Neuroimaging in Children With Inherited Metabolic Epilepsies

Abstract

Inherited metabolic epilepsies (IMEs) represent inherited metabolic disorders in which seizures, various in types and typically intractable, are one of the predominant manifestations and primary determinants of the overall outcome. A metabolic etiology should be suspected in any case of refractory seizures stemming from an undetermined cause. While the occurrence rate of individual IMEs is rare, their cumulative prevalence is high enough to pose a significant clinical challenge. Concurrently with genetic and metabolic tests, neuroimaging is considered part of the first tier of their investigation, attained with an aim to affirm or counter the phenotype. It may be normal or nonspecific; however, as described by this overview, there is an appreciable number of IMEs associated with distinct MRI or magnetic resonance spectroscopy patterns. Apart from narrowing or supporting their diagnoses, these neuroimaging patterns may serve as biomarkers to monitor treatment efficacy and outcome. Other advanced modalities and techniques, such as PET, fMRI, diffusion tensor imaging, MRI g-ratio mapping, and functional near-infrared spectroscopy, broaden our insights relating to their pathophysiology, clinical course, targeted treatment development, and prognosis.

Introduction

Inherited metabolic epilepsies (IMEs) represent inherited metabolic disorders (IMDs) in which seizures are a primary symptom.¹ Of the ∼1,500 IMDs, approximately 250 are considered to be IMEs, which are classically classified according to their pathogenesis: disorders characterized by impairments or accumulation of compounds with small or large molecular weights; defects in cellular energy metabolism; dependency or a lack of enzyme cofactors, trace minerals, and vitamins; or impairment in neurotransmitters.² One of every 5 IMEs is estimated to be responsive to a targeted therapy amending its biochemical defect and improving outcomes to different extents.³ Many of these treatment modalities are effective only if administered in a limited time window, typically at as young an age as possible.⁴ Hence, early identification of IMEs is critical. The clinical onset of IMEs ranges from the neonatal period to adulthood. It is often nonspecific, consisting of manifestations such as lethargy, feeding problems, and motor tone disturbances early in life and intellectual disability, movement disorders, and psychiatric problems in later stages. Various types of seizures, typically refractory, may occur at any stage and with different degrees of severity. Clinical suspicion of an IME arises because of drug-resistant seizures stemming from an unexplained etiology with or without other phenotypic features associated with a metabolic etiology. Initial investigations include metabolic tests and, nowadays, when feasible, gene sequencing. Neuroimaging, specifically MRI and proton magnetic resonance spectroscopy (¹H MRS), is also attained as first-tier screening, aimed to complement or refute the individual's phenotype.³ Not all the IMEs are associated with specific neuroimaging findings, and neuroimaging patterns may overlap across several IMEs. However, there are IMEs, including treatable ones,⁵ in which a distinct neuroimaging pattern can help to narrow, support, confirm, or disprove the diagnosis. This is especially pertinent in some IMEs that are diagnosed by newborn screening (NBS) programs in many countries (such as phenylketonuria [PKU], maple syrup urine disease [MSUD], propionic acidemia [PA], and methylmalonic acidemia [MMA]) because neuroimaging findings develop only if they are untreated. We present an overview of the neuroimaging findings in IMEs, interlaced with their pathophysiology and clinical approach. Considering the vast gamut of IMEs, we will focus on those for which neuroimaging is contributory and advanced modalities have been described.

General Considerations

Compared with CT or ultrasound, MRI has superior abilities to demonstrate soft-tissue contrast and multiplanar anatomic and pathologic detail. MRI protocols are often customized for the IME in question.⁶ If the differential diagnosis is broad, the protocol typically consists of T1-weighted and T2-weighted imaging, optimized forms of fast/turbo spin-echo pulse sequences for distinctness of gray/white matter differentiation,⁷ T2 fluid-attenuated inversion recovery (FLAIR) (with consideration of the expected signal intensity changes seen during the first years of life⁸), diffusion-weighted imaging (DWI), susceptibility-weighted imaging, arterial spin labeling perfusion, and magnetization transfer T1-weighted imaging (if a leukoencephalopathy is questioned).⁹ A wide range of neuroimaging findings have been associated with different IMEs (Table 1). An MRS may be key for its ability to reveal concentrations of different metabolites. The standard MRS protocol consists of single-voxel spectroscopy, point resolved spectroscopy, 35-millisecond echo time (TE), 1,500-millisecond repetition time, 128 signal averages, and, if feasible, longer TE acquisition (e.g., 144 or 288 milliseconds for 1.5T or 3T MRI, respectively). The placement of the voxel (typically 2 × 2 × 2 cm default) is determined according to the suspected disorder and structural abnormalities. The commonly sampled cerebral locations include the deep gray nuclei, occipital and midline parietal cortices, and relevant white matter areas. Sampling is typically not performed in regions of necrosis, hemorrhage, or calcification.⁹ Altered (age-dependent) MRS-derived metabolite ratios⁶ may support or confirm a considerable number of IMEs (Table 2). Other novel measures and techniques such as diffusion tensor imaging (DTI), MRI g-ratio mapping, fMRI, functional near-infrared spectroscopy (fNIRS), and PET can be used to elucidate additional components of functional neuronal circuitry, myelination, and presence of metabolites (Table 3). MRI g-ratio mapping and DTI can assess brain tissue microstructure. However, compared with DTI, through which the direction and degree of water diffusion and, accordingly, axonal fiber orientation and connectivity could be estimated, g-ratio mapping offers a more direct measure of myelin integrity by focusing on the periaxonal myelin sheath thickness.¹⁰ Applying MRI g-ratio mapping as a biomarker in IMEs has not been reported; however, this methodology could provide useful information in IMEs characterized by disrupted myelination, such as mitochondrial diseases, certain lysosomal storage diseases, and X-linked adrenoleukodystrophy. Analysis of the absorption of near-infrared light by fNIRS offers a noninvasive way to assess the level of oxygen saturation. The fNIRS outcome parameter “tissue oxygenation index (TOI)” serves as an indicator of the balance between oxygen supply and demand within tissue investigated. The metric resulting from the difference between baseline and follow-up values of the TOI, the delta tissue oxygen index (ΔTOI), may be applied to screen inherited disorders of energy metabolism such as mitochondrial diseases¹¹ and monitor various aspects of other IMEs such as urea cycle disorders (UCDs).¹²

