TABLE 1.
Pathophysiologic mechanisms that may underlie parkinsonism in genetic neurodevelopmental disorders
| Genetic condition | Mechanisms/pathophysiology that may be considered |
|---|---|
| Mitochondrial dysfunction | |
| HSD10 (HSD17B10) | HSD17B10 encodes an enzyme that is essential for mitochondrial maintenance. 48 Pathogenic variants may affect enzyme function and result in mitochondrial dysfunction. |
| Leigh syndrome (MT‐ATP6 and MT‐MFT) | Leigh syndrome is caused by over 50 different mitochondrial and nuclear encoded genes, most often affecting the respiratory chain and oxidative phosphorylation. 49 Mitochondrial dysfunction may result in brain stem and basal ganglia lesions. |
| Leigh‐like syndrome (MT‐TI) | MT‐TI is a mitochondrial gene of which pathogenic variants may result in mitochondrial dysfunction and basal ganglia lesions, similar to what has been proposed for Leigh syndrome. |
| MT‐CYB | MT‐CYB is a mitochondrial gene that encodes for a component of the respiratory chain. Pathogenic variants may result in mitochondrial dysfunction and progressive basal ganglia lesions, as has been proposed for Leigh syndrome. |
| POLG | POLG encodes a DNA polymerase that is essential for replication of mitochondrial DNA. Mice that were homozygous for variants that may disrupt the function of POLG protein exhibited premature aging. 50 , 51 |
| WARS2 | Pathogenic variants in WARS2, which encodes for the WARS2 protein located in the mitochondrion, may result in respiratory chain defects and nigrostriatal degeneration. 52 |
| Mitochondrial dysfunction combined with other mechanisms | |
| 22q11.2 deletion syndrome | The 22q11.2 deletion region encompasses several genes including COMT, essential for catecholamine degradation, and six mitochondrial genes. 53 , 54 , 55 Haploinsufficiency of these genes may result in dopamine autotoxicity and mitochondrial dysfunction. 56 |
| Down syndrome | Mitochondrial dysfunction, neuroinflammation, oxidative stress, and lysosomal dysfunction have all been reported in Down syndrome. 57 , 58 , 59 |
| Early infantile epileptic encephalopathy 4 (STXBP1) | Pathogenic variants in STXBP1 may cause significant impairment of complex I of the mitochondrial respiratory chain and may disrupt the self‐replicating aggregation of α‐synuclein. 60 |
| Glutaric aciduria type I (GCDH) | GCDH plays a key role in the catabolism of lysine, hydroxylysine, and tryptophan. Deficiency of GCDH leads to accumulation of glutaric acid and 3‐hydroxyglutaric acid that can induce neuronal death through excitotoxicity as well as mitochondrial dysfunction and altered neurotransmission. 61 |
| Mevalonic aciduria (MVK) | Pathogenic variants in MVK may result in mitochondrial dysfunction, impaired cholesterol biosynthesis, toxic basal ganglia mevalonate accumulation, and intracerebral inflammation. 62 , 63 |
| NR4A2 | Pathogenic variants in NR4A2 are implicated in development and survival of dopaminergic neurons in the substantia nigra, and may lower expression of genes associated with mitochondrial function and oxidative phosphorylation. 44 |
| Pyruvate carboxylase deficiency (PC) | PC encodes for pyruvate carboxylase, a mitochondrial enzyme that catalyzes pyruvate to oxaloacetate, intermediates in the Krebbs cycle and is important for neurotransmitter synthesis. 64 |
| SPG10 (KIF5A) | Axonal transport defect of mitochondria has been shown in a KIF5A knockout mouse model. 65 |
| Autophagic‐lysosomal system | |
| Alexander disease (GFAP) | GFAP encodes for glial fibrillary acidic protein (GFAP), an intermediate filament protein in astrocytes. GFAP accumulation has been associated with autophagy in astrocytic cells. 66 |
| BPAN (WDR45) | Pathogenic variants of WDR45, encoding for WIPI4 protein, may cause iron accumulation in the basal ganglia by impeding autophagy, 67 that may result in neuroinflammation and swelling of the substantia nigra. |
