Kufor-Rakeb syndrome (KRS) is a rare inherited and rapidly progressive form of Parkinson disease similar to Pallido-pyramidal syndrome and characterized by early onset between 11 and 16 years of age, dementia, supranuclear upgaze palsy and pyramidal degeneration. KRS patients usually present Parkinson disease signs such as bradykinesia, rigidity and tightening of the face muscles, but intention tremor is missing. The syndrome was named after the origin of a Jordanian family where it was first observed. Treatment with levodopa showed significant amelioration in the extrapyramidal function although limited to patients with a more recent disease onset. Some patients showed facial-faucial-finger mini-myoclonus, visual hallucinations and oculogyric dystonic spasm in a later stage.
In 1994, Najim Al-Din et al. assigned the name of Kufor-Rakeb syndrome to a severe form of Parkinsonism similar to pallido-pyramidal syndrome in a consanguineous family. Phenotypically normal parents were cousins and had 10 children, five of which were affected (including one female), one of them died of a respiratory infection after suffering from severe spastic paraplegia. This pattern prompted Najim Al-Din et al. (1994) to suggest an autosomal recessive inheritance for the condition. Apart from rigidity, bradykinesia and a mask-like face, signs such as dementia, lack of intentional tremor and a supranuclear upgaze paresis separate this disorder from pallido-pyramidal syndrome. Moreover, the syndrome is identified as rapidly progressive with initial atrophy of the globus pallidus and pyramids and subsequent general atrophy of the brain and onset is juvenile and subacute. Levodopa therapy resulted in variable but dramatic improvement, limited to extrapyramidal manifestations, within 48 hours in all affected subjects. However, only those with the shortest disease duration were rendered almost normal regarding the extrapyramidal manifestations. Hampshire et al. (2001) investigated the syndrome more closely and identified it as a nigro-striatal-pallidal-pyramidal neurodegeneration in the same family and linked it to a fragment of 9cM between markers D1S436 and D1S2843 on 1p36. A maximum multipoint lod score of 3.6 was obtained for the region containing markers D1S1592, D1S2826, D1S2644, and D1S199. Williams et al. (2005) investigated the surviving four patients of this family to further characterize Kufor-Rakeb syndrome as a distinct illness. All survivors had a normal birth and achieved developmental milestones. Onset started with general weakness, muscle stiffness and lethargy and progressed rapidly to a deterioration of motor function accompanied by involuntary jerky movements, and total dependence for daily activities. Later signs include visual hallucinations and dementia. Levodopa response peaked in the initial phase with excellent results only to subside and decrease to no effect and even dystonic posturing in one of the siblings. Williams et al. (2005) suggested a cortical involvement due to a facial-faucial-finger mini-myoclonus specific to KRS and subcortical implication due to the supranuclear gaze palsy. Ramirez et al. (2006) confirmed the implication of the ATP13A2 in the degradation of nigral neurons by identifying a homozygous 22bp duplication in exon 16 in all affected members of the original Jordanian family.