Gangliosidoses

The gangliosidoses are divided into two groups, referred to as GM1 and GM2. In the GM1 group, the primary enzyme deficiency is that of β-galactosidase. For the GM2 group, an abnormal accumulation of gangliosides is the result of a hexosaminidase deficiency.

Mucopolysaccharidoses

The mucopolysaccharidoses are the best known of the lysosomal abnormalities affecting predominately gray matter. The primary metabolic defect in this group of disorders is a failure to break down sulfates (dermatan, heparan, and keratan); thus mucopolysaccharides fill up and overburden the lysosomes within histiocytes of the brain, bone, skin, and other organs. Glycosaminoglycans accumulate with target organs such as the bone, liver, and brain. Eight subtypes have been defined; however, six distinct forms are now recognized within this classification scheme, based on which metabolite is involved. The six are referred to as Hurler (IH), Hunter (II), Sanfilippo (III), Morquio (IV), Maroteaux-Lamy (VI), and Sly (VII), with the classic prototypical disease being that of Hurler. Coarse facial and bony features, as well as complex skeletal manifestations, are well-known clinical characteristics for all of these disorders. Without treatment, death usually comes within the first decade of life.

All of these diseases are autosomal recessive except type II, Hunter, which is an X-linked recessive condition. Hydrocephalus is common, probably as a result of plugging of the pacchionian granulation.

Cerebral MRI demonstrates two major abnormalities:

Spinal stenosis is especially common in Morquio and Maroteaux-Lamy variants but may be demonstrated in other variants. Typical bullet-shaped vertebral bodies are characteristic (Fig. 33-1).

For the mucopolysaccharidoses, proton MRS reveals a broad resonance at 3.7 ppm, which is attributed to a composite of mucopolysaccharide molecules. After bone marrow transplantation, the resonance at 3.7 ppm decreases in the brain of some patients, which may aid in determining the efficacy of the therapy. N-acetylaspartate (NAA) levels may improve in response to treatment.

Neuronal Ceroid Lipofuscinoses

NCL is a disorder or group of disorders characterized by striking volume loss of brain parenchyma. NCL, which can be divided into six subtypes based on age at onset, is one of the most common neurodegenerative syndromes, with an incidence of 1 per 25,000 live births. The various subtypes are associated with different mutations in the CLN genes and have similar clinical manifestations occurring at different ages. These manifestations include seizures and abnormal eye movements, with subsequent vision loss, dementia, hypotonia, and speech and motor deficits. CSF neurotransmitter abnormalities also have been reported in patients with NCL.⁸ At pathology, these disorders are characterized by distinctive granular inclusions in neuronal lysosomes, called granular osmiophilic deposits. Imaging findings follow behind the clinical presentation in all but the infantile form of NCL and are dominated by progressive cerebral and cerebellar volume loss. Later stages of disease are characterized by development of a band of hyperintense signal in the periventricular white matter on T2-weighted images. In palmitoyl protein thioesterase-1 related NCL, isolated, symmetric dentate nucleus hyperintensities have been reported in early stages on T2-weighted images.⁹ Proton MRS has shown progressive decreases in NAA and relative increases in mI in persons with NCL.

Metachromatic Leukodystrophy

In persons with MLD, the primary metabolic defect is a deficiency in the enzyme arylsulfatase A, resulting in the accumulation of cerebroside sulfate within the lysosome. MLD has four subtypes: congenital, late infantile, juvenile, and adult. The late infantile subtype is the most common and presents from around 14 months to 4 years of age. The early presentations are an unsteady gait that progresses to severe ataxia and flaccid paralysis, dysarthria, mental retardation, and decerebrate posturing. Gallbladder involvement has been reported, possibly appearing before the onset of neurologic symptoms. Intestinal involvement also has been reported, specifically polypoid masses in one patient.¹⁰

Histologic analysis of the abnormal nervous tissue demonstrates a complete loss of myelin (demyelination) followed by axonal degeneration. Metachromatic granules are reported within engorged lysosomes in white matter and neurons and on peripheral nerve biopsies. Oligodendrocytes are reduced in number, and areas of demyelination predominate throughout the deep white matter region. Early sparing of the subcortical arcuate white matter fibers (“U” fibers) occurs until late in the disease process. An inflammatory response typically is absent, which accounts for a lack of enhancement in this disorder, but eventually, even myelinated white matter is replaced by astrogliosis and scarring. The corpus callosum is involved before significant progression, whereas subcortical white matter remains unaffected until the disease has progressed; atrophy is a late sign. Demyelination also can be seen in the posterior limbs of the internal capsule, descending pyramidal tracts, and the cerebellar white matter.¹¹ Thalamic changes may be common in primary MLD, and isolated cerebellar atrophy may be seen in some atypical later-onset variants. On T2-weighted images, there is marked hyperintensity of the white matter fiber tracts involving the cerebral hemispheres that may extend to the cerebellum, brainstem, and spinal cord. The findings further demonstrate diffuse deep white matter involvement with relative sparing of subcortical white matter. The findings initially are focal and patchy, but later, a diffuse, hyperintense T2 signal of the centrum semiovale develops. Two distinct white matter appearances have been noted that mimic what was previously considered to be pathognomonic of Pelizaeus-Merzbacher disease (PMD). Punctate areas of hypointensity (“leopard skin” appearance) and radiating patterns of linear tubular structures of T2 hypointensity (“tigroid” appearance) are seen, with areas of relatively normal-appearing white matter within the areas of demyelination. On T1-weighted images, the white matter fibers may be isointense with, or hypotense to, gray matter (Fig. 33-2).