Table 1.

Common MRI Patterns of Inherited Metabolic Epilepsies

Neuroimaging finding	Inherited metabolic epilepsy
Corpus callosum dysgenesis/agenesis	CDGs, Zellweger syndrome, glycine encephalopathy, PDE, PDD
Cortical atrophy	PA, MMA, UCDs (severe cases), NCL, MLD (late stages), Glut-1 (mild), creatine disorders, SSADHD (mild), CFD, PDE, PNPO deficiency, MELAS
Cystic encephalomalacia	ISOD/MoCo, Krabbe disease, Zellweger syndrome, mitochondrial diseases
Demyelination (hyperintense T2-weighted and hypointense T1-weighted white matter signals)	Krabbe disease, MLD (sparring U-fibers, radiating fibers, and a thin periventricular rim), PA, Zellweger syndrome, mitochondrial diseases, GM2 gangliosidoses, NCL, X-linked adrenoleukodystrophy
Hypomyelination (hyperintense T2-weighted and isointense or hyperintense T1-weighted white matter signals)	PKU, PA, MMA, Krabbe disease, Canavan disease, UCDs (severe cases), CDGs, NCL, creatine disorders, Zellweger syndrome, mitochondrial diseases, CFD, PDE, PNPO deficiency
Hypoplasia
Cerebellar	CDGs, Zellweger syndrome, glycine encephalopathy, PDE
Pontocerebellar	NCL, Zellweger syndrome, mitochondrial diseases
Intracerebral hemorrhage/stroke	PA, MMA, glutaric aciduria type I, mitochondrial diseases (MELAS, MERRF, Leigh syndrome, POLG1, CoQ deficiency, complex III deficiency), CDGs, PDE, UCD (CPS1, OTC deficiency, citrullinemia type 1), Canavan disease
Intramyelinic edema	MSUD, glycine encephalopathy
Lissencephaly	Zellweger syndrome
Optic nerve involvement	Krabbe disease (thickened), Zellweger syndrome, NCL, PDE, glutaric aciduria type 1
Polymicrogyria	Zellweger syndrome
Spongy degeneration	Canavan disease
Subdural hematomas	Glutaric aciduria type I, Menkes disease
Subependymal cysts	Zellweger syndrome, holocarboxylase synthetase deficiency, D-2 hydroxyglutaric aciduria, pyruvate dehydrogenase E1 alpha deficiency
T2-weighted hyperintensities
Basal ganglia	Glutaric aciduria type I, organic acidurias, Tay-Sachs and Sandhoff diseases, mitochondrial diseases, UCD
Brainstem	Mitochondrial diseases
Globus pallidi	ISOD/MoCo, SSADHD
Thalami	MSUD, PA, glutaric aciduria type I, NCL, Krabbe disease
Dentate nuclei	Mitochondrial diseases (such as Leigh syndrome), glutaric aciduria type I, Krabbe disease, SSADHD, L2-hydroxyglutaric aciduria
Tortuosity of intracranial vessels	Menkes disease
Widened sylvian opercula	Glutaric aciduria type I

Abbreviations: CDGs = congenital disorders of glycosylation; CFD = cerebral folate deficiency; CoQ = coenzyme Q10; CPS1 = carbamoyl phosphate synthetase 1; Glut-1 = glucose transporter 1; ISOD = isolated sulfite oxidase deficiency; MELAS = mitochondrial encephalopathy with lactic acidosis and stroke-like episodes; MERRFs = myoclonic epilepsy with ragged red fibers; MLD = metachromatic leukodystrophy; MMA = methylmalonic acidemia; MoCo = molybdenum cofactor deficiency; MSUD = maple syrup urine disease; NCL = neuronal ceroid lipofuscinosis; OTC = ornithine transcarbamylase; PA = propionic acidemia; PCD = pyruvate carboxylase deficiency; PDD = pyruvate dehydrogenase deficiency; PDE = pyridoxine-dependent epilepsy; PKU = phenylketonuria; PNPO = pyridoxine 5′-phosphate oxidase; POLG1 = DNA polymerase subunit gamma; SSADHD = succinic semialdehyde dehydrogenase deficiency; UCD = urea cycle disorder.

Table 2.

