title: Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability.
abstract: Mutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear gaze disturbance. However, the associated genotypes and phenotypes are poorly characterized due to the small number of patients described. Here, we report clinical, instrumental, and genetic findings in an Italian family with novel PARK9 and PARK15 mutations. The proband developed a severe progressive phenotype including juvenile-onset parkinsonism, pyramidal disturbances, cognitive decline, and oculomotor abnormalities. On the contrary, his brother only shows mild abnormalities (pyramidal, cognitive, and oculomotor) on the neurological examination at the age of 31 years. These two brothers both carry a novel homozygous PARK9 missense (p.G877R) and a novel heterozygous PARK15 mutation (p.R481C). The PARK9 mutation replaces a crucial residue for the ATPase activity, and is therefore most likely a loss-of-function mutation and disease-causing in homozygous state. The pathogenic significance of the PARK15 single heterozygous mutation remains unclear. In both sibs, DaTSCAN single photon emission computed tomography showed marked nigrostriatal dopaminergic defects, and transcranial magnetic stimulation detected prolonged central motor conduction time. MRI, including T2*-weighted imaging, detected no evidence of brain iron accumulation. This family, the third reported with homozygous PARK9 mutations and the first with mutations in two genes for atypical juvenile parkinsonism, illustrates that PARK9-linked disease might display wide intra-familial clinical variability and milder phenotypes, suggesting the existence of strong, still unknown, modifiers.
authors.affiliation: Department of Neurological Sciences, University of Naples Federico II, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Breedveld
authors.forename: Fiore
authors.initials: F
authors.lastname: Manganelli
authors.forename: Rosa
authors.initials: R
authors.lastname: Iodice
authors.forename: Chiara
authors.initials: C
authors.lastname: Pisciotta
authors.forename: Maria
authors.initials: M
authors.lastname: Nolano
authors.forename: Francesca
authors.initials: F
authors.lastname: Punzo
authors.forename: Mario
authors.initials: M
authors.lastname: Quarantelli
authors.forename: Sabina
authors.initials: S
authors.lastname: Pappatà
authors.forename: Alessio
authors.initials: A
authors.lastname: Di Fonzo
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bonifati
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis; D044783:F-Box Proteins / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D020125:Mutation, Missense; D020734:Parkinsonian Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D006180:Proton-Translocating ATPases / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C514983:ATP13A2 protein, human; D044783:F-Box Proteins; C489149:FBXO7 protein, human; D050505:Mutant Proteins; D006180:Proton-Translocating ATPases