TABLE 1.

Main neurodevelopmental disorders where mutations in autophagy proteins impacts disease.

Disease	Gene	Role in autophagy pathway	Main phenotype	References
Tuberous Sclerosis Complex	TSC1/2 complex	mTOR Inhibitor	Non malignant tumours, epilepsy, autism	[95, 96]
Fragile X Syndrome	Fmr1	mTOR Inhibitor	Intellectual disability, autism, seizures, hypersensitivity, attention deficit, hyperactivity, growth and craniofacial abnormalitites	[97, 98]
Neurofibromatosis	NF1	mTOR Inhibitor	Café'au lait spots, bening and malignant tumours, epilepsy (10%), autism	[91, 99]
Lhermitte-Duclos Disease	PTEN	mTOR Inhibitor	Gangliocytomas in cerebellum, ataxia, seizures, autism (with macrocephaly)	[100]
TBCK Encephaloneuropathy	TBCK	mTOR activator	Intellectual disability, coarse face, hypotonia, leukoencephalopathy, neuronopathy, seizures	[169]
BPAN	WDR45 (WIPI4)	Autophagosome formation and elongation Autophagosome-lysosome fusion	Iron accumulation in basal ganglia 1st phase (neurodevelopmental): global developmental delag, intellectual disability, psychomotor retardation, febrile seizures, autistic features 2nd phase (neurodegenerative): cognitive decline, dementia, dystonia, parkinsonism, optic nerve atrophy	[122,125, 127]
Intellectual disability associated to WIPI3	WDR45b (WIPI3)	Autophagosome formation and elongation Autophagosome-lysosome fusion	Intellectual disability	[123]
Vici Syndrome	EPG5	Autophagosome-lysosome fusion	Corpus Callosum agenesis, cataracts, cardiomyopathy, immunodeficiency, hypopigmentation, muscle and neurogenic anomalies, epilepsy, microcephaly and loss of learned skills	[122, 154–156]
Spastic Paraplegia 11	ZFVE26 (coding for spatacsin)	Lysosome Biogenesis	Spasticity, pyramidal weakness, corpus callosum affection, ataxia (less common)	[136,138, 139]
Spastic Paraplegia 15	KIAA1840 (coding for spastizin)	Autophagosome maturation Lysosome Biogenesis	Spasticity, pyramidal weakness, corpus callosum affection, ataxia (less common)	[136, 138, 139]
Spastic Paraplegia 49	TECPR2	Autofagosome formation (functional endoplasmic exit sites) Autophagosome-lysosome fusion	Spasticity, pyramidal weakness, corpus callosum affection	[147]
SNX14-associated autosomal recessive cerebellar ataxia	SNX14	Autophagosome-lysosome fusion	Poor coordination (ataxia), cerebellum atrophy and Purkinje cell loss, mental retardation, seizures	[122, 166, 167]
Ataxia related to Atg5	Atg5	Autophagosome elongation	Ataxia, mental Retardation, development delay	[170, 174]