Proton MRS studies have demonstrated reduced NAA, which is expected with neuroaxonal loss, but they also have revealed disturbances in glial cell metabolism associated with elevated mI and choline. The levels of NAA in white matter have been found to correlate with motor function in children with MLD.¹²

Globoid Cell Leukodystrophy (Krabbe Disease)

Globoid cell leukodystrophy (Krabbe disease) arises from a deficiency in the enzyme β-galactocerebrosidase, leading to the accumulation of cerebroside and galactosylsphingosine, which induces apoptosis in the oligodendrocyte cell lines. Globoid cell leukodystrophy, an autosomal-recessive disorder, has a frequency of 2 in 100,000 in a series reported from Sweden. It is seen predominantly in young children; however, the infantile form is the most common. Onset of symptoms usually begins between 3 and 5 months after birth with irritability. The disease continues to progress, with development of symptoms mimicking encephalitis with motor deterioration and atypical seizures. At the end stage of the disease, the child is in a vegetative state with decerebrate posturing. Elevated CSF protein has been reported, to a larger extent in adult phenotypes than in phenotypes affecting younger people.¹³ Positional ocular flutter has been reported in one patient with infantile Krabbe disease.¹⁴ In nerve conduction studies, the severity of abnormalities appears to correlate with the severity of clinical symptoms.¹⁵

The disease involves predominantly the white matter of the cerebral hemispheres, cerebellum, and spinal cord. Pathologic changes include a marked toxic reduction in the number of oligodendrocytes. Multinucleated cells that appear to be globoid, as well as reactive macrophages, are scattered throughout the white matter region. Hypomyelination may be extensive and eventually leads to gliosis and scarring in the white matter region. Gray matter involvement in the basal ganglia region also can be found with punctate calcification.

Delayed myelination may be the first finding noted on MRI in infants with this disorder. In infantile Krabbe disease, MRI findings may be normal, but as the disease progresses, classic Krabbe features emerge; this phenomenon is probably related to the immature myelination.¹⁶ The appearance of Krabbe disease on MRI is featured as one of either two patterns. A patchy hyperintense periventricular signal on T2-weighted images, consistent with hypomyelination, eventually may evolve into a more diffuse pattern in the white matter. In this form, involvement of the thalami with a hyperintense T2 signal often is present as well. A second pattern is a patchy low signal on T2-weighted images in a similar distribution to the hyperdense regions seen on CT, which is suspected to represent a paramagnetic effect from calcium deposition in the region. Additional early changes include increased density in the distribution of the thalami, cerebellum, caudate heads, and brainstem that may precede the abnormally low attenuation of white matter in the centrum semiovale. Symmetric enlargement of the optic nerves also has been described in persons with Krabbe disease, which is presumed to reflect accumulation of proteolipid in globoid cells. The distal optic nerves are primarily involved; however, a case has been described with proximal prechiasmatic enlargement of the nerves.¹⁷ At times, changes within the cerebellar white matter also have been reported, with hyperintensity on T2-weighted images. The findings within the spinal cord are visualized as atrophic changes. Diffuse volume loss and periventricular white matter abnormalities predominate in the latter stages of this disease (Fig. 33-3).

Proton MRS demonstrates the reduced NAA expected with neuroaxonal loss but also has revealed disturbances in glial cell metabolism associated with hypomyelination. In addition to a reduced NAA level, elevated levels of choline and mI also have been reported in this condition, which is consistent with the general neurodegenerative pattern as seen on proton spectroscopy.

DWI also has been applied in a limited number of patients with Krabbe disease. Loss of diffusion relative anisotropy was noted in the hyperintense areas as seen on T2-weighted images, which preceded those signal changes.

Zellweger Syndrome (Cerebrohepatorenal Syndrome)

ZS is an autosomal-recessive disease characterized by defective peroxisomal functions. Infants are symptomatic early, with hypotonia, seizures, large liver size, and limb and facial anomalies that are easily recognizable at birth. A diffuse lack of myelination throughout the white matter is noted, combined with cortical dysplasia. The gyri are broad, with shallow intervening sulci found mainly in the anterior frontal and temporal lobes but also over the convexities in the perirolandic area. The presence of a germinolytic cyst in the caudothalamic groove is common in persons with ZS, and one case of germinolytic cysts with hemorrhagic transformation has been reported.¹⁸ In one case, signal abnormality suggestive of demyelination was identified almost solely in the bilateral corticospinal tracts, in particular in the brainstem with concomitant motor losses.¹⁹ Variants of ZS also have been described that do not follow the typical prototype but demonstrate many common features to ZS. Clinical overlap may occur with other conditions, including neonatal ALD, infantile Refsum disease, and hyperpipecolic acidemia. Death usually comes with many of these conditions within the first two years of life (e-Fig. 33-4).

MRS performed in older patients with ZS and Refsum disease reveals similar features, with dramatic lipid and choline elevations, minor mI elevations, and reduced NAA levels for sampled white matter. For rhizomelic chondrodysplasia punctata, two studies report elevations of mobile lipids, mI-glycine, and acetate and reduced choline levels as consistent with a deficiency in plasmalogen biosynthesis. In contrast to ZS, infantile Refsum disease, and neonatal ALD, rhizomelic chondrodysplasia punctata does not feature liver disease, which is significant to account for the mI differences. To detect mI levels, a short echo technique (i.e., TE ≤35 msec) must be used to recognize a resonance appearing at 3.5 ppm. For MRS performed at 1.5 T, the mI resonance normally is distinct, with four of the molecule’s six methine protons magnetically indistinguishable, thereby coresonating at the same location (3.5 ppm). However, increased spectral dispersion inherent at higher field strengths (3 T) now produces two distinct resonances (3.5 and 3.6 ppm) for the four protons, effectively reducing the signal by half. Normal mI levels visually appear lower at higher field strengths in contrast to 1.5 T. Although some reports have found improved detection of mI at high field strength arising from increased signal/noise ratio, it may be problematic depending on the acquisition conditions. The usage of phased array coils with parallel imaging offers tremendous advantages for imaging. Unfortunately, in the clinical setting, inadequate methods currently exist for optimally combining the elements of the phased array coil for single voxel spectroscopy applications. A single coil element with inadequate signal averaging can provide a low signal-to-noise ratio, thereby limiting the ability to detect mI.

