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 with a predicted truncation of the protein at the C-terminal amino acid at position 59. The families linked to the PINK1 gene presented with a mean age at onset of 35 +- 8 years.

Myhre et al. (2008) investigated the significance of parkin and PINK1 mutations in the region by examining families from Jordan with a high incidence of consanguineous marriages, a recessive pattern of inheritance, and at least one patient with parkinsonism in each family. This study included 11 consanguineous families with 1-2 affected subjects with juvenile or young-onset parkinsonism. In total, the study group comprised of 17 affected members among 59 family members. Five families had only one affected member strictly classified as having young-onset sporadic parkinsonism. The age at onset was found to be on average 26.8 ± 5.8 years [range 19-36] covering cases defined as either young (? 21 and <40) or juvenile (<21) onset. The parents were unaffected with the absence of disease in several generations suggesting an autosomal recessive mode of inheritance. Clinical manifestations included marked response to levodopa (60%), sleep benefit (95%), observed L-dopa induced dyskinesia (90%), dystonic posture (90%), and a slow disease progression (90%). At the molecular level Myhre et al. (2008) identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain in the PINK1 gene. Both substitutions segregated with the disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in each of the two affected members. Myhre et al. (2008) also identified a deletion mutation in the parkin gene in one family. Additionally, Myhre et al. (2008) identified common polymorphisms in the two genes and these polymorphisms were found to be co-segregating within families. Myhre et al. (2008) concluded that the results obtained from this study further extend on the involvement of PINK1 mutations in recessive early-onset parkinsonism with clinical features similar to carriers of parkin mutations.

After identifying a homozygous threonine-to-methionine substitution at codon 313 in exon 4 of the PINK1 gene in a Saudi Arabian proband, Chishti et al. (2006) performed a mutation analysis on relatives of the proband. Clinical analysis revealed early-onset Parkinsonism in four members (age at onset 28-34), two of which were not available for genetic screening, but were from a consanguineous marriage. The other two were also from a first cousin marriage with parents healthy and heterozygous for the mutation. 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 whose age is lower than expected age of onset, thus not showing signs of Parkinsonism. The rest of the 21 screened subjects of this family, who are carrying only one mutant allele do not show any signs of the disease. Affected members showed tremor and bradykinesia with the absence of dementia, depression or cognitive impairment and responded 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 defect reported in Arab subjects. Ophtalplegia, dementia, autonomic failure and pyramidal syndrome were absent in the five living and three deceased patients. Present in all five living subjects were diurnal fluctuations and the good and sustained response to treatment with a slow progression of the disease. All affected members were from a consanguineous marriage. Three of the affected subjects, 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. They identified the mutation as a homozygous 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. 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) reported 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 age of onset of the disease in these patients was 15 (male), 21 (female), and 11 (male) years. The disease started in all three patients with bradykinesia. The age at examination of the patients was 35, 27, and 15 years, respectively. The three patients had rigidity and rest tremor. All of these patients showed improvement with levodopa with a daily dose of 375 mg, 250 mg, and 187.5 mg, respectively. The second and the third patients showed excellent response to this treatment without side effects over the following two years. The first patient suffered from facial dyskinesia and neck dystonia as side effects. Other related clinical conditions and precipitating factors were excluded in the three patients. At the molecular level, Cazeneuve et al. (2009) identified a novel complex large rearrangement of the PINK1 gene, consisting of a deletion of exons 4 to 8 at homozygous state in this family.

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.