Inherited Metabolic and Neurodegenerative Disorders

Chapter 33

Inherited Metabolic and Neurodegenerative Disorders

Inherited Metabolic Brain Disorders

Inherited metabolic brain disorders produce changes in brain metabolism and structure as a result of genetic mutations affecting enzyme function, protein, and mitochondrial expression. Clinically, children with metabolic brain disorders often present with nonspecific symptoms, such as hypotonia, seizures, and developmental delay, which often makes diagnosis difficult. A combination of neurologic symptoms with and without visceral manifestation and age at onset of symptoms often are important factors indicating an underlying inherited metabolic brain disorder. The diagnosis traditionally has been accomplished by laboratory analyses of biologic specimens (i.e., urine or blood) and tissue (muscle or fibroblast) biopsy. However, the increased availability of imaging studies incorporating advanced techniques, specifically magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) and MR spectroscopy (MRS), offers more diagnostic features, thereby improving the ability to recognize disease patterns and classify patients for metabolic and genetic investigations with candidate diseases prioritized from imaging and clinical features. Although the number of metabolic brain disorders is significant, neuroradiologists should be able to recognize the features of the key disorders outlined in this chapter.

Because these disorders generally are progressive, the classification of neurodegenerative features also is used appropriately as imaging findings worsen—for example, cortical volume loss, gliosis, and hypomyelination. The generic term “hypomyelination” is used to describe abnormal myelination, whether it is improperly formed or altered after formation, because distinguishing demyelination from dysmyelination is a pathologic analysis, not one that can be distinguished objectively by imaging alone. Because these diseases frequently or primarily involve the white matter, they often are put into a general category of leukodystrophy. The known leukodystrophies are genetic diseases involving defects in oligodendroglia function and myelinogenesis. The term “leukodystrophy” describes a chronic, progressive, destructive process of the white matter within the central nervous system (CNS) characterized by a metabolic disorder of myelin sheath formation and maintenance. It belongs to a larger group of so-called degenerative processes of the nervous system. These disorders often are characterized by a slow but progressive loss of nervous system structures. The clinical course is progressive and typically includes mental retardation with signs of long tract dysfunction, such as pyramidal and cerebellar disturbances with abnormal conduction of visual auditory and somatic sensory input as measured by evoked potentials.

In young children, more heavily T2-weighted sequences with a repetition time of 2500 to 3000 msec and time to echo (TE) of 100 to 200 msec should be obtained, especially in children younger than 5 years. It is difficult to evaluate the degree of myelination in children younger than 2 years because the normal myelination process does not begin until the fifth month of fetal gestation and proceeds rapidly during the first 2 years of life. Fluid-attenuated inversion recovery (FLAIR) imaging may be misleading before 18 months of age because it sharpens the difference between myelinated and even physiologically unmyelinated white matter. By 2 years of age, 90% of all the white matter fiber tracts have become myelinated, but myelination is incomplete, and some variability exists in the meeting of various milestones. In children younger than 2 years, the destructive process may not be adequately demonstrated on T2-weighted images. However, by 2 years of age and older, a destructive process in which there is hyperintensity of the white matter fibers on long T2-weighted images is demonstrated in the leukodystrophies instead of the normal hypointensity. In recent reports, contrast enhancement has been helpful because many of the newly recognized leukodystrophies have disruption of the blood-brain barrier. The end-stage appearance of all the leukodystrophies on computed tomography (CT) or MRI is marked generalized volume loss. Most leukodystrophies involve the central white matter in a symmetric fashion; Canavan disease is the exception. Patients with delayed myelination or symmetrically abnormal myelination from an earlier insult may have an imaging appearance similar to an early leukodystrophy, making radiologic diagnosis less accurate. Symptoms in these children may be similar to those in children with a leukodystrophy.

DWI provides information about the gross mobility of water. Cytotoxic and myelinic edema can produce a hyperintense signal of diffusion-weighted images. To distinguish this signal from a hyperintense signal arising from T2 weighting, an apparent diffusion coefficient (ADC) map can be generated easily. On an ADC map, cytotoxic and myelinic edema generates a hypointense signal, indicating a restriction of water diffusion. Diffusion tensor imaging holds the promise of providing microstructural details about the white matter by revealing the magnitude and direction of water movement along the axons. As myelination is detected, water molecules demonstrate reduced diffusivity and increased diffusion anisotropy. Abnormal myelin can be quantitated from changes in these properties using measures such as mean diffusivity and fractional anisotropy.

MRS is useful in the evaluation of metabolic diseases in children because many laboratory studies that test for systemic metabolic diseases often do not reveal abnormalities, especially when the metabolic derangements are within localized regions of the brain. When CNS involvement is demonstrated on anatomic MR images, the MRS spectrum is usually abnormal. In some metabolic disorders, abnormalities are observed in the MRS spectrum in the absence of anatomic MR abnormalities, that is, creatine deficiency syndromes.

In the evaluation of a possible metabolic disorder, acquiring both short- and long-echo spectra offers the most diagnostic utility. The use of a short echo time allows for the detection of metabolites with faster T2 decay, especially glutamine/glutamate and myo-inositol (mI). The long-echo spectra have a flatter baseline, which is important for the detection of lactate, a double resonance at 1.3 ppm. Identification of lactate within cerebral tissue typically reflects mitochondrial impairment and should raise suspicion of mitochondrial disease, with confirmation by a muscle biopsy and possibly laboratory analyses of serum or cerebrospinal fluid (CSF). Mitochondrial enzyme systems are involved in many key cell metabolic pathways—oxidative phosphorylation, oxidation of fatty acids and amino acids, and processes involved in the Krebs cycle and part of the urea cycle. Abnormal lactate accumulation detected in patients with mitochondrial disorders can reflect the following mechanisms: (1) a high degree of nonoxidative glycolysis resulting from impaired oxidative energy metabolism, (2) the use of anaerobic metabolism by infiltrating macrophages, and (3) damage to or loss of viable neuroaxonal tissue.