Altered Concentrations of MRS-Derived Metabolites Associated With Inherited Metabolic Epilepsies

Metabolite	Inherited metabolic epilepsy
	Increased	Decreased
Branched-chain amino acids, leucine, isoleucine, valine	MSUD
Choline-containing compounds	ISOD, MoCo, Krabbe disease	UCDs
Creatine + phosphocreatine		Creatine disorders
Cysteine and S-sulfocysteine	ISOD, MoCo
Glutamate/glutaminea	UCDs, ISOD, MoCo
Glutamate + glutamine	UCDs, Zellweger syndrome, Glut-1 deficiency
Glycine	Glycine encephalopathy
Lactate	ISOD/MoCo, PA, MMA, UCDs, MLD, mitochondrial diseases (lactate doublet)
Lipids	Zellweger syndrome, MLD, glutaric aciduria type I
Myoinositol	CDGs, GM2 gangliosides, NCL, Krabbe disease, MLD	UCDs, Zellweger syndrome
N-acetylaspartate	Canavan disease	ISOD/MoCo, PA, MMA, glutaric aciduria type I, CDGs, GM2 gangliosides, NCL, MLD, Krabbe disease, Zellweger syndrome, PDE
Phenylalanine	PKU
Pyruvate	BTBGD
Taurine	ISOD/MoCO, NCL
γ-Aminobutyric acid	SSADHD

Abbreviations: BTBGD = biotin-thiamine–responsive basal ganglia disease; CDGs = congenital disorders of glycosylation; Glut-1 = glucose transporter 1; ISOD = isolated sulfite oxidase deficiency; MLD = metachromatic leukodystrophy; MMA = methylmalonic acidemia; MoCo = molybdenum cofactor deficiency; MRS = magnetic resonance spectroscopy; MSUD = maple syrup urine disease; NCL = neuronal ceroid lipofuscinosis; PA = propionic acidemia; PDE = pyridoxine-dependent epilepsy; PKU = phenylketonuria; SSADHD = succinic semialdehyde dehydrogenase deficiency; UCD = urea cycle disorder.

^aDistinguishing Gln and Glu in MRS is challenging because their comparable chemical structures lead to overlapping signals in a standard spectrum. To separate them, targeted Glu/Gln pulse sequences have been developed.⁶⁰

Table 3.

Described and Potential Applications of Advanced Neuroimaging Modalities in IMEs

Advanced neuroimaging modality	Information provided	Inherited metabolic epilepsy
DTI	Magnitude, orientation, and degree of anisotropy of water molecules' diffusion; white matter tract abnormalities	Mitochondrial diseases, PKU, MMA, Niemann-Pick C, Krabbe disease, MLD, XLALD, OTC deficiency
PET	Assessment of metabolic processes through visualization of radioactive tracers	Mitochondrial disease, neurodegenerative lysosomal storage diseases (Gaucher, Niemann-Pick C, Krabbe, MLD), PKU, MSUD, SSADHD
fMRI	Cerebral blood flow and neuronal metabolism (blood oxygenation level–dependent signal); task-based and resting state	Potentially any IME, for phenotype characterization and monitoring functional and neuropsychological severity as part of disease progression and response to treatment
fNIRS	Noninvasive assessment of cerebral hemodynamics (estimation of the tissue oxygen index) in relation to cortical activity	Mitochondrial disorders, UCDs, potentially any IME in which energy metabolism is affected
MRI g-ratio mapping	Myelination integrity, as reflected by evaluation of the periaxonal myelin sheath thickness	Potentially any IME with myelination and white matter abnormalities

Abbreviations: DTI = diffusion tensor imaging; fNIRS = functional near-infrared spectroscopy; IME = inherited metabolic epilepsy; MLD = metachromatic leukodystrophy; MMA = methylmalonic acidemia; MSUD = maple syrup urine disease; OTC = ornithine transcarbamylase; PKU = phenylketonuria; SSADHD = succinic semialdehyde dehydrogenase deficiency; UCD = urea cycle disorder; XLALD = X-linked adrenoleukodystrophy.

Small-Molecule Disorders

Amino Acidemias

Phenylketonuria

Caused by a deficiency of phenylalanine hydroxylase in most cases and rarely of tetrahydrobiopterin, the neurodevelopmental and psychiatric manifestations in untreated PKU result from phenylalanine accumulation and neurotoxicity. Generalized-onset seizures and epileptic spasms occur in roughly one-fourth of cases. In many countries worldwide, PKU may be diagnosed by NBS programs. MRI findings of untreated individuals include hypomyelination, expressed as high T2-weighted signal intensity in the periventricular, subcortical, and frontal white matter.¹³ Those who are treated early on may also show white matter abnormalities. However, these do not reflect hypomyelination but rather intramyelinic edema, which is reversible with a low phenylalanine diet, the primary treatment of the disorder. In a study using automated fiber-tract quantification, it was shown that white matter damage appears in a posterior-to-anterior manner in patients with early treated PKU.¹⁴ Studies using DTI showed that widespread decreased white matter mean diffusivity is associated with increased phenylalanine levels and executive function problems in PKU. MRS may show a phenylalanine peak at 7.36 ppm when using a short TE. When diagnosis of PKU is delayed, the MRS-derived phenylalanine level may serve as a biomarker because it correlates with clinical severity.¹⁵

Maple Syrup Urine Disease

Impairment of the catabolism of valine, leucine, isoleucine, and their ketoacids resulting from deficiency of the branched-chain α-ketoacid dehydrogenase complex leads to the clinical presentation in MSUD, which also includes focal, generalized, and myoclonic seizures. NBS may identify MSUD in many countries. The untreated classic form of MSUD is associated with splitting of the myelin, expressed by MRI as DWI-restricted diffusion and a reduced apparent diffusion coefficient (ADC) reflecting the intramyelinic edema, predominantly in regions containing myelin: the cerebellum, dorsal brainstem, posterior limb of the internal capsule, and posterior centrum semiovale.¹⁶ DTI studies further support these notions by showing decreased fractional anisotropy values. MRS is strongly suggestive of MSUD when exhibiting a broadened peak complex at 0.9 ppm that inverts at an intermediate TE due to branched-chain amino acids and ketoacids. To eliminate the overlapping peaks of lipids at 0.9 ppm, a longer echo time may be used.¹⁷

Isolated Sulfite Oxidase Deficiency/Molybdenum Cofactor Deficiency

Pathogenic variants in SUOX result in isolated sulfite oxidase deficiency (ISOD), and deficiency of sulfite oxidase can also be caused by errors in the metabolism of molybdenum cofactor (due to pathogenic variants in MOCS1, MOCS2, or MOCS3). Clinical symptoms are present early in life and may mimic those of hypoxic-ischemic encephalopathy (HIE). Myoclonic and focal intractable seizures predominate. ISOD is associated with neuroimaging patterns of early diffuse cystic leukomalacia or selective involvement of the basal ganglia and cerebellum if onset occurs later. The findings in molybdenum cofactor deficiency are comparable, with more cortical and subcortical white matter involvement. The neuroimaging components that distinguish these disorders from HIE include the symmetry of involvement, lack of predominantly involved border arterial zones, sparring of thalamic areas, and inclusion of the caudate head. MRS investigations may reveal increased taurine, S-sulfocysteine, cysteine, and lactate and decreased N-acetylaspartate (NAA). As opposed to HIE, choline is often increased.¹⁸

Organic Acidurias

Propionic Acidemia and Methylmalonic Acidemia

Both conditions are associated with early infantile epileptic and developmental encephalopathy, epileptic spasms, and myoclonic and other seizure types. Early neuroimaging findings may be normal or show mild degrees of edema. PA and MMA may be diagnosed by NBS, and if untreated, individuals may exhibit subcortical white matter necrosis and cortical and cerebellar atrophy. The basal ganglia are involved in MMA > PA (Figure 1). During acute decompensation, hyperintense T2-weighted signal in the globus pallidi may be seen and can resolve over time. In MMA, MRS findings may demonstrate decreased NAA and an increased lactate peak during acute decompensations.¹⁹ In PA, MRS may also show decreased NAA and an increased glutamine/glutamate ratio.²⁰

Figure 1. Neuroimaging of an Adolescent With Methylmalonic Acidemia.

Axial T2-weighted MRI sequences show T2 prolongation in the bilateral basal ganglia, consistent with encephalomalacia (A and B). A sagittal T1 image (C) demonstrates cerebellar volume loss and mild callosal hypoplasia.

Glutaric Acidemia Type I

Pathogenic variants in GCDH encoding glutaryl-CoA dehydrogenase result in glutaric aciduria type I. A metabolic decompensation occurring between 6 and 18 months of age typically incites striatal injury manifesting with encephalopathy, acute dystonia, and, at times, seizures. MRI of affected presymptomatic individuals is characterized by a dysgenetic operculum, enlargement of the posterior mesencephalic cistern, and a cyst-like space in the middle cranial fossa including CSF that communicates with widened frontotemporal and sylvian fissure spaces. Bridging veins lying within these spaces may be readily torn, resulting in subdural hematomas. This finding, in addition to retinal hemorrhages that also characterize the disorder, may raise suspicion of nonaccidental trauma and should be considered in its differential diagnosis. Basal ganglia swelling, hyperintense T2-weighted signal, and restricted diffusion are also associated with glutaric acidemia type I. Typically, but not universally, basal ganglia involvement occurs as a sequela of metabolic decompensation. Once lesioned, the basal ganglia atrophy with time and signal hyperintensity persist in T2-weighted and FLAIR sequences. In profound cases, involvement of the thalami and dentate nuclei may also be seen. The MRS findings associated with glutaric acidemia type I are increased lipid peaks at 0.9 and 1.3 ppm and decreased NAA. During metabolic decompensation, an increase in the lactate peak may be observed.²¹

Canavan Disease

Pathogenic variants in ASPA encoding aspartoacylase hinder the ability to hydrolyze NAA into acetate and aspartate, leading to progressive spongy degeneration of white matter. Encephalopathy onset is in infancy, including generalized seizures in half of cases. The cortical spongiform changes are reflected by MRI findings of diffuse T1/T2 prolongation (and DWI-restricted diffusion in the active phase) in white matter, including the subarcuate U-fibers, lateral thalami, globus pallidi, corpus callosum, and internal capsules, sparring the pulvinar, caudate nuclei, putamen, and periventricular white matter.²² A pathognomonic MRS finding consists of an increased NAA peak at 2.01 ppm.²³

