Page 43 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

DNAJC6 SYNJ1 Angelman syndrome,
involving UBE3A
Partial 6q trisomy,
involving PRKN PTRHD1 Cerebrotendinous
xanthomatosis
(CYP27A)
Incontinentia
pigmenti (IKBKG) Klinefelter syndrome L2-hydroxyglutaric
aciduria (L2HGDH)
Menkes disease
(ATP7A) Molybdenum
cofactor deficiency
type B (MOCS2)
Partial 4q trisomy,
involving SNCA
Phosphoglycerate
kinase deficiency I
(PGK1)
SCA27 (FGF14) Smith-Magenis
syndrome (RAI1) Parkinsonism in GNDs
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.62
SYNJ1 encodes a phosphoinositide phosphatase called synaptojanin1
and plays an important role in early endosomal compartments and
clathrin-mediated endocytosis.63
Ubiquitin-proteasome system
2
UBE3A encodes the Ubiquitin-Protein Ligase E3A, part of the ubiquitin-
proteolytic pathway,64 that has been suggested to be involved in the
clearance of alpha-synuclein.65
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.67
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 Alfa-
synuclein homeostasis is maintained by proper function of the ubiquitin-
proteasome system.
Other
Accumulation of cholesterol and cholestanol cause neurotoxicity and
axonopathy.69
It has been suggested that pathogenic variants in IKBKG, involved in
neuronal anti-apoptotic signaling, may cause neurodegeneration.70
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, 72
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.73
Haploinsufficiency of ATP7A, encoding a transmembrane copper-
transporting ATPase, may result in dysregulation of copper metabolism
in the basal ganglia.74, 75
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.77
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.78
Phosphoglycerate kinase is an important enzyme in the glycolytic
pathway. It has been suggested that neuronal damage occurs as a
consequence of energy failure.79
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.80
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
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