Kufor-Rakeb Syndrome

A number sign (#) is used with this entry because of evidence that Kufor-Rakeb syndrome (KRS), also known as Parkinson disease-9 (PARK9), is caused by homozygous or compound heterozygous mutation in the ATP13A2 gene (610513), which encodes a lysosomal type 5 ATPase, on chromosome 1p36.

Description

Kufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; see 234200) (summary by Bruggemann et al., 2010).

For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600.

Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia-78 (SPG78; 617225), an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017).

Clinical Features

Najim Al-Din et al. (1994) reported 5 offspring of a consanguineous Jordanian couple with clinical features similar to those of idiopathic Parkinson disease and pallidopyramidal syndrome (PARK15; 260300). The family originated from the Kufor-Rakeb region in Jordan. These included a mask-like face, rigidity, and bradykinesia. Rapidly progressive onset of symptoms was between 12 and 16 years of age. Intention tremor was not seen; spasticity, supranuclear upgaze paresis, and dementia were additional features seen in these individuals but not seen in Parkinson disease. Treatment with levodopa resulted in improvement in symptoms. MRI scans of the brain showed globus pallidus atrophy and later generalized brain atrophy. Najim Al-Din et al. (1994) named this Kufor-Rakeb syndrome, after the community from which the affected individuals originated.

Williams et al. (2005) further characterized the clinical picture in the original Jordanian family and identified several new features, including facial-faucial-finger mini-myoclonus, visual hallucinations, and oculogyric dystonic spasms. The authors noted that neurologic features had a subacute onset, resulting in severe motor handicap within a year of onset and involving the basal ganglia, corticospinal and vertical gaze pathways, and cerebral cortex.

Di Fonzo et al. (2007) reported a Brazilian man who was diagnosed with levodopa-responsive parkinsonism at age 12 years. On examination at the age of 18, he had severe akinetic-rigid parkinsonism with episodic levodopa-induced choreic dyskinesias, visual hallucinations, and aggressive behaviors. However, his mental status remained good, and he was cognitively intact between episodes. Other features included supranuclear vertical gaze paresis, diffuse cerebral atrophy, and lip/chin tremor. He did not have myoclonus or tremor in the limbs.

Crosiers et al. (2011) reported a boy, born of consanguineous Afghan parents, with KRS confirmed by genetic analysis (610513.0006). The patient had mild mental retardation before onset of fine tremor of the hands and dystonic posturing of the neck at age 10 years. He also had slow vertical saccades, hypomimia, facial myoclonus, and dystonia. Cognitive function deteriorated rapidly, and he had dementia by age 11. Bradykinesia and rigidity were partially responsive to L-DOPA therapy, but he developed dyskinesias. The patient also had visual hallucinations and psychosis, and nuclear imaging showed decreased dopamine transporter binding in the right caudate nucleus and bilateral putamina. The heterozygous deletion was also found in each unaffected parent, as well as in a brother who had mild mental retardation, tremor, and decreased dopamine transporter binding in the putamina. Crosiers et al. (2011) speculated that heterozygosity for the mutation may have contributed to the brother's phenotype.

Santoro et al. (2011) reported 2 Italian brothers with Kufor-Rakeb syndrome who showed marked phenotypic variability. The more severely affected brother, who had a history of perinatal asphyxia, developed slowly progressive parkinsonism at age 10 years, followed by pyramidal signs, extrapyramidal signs, and cognitive impairment. At age 41 years, he showed dysphagia, dysarthria, abnormal eye movements, hypomimia, mini-myoclonus of the facial muscles, dystonia, and spasticity. The 31-year-old brother had difficulty in school, mild gaze palsy, hyperreflexia, mildly increased axial tone, and mild rigidity, but was otherwise asymptomatic. Transcranial magnetic stimulation in both patients showed prolonged central motor conduction times, and brain imaging showed decreased dopamine transporter density in the striatum. There was also cerebral and cerebellar cortical atrophy. There was no evidence of iron accumulation in the basal ganglia. Santoro et al. (2011) concluded that unknown modifiers were responsible for the observed intrafamilial phenotypic variation.

