Recently, a new form of autosomal recessive early-onset parkinsonism (PARK20), due to mutations in the gene encoding the phosphoinositide phosphatase, Synaptojanin 1 (Synj1), has been reported.
Non-motor features and cardiac sympathetic innervation were assessed in two siblings affected by parkinsonism who harboured the homozygous Arg258Gln mutation in the SYNJ1 gene.
Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology.
Two consanguineous families were initially reported (one of Sicilian and one of Iranian origins), with the same SYNJ1 homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features.
The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis.
We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions.