TABLE I. Small molecule defects and vitamin-related disorders: neurodevelopmental phenotypes, brain MRI, and clinical outcome.

GROUP OF DISEASES OR MOLECULES	ANTENATAL BRAIN ABNORMALITIES Structural defects, abnormal head growth	POSTNATAL BRAIN ABNORMALITIES at anytime of the postnatal development	MAIN NEUROLOGICAL SYMPTOMS Mimicking what kind of neurodevelopmental disorder?	OUTCOME Early death? Stability - Improvement? Neurodegeneration?	REF
Small molecules:ACCUMULATION	In general no antenatal manifestations	In general normal or subtle abnormalities (except decompensations)	Free interval. Most are efficiently treatable and can be screened at birth	In general, with treatment, constant improvement	1, 29
AMINOACID CATABOLISM. Diagnosis on AA chromatography. Postnatal neurodevelopmental disruption. Abnormal synaptic signaling, excitotocity (and other specific mechanisms), connectivity alterations, mostly circuitries involved in executive functions. Under treatment, in general mimicking ADHD and learning disabilities
Phenylalanine PKU	Not described Maternal PKU: congenital microcephaly, ventriculomegaly, hypoplastic cerebral white matter, and delay of myelination	White matter T2 reversible hyperintensities	- Untreated: profound ID. Neuropsychiatric and behavioral AUTISM-like manifestations - Even under strict diet may still present ADHD, NPSY (anxiety, depression) Learning disabilities	Stability. NDEV disorder Outcome in long-term treated patients at older ages not reported. Diet discontinuation may produce NDEG in adults/elderly patients	1
Homocysteine Homocystinurias	Not described in CBS Remethylation defects may present as congenital hydro-cephalus	- Reversible WM lesions in CBS - Hemorrhagic/ischemic stroke	- Untreated: ID, NPSY, stroke - Even on strict treatment: ADHD, NPSY (obsessions, depression), Learning disabilities	Stability. NDEV disorder although unknown evolution in elderly patients	1
Leucine MSUD	Not described	WM T2 reversible hyperintensities	- Untreated: ID, spasticity - Even under strict treatment: ADHD, NPSY, Learning disabilities	Stability. NDEV disorder although unknown evolution in elderly patients	1
Ammonia, Glutamate, Glutamine (in UCD)	Not described	WM T2 reversible hyperintensities	- Even under strict treatment: ADHD, NPSY, Learning disabilities - Cerebral palsy-like in arginase deficiency and HHH	Stability. NDEV disorder although unknown evolution in elderly patients	1
ORGANIC ACIDURIAS (OA): Diagnosis on OA/Acylcarnitines (GCMS) Postnatal neurodevelopmental disruption. Neurobiological mechanisms similar to AA accumulation but associated with energy depletion. Classic OA under treatment mimic ADHD and learning disabilities whereas “cerebral” OA mimic cerebral palsy (CP) and some of them produce NDEG.
Propionic, Methylmalonic, Isovaleric acidurias	Not described	WM T2 and basal ganglia hyperintensities that may be reversible	- Untreated: ID, Cerebral palsy-like (spasticity, movement disorders)- Even under strict treatment: ADHD, NPSY, Learning disabilities, Optic atrophy	Stability. NDEV disorder although unknown evolution in elderly patients	1
Cerebral organic acidurias (COA):Glutaric type 1	Immature gyration pattern Bitemporal (biopercular) hypoplasia	Macrocephaly Subdural hematoma Basal ganglia lesions WM hyperintensities	- Acute encephalopathy (first 2 years of life), BG lesions. Dyskinetic CP - Mild forms: motor delay versus normality - Tremor, orofacial dyskinesia in adolescence in previously asymptomatic patients	- After acute BG injury, very similar to dyskinetic CP of other causes (stability but episodes of exacerbation that may lead to status dystonicus) - Unknown in older patients	1
Other COA: L2 OH glutaric; D2 OH glutaric; DL OH glutaric aciduria* Canavan disease (N-AAA)	L2OH glutaric: cerebellar hypoplasia N-AAA: Soft, gelatinous WM Loss of myelinated arcuated fibres	Characteristic white matter and cerebellar involvement, cortical atrophy	L2OH: Progressive cognitive deterioration in infancy with ataxia, seizures, pyramidal signs. Mild forms may mimic ID D2OH: Severe neonatal encephalopathy (seizures, early death) N-AAA: macrocephaly, early regression, progressive spasticity, optic atrophy, death	All these diseases evolve towards NDEG, with different degrees of severity and natural history	1
SMALL CARBOHYDRATE MOLECULE ACCUMULATION: diagnosis on plasma and urine biomarkers