Neuroradiologic Features

Bruggemann et al. (2010) reexamined members of the Chilean family with KRS reported by Ramirez et al. (2006). One 45-year-old patient with the full disorder and compound heterozygous mutations in the ATP13A2 gene (610513.0001 and 610513.0002) had parkinsonism with dementia. The 79-year-old mother, who was heterozygous for 1 of the mutations, had parkinsonism and anosmia. Four heterozygous sibs of the proband ranging in age from 48 to 62 years, showed subtle extrapyramidal signs, including reduced arm swing and tremor. Neuroimaging showed markedly reduced dopamine transporter (126455) activity in the mother and the fully affected individual, but only a unilateral mild reduction in 1 of the heterozygous sibs. Neuroimaging of the fully affected individual showed decreased loss of gray matter volume in multiple brain regions, including the motor cortices, caudate, thalamus, prefrontal cortex, and cerebellum, and well as evidence of iron accumulation in the basal ganglia. Bruggemann et al. (2010) suggested that heterozygous ATP13A2 mutations may cause an age-dependent impairment of nigrostriatal function.

Schneider et al. (2010) reported a 40-year-old man, born of consanguineous Pakistani parents, with KRS. He had mild school difficulties in childhood, but onset of major symptoms occurred at age 16, when he presented with behavioral abnormalities and extrapyramidal symptoms. The disorder was progressive, and he developed severe parkinsonism, pyramidal signs, dystonia, restricted ocular movements, and hypomimia. Brain MRI showed diffuse brain atrophy, flattening of the caudate nuclei, and iron deposition in the basal ganglia. Cognition remained relatively intact.

Clinical Variability

Carlier and Dubru (1979) reported 4 Belgian sibs with familial juvenile parkinsonism with onset around age 14 years. Clinical features included progressive stiffness in the limbs, abnormal gait, akinesia, cogwheel rigidity, poor facial expression, and severe dysarthria. The oldest sib developed tremor. Treatment with L-DOPA resulted in clinical improvement. In a follow-up of the family reported by Carlier and Dubru (1979), Tome et al. (1985) noted that the initial symptoms in the affected sibs began at around 8 years of age and consisted of learning difficulties requiring special schooling. Motor difficulties occurred several years later. In addition to parkinsonism, the patients had upper motor neuron signs with spasticity, pseudobulbar syndrome, extrapyramidal symptoms, choreic movements, slow extraocular eye movements, and cognitive decline. Brain imaging showed subcortical and cortical atrophy in 3 patients. All also developed a peripheral neuropathy predominantly manifest as loss of sensation in the distal lower limbs. Sural nerve and muscle biopsy of 2 patients showed concentric lamellar osmiophilic inclusions suggestive of a storage deposit disease, which the authors concluded did not resemble those seen in neuronal ceroid lipofuscinosis (see, e.g., CLN1, 256730).

De Volder et al. (1990) concluded that the Belgian sibs reported by Carlier and Dubru (1979) had a form of neuronal ceroid lipofuscinosis with vacuolated lymphocytes observed in all patients. Nerve and muscle biopsy from the oldest sib showed autofluorescent lipopigments and fingerprint-like profiles. This patient, who was the most severely affected, also had seizures, myoclonic jerks, urinary incontinence, and severe intellectual impairment. PET scanning of all 4 sibs revealed a decrease of glucose utilization in all gray structures but more marked at the level of the thalamus and posterior association cortex. The severity of metabolic anomalies correlated with the degree of clinical impairment and with disease duration.

Bras et al. (2012) noted that the patients in the Belgian family developed dyskinesias following L-DOPA treatment. The oldest patient became wheelchair-bound at age 25 years and died of pulmonary embolism at age 36. Postmortem examination showed abundant neuronal and glial lipofuscinosis involving the cortex, basal nuclei, and cerebellum, with whorled lamellar inclusions typical of CLN in electron microscopy. Lipofuscin deposits were confirmed in the retina, although she had no apparent retinal involvement. The entity in this family was referred to by Bras et al. (2012) as neuronal ceroid lipofuscinosis (CLN12).

Inheritance

Najim Al-Din et al. (1994) concluded that autosomal recessive inheritance of Kufor-Rakeb was likely because the unaffected parents in the family they reported were consanguineous, 5 of their 9 offspring were affected, and 1 was female.

