Inherited Metabolic and Neurodegenerative Disorders

Gangliosidoses

The gangliosidoses are divided into two groups, referred to as GM1 and GM2. In the GM1 group, the primary enzyme deficiency is in β-galactosidase, and in the GM2 group there is a hexosaminidase deficiency.

Mucopolysaccharidoses

The mucopolysaccharidoses are the best known of the lysosomal abnormalities affecting predominately gray matter. The primary metabolic defect is a failure to break down sulfates (dermatan, heparan, and keratan); mucopolysaccharides fill 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 Hurler syndrome. All of these diseases are autosomal recessive except Hunter (type II), which is an X-linked recessive condition. Coarse facial features and complex skeletal manifestations are well-known clinical characteristics for all of these disorders. Without treatment, death usually comes within the first decade of life.

MRI demonstrates two major abnormalities ( Fig. 33.1 ): (1) diffuse patches of hyperintensity on T2-weighted images resulting from accumulation of mucopolysaccharide in neurons and astrocytes and degenerative effects on myelin, and (2) prominent cystic or perivascular spaces resulting from metabolite accumulation within histiocytes located in perivascular areas, which is the most characteristic imaging feature; reversal of these changes after bone marrow transplantation has been reported. Hydrocephalus is common, probably as a result of plugging of the pacchionian granulations. Spinal stenosis is especially common in Morquio and Maroteaux-Lamy variants but may be demonstrated in other variants. Bullet-shaped vertebral bodies are characteristic.

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 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 have been reported. At pathology, these disorders are characterized by distinctive granular inclusions in neuronal lysosomes (granular osmiophilic deposits). Imaging findings lag the clinical presentation in all but the infantile form of NCL and are dominated by progressive cerebral and cerebellar volume loss. Later disease stages are characterized by the 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 T2 hyperintensities have been reported in early stages. Proton MRS has shown progressive decreases in NAA and relative increases in mI in persons with NCL.

Metachromatic Leukodystrophy

The primary metabolic defect in MLD is a deficiency in the enzyme arylsulfatase A, resulting in lysosomal accumulation of cerebroside sulfate. 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.

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. An inflammatory response typically is absent, which accounts for a lack of enhancement, but eventually even myelinated white matter is replaced by astrogliosis and scarring. The corpus callosum is involved early, whereas subcortical arcuate white matter fibers (“U” fibers) 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. 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 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) and globoid cell leukodystrophy (Krabbe disease). 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 hypointense 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.

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 oligodendrocyte cell lines. It is an autosomal-recessive disorder with a frequency of 2 in 100,000. Onset of symptoms usually begins between 3 and 5 months after birth with irritability. Disease progression leads to 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, more so in adult phenotypes than in phenotypes affecting younger people. In nerve conduction studies, the severity of abnormalities appears to correlate with the severity of clinical symptoms.

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

In infantile Krabbe disease, MRI findings may be normal or show delayed myelination, but as the disease progresses, classic Krabbe features emerge. The appearance of Krabbe disease on MRI is featured as one of either two patterns. The first is a patchy hyperintense periventricular signal on T2-weighted images, consistent with hypomyelination, which eventually may become more diffuse; involvement of the thalami is often present as well. The 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. The distal optic nerves are primarily involved; however, a case has been described with proximal prechiasmatic enlargement of the nerves. T2 hyperintensity within the cerebellar white matter has been reported. 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 ). Midbrain morphology on midsagittal MR images reflects the extent of neurodegeneration in Krabbe disease. The morphology of the midbrain (i.e., convex, flat, concave) appears to be a reliable tool in assessing the clinical progression of the disease. On MRI of the spine, abnormal thickening of the cauda equina roots is observed in Krabbe disease.

Proton MRS demonstrates the reduced NAA expected with neuroaxonal loss but also has revealed disturbances in glial cell metabolism associated with hypomyelination. Elevated levels of choline and mI also have been reported, which is consistent with the general neurodegenerative pattern seen on proton spectroscopy. DWI also has been applied in a limited number of patients with Krabbe disease; loss of diffusion relative anisotropy preceded changes in T2 hyperintensity.

Zellweger Syndrome (Cerebrohepatorenal Syndrome)

ZS is an autosomal-recessive disease characterized by defective peroxisomal functions. Infants are symptomatic early, with hypotonia, seizures, hepatomegaly, and limb and facial anomalies that are easily recognizable at birth. MRI shows a diffuse lack of myelination throughout the white matter, 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 ( e-Fig. 33.4 ). The presence of a germinolytic cyst in the caudothalamic groove is common and may have hemorrhage. In one case, signal abnormality suggestive of demyelination was identified almost solely in the brainstem corticospinal tracts. 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 2 years of life.

MRS in older patients with ZS and Refsum disease reveals similar features, with dramatic lipid and choline elevations, minor mI elevations, and reduced NAA levels in sampled white matter. For rhizomelic chondrodysplasia punctata, two studies report elevations of mobile lipids, mI-glycine, and acetate and reduced choline. 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) produces two distinct resonances (3.5 and 3.6 ppm) for the four protons, effectively reducing the signal by half. 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.

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 presents with hypotonia in the first months of life but without many of the facial features of ZS. Cortical dysplasia can be found, as well as hypomyelination, in cerebral white matter ( Fig. 33.5 ).

Adrenoleukodystrophy

X-linked ALD is the prototypical peroxisomal disorder in which organelle morphology is 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, 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.

CT and MRI findings in X-linked ALD show predominately posterior involvement that, over time, progresses anteriorly 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 ).

Proton MRS demonstrates 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 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, and monitoring after treatment. Stabilization and partial reversal of metabolic abnormalities is demonstrated in some patients.