Table A1.

Inborn errors of metabolism with unique MRS and MRI profiles that can be suggestive or diagnostic *.

Disorder	Classification	Defect + Metabolic Consequence	Key MRS Metabolite (ppm) or MRI Feature
Maple syrup urine disease (MSUD) *	Amino aciduria	Defect in branched-chain keto-acid dehydrogenase enzyme ➔ ↑ branched chain amino acids and ketoacids (BCAAs, BCKAs)	↑ BCAAs + BCKAs (0.9) Intramyelinic edema involving cerebrum, cerebellum, brainstem
Non-ketotic hyperglycinemia (NKH) *	Amino aciduria	Defective mitochondrial enzyme involved in glycine cleavage ➔ ↑ glycine	↑ Glycine (3.5) Intramyelinic edema, Hypogenesis corpus callosum, vermian hypoplasia
Phenylketonuria (PKU) *	Amino aciduria	Phenylalanine hydroxylase deficiency	↑ Phenylalanine (7.37) Periventricular and subcortical white matter (WM) abnormalities
Glutaric Aciduria type I (GA-I) *	Organic aciduria	Enzyme deficiency altering lysine, hydroxylysine, tryptophan metabolism➔ ↑ glutaric acid, hypoglycemia	Poorly formed operculum, widened sylvian fissures and frontotemporal subarachnoid spaces, basal ganglia (BG) lesions
L-2-hydroxyglutaric aciduria (L2HGA) *	Organic aciduria	Mitochondrial enzyme L2HGDH mutation➔ ↑ L-2-hydroxyglutaric acid	Initial frontal and subcortical WM, with later confluent WM and BG abnormality. Dentate nuclei lesions
Methylmalonic acidemia (MMA)	Organic aciduria	Defect in methylmalonyl- coenzyme A mutase➔ ↑ methylmalonic acid, glycine, ammonia	Cerebral WM and globus pallidus lesions
Propionic acidemia	Organic aciduria	Defect in propionyl-coenzyme A carboxylase	↑ propionic acid, glycine Cerebral WM and striatum lesions
Urea cycle defects (UCD)	Urea cycle defects (UCD)	Deficiency in detoxification of ammonia to urea➔ ↑ ammonia, glutamine	↑ Glu ± ↓ mI and Cho Cortical and subcortical lesions usually sparing thalamus
α-Mannosidosis *	Lysosomal	Deficiency of α-mannosidase	Mannose-rich oligosaccharides (3.5–3.9) Hypomyelination Leukodystrophy (LD)
Fucosidosis *	Lysosomal	Deficiency of α-L-fucosidase needed to metabolize fucose-containing compounds	Carbohydrate-containing macromolecules (3.8–3.9) Fructose (1.2 doublet); inverts at intermediate echo time Hypomyelination, thalamic and GP T2 hypointensity
Globoid cell leukodystrophy (Krabbe disease)	Lysosomal	Galactocerebroside β-galactosidase deficiency ➔ globoid cell accumulation	Thalamic T2 hypointensity Centrifugal gradient LD, tigroid WM pattern, cranial nerve enhancement, optic nerve enlargement
Metachromatic leukodystrophy (MLD)	Lysosomal	Decreased arylsulfatase A enzyme activity ➔ metachromatic sulfatide deposits	Centrifugal gradient LD, tigroid WM pattern, cranial nerve enhancement
Mucopolysaccharidosis (MPS) *	Lysosomal	Deficiencies in lysosomal hydrolases responsible for metabolizing mucopolysaccharides (a.k.a. glycosaminoglycans)	Mucopolysaccharides (3.6–3.7) ↑ Cho Enlarged perivascular spaces, ventriculomegaly, WM lesions, dysostosis multiplex, CVJ stenosis
Salla disease *	Lysosomal	Defect in sialic acid transport ➔ N-acetyl neuraminic acid	↑ N-acetyl neuraminic acid (2) Diffuse WM abnormality
Tay-Sachs and Sandhoff (GM-2 gangliosidosis)	Lysosomal	Reduced beta-hexosaminidase enzyme➔ ↑ GM2-ganglioside accumulation	Sandhoff (N-acetylhexosamine metabolite at 2.1) Thalamic T2 hypointensity Striatum T2 hyperintensity
X-linked adrenoleukodystrophy (ALD) *	Peroxisomal	Inability to oxidize long-chain fatty acids (VLCFA) into short-chain fatty acids ➔ accumulation of long-chain fatty acids	Peri-trigonal T2 hyperintensity and restricted diffusion Posteroanterior & centrifugal gradient
Zellweger syndrome *	Peroxisomal	Decreased dihydroxyacetone phosphate acyl transferase (DHAP-AT) activity. Peroxisomal function crucial to neuronal migration.	Lipids (0.87, 1.27) peri-sylvian polymicrogyria, germinolytic cysts