Neonatal Adrenoleukodystrophy

Neonatal ALD is characterized by the presence of multiple recognizable enzyme deficiencies with grossly normal but deficient numbers of peroxisomes. Specific conditions include pipecolic and phytanic acidemia and a deficiency of plasmalogen synthetase. This condition also presents with hypotonia in the first months of life but without many of the facial features of ZS. Cortical abnormalities in the form of a dysplasia can be found in this condition, as well as hypomyelination in cerebral white matter (Fig. 33-5).

Adrenoleukodystrophy

X-linked ALD is the prototypical peroxisomal disorder in which the morphology of the organelle is found to be normal on electron microscopy but a single enzyme defect, acyl-CoA synthetase, along with a failure of incorporation into cholesterol esters for myelin synthesis, leads to the accumulation of very-long-chain fatty acids and progressive CNS deterioration in the form of a chronic progressive encephalopathy. This “classic” form of ALD is an X-linked disorder with a clinical onset between the ages of 5 to 7 years that includes behavioral problems, followed by a rapidly progressive decline in neurologic function and death within the ensuing 5- to 8-year period. The first indication of this condition may include mental status changes or a decline in school performance, progressing to subtle alterations in neurocognitive function, and ultimately resulting in severe spasticity and visual deficits, leading finally to a vegetative state and death. Childhood cerebral ALD, although rare, can present with raised intracranial pressure (ICP) and an elevated level of CSF protein.²⁰

X-linked ALD has been described with a typical appearance on CT and MRI with predominately posterior involvement that, over time, progresses from posterior to anterior into the frontal lobes and from the deep white matter to the peripheral subcortical white matter. On CT, the involvement appears as symmetrical low attenuation in a butterfly distribution across the splenium of the corpus callosum, surrounded on its periphery by an enhancing zone (inflammatory intermediate zone). Three zones are readily distinguished on MR: an inner zone of astrogliosis and scarring corresponds to the low density zone seen on CT that appears hypointense on T1-weighted images and hyperintense on T2-weighted sequences; an intermediate zone of active inflammation that appears isointense on T1-weighted images and isointense or hypointense on T2-weighted images; and an outer zone of active demyelination that appears minimally hypointense on T1-weighted images and hyperintense on T2-weighted scans. Enhancement after administration of gadolinium is demonstrated within the intermediate zone of active inflammation and may disappear as the first change after bone marrow transplantation (Fig. 33-6).

Patients with X-linked ALD who are evaluated with proton MRS demonstrate abnormal spectra within regions of abnormal signal, as well as white matter that appears normal. The spectral profile for normal-appearing white matter of neurologically asymptomatic patients is characterized by slightly elevated concentrations of composite choline compounds, with an increase of both choline and mI reflecting the onset of demyelination. Markedly elevated concentrations of choline, mI, and glutamine in affected white matter suggest active demyelination and glial proliferation. A simultaneous reduction of the concentrations of NAA and glutamate is consistent with neuronal loss and injury. An elevated lactate level is consistent with inflammation and/or macrophage infiltration. The more severe metabolic disturbances in persons with ALD correspond to progressive demyelination, neuroaxonal loss, and gliosis leading to clinical deterioration and, eventually, death. The detection of MRS abnormalities before the onset of neurologic symptoms may help in the selection of patients for bone marrow transplantation and stem cell transplantation. Stabilization and partial reversal of metabolic abnormalities is demonstrated in some patients after they undergo therapies. The spectral profiles can be used to monitor disease evolution and the effects of therapies.

Kearns-Sayre Syndrome

A group of clinical syndromes arising from mtDNA rearrangements, either deletions or duplications, includes Kearns-Sayre syndrome, Pearson syndrome, and progressive external ophthalmoplegia. A brief discussion about Kearns-Sayre syndrome is presented.

Kearns-Sayre syndrome is a mitochondrial cytopathy characterized by external ophthalmoplegia, retinal pigmentary degeneration, and conductive hearing block. Ragged red fibers indicative of a defect in the respiratory chain of mitochondria are demonstrated on muscle biopsy, in common with mitochondrial encephalomyopathy, lactic acidosis, and strokelike symptoms (MELAS) and myoclonic epilepsy with ragged red fibers (MERRF) syndromes. The heart is often affected, causing conduction defects, which progress to heart block, manifesting as heart failure.²¹ Choroid plexus failure also has been reported.²² Cerebral MRI demonstrates diffuse, patchy areas of hyperintensity on T2-weighted images. In the presence of calcification, both the basal ganglia and dentate regions also may show hyperintense T1-weighted signal. On T2/FLAIR images, bilateral involvement of the thalamus, basal ganglia, and brainstem are observed. Cerebral and, more frequently, cerebellar atrophy often are observed.²³ Ocular myopathy characterizes some patients affected by Kearns-Sayre syndrome (e-Fig. 33-7).