Clinical Management

Najim Al-Din et al. (1994) described variable but dramatic improvement, limited to extrapyramidal manifestations, within 48 hours in response to levodopa therapy in all of their patients. However, only those with the shortest disease duration were rendered almost normal regarding the extrapyramidal manifestations. Williams et al. (2005) noted the occurrence of a striking and sustained but waning response to L-DOPA, describing narrowing of the therapeutic window with the emergence of peak-dose dyskinesias, increased spasticity, and cognitive decline.

Mapping

By use of autozygosity mapping in the kindred studied by Najim Al-Din et al. (1994), Hampshire et al. (2001) identified a 9-cM region between markers D1S436 and D1S2843 on chromosome 1p36 likely to contain the gene associated with this phenotype. A maximum multipoint lod score of 3.6 was obtained for the region containing markers D1S1592, D1S2826, D1S2644, and D1S199.

Molecular Genetics

By mutation screening or linkage analysis, Ramirez et al. (2006) excluded known autosomal recessive Parkinson disease genes and loci from involvement in the phenotype in a large nonconsanguineous Chilean family. They found linkage to a 23-cM region bordered by D1S2736 and D1S2644, between the PARK7 (606324) and PARK6 (605909) loci. Using sequence analysis, Ramirez et al. (2006) found loss-of-function mutations in a predominantly neuronal P-type ATPase gene, ATP13A2 (610513), as the cause of Kufor-Rakeb syndrome. Affected members of the Chilean family were compound heterozygous for a deletion and a splice site mutation (see 610513.0001), and affected members of the original Jordanian family were homozygous for 22-bp duplication in exon 16 (610513.0003).

In a Brazilian man with KRS, Di Fonzo et al. (2007) identified a homozygous mutation in the ATP13A2 gene (G504R; 610513.0004). Two unrelated Italian patients with early-onset parkinsonism at age 30 and 40 years, respectively, carried heterozygous ATP13A2 mutations, suggesting that heterozygous mutations may increase risk for development of the disease.

In a 40-year-old man, born of consanguineous Pakistani parents, with KRS, Schneider et al. (2010) identified a homozygous 2-bp insertion in the ATP13A2 gene (610513.0005).

In 2 Italian brothers with Kufor-Rakeb syndrome, Santoro et al. (2011) identified a homozygous missense mutation in the ATP13A2 gene (G877R; 610513.0008). Each brother and the unaffected mother also carried a heterozygous R481C mutation in the FBXO7 gene (605648); biallelic mutation in the FBXO7 gene causes early-onset PARK15 (260300). The FBXO7 mutation occurred at a highly conserved residue and was not found in 318 control chromosomes, but the significance of this finding was unclear.

In 3 Belgian sibs with KRS, originally reported by Carlier and Dubru (1979), Bras et al. (2012) identified a homozygous missense mutation in the ATP13A2 gene (M810R; 610513.0007). The mutation was found by exome sequencing and segregated with the disorder in the family. It was not present in the dbSNP (build 135) or 1000 Genomes Project databases. Functional studies were not performed. Because some of the patients had neuropathologic findings consistent with neuronal ceroid lipofuscinosis, Bras et al. (2012) designated the disorder CLN12.

Animal Model

Farias et al. (2011) determined that a homozygous truncating mutation (1623delC) in exon 16 of the Atp13a2 gene is responsible for autosomal recessive, adult-onset neuronal ceroid lipofuscinosis (NCL) in Tibetan terriers (Riis et al., 1992). Behavioral changes in these dogs were first noted between age 4 and 9 years, and brain tissue showed autofluorescent membrane-bound cytoplasmic inclusions with varied ultrastructure in neurons, consistent with a diagnosis of NCL. Although homozygous truncating mutations in human ATP13A2 cause Kufor-Rakeb syndrome (KRS), another neurodegenerative disease, the phenotype differs between terriers and humans. Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients, and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. However, both show generalized brain atrophy, behavioral changes, and cognitive decline. The findings suggested that KRS may be a type of adult-onset NCL; however, sequencing of the ATP13A2 gene in 28 patients with adult-onset NCL (Kufs disease; CLN4A, 204300) failed to reveal any variants likely to be disease-causing. Analysis of brain tissue from patients with KRS is necessary to confirm the hypothesis that KRS is a neuronal ceroid lipofuscinosis.