Urea Cycle Disorders

The shared pathophysiologic outcome of this group of disorders is the inability to eliminate nitrogen that results from catabolic processes of proteins and carbohydrates. Clinical symptoms of fluctuating encephalopathy are primarily related to hyperammonemia, and seizures may be clinical or electrographic only. Neuroimaging findings are often nonspecific. However, during UCD-associated hyperammonemia, MRI patterns may include centralized edema involving the paracentral regions, peri-insular subcortical U-fibers, basal ganglia, and various asymmetric cortical lobes. Sparing of the thalami may distinguish UCDs from HIE. In severe cases, hypomyelination, cortical atrophy, and gray-white junctional cystic lesions may be visualized. During hyperammonemia, MRS typically demonstrates increased glutamine, lactate, and Glx (the combined concentrations of glutamine and glutamate) and decreased myoinositol (MI) and choline peaks.²⁴ An example of fMRI utilization is provided in ornithine transcarbamylase (OTC) deficiency, the most common UCD. fMRI studies examining the executive dysfunction associated with this disorder showed that hyperammonemia in OTC-deficient individuals correlated with reduced functional connectivity of 2 resting-state networks, the default mode network, and set-maintenance network.²⁵

Large-Molecule Disorders

Congenital Disorders of Glycosylation

This diverse group of multisystemic disorders is caused by dysfunctional glycosylation of N-linked and O-linked glycoproteins and glycolipids. Among the multisystemic manifestations characterizing these disorders, intractable epilepsy, including almost every seizure type, is common. Neuroimaging may be initially normal or show an early or later onset of a broad range of abnormalities such as progressive cortical, cerebellar, and supratentorial white matter volume loss; pontocerebellar hypoplasia; corpus callosum defects; Dandy-Walker malformation; and other structural malformations.²⁶ The coagulopathy associated with these conditions may lead to intracranial hemorrhages, and stroke-like episodes are also observed.²⁷ MRS patterns may consist of elevated MI and a decreased NAA/Cr ratio.²⁸

Lysosomal Storage Disorders

Tay-Sachs and Sandhoff Diseases (GM2 Gangliosidoses)

Driven by pathogenic sequence variants in HEXA and HEXB (encoding hexosaminidase A and B, respectively), the GM2 gangliosides accumulated in lysosomes of affected individuals lead to neurologic compromise occurring in an acute (including seizures), subacute, and chronic clinical course. Early neuroimaging patterns consist of MRI T1 and T2 relaxation times that are shortened in the thalami and prolonged in the basal ganglia, as well as myelination abnormalities that become more pronounced with disease progression. The initial neuronal inflation is replaced by atrophy as neurons are lost. Notably, basal ganglia involvement and peritrigonal hyperintensity have a stronger association with type I (early-onset, rapid progression phenotype) of these disorders while a normal MRI or infratentorial atrophy is more common in type II (variable and later onset).²⁹ MRS studies demonstrate a progressive decline in NAA and an increase in gray matter MI.³⁰

Neuronal Ceroid Lipofuscinosis

This group of disorders is caused by pathologically stored lipopigments. Depending on the CLN affected, clinical onset may occur early or later in childhood and consist of neurodevelopmental regression; movement disorders; vision loss; and myoclonic, atonic, and other forms of generalized seizures. The infantile-onset form of the disorder (CLN1) is characterized by profound cortical and brainstem atrophy, T2-weighted hyperintensities in the white matter, and relative hypointensities in the basal ganglia and thalami.³¹ MRS demonstrates elevated MI and taurine and decreased NAA.³² Disease forms with onset later in childhood present with atrophy greater in infratentorial than in supratentorial regions. Radiographic evidence of demyelination is most pronounced in the periventricular areas, internal capsules, and thalamic internal medullary lamina.³¹ MRS findings are similar to those of the infantile forms and may also show an elevated glutamate/glutamine ratio.³³

Globoid Cell Leukodystrophy (Krabbe Disease)

Different degrees of galactocerebrosidase deficiency (variant GALC) lead to different clinical onset periods ranging from infancy to adulthood. Among other signs of encephalopathy and motor dysfunction, focal and generalized seizures and epileptic spasms occur, the latter of which may be hard to differentiate from the muscular spasms characterizing the disorder. Early in the disease course, neuroimaging may be normal or exhibit minimal T2-weighted hypointensities in the dentate nuclei and corticospinal tracts. With disease progression, demyelination and later cystic degeneration expand into cerebellar areas and other cortical regions such as the peritrigonal white matter, posterior limbs of the internal capsules, and posterior corpus callosum. Predominant involvement of the dentate hila and posterior cerebral white matter may form a centrifugal and posteroanterior gradient and a tigroid pattern. Enlargement of the optic nerves and chiasm may also be noted. Eventually, focal necrosis may ensue in calcified areas, most commonly observed in the corticospinal tracts.³⁴ In the infantile forms of the disorder, MRS reveals increased MI and choline and decreased NAA. In the adult-onset forms, the MRS may not show any abnormality.³⁵