Melas Syndrome

Several clinical syndromes arising from point mutations in mtDNA are encountered. The most noticeable are MELAS syndrome, MERRF syndrome, neurogenic weakness and ataxia with retinitis pigmentosa syndrome, and Leber hereditary optic neuropathy. MELAS syndrome often is caused by an A3243G point mutation in tRNA-leu^UUR or the MTTL1 gene (80% of cases). Other phenotypes can result in the A3243G point mutation (e.g., maternally inherited deafness and diabetes). The clinical presentation of MELAS syndrome resembles that of cerebral infarction; however, the “infarcts” are affected without the usual arterial stroke patterns. Age of onset is usually between 2 and 11 years. The basal ganglia and parietal and occipital lobes are most commonly involved. Cerebral MRI demonstrates areas of hyperintensity on T2-weighted images with volume loss presenting as a late development.

Proton MRS has been used to aid diagnosis of mitochondrial disorders, with the assumption that elevation of lactic acid is a primary feature. However, positive lactate at spectroscopy does not necessarily equal the presence of a mitochondrial disorder, and the absence of lactate on MRS does not rule out a defect in mitochondrial function. Proton MRS in patients with MELAS syndrome can demonstrate variable results as strokelike lesions emerge and evolve. Proton MRS details energy failure with increased lactate and decreased creatine. Elevation of lactate in the acute and subacute stages typically is observed, with subsequent declines in NAA and creatine, consistent with neuroaxonal injury that may or may not be reversible. It has been reported that both increase of lactate peaks in MRS and state of hyperperfusion in continuous arterial spin labeling images are both indicative of active lesions.²⁴ Reports have shown that MELAS syndrome is differentiated from ischemic stroke because of its longer ADC decline. Another distinctive characteristic of MELAS syndrome is the gradual spread of the core of the edematous lesion, a contributing factor to the prolonged ADC decline²⁵ (Fig. 33-8).

Leigh Syndrome (Subacute Necrotizing Encephalomyelopathy)

Disorders arising from defects in nDNA are numerous; however, the most commonly encountered syndrome is Leigh syndrome. The genetic defect of Leigh syndrome can arise from several sources, including pyruvate dehydrogenase complex deficiency, complex I deficiency, complex V deficiency with adenosine triphosphatase 6 mutation, and cytochrome oxidase deficiency with SURF1 mutation. This group of disorders characteristically presents at 3 months to 2 years of age but may begin with symptoms of hypotonia in the newborn period or even in adulthood. Clinical signs include ophthalmoplegia, cerebellar signs, and spasticity, which are slowly progressive. Other features include psychomotor regression, extrapyramidal signs, blindness, nystagmus, respiratory compromise, or cranial nerve palsies. Onset of symptoms within the first years of life typically portends a rapid downhill course. A later onset of symptoms is generally associated with slower progression (Fig. 33-9 and e-Fig. 33-10).

Pathologically, this syndrome involves both gray and white matter of the brain and spinal cord. Common sites of anatomic involvement include the basal ganglia, specifically the globus pallidus and putamina, and the thalami, midbrain, pons, cerebellum, and medulla. Pathologic changes include spongiform degeneration, demyelination, and vascular compromise/proliferation.

An abnormal low signal on T1-weighted images or a high signal on T2-weighted images in the basal ganglia, periaqueductal gray matter, and brainstem/cerebellum are characteristic of this group of disorders. Bilateral symmetric lesions in the basal ganglia (globus pallidus and putamen) characterized by a hypointense signal on T1-weighted images and a hyperintense signal on T2-weighted images is highly suggestive of this condition and should prompt further clinical investigation for signs of lactic acid in the serum or CSF. Late involvement may manifest as regions of an abnormal hyperintense signal on T2-weighted images in the centrum semiovale.

Proton MRS images obtained from the basal ganglia, occipital cortex, and brainstem show elevations in lactate, which are most pronounced in regions where abnormalities are seen with routine T2-weighted MRI. Proton MRS images in regions of abnormal MRI signal also reveal a decrease in the NAA/creatine ratio and an increase in the choline/creatine ratio, representing neuronal loss and breakdown of membrane phospholipids. Some evidence indicates that a reduction of lactate levels may correlate with response to therapy, such as dichloroacetate and coenzyme Q10.

Pantothenate Kinase-Associated Neurodegeneration

Pantothenate kinase-associated neurodegeneration, also called neurodegeneration with brain iron accumulation (NBIA), is caused by mutations in the gene that encodes pantothenate kinase 2 (PANK2). PANK2 is necessary for the production of coenzyme A in mitochondria. Other similar mutations result in atypical presentations of the same syndrome. “Classic” NBIA has an early onset of disease in infancy, with rapid progression of gait impairment, development of choreoathetoid movements, rigidity, dysarthria, and cognitive decline. Dystonia is a prominent feature of this disorder. All of these clinical manifestations reflect the impact of the disease upon the basal ganglia and striatum. Atypical NBIA has a later presentation with slower progression (Fig. 33-11).

Menkes Disease

Menkes disease (also known as trichopoliodystrophy or kinky-hair syndrome) is an X-linked recessive mitochondrial cytopathy. The disease may commence in utero and has been recognized at birth. It appears in males with the clinical features of hypotonia, seizures, spastic quadriplegia, and profound retardation with sparse, fragile hair that is easily broken. Growth failure and microcephaly are common. Absorption of copper from the gastrointestinal tract is decreased. The defective intracellular binding and membrane transport of copper are related to an abnormal metallothionein, a copper-binding protein. Decreased activity of copper-dependent enzymes is found in the liver, brain, and white cells.

Plain radiographs may demonstrate wormian bones in the skull, rib fractures, and metaphyseal infarctions in long bones. Neuroimaging findings include cerebral volume loss and subdural collections, and cerebral angiography shows dilated and tortuous vessels within the circle of Willis. Basal ganglia lesions have been reported in advanced stages; however, a case documented basal ganglia involvement in a patient in the early stages of Menkes disease.²⁶ A hyperintense signal within white matter on T2-weighted images indicates a lack of myelination with this disorder, but this finding may be related to a relative lack of blood flow as a result of the vascular involvement. The combination of extracerebral collections and metaphyseal infarctions may simulate battered child syndrome (Fig. 33-12).