Galactosemias (Galactose, Galactose-1-P Galactitol)	Not reported	White matter T2 reversible hyperintensities	Even on strict diet delayed speech development, verbal dyspraxia, difficulties in spatial orientation and visual per-ception, ID, anxiety, depression. Mimics ID and learning difficulties	Stability. NDEV disorder although unknown evolution in elderly patients	1
METAL ACCUMULATION: Diagnosis on specific metals, protein carriers, brain MRI features, molecular analysis. Postnatal developmental disruption, mainly motor signs mimicking CP but later on progressive neurodegeneration
Copper ATP7B transporter	Not described	“Eye of the panda” sign (lenfiform nuclei, thalamus, midbrain and pons). Atrophy of cerebral and cerebellar cortex	Wilson disease: bulbar dysfunction, tremor, rigidity, behavioral, and mood disturbances in 1st decade	NDEG without treatment	30
Iron: NBIA (PKAN, CoASY, PLA2G6, C19oef12, FAH2, WDR45, ATP13A2, FTL, DCAF17, SCP2, GTPBP2)	Not described (every defect has different pathophysiological mechanisms; brain iron accumulation is probably a paraphenomenon)	T2 pallidum hypointensity, leading to the “eye of the tiger” sign. WM alterations may be also present. Cortical and cerebellum atrophy	More than 10 genetic recognized conditions so far included in the NBIA syndromes. Some of them mimic NDEV disorders:- INAD due to PLA2G6 and early forms of PKAN mimic CP- BPAN mimic Retts	NDEG is the natural evolution. No effective treatments so far	30
Manganese SLC30A10 and SLC30A14 transporters	Not described	Hyperintense T1, hypointense T2 signals on basal ganglia	Early dystonia-parkinsonism mimicking dystonic CP; hepatic dysfunction is associated	NDEG is the natural evolution. But may improve on chelation treatment	30
Small molecules: DEFICIENCIES	Frequent antenatal manifestations, in particular congenital microcephaly	Wide variety of findings, from normal to severe alterations	Most have congenital or very early manifestations, mimicking CP or ID with NPSY signs. Late-onset presentations may occur	Many of them have a treatment with a variable response depending on the particular defect	1, 29, 32
AMINO ACID DEFECTS: Diagnosis on AAC (B, U, CSF), molecular analysis. Prenatal disruption of crucial neurodevelopmental programs. While BCAA deficiencies produce ID, ASD and the clinical spectrum of the synaptopathies, the other AA defects may cause severe antenatal malformations
Large neutral AA transporter (SLC7A5) and BCDHK Low BCAA	Congenital microcephaly may be present with no other alterations in the brain MRI	Hypomyelination	Mimicking NDEV disorders, in particular ID with NPSY signs, mostly autism spectrum disorder (ASD)	NDEV disorder: Stability towards improvement with treatment (BCAA supplementation)	33, 35
Glutamine synthetase Low P glutamine	Complete agyria, hypomyelination, periventricular cysts, Cerebral atrophy	The same abnormalities found at early stages	Severe encephalopathy. Severe epilepsy	Early death. Severe disease involving crucial biological processes and probably incompatible with life	37
Serine defects 3-PGDH(**) PSAT1, PSP Serine (SL-C1A4) transporter Low P serine	Lissencephaly, microcephaly in Neu Laxova syndrome (congenital form) HM. Hypoplasic cerebellum CC Absent vs hypoplasia	Mild forms may display microcephaly and hypomyelination	- Severe encephalopathy: microcephaly, spastic tetraparesis, cataracts, epilepsy. Mimicking congenital infections - Mild forms: ID and epilepsy	NDEV disorder: stability towards improvement with L-serine supplementation	36
Asparagine synthetase Low to Nl P asparagine	Simplified gyri Decreased cerebral volume, congenital microcephaly	The same abnormalities found at early stages	Profound developmental delay, early-onset intractable seizures, axial hypotonia with severe appendicular spasticity	Early death. Severe disease involving crucial biological processes and probably incompatible with life	38
NEUROTRANSMITTER DEFECTS: Monoamines and amino acids that behave as neurotransmitters MONOAMINES: Diagnosis mostly on CSF pterins and NT metabolites. Some BH4 deficiencies and DNAJC12 have high plasma phe levels. Low brain dopamine disrupt neurodevelopmental programs probably at early prenatal stages, symptoms may appear at diverse ages and mimic CP AMINO ACIDS that behave as neurotransmitters: Diagnosis based on P, U, CSF analysis. Molecular analysis. Probably prenatal disruption of neurodevelopmental programs although brain malformations are not common. They present with the clinical spectrum of the synaptopathies and some particular defects as severe global encephalopathies.
