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Chapter 240SPG11 (SPG11) Pathogenic variants of SPG11 encoding spatacsin, a protein mediating autophagic lysosome reformation may cause abnormal lysosomal storage.44Tay-Sachs disease (HEXA)HEXA encodes for β-hexosaminidase A, a lysosomal enzyme thatdegrades GM2 ganglioside. Deficiency of this enzyme A has been associated with GM2 ganglioside accumulation nerve cells.45X-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.46Neurotransmitter metabolism6p25 deletion, involving FOXC1 Pathogenic variants in FOXC1 may affect genes involved in dopamine synthesis and dopaminergic neuronal development.47, 48Dihydropteridine reductase deficiency (QDPR)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.49DNAJC12 DNAJC12 has a critical role in chaperoning amino-acid hydrolase interactions required for catecholamine synthesis.50Dopamine 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.51Dravet syndrome (SCN1A)SCN1A, that encodes a voltage-gated sodium channel, may lead to impaired neurotransmitter release.52GTP cyclohydrolase 1 deficiency, doparesponsive dystonia (GCH1)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.53Neurofibromatosis 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.54Phenylketonuria (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.55, 56PPP2R5D 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 activityof PP2A influences tyrosine hydroxylase and subsequently may affect dopamine synthesis.57, 58Sepiapterin reductase deficiency (SR)Deficiency of sepiapterin reductase, essential for tetrahydrobiopterin biosynthesis, may result in disturbed dopaminergic and serotonergic neurotransmission.59Tyrosine hydroxylase deficiency, doparesponsive dystonia (TH)Deficiency of tyrosine hydroxylase, the rate-limiting step in dopamine biosynthesis, may lead to a shortage of dopamine.60Endosomal traffickingCLTC 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