Metachromatic Leukodystrophy

Arylsulfatase A deficiency, which is mostly caused by sequence variants in ARSA but also by those in PSAP encoding saposin B, results in abnormal degradation of sulfated glycolipids, predominantly galactosyl-3-sulfate ceramides. Depending on the genotype, clinical signs appear between late infancy and adulthood and include progressive neurodevelopmental and psychiatric regression, peripheral neuropathy, and speech and swallowing difficulties. Focal seizures are typically seen later in the disease course. Neuroimaging is exceptionally important as part of the investigation of this disorder because MRI findings may precede clinical symptoms, and hematopoietic stem cell transplantation (HSCT) may slow or halt disease progression only if given before the onset of neurodevelopmental signs.³⁶ Moreover, atidarsagene autotemcel (Libmeldy), recently approved by the FDA,³⁷ is an autologous hematopoietic stem cell gene therapy (with a lentiviral vector encoding ARSA), which has shown efficacy and safety in children with early-onset metachromatic leukodystrophy (MLD) by abating demyelination and cortical trophy and the decline of cognitive and motor functions.³⁸ Early neuroimaging of untreated individuals is characterized by longer T1/T2 relaxation times representing hypomyelination mixed with normally myelinated areas. U-fibers are spared, as are a thin periventricular rim and radiating white matter fibers in the centrum semiovale, forming a radiographic pattern commonly known as “tiger stripes.” With disease progression, global atrophy and, correspondingly, ventriculomegaly are seen. An MLD-specific MRI scoring method based on the extent of white matter involvement and diffuse atrophy has been developed.³⁹ MRS findings of lower NAA and glutamate and higher MI and lactate have been described and shown to be significantly associated with a worse outcome. Creatine and Glx values were shown to be possible biomarkers of disease severity.⁴⁰

Peroxisomal Biogenesis Disorders

Pathogenic variants in at least 13 PEX genes (encoding peroxins) are linked to Zellweger syndrome, the prototypical peroxisomal biogenesis disorder. Almost every organ system is damaged by this rapidly progressive and fatal disorder. Seizures are common in many focal and generalized forms, including atypical flexor spasms. Neuroimaging shows hypomyelination (typically diffuse but can be only periventricular); malformations of cortical migration such as polymicrogyria, lissencephaly, and failure of operculization; hypoplastic corpus callosum, internal capsule, cerebellum, and brainstem; dysplastic olivary nuclei; and periventricular cysts.⁴¹ MRS demonstrates a reduction of NAA and MI, accumulation of lipids, and increased glutamate and glutamine as a reflection of hepatocellular injury.⁴²

Disorders of Energy Metabolism

Glucose Transporter 1 Deficiency

This disorder is caused by impairment in glucose transport across the blood-brain barrier due to a dysfunctional glucose transporter 1 (Glut-1) (encoded by SLC2A1). Seizures occur in most affected individuals and can be of any type. Atypical absence seizures are notable. Neuroimaging can be normal or show nonspecific abnormalities such as mild cortical hypotrophy.⁴³ Of interest, leukoencephalopathy has been described to reverse in response to the ketogenic diet.⁴⁴ One report described an increased MRS-derived Glx/creatine ratio in Glut-1 individuals, proposing that higher glutamate and glutamine may have a compensatory neuroprotective role in the glucose-reduced environment.⁴⁵

Creatine Biosynthesis and Transport Deficiencies

Deficiencies of the enzymes involved in the two-step pathway of creatine synthesis (arginine:glycine amidinotransferase [encoded by AGAT] and guanidinoacetate N-methyltransferase [encoded by GAMT]) or its transporter (encoded by SLC6A8) lead to these disorders. Variable degrees of intellectual disability and expressive language difficulties have been described, as well as focal, tonic-clonic, myoclonic, atonic, and absence seizures. MRI can be nonspecific or demonstrate mild white matter abnormalities and cortical volume loss, primarily in creatine transporter deficiency. Treatment-reversible T2-weighted hyperintense signals in the globus pallidi have been noted in GAMT deficiency. MRS is strongly suggestive of these diagnoses by showing low creatine and phosphocreatine peaks at short and long echo ranges (Figure 2). If the peaks are diminished to less than 10% of normal values, it is regarded as confirmatory. In GAMT deficiency, the guanidinoacetate peak is abnormally broad. Follow-up MRS studies have been demonstrated to assess treatment response.⁴⁶

Figure 2. Neuroimaging of an Adolescent With Creatine Transporter Deficiency.

Anatomic MRI was normal, and MRS demonstrated a diminutive creatine peak (arrow). MRS = magnetic resonance spectroscopy; NAA = N-acetylaspartate.