Monoamine synthesis defects: (TH, AADC, DNA-JC12, BH4 deficiencies: GTPCH, SR, DHPR, PTPS)	No antenatal malformations described. In severe forms congenital microcephaly can be present	In general normal brain MRI although mild nonspecific findings have been found in some cases. BG calcifications can appear in DHPR	- Very severe forms may cause congenital microcephaly and may be incompatible with life - Early encephalopathies with hypokinetic-rigid and dystonia mimicking CP - Parkinsonism, - L-Dopa responsive dystonia	NDEV disorder: Stability towards improvement with treatment (L-Dopa, 50HT and related molecules)	44
Monoamine transport defects: DAT, VMAT2	Not described	In general normal brain MRI	- DAT may present as a severe dyskinetic CP that evolves towards parkinsonism - VMAT2 presents as dystoniaparkinsonism	DAT may have a NDEG progression. VMAT2 has a similar outcome and treatment than biogenic amine defects	44
GABA defects SSADH (High P/CSF GABA) GABAT (Low CSF GABA)	Spongiform leukodystrophy in GABAT	Pallidum hyperintensity, WM lesions, cerebellar atrophy in SSADH	- SSADH may present as ID and NPSY signs (ASD and others), epilepsy and ataxia - GABAT Early mortality and profound developmental impairment	SSADH: Stability although progression of epilepsy has been reported in adults Outcome in patients at older ages not reported	44
Glycine NKH: GCS and lipoate disorders High P/CSF Glycine	Cerebellar hypoplasia Cysts CC absent vs hypoplasia Diffusion restriction pattern in the brain stem (these diseases are also related to AA accumulation defects)	WM lesions in particular in lipoate related hyperglycinemias	- Severe neonatal encephalopathy, epilepsy, hypotonia, spasticity, profound mental retardation - Mild forms: Moderate ID, NPSY signs (ADHD, behavioral problems), seizures, chorea episodes	Early death in the severe forms Stability in mild forms although no long-term outcomes have been reported	1
GABA, glutamate and glycine receptors and transporters	Congenital polymicrogyria has been described in glutamatergic NMDA receptors. In G I uta mate transporter (SLC25A22): abnormal gyration. CC hypoplasia and congenital microcephaly	No specific patterns have been reported	Diverse signs in the spectrum of the synaptopathies: epilepsy, ID, NPSY problems Glycine receptors and transporters: hyperekplexia Glutamate transporter: severe congenital encephalopathy, epilepsy, severe psychomotor delay	Severe mutations in the glutamate receptors lead to early death Stability versus improvement with clonazepam in some forms of hyperekplexia	1, 44
AGC1 (SLC25A12) Low CSF NAA, high lactate	Global hypomyelination (this disease is also an energy defect)	BG hyperintensity, delayed myelination, reduced NAA in brain MRS, cerebellar atrophy	Arrested psychomotor development, hypotonia, infantile onset epilepsy	Severe encephalopathy. Long-term outcome not reported	1, 44
METAL DEFICIENCIES: Diagnosis on specific metals and protein disruption since they present with severe early encephalopath
Copper (low serum copper and ceruleoplasmin ATP7A)	Brain vascular tortuosities	Cephalhematomas, vascular tortuosity	Menkes disease is a severe early encephalopathy. Seizures, hypotonia, loss of developmental milestones Mild forms (occipital horn syndrome) may present with mild to moderate ID	Menkes disease is a NDEG disorder	30
AP1S1 (Low serum cerulopasmin and copper)	Not reported (MEDNIK syndrome is also a trafficking disorder)	Mild T2 hyperintensity of caudate and putamen, brain atrophy	Multisystem disease. Dysmorphic features, Ichthyosis, ID, deafness, peripheral neuropathy, hepatopathy	Liver copper overload treatable by zinc acetate therapy This disease may be progressive, but there are no outcome reports	43
