Ibanez et al. (2006) identified eight novel mutations in 177 patients chosen according to at least two of the cardinal signs rest tremor, bradykinesia and rigidity, and a good response to levodopa with an onset earlier than 60 years of age. Familial character was determined with at least one affected family member for each patient and an autosomal recessive inheritance pattern. The study was conducted in Europe, although 16 of the patients originated from Algeria. After screening for parkin and PINK1 mutations, linkage analysis with polymerase chain reaction revealed 34 families linked to PARK6 and 7 patients representing 4% of the cohort tested positive for PINK1 mutations. In the Algerian consanguineous family, a single nucleotide deletion was found on exon 8, c.1558delG resulting in the frameshift mutation L519fsX522 and the predicted truncation of the protein at the 59 C-terminal amino acid. Parents were related and healthy with five children, three of which were affected (two females and one male) with onset at 40 years of age. Only the male was available for the study and was found to have the homozygous L519fsX522 mutation.

Myhre et al. (2008) investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset Parkinsonism for mutations both in the parkin and PINK1 gene. In the PINK1 gene, Myhre et al. (2008) identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain. Both substitutions segregated with disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in two affected each.

Chisti et al. (2006) identified a mutation at codon 313 in exon 4 of the PINK1 gene in a Saudi Arabian proband. The homozygous ACG-to-ATG mutation results in a substitution of threonine by methionine. The rest of the family of the proband, including a parent, seven of the proband's siblings, his offspring and the offspring of the proband's sibling, were screened for the same mutation. The family is highly inbred with three consanguineous marriages. The clinical analysis revealed early-onset Parkinsonism in four members (age at onset 28-34). The original proband is in turn married to his first cousin, who is carrier of the mutation and has six children, three of which are homozygous for the T313M mutation, although their age was lower than the expected age of onset, thus not showing signs of Parkinsonism. Subjects heterozygous for T313M do not show any signs of the disease. Affected members show tremor and bradykinesia with the absence of dementia, depression or cognitive impairment and respond well to treatment with levodopa, although two experienced a deterioration of the response after 4 years.

[See also Sudan > Cazeneuve et al., 2009].

Leutenegger et al. (2006) identified a novel mutation in the PINK1 gene linked to juvenile onset Parkinsonism. The disease manifested itself between the ages of 9 to 17 in eight family members from Sudan, with no family history of tremor in the previous two generations. After Algeria, this is the only PINK1 mutation reported in Arab subjects. Atypical neurological signs were absent in five living and three deceased patients. Good and sustained response to treatment with a slow progression of the disease was present in all five subjects. All affected members came from a consanguineous marriage. Three of the affected members, all females, died of the disease at an age between 20 and 25 years. Leutenegger et al. (2006) excluded Parkin and DJ1 loci with microsatellite markers. Yet, they found a mutation a transversion c.650C-A in exon 2 that causes a substitution of a highly conserved alanine to aspartic acid at position 217, within the kinase domain in the predicted ATP orientation site. All affected members were homozygous for the A217D mutation and the parents of three of them carry one mutant allele, but the heterozygous genotype did not appear to result in Parkinsonism. Leutenegger et al. (2006) suggested the presence of a relationship between the location of the mutation and its vicinity inhibiting the reduction of a protein involved in cell apoptosis and the juvenile onset of the disease.

Cazeneuve et al. (2009) studied three affected sibs (one female and two males) with early onset Parkinson's disease (EOPD) born to a consanguineous Sudanese family living in a village in Central Sudan and belonging to a large tribe originating from the Central Region of Saudi Arabia. The patients were found to be homozygous for a novel deletion of exons 4 to 8 in the PINK1 gene. Breakpoint analysis revealed a complex rearrangement combining a large deletion and the insertion of a sequence duplicated from the dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST) gene intron 2, located near the PINK1 gene. As breakpoint sequences displayed only three base pairs of homology, Cazeneuve et al. (2009) predicted that this rearrangement may result from a Fork Stalling and Template Switching mechanism. This third large rearrangement of PINK1 enlarges the mutation spectrum and, together with recent published data in Tunisian patients with EOPD, points out that PINK1 gene analysis, including search for large rearrangement, should be considered in early onset recessive Parkinson disease patients, particularly those from Arab origin.

After PINK1 sequencing and dosage analysis, Ishihara-Paul et al. (2008) reported three novel homozygous mutations (Q129X, Q129fsX157, G440E) and one previously identified (Q456X) in 46 Tunisian subjects with early-onset Parkinsonism (age at onset 36 +- 12 years) and showed a more rigid presentation and slower progression than non-familial Parkinson disease.