Mitochondrial Diseases

This heterogeneous group of disorders stems from pathogenic variants in mitochondrial DNA (mtDNA) or nuclear DNA, leading to hundreds of different entities classified into disorders affecting the respiratory chain subunits, assembly factors, electron carriers (coenzyme Q10 and cytochrome C), mtDNA maintenance, mitochondrial dynamics, homeostasis, and quality control and defects in other intramitochondrial processes (e.g., fatty acid oxidation and anaplerosis), cofactors, and toxic compounds.⁴⁷ Their principal pathophysiologic outcome is a lack of normal intracellular energy production or utilization, as well as impairment of other mitochondrial functions such as detoxification of reactive oxygen species, removal of misfolded proteins, and apoptosis. Mitochondrial diseases present with a wide spectrum of multisystemic manifestations, including neurologic. Seizures are associated with many disorders from this group, but not all. Notable syndromes presenting with seizures include, for example, subacute necrotizing encephalomyelopathy (Leigh syndrome), mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), and POLG1-related mitochondrial encephalopathy.⁴⁸ Accordingly, with the heterogeneity of these diseases, neuroimaging findings are variable. Many MRI and MRS patterns can support a mitochondrial-related etiology; however, it is seldom that neuroimaging is diagnostic for a specific mitochondrial disease. MRI may demonstrate symmetric involvement of the basal ganglia, thalami, brainstem, white matter, periaqueductal gray matter, substantia nigra, dentate nuclei, white matter, and mammillary bodies. In MELAS, for example, evidence of an acute or chronic cerebrovascular injury could be seen. In LBSL, signal abnormalities are classically observed in the periventricular and deep cerebral white matter, posterior limb of the internal capsule, and specific brainstem and spinal cord tracts, and phenotypes presenting with profound cerebral hypoplasia or atrophy without long tract white matter involvement have also been reported.⁴⁹ Increased lactate on MRS is sensitive but not specific to mitochondrial diseases because it may be seen in other instances of disturbed energy metabolism and lactic acidosis.⁵⁰ Notably, fNIRS may serve as a diagnostic biomarker of mitochondrial diseases, because compared with other neurogenetic conditions, mitochondrial diseases were shown to be associated with greater variability between the baseline and lowest TOI (ΔTOI) after a vascular occlusion test.¹¹

Neurotransmitter Disorders

Glycine Encephalopathy

Defects in one of several genes (predominantly GLDC and AMT but also LIAS, GLYT1, GLYT2, BOLA3, and GLRX5) encoding for components of the multienzyme complex amenable for glycine cleavage result in this disorder. Myoclonic seizures and epileptic spasms occur at early stages, accompanying other signs of encephalopathy. Neuroimaging findings consist of structural malformations such as corpus callosum agenesis and cerebellar vermis hypoplasia, as well as white matter vacuolization due to myelin splitting and intramyelinic edema, expressed by restricted diffusion on DWI mirrored by low ADC values (chiefly in the internal capsules, brainstem, and cerebellum) (Figure 3). MRS demonstrates a glycine peak at 3.55 ppm (Figure 3), which is optimally obtained using long echo time because in the shorter echo time, there is a reduced ability to differentiate its peak from normal MI. Follow-up MRS studies may be used to monitor therapy.

Figure 3. Neuroimaging of an Infant With Glycine Encephalopathy.

(A) A sagittal T2-weighted MRI sequence shows a foreshortened and thinned corpus callosum consistent with dysgenesis. (B) An axial DWI sequence displays diffusion restriction along early myelinating structures of the anterior and posterior limbs of the internal capsule. (C) MRS of intermediate echo time (135 milliseconds) demonstrates an abnormally elevated peak at approximately 3.55 ppm (the peak was elevated in all the parenchymal voxels). DWI = diffusion-weighted imaging; MRS = magnetic resonance spectroscopy.

Succinic Semialdehyde Dehydrogenase Deficiency

Homozygous or compound heterozygous pathogenic variants in ALDH5A1 lead to absence of, or functional or structural impairment in, succinic semialdehyde dehydrogenase (SSADH), a key enzyme in the catabolic pathway of γ-aminobutyric acid (GABA). The accumulated GABA and associated cortical excitatory-inhibitory imbalance result in various manifestations of the disorder, including developmental delay, movement disorders, communication and behavior problems, and seizures (focal and generalized), which are present in approximately 50% of the patient population. Neuroimaging findings may be normal or show cortical or cerebellar volume loss and T2-weighted hyperintensities in the globus pallidi, subthalamic nuclei, and cerebellar dentate nuclei⁵¹ (Figure 4). An increased burden of enlarged perivascular spaces suggesting possible glymphatic dysfunction has been associated with sleep disturbances in this disorder.⁵² MRS displays an increased GABA/NAA ratio, demonstrated in all regions of interest studied (basal ganglia, occipital cortex, and posterior cingulate gyrus).⁵¹ Of interest, decreased GABA levels over the first decade of life, hypothesized as related to chronic use–dependent downregulation of GABA receptors demonstrated using flumazenil PET,⁵³ seem to correlate with changes in the clinical phenotype, including worsening seizures. An additional application for assessing myelination and neuronal conduction velocity in SSADH deficiency uses g-ratio mapping of MRI. In this technique, determinants of myelination are estimated by quantification of the ratio of the caliber of myelinated axons to the total axonal cross-sectional size (including its encasing myelin sheath).¹⁰ A significant decrease in myelin integrity was demonstrated in SSADH-deficient individuals compared with controls (Figure 5).

Figure 4. Neuroimaging of an Adolescent With Succinic Semialdehyde Dehydrogenase Deficiency.

(A) An axial T2-weighted MRI sequence shows symmetric patchy T2 prolongation in the bilateral globus pallidi. (B) A sagittal T1-weighted MRI sequence demonstrates mild cerebellar volume loss with more severe vermis involvement.

Figure 5. MRI g-Ratio Mapping in SSADH Deficiency.

MRI g-ratio mapping images of (A) an adult and (B) a healthy control with SSADH deficiency. Axial, sagittal, and coronal MRI planes are displayed from top to bottom. The MRI g-ratio is quantified from myelin-sensitive imaging (macromolecular tissue volume) and diffusion-derived neurite orientation dispersion and density imaging data. The higher g-ratio (denser red coloring) corresponding to myelin thinning indicates decreased myelin integrity in the SSADH-deficient patients compared with the healthy control. SSADH = succinic semialdehyde dehydrogenase.

