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Parkinsonism in GNDs412DNAJC6 DNAJC6 encodes for auxilin, a neuronally expressed J-chaperone protein involved in the uncoating of clathrin-coated vesicles, that is necessary for the regeneration of synaptic vesicles. Impaired uncoating is thought to lead to neurotransmission deficits.62SYNJ1 SYNJ1 encodes a phosphoinositide phosphatase called synaptojanin1 and plays an important role in early endosomal compartments and clathrin-mediated endocytosis.63Ubiquitin-proteasome systemAngelman syndrome, involving UBE3AUBE3A encodes the Ubiquitin-Protein Ligase E3A, part of the ubiquitinproteolytic pathway,64 that has been suggested to be involved in the clearance of alpha-synuclein.65Partial 6q trisomy, involving PRKN Pathogenic variants of PRKN are associated with early-onset autosomal recessive Parkinson’s disease.66 PRKN encodes the E3 Ubiquitin-Protein Ligase Parkin, involved in mitophagy, and possibly in the formation of Lewy bodies.67PTRHD1 PTRHD1 encodes for peptidyl-tRNA hydrolase that belongs to the PTH2 family. The deduced ubiquitin-like domain-binding protein is thought to suppress ubiquitin-mediated protein degradation.68 Alfasynuclein homeostasis is maintained by proper function of the ubiquitinproteasome system.OtherCerebrotendinous xanthomatosis (CYP27A)Accumulation of cholesterol and cholestanol cause neurotoxicity and axonopathy.69Incontinentia pigmenti (IKBKG) It has been suggested that pathogenic variants in IKBKG, involved in neuronal anti-apoptotic signaling, may cause neurodegeneration.70Klinefelter syndrome Melatonin may have a neuroprotective role in Parkinson’s disease. It has been suggested that reduced melatonin levels in Klinefelter syndrome may play a role in the development of parkinsonism.71, 72L2-hydroxyglutaric aciduria (L2HGDH)L2HGDH encodes for l-2-hydroxyglutarate (L2HG) dehydrogenase that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate. L2HG deficiency may result in impaired hippocampal neurogenesis and neurodegeneration in adult mouse brains.73Menkes disease (ATP7A) Haploinsufficiency of ATP7A, encoding a transmembrane coppertransporting ATPase, may result in dysregulation of copper metabolism in the basal ganglia.74, 75Molybdenum cofactor deficiency type B (MOCS2)MOCS2 encodes for molybdenum cofactor. Deficiency leads to loss of sulfite oxidase activity, resulting in cumulative metabolic effects on the basal ganglia.76 Elevated concentrations of S-sulfocysteine and toxic sulfite may trigger neuronal apoptosis.77Partial 4q trisomy, involving SNCASNCA encodes α-synuclein, the primary component of Lewy bodies. Thepatient with partial 4q trisomy had a de novo SNCA duplication. Other genes in the duplicated region may have contributed to the phenotype.78Phosphoglycerate kinase deficiency I (PGK1)Phosphoglycerate kinase is an important enzyme in the glycolytic pathway. It has been suggested that neuronal damage occurs as a consequence of energy failure.79SCA27 (FGF14) FGF14, expressed in axons of the striatopallidal and striatonigral pathways, encodes a regulatory protein of voltage-gated sodium channels (Nav1.6). Haploinsufficiency of FGF14 may alter expression of sodium channels with impaired firing of Purkinje neurons.80Smith-Magenis syndrome (RAI1) Pathogenic variants of RAI1 may result in an inversion of circadian melatonin secretion with a lack of nocturnal melatonin, that may play a role in the development of parkinsonism.71, 72, 81