Biotin-thiamine responsive basal ganglia disease	Thiamine metabolism	Mutation in SCL19A3 gene encoding a thiamine transporter	Leigh-like phenotype Pyruvate (2.37)
Leigh disease (subacute necrotizing encephalopathy)	Mitochondrial	Multiple mutations in mitochondrial or nuclear DNA	↑ Lac (1.33) Pattern of symmetric basal ganglia or brainstem abnormalities
Leukoencephalopathy with brainstem and spinal cord involvement (LBSL)	Mitochondrial	Mitochondrial aspartyl-tRNA synthetase deficiency	↑ Lac (1.33), mI, Cho, ↓ NAA Diffuse cerebral volume loss, involvement of brain and spine
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and POLG-related mitochondrial disorders	Mitochondrial	Mutations in mitochondrial DNA	↑ Lac (1.33) Non-territorial and basal ganglia “stroke-like” lesions Peri-rolandic parenchyma and thalami preferentially affected in POLG-related disorders
Pyruvate dehydrogenase complex (PDHc) deficiency *	Mitochondrial	Impaired pyruvate to acetyl-coA conversion and lactate accumulation	Pyruvate (2.37), ↑ Lac Leigh disease pattern Germinolytic cysts Periventricular necrosis
Molybdenum cofactor deficiency (MCD) and Sulfite Oxidase Deficiency (SOD)	Amino aciduria/Electron transport chain	Defect in amino acid metabolism, involved in electron transport chain	↑ taurine (3.2–3.4), ↑ S-sulocysteine (3.6), ↑ cysteine (2.9–3), ↑ Glx, ↑ Lac, ↑ Cho, ↓ NAA. Caudate head involved, thalamic sparing.
Succinate dehydrogenase (SDH) deficiency *	Mitochondrial	Absent/insufficient oxidation of succinate ➔ fumarate and electron delivery to the respiratory chain	Succinate (2.4), ↑ Lac (1.33) Leigh disease pattern
Alexander disease *	Leukodystrophy (Macrocephalic)	Astrocytopathy resulting in defect in myelin deposition	Frontal predominant WM disease and striatum involvement, enhancement, ↑ mI and sI
Canavan disease *	Leukodystrophy (Macrocephalic)	Inability to metabolize N-acetyl asparate (NAA) into asparate and acetate	↑↑ NAA Diffuse WM and thalamic lesions sparing striatum
Menke’s Disease	Metal Metabolism	Copper metabolism Defect	Circle of Willis tortuosity and elongation universal, ± WM changes, vermian hypoplasia, atrophy, subdural collections
Pantothenate kinase associated neuro- degeneration (PANK)	Metal Metabolism	Neurodegeneration with brain iron accumulation	“Eye-of-the-tiger” sign—peripheral and central globus pallidus T2 hypointensity
Wilson’s Disease	Metal Metabolism	Copper metabolism Defect	T1 hyperintensity in globus pallidus ± striatum and/or upper brainstem (11 years) T2 hyperintensity in putamen, globus pallidus, caudate, thalamus, brainstem (13 years)
Aicardi–Goutières syndrome	Miscellaneous	Defect in genes involved in nucleotide metabolism and/or sensing	Classic Triad: Calcifications, WM disease, atrophy Various other features correlate with genotype
Carnitine palmitoyltransferase (CPT)	Miscellaneous	Disorder of lipid metabolism	↑↑ Lipid
Creatine deficiency disorders *	Miscellaneous	Disorders of biosynthesis and transport of creatine	Reduced or absent Cr (3) MRI may be normal
Galactosemia *	Miscellaneous	Deficiency of galactose-1-phosphate enzyme ➔ ↑galactose-1-phosphate and galactitol	Galactitol (3.7): doublet at short TE, peak inversion at intermediate TE; ↓ mI
Congenital disorder of glycosylation Type 1a (CDG-1a)	Miscellaneous	Mutation in gene encoding PMM2 ➔ abnormal glycosylation of N-linked oligosaccharides	Marked cerebellar volume loss with diffuse cerebellar T2 hyperintensity. Progressive volume loss of pons, cerebellum, and supratentorial WM. ↓ NAA/Cr ratio, ↑mI
Muscular dystrophy- dystroglycanopathy (congenital with brain and eye anomalies) *	Miscellaneous	Reduced glycosylation of Alpha-dystroglycan	Extensive malformations of cortical developmental (i.e., cobblestone lissencephaly, kinked z-shaped brainstem, midline pontine clefting)