Manganese (Low blood Mn and Zn) SLC39A8	Cerebellar atrophy	Severe atrophy of cerebellar vermis and hemispheres	Severe encephalopathy, hypotonia, seizures, strabismus, profound ID	Stability, mild NDEV achievements Progressive cerebellar signs reported in one family (NDEG?)	41, 42
BRAIN ENERGY MOLECULE TRANSPORTER DEFECTS: Diagnosis on B and CSF glucose/lactate/KB. RBC glucose and lactate uptake. Due to the energy characteristics of the prenatal brain and the newborn, these diseases should produce post-natal neurodevel-opmental disruptions. They mimic CP and ID
GLUT 1 deficiency (low CSF glucose)	Not reported	Normal brain MRI. Severe forms may have microcephaly	- Early infantile severe epilepsy - Motor dysfunction that may be diverse and combined: cerebellar ataxia/dyspraxia, pyramidal signs, dyskinesias, mimicking CP - ID may be associated	Improvement with ketogenic diet and other anaplerotic treatments (such as triheptanoin)	62
Monocarboxylicacid transporter (lactate, pyruvate, ketone bodies) SLC16A1	Not reported		Recurrent attacks of ketoacidosis. Moderate ID in homozygous forms	Stability of ID although no long-term outcomes reported	63
FATTY ACID TRANSPORTER and SYNTHESIS DEFECTS: Diagnosis on FFA profile, lipidomics, molecular investigations
DHA transporter: MFSD2A High plasma LPC (Low brain DHA?)	Cortical malformation, gross hydrocephaly, hugely dilated lateral ventricles cerebellar/brain stem hypoplasia/atrophy	The same antenatal manifestations, microcephaly	Severe encephalopathy: developmental delay, hypotonia, hyperreflexia, spastic quadriparesis, seizures	Lethal microcephaly syndrome	34
FA elongation: ELOVL4 (NL serum FA)	Not reported	Cerebellar atrophy	Severe encephalopathy: Ichthyosis, seizures, ID, spasticity resembling Sjogren Larsson (mimicking CP) Spinocerebellar ataxia. Retinopathy	NDEG disease Neonatal death reported in a mouse model	40, 49
Fatty aldehyde dehydrogenase (FALDH)	Not reported	Not reported	Sjogren Larsson syndrome: Congenital pruritic ichthyosis with bilateral spastic paraparesis, dysarthria, mild ID Mimic CP	Not enough information about outcome	49
ELOVL5 Low serum C20-4, C22-6	Not reported	Cerebellar atrophy	Spinocerebellar ataxia	NDEG disease	49
VITAMIN/COFACTOR DEFECTS: Diagnosis on AAC, OAC, folates, B12, molecular investigations1
Biotin Biotinidase	Not reported	WM and BG abnormalities have been described	Biotin responsive MCD deficiency Seizures, developmental delay. Hearing loss. Crisis. Optic atrophy	Early treatment with biotin is very efficient. Stability towards improvement.	1
B12 Cobalamin C	Congenital hydrocephalus Hypomyelination and ventriculomegaly in HCFC1	Similar to antenatal	Progressive neurological deterioration crisis, abnormal movements, seizures, microcephaly	HCFC1 may cause early death Other causes: Stability towards improvement	1
Folic acid (FOLR) MTHFR	Not reported	Hypomyelination, cerebellar atrophy, microcephaly, enlarged ventricles	Progressive encephalopathy, seizures, microcephaly, psychiatric disorders	If treated, stability towards improvement	1
B6 (pyridoxine) Antiquitin PNPO	May have hypoxicencephalopathy like features. Thin CC	Subtle, nonspecific findings	Neonatal pyridoxine-dependent epilepsy Some cases with encephalopathy PLP dependent epilepsy	Stability towards improvement PNPO has been related to early death	1