Glutaric Aciduria

Glutaric aciduria type I is an organic aciduria resulting from deficiency of the enzyme glutaryl-CoA dehydrogenase, which is involved in the metabolism of hydroxylysine, lysine, and tryptophan. It is autosomal recessive in origin. Presentation may be acute with encephalopathy or chronic with multiple neurologic abnormalities, including hypotonia, ataxia, dysmetria, and delayed achievement of milestones.

Brain MRI demonstrates hyperintensity on T2-weighted images in the basal ganglia, especially the putamen, but also in the caudate nucleus and globus pallidus. Myelination is delayed. Bilateral temporal arachnoid cysts and enlarged frontotemporal spaces with subdural hematomas may be found. As a consequence, this rare disorder is sometimes considered as a differential diagnosis in children with nonaccidental trauma. The development of T2 prolongation in the basal ganglia and periventricular white matter would support the diagnosis of glutaric aciduria type I in such cases. The enlargement of extraaxial spaces makes glutaric aciduria type I one of the metabolic diseases associated with macrocrania. Unlike in Alexander disease and Canavan disease, the macrocrania does not reflect megalencephaly. Enlargement of the sylvian fissure has been correlated with severity of the enzyme deficiency. Acute striatal necrosis is the main cause of death during infancy; it can be visualized as usually symmetric, strokelike signal hyperintensity on T2-weighted and diffusion-weighted MRI, bilateral striatal lucency on CT, or a sharp decline of fluorodeoxyglucose uptake on positron emission tomography.²⁷ Prenatal MRI has been shown to be useful in identifying GA1, revealing focal reduction of the anterior pole of both temporal lobes with widening of the liquoral space²⁸ (Fig. 33-13).

Methylmalonic and Proprionic Acidemias

Methylmalonic acidemia results from a deficiency in methylmalonyl CoA mutase, an enzyme required for the conversion of methylmalonic CoA to succinyl CoA, which is necessary for the proper metabolism of the amino acids methionine, threonine, isoleucine, and valine. The high levels of methylmalonic acid resulting from the enzyme deficiency inhibit succinate dehydrogenase, which disrupts aerobic metabolism in the mitochondria. A relatively milder form of the disease is caused by deficiency of the cobalamin coenzyme. Propionic aciduria is a result of a deficiency in propionyl-CoA carboxylase and presents in a similar fashion (e-Fig. 33-14).

Epilepsy is common in patients with methylmalonic acidemia, and cardiac involvement, including cardiomyopathy, arrhythmias, carnitine deficiency, and structural heart disease, have been reported.29,30 Hyperglycemia also has been reported.³¹ On imaging, parenchymal volume often is decreased, with delays in myelination. Optic neuropathy also has been reported.³² Like other mitochondrial-based syndromes, the organic acidemias have a strong tendency to cause lesions in the basal ganglia, most particularly the globus pallidus. Lesions in the globus pallidus are striking in their stereotypical appearance from patient to patient. Affected areas will appear low in attenuation on CT and hyperintense on T2-weighted MRI. Strokelike episodes similar to MELAS occasionally may be encountered. DWI will show restricted diffusion in affected regions. Proton MRS has shown decreases in NAA and elevation of lactate levels. Lactate elevation also can be found in the CSF, which is important for narrowing the differential diagnosis.

Phenylketonuria

Phenylketonuria is an autosomal-recessive disorder resulting from enzyme deficiencies (phenylalanine hydroxylase, dihydrobiopterin reductase, and dihydrobiopterin biosynthesis) that impair the ability to convert phenylalanine to tyrosine, thereby producing the accumulation of neurotoxic acids. Its frequency is on the order of 1 : 14,000 live births.

Brain MRI appearances initially demonstrate symmetric hyperintense areas on T2-weighted images in the periatrial white matter. Extension occurs into the optic radiations and periventricular frontal white matter with more severe involvement and contrast enhancement. In untreated patients, it has been reported that diffuse white matter pathology is evidence of hypomyelination; however, white matter abnormalities in patients who are treated early are indicative of intramyelinic edema.³³ Hyperintensity in multiple areas on T1-weighted images has been reported, corresponding to subcortical parenchymal calcification.

White matter alterations revealed on MRI studies in patients with phenylketonuria correlated to blood phenylalanine concentrations and to brain phenylalanine concentrations measured by proton MRS. MRS may demonstrate an abnormal peak at 7.30 ppm resulting from elevated phenylalanine. Interindividual variations of blood-brain barrier phenylalanine transport constants and variations of the individual brain phenylalanine consumption rate are responsible for the patient differences.

Maple Syrup Urine Disease

MSUD is a rare autosomal-recessive disorder caused by defective oxidative decarboxylation of three branched-chain amino acids: valine, isoleucine, and leucine. The accumulation of metabolites in the urine leads to the characteristic odor, which resembles that of maple syrup. Although cerebral imaging findings initially may be unremarkable, diffuse cerebral edema develops with subsequent residual areas of hyperintensity in the dorsal brainstem and pons. Proton MRS of the brain appears to be useful for examining patients who have MSUD in different metabolic states. The accumulation of abnormal branched-chain amino acids and branched-chain alpha-ketoacids appear as a broad peak at 0.9 ppm accompanied by an elevated lactate level. The presence of cytotoxic or intramyelinic edema as evidenced by restricted water diffusion on DWI, with the presence of lactate on spectroscopy, could imply cell death. However, in the context of metabolic decompensation in MSUD, it appears that changes in cell osmolarity and metabolism can reverse completely after metabolic correction. Classification of MSUD includes a form that is responsive to thiamine (Fig. 33-15).

