Clinical Features^13,14

Male Patients

Female Patients

Approximately 50% of women heterozygous for the adrenoleukodystrophy gene develop pure adrenomyeloneuropathy in middle age or later.¹⁶ The onset is later, and progression is slower than in male patients, but disability may be severe, necessitating the use of a wheelchair. Inflammatory brain disease¹⁷ and clinically or biochemically demonstrable adrenal insufficiency¹⁸ are rare in this disorder. They are present in about 1% of women heterozygous for the adrenoleukodystrophy gene.

Pathology

Neuroimaging

Genetics

The mode of inheritance is usually classified as X-linked recessive, but the fact that 50% of heterozygous women are neurologically symptomatic indicates that a designation as X-linked is more accurate, as proposed by Dobyns and associates.⁴⁴ The disease incidence is estimated at 1 per 17,000 and appears to be the same in all ethnic groups.⁴⁵ The defective gene has been mapped to Xq28.⁴⁶ The gene codes for a peroxisomal membrane protein, adrenoleukodystrophy protein (ALDP).⁴⁷ ALDP is a member of the adenosine triphosphate-binding cassette (ABC) transporter superfamily.⁴⁸ Forty-eight mammalian ABC transporters are estimated to exist. They transport a variety of substrates, including ions, sugars, amino acids, proteins, and lipids.⁴⁹ Four mammalian peroxisomal ABC transporters have been identified and are designed as subgroup ABCD. The gene deficient in X-ALD has been assigned the name ABCD1. ABCD2 may also be relevant to X-ALD (see section on therapy). ABCD2, which has been mapped to 12q11, codes for the adrenoleukodystrophy-related protein ALDR, which has 66% homology with ALDP⁵⁰ and can substitute for some of the functions of ALDP.^51,52

More than 500 mutations in ALDP have been identified in patients with X-ALD⁵³ and are updated in the X-linked Adrenoleukodystrophy Database website (www.x-ald.nl). Fifty-seven percent of the mutations are nonrecurrent, and many are unique to a kindred. Of all the mutations, 55.9% were found to be missense mutations, 27.1% nonsense mutations, 3.9% small in-frame amino acid insertions or deletions, and another 3.9% large deletions of one or more exons.⁵³ No correlation between phenotype and genotype has been demonstrated. A single mutation may be associated with a wide range of phenotypes.⁵⁴ It is common for widely varying phenotypes to co-occur in the same family. The action of a modifier gene has been postulated.^55,56

Diagnosis

Definitive diagnosis of X-ALD depends on the demonstration of biochemical abnormalities and on results of mutation analysis. Demonstration of characteristic abnormalities in the levels of saturated VLCFAs in plasma is the most frequently used test.⁵⁷ Statistically significant increases in the levels of hexacosanoic acid (C26:0) and in the ratios of C26:0 to C24:0 and to C22:0 are present in more than 99% of male patients with adrenoleukodystrophy and in approximately 85% of women heterozygous for the X-ALD gene.⁵⁸ Increases in VLCFA levels in patients with other peroxisomal disorders, such as Zellweger’s syndrome, neonatal adrenoleukodystrophy, and infantile Refsum’s disease,⁵⁹ can usually be distinguished easily on the basis of clinical manifestation and tests of the other peroxisomal functions. Patients on the ketogenic diet may produce false-positive results⁶⁰; VLCFA levels are also increased in cultured skin fibroblast,⁶¹ and study of cultured fibroblasts can be helpful when results of plasma samples are equivocal. VLCFA levels are also increased in red blood cell membranes,^16,62 in leukocytes,⁶³ and in cultured amniocytes⁶⁴ and chorionic villus cells.⁶⁵

The plasma VLCFA assay⁵⁷ is highly reliable for the identification of affected male patients. Abnormalities are already present on the day of birth.⁵⁷ There are two reports of false-negative test results in a total of three male patients with X-ALD,^66,67 but this has not observed in more than 100 affected male patients.⁵⁷ In contrast, false-negative results occur in 15% to 20% of women heterozygous for the X-ALD gene. Because of this, mutation analysis is much preferred for the determination of carrier status in women at risk for X-ALD. More than 500 pathogenic mutations in the ABCD2 gene have been identified in patients with X-ALD⁵³ and are updated in the X-linked Adrenoleukodystrophy Database website. Reliable methods for their identification in affected men and in heterozygous women have been published.⁶⁸ The first step is to define the nature of the mutation in affected male family members or in a family member who is an obligate carrier. Once the mutation is found in a nuclear family member or a more distant relative, it can be determined whether this mutation exists in lymphoblasts or cultured fibroblasts of the at-risk person. VLCFA analysis in cultured amniocytes or chorion villus samples is a valuable technique for the identification of affected fetuses.⁶⁵ However, false-negative results have been reported,^69,70 and confirmation by mutation analysis should be performed when the nature of the mutation has been defined in an affected male patient or obligate heterozygote family member.