Mitochondrial TPP transporter (SLC25A19) Thiamine transporter (SLC19A3)	SLC25A19: Extreme microcephaly lissencephaly, dysgenesis of the corpus callosum, spinal dysraphic state	SLC19A3: Basal ganglia necrosis	SLC25A19: Amish lethal microcephaly: extreme microcephaly SLC19A3: Recurrent BG involvement, thiamine-responsive	SLC25A19: Early death. One case of long-term survival with profound ID and microcephaly has been reported SLC19A3: may be fully reversible with thiamine (improvement)	1
TPP kinase	Not reported	Increased signal intensities in the corticospinal tract at the medulla oblongata, and increased intensities in the dorsal pons. BG necrosis	Psychomotor retardation, severe encephalopathy, dystonia, ataxia	Stability after symptom onset although not enough information about outcome has been reported	1
AA: amino acids; AAC: aminoacid chromatography; ADHD; attention deficient hyperactivity disorder; AGC1: aspartate glutamate mitochondrial carrier; AADC: aromatic amino acid decarboxylase; AD: autosomal dominant; AR: autosomal recessive; ASD: autism spectrum disorder; BCDHK: branched chain dehydrogenase kinase; BG: basal ganglia; BPAN: β propeller associated neurodegeneration; CC: corpus callosum; CoASY: coenzyme A synthetase; COA: cerebral organic acidurias; CP: cerebral palsy; CSF: cerebrospinal fluid; DAT: dopamine transporter; DHA: docosahexanoic acid; DHPR: dihydropterine reductase; D-P: dystonia parkinsonism; DNAJC12: chaperone associated with complex assembly, protein folding, and export; DRD: dopa responsive dystonia; ELOV: fatty acid elongase; FA: fatty acid; FOLR: folate receptor, mutations leading to brain folate depletion; GABA: γ-aminobutyric acid; GABAT: GABA transaminase; GCMS: Gas chromatography mass spectrometry; GCS: glycine cleavage system; GTPCH: guanosine triphosphate cyclohydroxilase; HCFO: gene responsible for X-linked cobalamin deficiency; HM: hypomyelination; HVA: homovanillic acid; ID: intellectual disability; INAD: infantile neuroaxonal dystrophy; KB: ketone bodies; LPC: lysophosphatidylcholine; MCD: multiple carboxylase; MHBD:2-methyl-3-Hydroxybutyryl-CoA dehydrogenase; MHPG: 3-Methoxy-4-hydroxyphenylglycol; MSUD: maple syrup urine disease; MTHFR: methylene tetrahydrofolate reductase; NAA:N-acetyl aspartate; NBIA: neurodegeneration with brain iron accumulation; NDEG: neurodegeneration; NDEV: neurodevelopmental; NPSY: neuropsychiatric; OAC: organic acid chromatography; SDE: syndrome; WM: white matter; NL: neu-laxova, severe form of serine synthesis deficiency. NKH: non ketotic hyperglycinemias; OA: organic acid; NR: not reported; OGC: oculogyric crisis; PHE: phenylalanine; PKAN: pantothenate kinase-associated neurodegeneration; P:plasma; PKU: phenylketonuria; PLP: pyridoxal 5'-phosphate; PNPO: pyridox(am)ine 5'-phosphate oxidase; PSAT1: phosphoserine aminotransferase; PSP: phosphoserine phosphatase; PTPS: PVC: paraventricular cysts; PVM: periventricular leucomalacia; RBC: red blood cell; SR: sepiapterine reductase; SSADH: succinyl adenosine dehydrogenase; TH: tyrosine hydroxylase; TPP: thiamine pyrophosphate; U: urine; UCD: urea cycle disorders; VMAT: brain vesicular monoamine transporter 2; WM: white matter; 3-PGDH: 3-Phosphoglycerate Dehydrogenase Deficiency; 5-HIAA: 5-hydroxyindolaceticacid; 5-OH-T5 hydroxytryptophane Important and frequent manifestations and outcome are in bold. (*) SLC25A1 citrate mito carrier. (**) This variation of clinical manifestations may be common in many other disorders. Severe defects affect early developmental stages and behave as brain malformations whereas mild forms may present as “synaptopathies.”