| Christianson syndrome (SLC9A6) | SLC9A6 encodes the endosomal Na+/H+ exchanger 6 and is involved in endosomal luminal pH and trafficking, synapse development, and plasticity. 68 Findings in Slc9a6 knock‐out mice were consistent with endosomal‐lysosomal dysfunction. 69 |
| DOORS syndrome (ATP6V1B2) | ATP6V1B2 encodes a subunit of the lysosomal transmembrane proton pump. Altered lysosomal pH is associated with chronic changes in autophagy. 70 |
| JNCL (CLN3) | CLN3 is involved in autophagic‐lysosomal function. CLN3 is required for fusion of autophagosomes to lysosomes. 71 |
| Mucolipidosis type II (GNPTAB) | Pathogenic variants in GNPTAB, that encodes for GlcNAc‐1‐phosphotransferase, may cause lysosomal accumulation of nondegraded material, leading to neuronal dysfunction. 72 |
| NUS1 | Deficiency of NUS1, encoding the Nogo B receptor, may result in lysosomal defects, most likely caused by lysosomal cholesterol accumulation. 73 |
| RAB39B | Ras‐related proteins play an essential role in neuronal maintenance, survival and synapse formation. It has been suggested that RAB39B plays a role in autophagy of dopaminergic neurons. Loss of function may impair the clearance of α‐synuclein. 74 , 75 |
| SPG15 (ZFYVE26) | Pathogenic variants of ZFYVE26 encoding spastizin, a protein mediating autophagic lysosome reformation, are believed to cause abnormal lysosomal storage. 76 |
| SPG11 (SPG11) | Pathogenic variants of SPG11 encoding spatacsin, a protein mediating autophagic lysosome reformation may cause abnormal lysosomal storage. 77 |
| Tay‐Sachs disease (HEXA) | HEXA encodes for β‐hexosaminidase A, a lysosomal enzyme that degrades GM2 ganglioside. Deficiency of this enzyme A has been associated with GM2 ganglioside accumulation nerve cells. 78 |
| X‐linked parkinsonism with spasticity (ATP6AP2) | ATP6AP2 encodes an accessory unit of an essential lysosomal enzyme. Haploinsufficiency of ATP6AP2 may lead to autophagy defects, disrupted presynaptic transmission, and neurodegeneration. 79 |
| Disorders of neurotransmitter metabolism | |
| 6p25 deletion, involving FOXC1 | Pathogenic variants in FOXC1 may affect genes involved in dopamine synthesis and dopaminergic neuronal development. 80 , 81 |
| Dihydropteridine reductase deficiency (QDPR) | Deficiency of dihydropteridine reductase, that is required for resynthesis of tetrahydrobiopterin, an essential cofactor for the activity of phenylalanine‐, tryptophan, and tyrosine hydroxylases, may impair neurotransmitter synthesis. 82 |
| DNAJC12 | DNAJC12 has a critical role in chaperoning amino‐acid hydrolase interactions required for catecholamine synthesis. 83 |
| Dopamine transporter deficiency syndrome (SLC6A3) | SLC6A3 encodes for the dopamine transporter (DAT). DAT deficiency syndrome may lead to impaired DAT activity, apoptotic neurodegeneration, and dopamine toxicity. 84 |
| Dravet syndrome (SCN1A) | SCN1A, that encodes a voltage‐gated sodium channel, may lead to impaired neurotransmitter release. 85 |
| GTP cyclohydrolase 1 deficiency, dopa‐responsive dystonia (GCH1) | GTP cyclohydrolase 1 is important for the biosynthesis of tetrahydrobiopterin, an essential cofactor for the activity of phenylalanine, tryptophan, and tyrosine hydroxylases. Deficiency of this enzyme may disrupt neurotransmitter synthesis. 86 |
| Neurofibromatosis type I (NF1) | NF1, a tumor suppressor gene, encodes for neurofibromin. Among other genes, it is involved in the activation of GTPase, mTOR signaling, learning (via impaired long‐term potentiation), and regulation of dopamine homeostasis. 87 |
| Phenylketonuria (PAH) | PAH encodes for phenylalanine hydroxylase. Deficiency results in a decreased conversion of phenylalanine to tyrosine. Phenylalanine inhibits dopamine and serotonin synthesis in the brain by inhibition of tyrosine and tryptophan transport, and inhibition of tyrosine and tryptophan hydroxylases. 88 , 89 |