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia occurs when a metabolic defect impairs the conversion of glycine to serine, resulting in an accumulation of glycine within the CNS. The toxic effects of an elevated glycine level present in the neonatal period as lethargy, hypotonia, myoclonus, and seizures that may lead to an unresponsive state with apnea. Prognosis is poor, with few patients surviving beyond the neonatal period.

Pathology in nonketotic hyperglycinemia is characterized by vacuolation, astrocytosis, and demyelination, also called vacuolating myelinopathy. Because these changes only occur in myelinated white matter, in the neonate they are restricted to the dorsal limbs of the internal capsule, dorsal brainstem, pyramidal tracts in the coronal radiata, and lateral thalamus. A long tractlike lesion involving the spinal cord has been reported in persons with late-onset disease.³⁴ On MR, these areas will show a hyperintense signal on T2-weighted images and restricted diffusion on DWI. Volume loss ensues and may be present at birth as a result of the toxic effects of glycine in utero. Proton MRS can detect the accumulated glycine itself, as a distinct resonance at 3.55 ppm. In patients with nonketotic hyperglycinemia, elevated cerebral glycine can be measured with proton MRS. Using long echo times, such as 288 ms, MRS reveals glycine at 3.5 ppm. With use of short echo times, the resonance at 3.5 is a composite of mI and glycine. Select metabolite ratios (NAA, mI, and glycine) appear to correlate with the patient’s course (Fig. 33-16).

Canavan Disease

Canavan disease is an autosomal-recessive disorder arising from a deficiency of the enzyme aspartoacyclase, which results in the accumulation of NAA acid in the brain. Three clinical subtypes—infantile, juvenile, and adult—are recognized. The most common is the infantile type, which usually presents within the first 6 months of life with hypotonia, irritability, and enlarging head size, leading to spasticity, blindness, choreoathetoid movement, and myoclonic seizures.

The diagnosis is made by demonstrating increased amounts of NAA in the urine and plasma. On histologic examination, the disease is seen to begin in a peripheral location, involving the U fibers of the subcortical white matter of the cerebral hemispheres. Later, the abnormality involves the deep white matter structures of both cerebral hemispheres, and eventually it extends to the cerebellum and spinal cord. The involvement of the U fibers of the white matter is diffuse, with evidence of vacuoles within the subcortical white matter and extending into the adjacent cortex.

The MRI findings are related to the myelin degeneration of the white matter tracts. The first change detected is hyperintensity on T2-weighted images of the subcortical U fibers. Eventually there is diffuse involvement of all the white matter fiber tracts in both cerebral hemispheres. In the later stages of the disease, volume loss of the cerebral hemispheres occurs. Enlarged perivascular spaces, likely reflecting spongiform degeneration of the white matter, has been described in one patient.³⁵ MRS demonstrates marked elevation of the NAA peak, which is diagnostic for Canavan disease (Fig. 33-17).

Alexander Disease

Missense mutations in the gene encoding for glial fibrillary acidic protein (GFAP) are found in all three clinical variants (infantile, juvenile, and adult) of Alexander disease. In brain biopsy specimens, Rosenthal fibers label extensively for GFAP upon immunocytochemistry. The mutations in Alexander disease are heterozygous and dominant, and accordingly most cases are sporadic. The most commonly encountered variant of Alexander disease is the infantile form, which presents in the first 2 years of life with megalencephaly and developmental delay and frequently with seizures. Children with the infantile form of the disease rarely survive to the second decade. The juvenile form presents after 4 years of age with speech and swallowing difficulties, ataxia, and spasticity. Progression is slower, with a more prolonged survival. Adult-onset disease has a more variable clinical presentation and occasionally is diagnosed incidentally at autopsy.

The diagnosis traditionally has been performed via a brain biopsy. The predominant histologic feature is a considerable amount of Rosenthal fibers within the white matter. Most commonly, the disease begins in the periventricular white matter, usually involving the frontal lobes and then extending into the parietotemporal and then the occipital regions. Eventually, involvement of the cerebellar white matter and spinal cord occurs. CSF oligoclonal bands have been reported in the adult-onset variant.³⁶

The MRI findings demonstrate macrocephaly with hyperintensity on T2-weighted images involving the white matter areas, which commonly is seen in the frontal areas with progression posteriorly to involve other parts of the cerebral hemispheres. According to van der Knapp et al.,³⁷ the findings of frontal predominance, a periventricular rim of high-T2/low-T1 signal, involved central gray matter and brainstem, plus enhancement of portions of the involved areas are very characteristic of this disease (Fig. 33-18).

van der Knapp et al³⁸ identified five characteristics of Alexander disease on MRI that can be applied to suspected cases to make a presumptive diagnosis. These characteristics are (1) extensive cerebral white matter changes with frontal predominance, (2) a periventricular rim with a high signal on T1-weighted images and a low signal on T2-weighted images, (3) signal abnormalities with swelling or volume loss in the basal ganglia and thalami, (4) brainstem signal abnormalities, and (5) contrast enhancement of one or more of the following structures: ventricular lining, periventricular rim of tissue, white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, or brainstem structures. Although many of these abnormalities may be seen in other leukodystrophies, the association of four or more appears to be relatively specific for Alexander disease. The extent and pattern of contrast enhancement and the distinctive periventricular rim of abnormal signal are not encountered in many other processes. This leukodystrophy is one of the few in which the administration of contrast material provides specific additional information that can lead to the correct diagnosis by imaging.