This chapter includes as a reference a large listing of metabolic brain diseases encountered in the imaging setting (see Tables 33-1 to 33-10). For convenience, the recognized metabolic or genetic defect and the patterns of inheritance are summarized. However, because of space limitations, the following discussion will address only the most commonly encountered of these rare disorders.

Lysosomal Storage Diseases

Many neurodegenerative diseases are characterized by the accumulation of nondegradable molecules in cells or at extracellular sites in the brain. One such family of diseases is lysosomal storage disorders, which result from defects in various aspects of lysosomal function. The lysosomes are intracellular organelles responsible for degrading lipids, proteins, and complex carbohydrates. In most lysosomal disorders, the genetic mutation resulting in the absence or partial deficiency of an enzyme or protein is known and functionally understood. For most of the lysosomal diseases, the substrate for the defective enzyme builds up, leading to intralysosomal storage. Although the diseases are complex, mechanical disruption of the cell as a result of the storage of nondegradable material leads to cellular dysfunction. In general, the pathology primarily involves neuronal dysfunction rather than loss, with the exception of differential loss of Purkinje cells that characterize several storage diseases, including Niemann-Pick disease type C and the massive cell loss that occurs in the neuronal ceroid lipofuscinoses (NCLs). It is not known whether the storage material affects cellular function only when it begins to accumulate in extralysosomal sites or if problems in cell homeostasis are triggered while the material is still confined to the lysosome.

Lysosomal disorders typically are inherited as autosomal-recessive traits; they usually afflict infants and young children, involve brain pathology, and are untreatable. However, adult-onset forms exist. The collective frequency of lysosomal storage diseases is estimated to be approximately 1 in 8000 live births, with some occurring at high frequency in select populations. The common biochemical hallmark of these diseases is the storage of macromolecules in the lysosome.

Lysosomal disorders primarily affecting gray matter include the gangliosidoses, mucopolysaccharidoses, and NCLs. Two of the more common lysosomal disorders, metachromatic leukodystrophy (MLD) and Krabbe disease, demonstrate abnormalities in white matter. However, broader involvement of gray and white matter often occurs in later stages of lysosomal disease progression.


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.

GM1 Gangliosidosis

Three types of GM1 gangliosidosis exist: type I (infantile), type II (late infantile/juvenile), and type III (adult). An intermediate form between infantile and juvenile has been reported.1 The clinical presentation of GM1 gangliosidosis typically occurs in infancy; its features include seizures, decerebrate posturing, pitting edema of the face, hypotonia, developmental delay, hepatosplenomegaly, macrocephaly, and cherry red spots involving the macula of the retina. Additional features include broad digits, kyphoscoliosis, skeletal dysplasia with widening of the metabphyses, and dermal pigmentary lesions.2 The course is progressive, with death common within 2 years of life. A juvenile form presents during the second year of life with progressive ataxia but without many features of the infantile variety.

The underlying deficiency of β-galactosidase results in accumulation of GM1 ganglioside in both gray and white matter of the cerebrum, brainstem, cerebellum, and spinal cord. Results of cerebral MRI initially are normal, with subsequent loss of cortical gray matter. Secondary changes to the white matter manifest later and typically exhibit an abnormal, nonspecific, patchy, hyperintense T2 signal within the centrum semiovale. Hypointensity of the thalami on T2-weighted images also has been reported.3

GM2 Gangliosidosis

The most common forms of GM2 gangliosidoses include Tay-Sachs disease and Sandhoff disease. Tay-Sachs disease arises with β-N-acetylhexosaminidase-A isoenzyme deficiency in Jewish children of eastern European descent. Onset is usually before the age of 1 year with irritability, hypotonia, seizures, blindness, and cherry-red spots on the macula in 90% of patients. Death usually results by 2 to 3 years of age. Sandhoff disease is attributed to a deficiency of A and B isoenzymes of hexosaminidase. The clinical course is similar to that of Tay-Sachs disease. There is visceral involvement, including hepatomegaly and cardiac and renal tubular abnormalities. Brain MRI in the early stages demonstrates increased T2 signal in the basal ganglia, particularly with the enlarged caudate nuclei. Later, cortical and deep gray matter volume loss occurs with patchy increases in T2 signal in the white matter. Thalamic involvement is more reflective of Sandhoff disease. In adult-onset Sandhoff disease, lower motor neuron involvement has been reported. Whereas cerebellar atrophy may vary, it does not appear to be correlated with clinical severity.4 In persons with Tay-Sachs disease, the thalami may be hypointense on T2-weighted images and hyperintense on T1-weighted images because of calcium deposition. It has been reported that T2-weighted hyperintensity in cerebral matter is indicative of abnormal myelin production and active demyelination.5 Asymmetrical swelling and high T2 intensity in the white matter and basal nuclei of the right hemisphere has been reported. Elevated levels of cytokines have been reported, possibly indicating inflammation as a contributing factor to the progression of gangliosidosis.6 In the B1 variant of GM2 gangliosidosis, the bilateral thalami may appear hyperdense/hyperintense on CT/T1-weighted MRI and show a T2-hypointense signal in the ventral thalami and a hyperintense signal in the posteromedial thalami. Other findings in this variant include involvement of the medullary lamellae, bilateral T2 hyperintense/swollen basal ganglia, diffuse white matter hyperintensity on T2-weighted images, and brain atrophy in later stages.7


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.

Dec 20, 2015 | Posted by in PEDIATRIC IMAGING | Comments Off on Inherited Metabolic and Neurodegenerative Disorders

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