| PPP2R5D | PPP2R5D encodes a regulatory subunit of protein phosphatase‐2A (PP2A), an intracellular serine/threonine phosphatase. PP2A regulates phosphorylation of one site (S129) of α‐synuclein. Increased activity of PP2A influences tyrosine hydroxylase and subsequently may affect dopamine synthesis. 90 , 91 |
| Sepiapterin reductase deficiency (SR) | Deficiency of sepiapterin reductase, essential for tetrahydrobiopterin biosynthesis, may result in disturbed dopaminergic and serotonergic neurotransmission. 92 |
| Tyrosine hydroxylase deficiency, dopa‐responsive dystonia (TH) | Deficiency of tyrosine hydroxylase, the rate‐limiting step in dopamine biosynthesis, may lead to a shortage of dopamine. 93 |
| Endosomal trafficking | |
| CLTC | A defective clathrin heavy chain polypeptide protein, caused by pathogenic variants of CLTC, may result in depletion of biogenic amines by altering their synaptic turnover. 94 |
| DNAJC6 | DNAJC6 encodes for auxilin, a neuronally expressed J‐chaperone protein involved in the uncoating of clathrin‐coated vesicles, which is necessary for the regeneration of synaptic vesicles. Impaired uncoating is thought to lead to neurotransmission deficits. 95 |
| SYNJ1 | SYNJ1 encodes a phosphoinositide phosphatase called synaptojanin1 and plays an important role in early endosomal compartments and clathrin‐mediated endocytosis. 96 |
| Ubiquitin‐proteasome system | |
| Angelman syndrome, involving UBE3A | UBE3A encodes the ubiquitin‐protein ligase E3A, part of the ubiquitin‐proteolytic pathway, 97 that has been suggested to be involved in the clearance of alpha‐synuclein. 98 |
| Partial 6q trisomy, involving PRKN | Pathogenic variants of PRKN are associated with early‐onset autosomal recessive Parkinson's disease. 99 PRKN encodes the E3 ubiquitin‐protein ligase Parkin, involved in mitophagy, and possibly in the formation of Lewy bodies. 100 |
| PTRHD1 | 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. 101 α‐Synuclein homeostasis is maintained by proper function of the ubiquitin‐proteasome system. |
| Other | |
| Cerebrotendinous xanthomatosis (CYP27A) | Accumulation of cholesterol and cholestanol cause neurotoxicity and axonopathy. 102 |
| Incontinentia pigmenti (IKBKG) | It has been suggested that pathogenic variants in IKBKG, involved in neuronal anti‐apoptotic signaling, may cause neurodegeneration. 103 |
| Klinefelter 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. 104 , 105 |
| L2‐hydroxyglutaric aciduria (L2HGDH) | L2HGDH encodes for l‐2‐hydroxyglutarate (L2HG) dehydrogenase that oxidizes L‐2‐hydroxyglutarate to α‐ketoglutarate. L2HG deficiency may result in impaired hippocampal neurogenesis and neurodegeneration in adult mouse brains. 106 |
| Menkes disease (ATP7A) | Haploinsufficiency of ATP7A, encoding a transmembrane copper‐transporting ATPase, may result in dysregulation of copper metabolism in the basal ganglia. 107 , 108 |
| Molybdenum 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. 109 Elevated concentrations of S‐sulfocysteine and toxic sulfite may trigger neuronal apoptosis. 110 |
| Partial 4q trisomy, involving SNCA | SNCA encodes α‐synuclein, the primary component of Lewy bodies. The patient with partial 4q trisomy had a de novo SNCA duplication. Other genes in the duplicated region may have contributed to the phenotype. 111 |
| Phosphoglycerate 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. 112 |
| SCA27 (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. 113 |
| Smith‐Magenis syndrome (RAI1) | Pathogenic variants of RAI1 may result in an inversion of circadian melatonin secretion with a lack of nocturnal melatonin, which may play a role in the development of parkinsonism. 104 , 105 , 114 |