Vitamin Dependencies

Biotin-Thiamine–Responsive Basal Ganglia Disease

Pathogenic variants in SLC19A3 disrupting a thiamine transporter lead to biotin-thiamine–responsive basal ganglia disease. As its name implies, the disorder is considered treatable, with biotin and thiamine supplementation ensuing in clinical and neuroradiologic bettering. Untreated cases manifest with a phenotype resembling Leigh syndrome and MRI findings of evolving multifocal basal ganglia > thalami lesions that may progress over time into encephalomalacia, gliosis, and necrosis.⁵⁴ MRS may show an abnormal pyruvate peak at 2.4 ppm.⁵⁵

Cerebral Folate Deficiency

Cerebral folate deficiency represents a heterogeneous group of disorders in which 5-methyltetrahydrofolate concentrations are low in the CSF and normal in plasma. They may stem from a FOLR1 transportopathy, a severe form of methylene tetrahydrofolate reductase deficiency, dihydrofolate reductase deficiency, 5,10-methyltetrahydrofolate synthetase deficiency, mitochondrial disorders, serine deficiency, and medication (e.g., valproate) toxicity. MRI may be variably abnormal, showing atrophy of the cortex and cerebellum and hypomyelination. MRS findings of reduced choline and MI are another indication of white matter damage.⁵⁶ Parameters derived from combined quantitative MRI techniques such as magnetization transfer imaging enable monitoring of myelination in individuals with FOLR1 deficiency, providing a potential platform for long-term management.⁵⁷

Pyridoxine-Dependent Epilepsy and Pyridoxine 5′-Phosphate Oxidase Deficiency

Pyridoxine-dependent epilepsy (PDE) and pyridoxine 5′-phosphate oxidase (PNPO) deficiency (resulting from abnormally formed or absent alpha-aminoadipic semialdehyde dehydrogenase [encoded by ALDH7A1] and pyridox(am)ine-5′-phosphate oxidase [encoded by PNPO], respectively) represent 2 of the more common epileptic encephalopathies associated with pyridoxine (vitamin B6) metabolism. Refractory seizures commonly present in the first days of life. As is the case with other treatable IMEs, diagnosis of these disorders is meaningful because they are responsive to pyridoxine (PDE) or its vitamer, pyridoxal-5-phosphate (PNPO deficiency). Normal neuroimaging has been associated with a better neurodevelopmental outcome. Other characteristic findings include cortical volume loss, ventriculomegaly, and hypomyelination. In PDE, cerebellar hypoplasia, corpus callosum abnormalities, heterotopias, mega cisterna magna, and optic nerve hypoplasia have been variably demonstrated. Intracerebral hemorrhage and venous thromboses are also described in the neonatal period.⁵⁸ On MRS, neuronal loss reflected by a decreased NAA/creatine ratio was documented in the frontal and posterior cortical quadrants.⁵⁹

Conclusions

Individually, IMEs are rare, but their combined occurrence rate is high, posing a clinical challenge for neurologists. Along with genetic and metabolic tests, neuroimaging is an essential component of their diagnosis, which may be especially rewarding in treatable cases. Neuroimaging may be normal, nonspecific, or overlapping; however, there is a considerable number of IMEs that are associated with distinct patterns on MRI and MRS. These not only narrow or support diagnoses but also serve as biomarkers of treatment efficacy and outcome. Other newer modalities and techniques, such as PET, fMRI, DTI, MRI g-ratio mapping, and fNIRS, enable further insights into pathophysiologic and prognostic aspects of these disorders.

Glossary

ΔTOI

delta tissue oxygen index

ADC

apparent diffusion coefficient

DTI

diffusion tensor imaging

DWI

diffusion-weighted imaging

FLAIR

fluid-attenuated inversion recovery

fNIRS

functional near-infrared spectroscopy

GABA

γ-aminobutyric acid

Glut-1

glucose transporter 1

HIE

hypoxic-ischemic encephalopathy

IME

inherited metabolic epilepsy

IMD

inherited metabolic disorder

ISOD

isolated sulfite oxidase deficiency

LBSL

leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

MELAS

mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

MI

myoinositol

MLD

metachromatic leukodystrophy

MMA

methylmalonic acidemia

MRS

magnetic resonance spectroscopy

MSUD

maple syrup urine disease

mtDNA

mitochondrial DNA

NAA

N-acetylaspartate

NBS

newborn screening

OTC

ornithine transcarbamylase

PA

propionic acidemia

PDE

pyridoxine-dependent epilepsy

PKU

phenylketonuria

PNPO

pyridoxine 5′-phosphate oxidase

SSADH

succinic semialdehyde dehydrogenase

TE

echo time

TOI

tissue oxygenation index

UCD

urea cycle disorder

Author Contributions

I. Tokatly Latzer: drafting/revision of the manuscript for content, including medical writing for content. E. Yang: drafting/revision of the manuscript for content, including medical writing for content. V.L. Pimenta de Figueiredo: drafting/revision of the manuscript for content, including medical writing for content. S.Y. Huang: drafting/revision of the manuscript for content, including medical writing for content. T. Matsubara: drafting/revision of the manuscript for content, including medical writing for content. P.L. Pearl: drafting/revision of the manuscript for content, including medical writing for content.

Study Funding

No targeted funding reported.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.