Brockmann et al.³⁹ used localized proton MRS to assess metabolic abnormalities in gray and white matter, basal ganglia, and cerebellum of four patients with infantile Alexander disease identified with heterozygous de novo mutations in the gene-encoding GFAP. Elevated concentrations of mI in conjunction with normal or increased choline compounds in gray and white matter, basal ganglia, and cerebellum point to astrocytosis and demyelination. Neuroaxonal degeneration, as reflected by a reduction of NAA, was most pronounced in cerebral and cerebellar white matter.

Megalencephalic Leukoencephalopathy with Subcortical Cysts

Megaloencephalic leukoencephalopathy with subcortical cysts typically presents in infancy or childhood with macrocrania, developmental delay, seizures, and motor disability. MRI demonstrates widespread signal abnormalities throughout the white matter, with sparing of deep structures. Cysts typically are identified in the subcortical temporal lobes and less frequently in the frontal, parietal, or occipital lobes. Despite the extensive abnormalities on imaging, many affected patients achieve a high level of normal function. The genetic source of the condition has been traced to a gene on the long arm of chromosome 22 (22q13.33), the MLC1 gene. The disease is inherited in an autosomal-recessive pattern, and because of the variable phenotype, identification of a single case should prompt further investigation and genetic counseling (e-Fig. 33-19).

Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Elevated White Matter Lactate

Leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate recently has been described based on the MRI characteristics. Initial childhood development is generally unremarkable; the onset of presentation for leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate occurs in childhood with motor deterioration. The MRI pattern is quite distinct. The progressive white matter abnormalities spread from the periventricular region outward with sparing of the subcortical U fibers. The corpus callosum is affected with posterior preference. The pyramidal tracts are affected over their entire length from the posterior limb of the internal capsule and brainstem into the lateral corticospinal tracts of the spinal cord. The sensory tracts are involved from the dorsal columns in the spinal cord, the medial lemniscus through the brainstem up to the level of the thalamus, and the corona radiata above the level of the thalamus. The cerebellar involvement progresses over time to the point of significant volume loss. Clinical severity and the extent of neurologic abnormalities on MRI do not appear to correlate⁴⁰ (e-Fig. 33-20).

Galactosemia

Galactosemia is the result of a deficiency in galactose-1-phosphate uridyl transferase, which is an enzyme essential for the metabolism of galactose. It presents in infants soon after the introduction of cow’s milk into the diet. Clinical features include failure to thrive, hepatomegaly with jaundice, vomiting and diarrhea, cataracts, increased ICP, and mental deterioration. It can be identified by the presence of increased reducing substances in the stool. Neurologic dysfunction is the result of hypoglycemia and the accumulation of galactose, galactose-1-phosphate, and galactitol in the brain and eye. In adult forms, low bone density often is observed.⁴¹

On CT, diffuse low attenuation of white matter mimicking diffuse edema often is present. The most consistent early finding on MRI is a delay in myelination, which may appear as persistence of a hyperintense signal in the peripheral white matter on T2-weighted images. These signal abnormalities may be more widespread in older children as a result of demyelination. Patchy areas of focal increased signal on T2-weighted images also have been reported and are thought to represent damaged areas of white matter. Eventually a pattern of mild cerebral or cerebellar volume loss is found.

Brain edema may occur in infants with galactosemia and has been associated with accumulation of galactitol.

Creatine Deficiency

Inborn errors of creatine metabolism, specifically defects in creatine synthesis and transport, recently have been reported. In many brain structures, including the cortex and basal ganglia, arginine glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) are expressed in a disassociated way rather than being coexpressed, leading to the thought that guanidinoacetate must be transported from AGAT to GAMT.⁴² Proton MRS clinical studies have led to the discovery of three creatine deficiency syndromes: creatine transporter deficiency syndrome, AGAT deficiency, and (3) GAMT deficiency. Several patients have been found to have a markedly diminished or absent creatine signal with proton MRS. If proton MRS reveals the absence of creatine in the brain, serum and urine creatine assessments may give a preliminary indication of whether there is a synthesis defect (diminished creatine) or a transport defect (elevated creatine). In cases of synthesis defects, proton MRS can monitor increasing brain creatine concentration with oral supplementation, which offers improvement of some symptoms but not recovery of normal function (Fig. 33-21).

Pelizaeus-Merzbacher Disease and Disorders of Myelin Proteolipid Protein

PMD is condition that manifests as a primary defect in myelin formation. It is the prototypical hypomyelination syndrome, in that the imaging appearance is of an otherwise normal brain that is severely delayed in its formation of myelin.

Mutations or duplications of the gene-encoding myelin proteolipid protein (PLP; Xq22.2) produce variable clinical manifestations resulting from alterations in this gene. Spastic paraplegia type 2 is characterized by lower limb spasticity alone. Persons with “complicated” spastic paraplegia type 2 exhibit cerebellar ataxia, nystagmus, and a pyramidal syndrome. The more severe phenotypic manifestations traditionally have been categorized as PMD and result in alterations of multiple functional systems, with symptoms including nystagmus and compromises in respiratory function, with associated severe disability and morbidity.

The classic descriptions of PMD divide it into several different subtypes. The most common presentation is that of the slowly progressive “classic” form that presents in infancy with early nystagmus (“dancing eyes”), poor head control, spasticity, ataxia or extrapyramidal movement disorders, and severe developmental delay. These findings slowly progress, usually leading to death in late adolescence or young adulthood. A second pattern (connatal, or the Seitelberger type) begins in the neonatal period and is more rapidly progressive, with death typically occurring in the first decade.

