Page 42 - Characterization of genetic neurodevelopmental disorders at adult age, with a focus on 22q11.2 deletion syndrome - Emma Boersma

Chapter 2
SPG11 (SPG11) Tay-Sachs disease
(HEXA)
X-linked parkinsonism
with spasticity
(ATP6AP2)
6p25 deletion,
involving FOXC1 Dihydropteridine
reductase deficiency
(QDPR)
DNAJC12 Dopamine
transporter deficiency
syndrome (SLC6A3)
Dravet syndrome
(SCN1A)
GTP cyclohydrolase
1 deficiency, dopa-
responsive dystonia
(GCH1)
Neurofibromatosis
type I (NF1) Phenylketonuria
(PAH)
PPP2R5D Sepiapterin reductase
deficiency (SR)
Tyrosine hydroxylase
deficiency, dopa-
responsive dystonia
(TH)
CLTC 40
Pathogenic variants of SPG11 encoding spatacsin, a protein mediating
autophagic lysosome reformation may cause abnormal lysosomal
storage.44
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.45
ATP6AP2 encodes an accessory unit of an essential lysosomal enzyme.
Haploinsufficiency of ATP6AP2 may lead to autophagy defects, disrupted
presynaptic transmission and neurodegeneration.46
Neurotransmitter metabolism
Pathogenic variants in FOXC1 may affect genes involved in dopamine
synthesis and dopaminergic neuronal development.47, 48
Deficiency of dihydropteridine reductase, that is required for resynthesis
of tetrahydrobiopterin, an essential cofactor for the activity of
phenylalanine-, tryptophane- and tyrosine hydroxylases, may impair
neurotransmitter synthesis.49
DNAJC12 has a critical role in chaperoning amino-acid hydrolase
interactions required for catecholamine synthesis.50
SLC6A3 encodes for the dopamine transporter (DAT). DAT deficiency
syndrome may lead to impaired DAT activity, apoptotic neurodegeneration
and dopamine toxicity.51
SCN1A, that encodes a voltage-gated sodium channel, may lead to
impaired neurotransmitter release.52
GTP cyclohydrolase 1 is important for the biosynthesis of
tetrahydrobiopterin, an essential cofactor for the activity of phenylalanine-,
tryptophane and tyrosine hydroxylases. Deficiency of this enzyme may
disrupt neurotransmitter synthesis.53
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.54
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.55, 56
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.57, 58
Deficiency of sepiapterin reductase, essential for tetrahydrobiopterin
biosynthesis, may result in disturbed dopaminergic and serotonergic
neurotransmission.59
Deficiency of tyrosine hydroxylase, the rate-limiting step in dopamine
biosynthesis, may lead to a shortage of dopamine.60
Endosomal trafficking
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.61