Parkinson's disease affects 1-2% of people aged >65 years and up to 4% of individuals aged >85 years [9]. With regard to sporadic Parkinson's disease, symptom onset before the age of 50 is uncommon. By contrast, PD9 usually manifests in adolescence or young adulthood. It is therefore classified as a juvenile or early-onset form of the disease. Although the patients' mean age at symptom onset is 15 years, the onset of clinical disease may occasionally be delayed until old age: PD9 has been diagnosed in patients aged 12-63 years [4] [5]. PD9 has originally been described in Jordanians but has later been reported in a Chilean kindred and isolated individuals of non-Jordan Arab, Brazilian, East Asian, and European origin [3] [4] [7] [8] [12] [13]. Affected individuals proved to be homozygous or compound heterozygous for pathogenic ATP13A2 mutations. Of note, heterozygous carriers may develop mild symptoms in adulthood and if this is the case, parkinsonism usually dominates the clinical picture [3] [4] [14].

While the triggers of neurodegeneration remain largely unknown, it is the key process in the pathogenesis of Parkinson's disease. Histological hallmarks of Parkinson's disease comprise the selective loss of dopaminergic neurons in the pars compacta of the substantia nigra, which is accompanied by depigmentation and gliosis. Neuronal loss may also be observed in the locus ceruleus, pedunculopontine nucleus, raphe nucleus, dorsal motor nucleus of the vagal nerve, olfactory bulb, parasympathetic as well as sympathetic post-ganglionic neurons, Mynert nucleus, amygdaloid nucleus and cerebral cortex [15]. These histological features can, however, only be confirmed at autopsy.

It has been hypothesized that the accumulation of dysfunctional, abnormally folded or insufficiently degraded protein leads to nigral degeneration [15]. With regard to hereditary forms of Parkinson's disease, the amassment of such proteins is likely related to the underlying gene defect. For instance, Parkinson's disease type 1 is presumably caused by dysfunctional α-synuclein, subsequent deficiencies in neurotransmitter release, and the intracellular accumulation of aberrant α-synuclein and dopamine-derived neurotoxic metabolites. According to current knowledge, the latter can't be metabolized to non-toxic neuromelanin, which may explain hypopigmentation of the substantia nigra and neuronal death [16]. Concerning PD9, it may be speculated that mutations in the ATP13A2 gene interfere with lysosomal function, disturbing protein break down at a large scale. Protein that cannot be degraded may accumulate in the respective cells and according to the results of expression studies, these are principally neurons.

Such protein may aggregate in so-called Lewy bodies. Besides the loss of dopaminergic neurons in the substantia nigra, these eosinophilic inclusions are the second most important histological finding in most forms of Parkinson's disease. To date, post-mortem studies have not been performed in PD9 patients, though, and it cannot yet be confirmed if this entity is associated with Lewy body formation [3].

Affected families may benefit from genetic counseling. Consanguineous marriage and reproduction greatly enhance the likelihood of homozygosity for pathogenic variants of the ATP13A2 gene [2] [7], and people should be advised against them. Pregnant women from affected families may be recommended pre- or postnatal analysis to see whether their child is homozygous or compound heterozygous for pathogenic ATP13A2 mutations.

PD9 has first been described in 1994. Najim al-Din and colleagues reported five siblings of an Arab family originating from the Kufor-Rakeb region in Jordan to suffer from pallido-pyramidal degeneration, supranuclear gaze palsy, and dementia. They were born to apparently healthy consanguineous parents, which is why autosomal recessive inheritance has promptly been assumed [2]. Years later, the underlying mutation could be identified: PD9 patients are homozygous or compound heterozygous for pathogenic mutations in the ATP13A2 gene [11]. The molecular function of the enzyme encoded by ATP13A2 could not yet be defined, but the gene product is assumed to play a role in the maintenance of intracellular ion homeostasis and lysosomal function.

PD9 is a form of juvenile-onset Parkinson's disease. First symptoms are usually presented by otherwise healthy children aged 10-15 years. PD9 follows a progressive course and while the initial responses to levodopa therapy are highly promising, the efficacy of this drug tends to wear off, leaving patients in a very narrow therapeutic window between akinetic-rigid states and severe drug-induced dyskinesias [8]. Although they may survive over decades, their quality of life is generally very low in advanced stages of the disease, and they are highly dependent on care.

Parkinson's disease is the second most common neurodegenerative disorder, second only to Alzheimer's disease. Most cases of Parkinson's disease are deemed sporadic. They are assumed to be triggered by environmental factors that exert particularly unfavorable effects in genetically predisposed patients. By contrast, familial clustering is occasionally observed and has been related to mutations passed on from generation to generation, similar to what happens in well-known hereditary disorders. Hereditary Parkinson's disease may then be diagnosed. There are distinct types of hereditary Parkinson's disease and they differ with regards to the underlying mutation and associated disorders. One of these types is Parkinson's disease type 9 (PD9). PD9 is caused by genetic defects that have been inherited from the parents, which is why this disease is more common where consanguineous marriage is practiced.

PD9 usually manifests in adolescence. Patients aged 12-15 years may become clumsy and slow, tend to fall, and often don't perform in school as they are supposed to do. They develop muscle rigidity, tremor and bradykinesia, which are typical of Parkinson's disease, and dementia. Additionally, most PD9 patients suffer from vertical gaze palsy and pyramidal signs such as spasticity. Temporary relief can be achieved with levodopa, but disease progression can't be halted. The majority of patients eventually loses their abilities to communicate, to use their hands, arms, and legs, and thus becomes dependent on care.

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