Imaging demonstrates a marked delay in myelination from the onset. Whereas many metabolic or neurodegenerative processes are associated with delayed myelination, the absence of other imaging findings is characteristic of the early stages of the PLP gene disorders. On CT, hypomyelination can be appreciated as diffuse low attenuation of white matter. The characteristic normal progression of myelination as detected by MRI in the first 2 years of life is well documented in multiple texts. T1-weighted images show a steady development of shortening (bright signal) in white matter tracts as they acquire myelin during the first 10 to 12 postnatal months. A similar advance of T2 shortening (dark signal) can be seen during the 6- to 24-month time frame. This steady progression is entirely absent or severely slowed in persons with the PLP gene disorders. Myelination that does occur tends to be patchy, without the characteristic predictable distribution within the white matter tracts. In the later stages of disease, white matter volume may decrease, with thinning of the corpus callosum and excess mineralization in the basal ganglia.

Diffusion tensor imaging has been reported to be effective for detecting subtle changes in the microstructure of the white matter, such as abnormal myelination, even when findings of MRI and MRS are normal.⁴³

Diminished values of NAA and mild elevations of choline have been reported when MRS is performed in patients with PMD, indicating axonal injury and secondary gliosis. Plecko et al.⁴⁴ found heterogeneous cerebral metabolite patterns in patients with PMD and Pelizaeus-Merzbacher–like disease, indicating a mixture of unspecific changes as a result of primary hypomyelination and secondary gliosis and demyelination. However, neither MRI nor MRS provided unique patterns to allow differentiation between patients with PMD and Pelizaeus-Merzbacher–like disease.

Huntington Disease

Huntington disease (HD) is an autosomal-recessive degenerative disorder that is uncommon in children, with most cases presenting after the fourth decade. HD is characterized by a movement disorder. Cerebellar symptoms, seizures, rigidity, and mental retardation are common. Caudate volume loss is demonstrated on MRI, although cortical changes also may be detected.⁴⁵ Bilateral areas of hyperintensity may be seen in the basal ganglion on T2-weighted images. Global atrophy in persons with HD shows a disproportionate relationship to caudate involvement.⁴⁶ In pre-HD, gray matter change has been reported to be specific to regions consistent with basal ganglia-thalamocortical pathways, whereas white matter changes were much more generalized.⁴⁷ White matter diffusivity abnormalities also have been reported in the corpus callosum and external/extreme capsules.⁴⁸ In premanifest gene carriers, the white matter pathway of the sensorimotor cortex is impaired.⁴⁹ Changes in the hypothalamic region have been reported in prodromal HD and appear to be one of the earliest evident features of this disease.⁵⁰

Fahr Disease

Fahr disease comprises a group of disorders that have basal ganglia calcification. Mental deterioration and growth retardation have been described. Cerebral MRI demonstrates areas of signal void within the basal nuclei and dentate nuclei on T1- and T2-weighted images. The appearances correlate with the areas of calcification on CT. Transcranial sonography also has been reported to be useful for visualizing calcifications of the basal ganglia.⁵¹

Wilson Disease

Hepatolenticular degeneration, or Wilson disease, is inherited in an autosomal-recessive fashion and is a result of an inborn error in copper metabolism. Ceruloplasmin, the serum transport protein for copper, is deficient, with resultant copper deposition in various sites. This disease typically presents in young adults with chronic hepatic insufficiency and neurologic deterioration. Copper fails to be excreted in the bile and thus accumulates in the body, especially in liver, brain, kidney, and red blood cells. The clinical presentation is primarily that of extrapyramidal signs, hepatic insufficiency, and the presence of Kayser-Fleischer corneal rings. Either the hepatic toxicity or the neurologic findings may predominate. Neurologic dysfunction begins with changes in mentation, abnormalities in speech or language, and difficulty swallowing, all of which may progress with time.

On CT, the basal ganglia are typically low in attenuation, especially the globus pallidus and putamen arising from copper accumulation. Volume loss of these structures eventually follows. The white matter also may appear low in attenuation, with volume loss eventually leading to compensatory dilatation of the lateral ventricles. On MRI, the basal ganglia are hyperintense on T1-weighted images and the first echo of the T2-weighted sequence, as seen with other causes of hepatic dysfunction. These same regions typically are hyperintense on T2-weighted images early in the course of the disease, but the hyperintense signal may decrease late in the disease associated with an increase in signal on the T1-weighted images. The white matter demonstrates progressive increase in T2-signal as a result of demyelination and gliosis. Corpus callosum abnormalities also have been reported.⁵² The presence of signal changes involving the basal ganglia, thalami, and brainstem; the “face of giant panda” sign; midbrain tectal plate signal changes; or central pontine myelinolysis-like changes all can be considered to be diagnostic of Wilson disease.⁵³

Dali, C, Hanson, LG, Barton, NW, et al. Brain N-acetylaspartate levels correlate with motor function in metachromatic leukodystrophy. Neurology. 2010;75(21):1896–1903.

Ergül, Y, Nili, K, Sagygili, A, et al. Kearns-Sayre syndrome presenting as somatomedin C deficiency and complete heart block. Turk Kardiyol Dern Ars. 2010;38(8):568–571.

Kamate, M, Hattiholi, V. Normal neuroimaging in early-onset Krabbe disease. Pediatr Neurol. 2011;44(5):374–376.

Miller, E, Widjaja, E, Nilsson, D, et al. Magnetic resonance imaging of a unique mutation in a family with Pelizaeus–Merzbacher disease. Am J Med Genet A. 2010;152A:748–752.

Toscano, M, Canevelli, M, Giacomelli, E, et al. Transcranial sonography of basal ganglia in calcifications in Fahr disease. J Ultrasound Med. 2011;30(7):1032–1033.

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