Pathogenesis

Therapy

Three forms of therapy are in current use: (1) adrenocortical hormone replacement; (2) HCT; and (3) dietary therapy with Lorenzo’s oil.

Clinical Manifestations

There are late infantile, juvenile, and adult manifestations. In about 75% of patients, the late infantile and juvenile forms are equally divided in frequency. The other 25% have the adult form.¹¹³

Pathology

The pathology of MLD in the nervous system is characterized primarily by demyelination and deposits of metachromatic granules in the central and peripheral nervous systems. High-resolution electron microscopy of the storage granules revealed that the inclusions are surrounded by a membrane, which suggests that they are located in the lysosome.¹¹⁵ The central white matter is reduced in amount, is firm, and in severely affected regions may show cavitation of spongy degeneration. The subarcuate fibers are usually spared. There is moderate to severe loss of myelin sheaths. The intrafascicular oligodendrocytes are reduced in number. There is a striking accumulation of metachromatic granules in macrophages that are prominent in perivascular spaces and also in oligodendrocytes and in neurons. Immunocytochemical studies have shown that the accumulated material in neurons and glial cells contains sulfatide.¹¹⁸ The cerebellum is atrophic with severe demyelination, prominent gliosis, storage granules, and a reduction of Purkinje cells. The peripheral nervous system shows segmental demyelination. Metachromatic granules are present in Schwann cells and in endoneurial macrophages.

Neuroimaging

MRI reveals periventricular white matter abnormalities with a symmetrical distribution.¹¹⁹ In juvenile and adult cases, there is preferential frontal lobe involvement. The arcuate fibers are relatively spared. The corpus callosum is invariably affected. The posterior limb of the internal may be involved. Brainstem lesions in the pyramidal tract may be observed, and the cerebellar white matter may be involved. Contrast enhancement is usually absent; this helps differentiate MLD from X-ALD, in which enhancement is often prominent. Diffusion-weighted images vary with the stage of the illness. Oguz and associates reported that diffusion was restricted in the early stage and increased in the later stage.¹²⁰

MRI in MLD often exhibits radially oriented hypointense stripes in T2-weighted hyperintense areas. Postmortem studies in which neuroimaging patterns were correlated precisely with histopathological findings revealed that the stripes corresponded to perivenular zones in which there was relative preservation of myelin, together with the accumulation of lipid-laden glial cells.¹²¹

Genetics

The mode of inheritance is autosomal recessive. The incidence of late infantile MLD varies in different countries.¹¹⁵ MLD appears to be most common in northern Sweden, where the incidence is estimated to be 1 per 40,000 among some groups, and among Arabs living in Israel. In France and in Germany, the incidence was estimated to be 1 per 130,000 to 1 per 170,000.

The defective gene has been mapped to locus 22q13. It codes for arylsulfatase A, which catalyzes the desulfation of 3-sulfogalactosyl-containing glycolipids. Four such glycolipids have been identified.¹¹⁵ Of these, galactosylceramide-3-sulfate is present in the highest concentration and most relevant to MLD.

Diagnosis

The laboratory diagnosis of MLD depends on the demonstration of decreased arylsulfatase A activity and increased excretion of sulfatide in urine. The arylsulfatase A assay is performed in peripheral blood leukocytes or cultured fibroblasts.¹²⁵ The major problems in the enzymatic diagnosis is the frequent occurrence of the clinically benign pseudodeficiency alleles, which reduce arylsulfatase A activity. Measurement of urinary sulfatide excretion is key to the distinction between MLD and pseudodeficiency. This excretion is markedly increased in patients with MLD and normal in patients with pseudodeficiency or in persons heterozygous for the MLD-causing mutation.¹²⁶ MLD and pseudodeficiency can also be distinguished by the sulfatide loading assay.¹²⁷ Patients with multiple sulfatase are distinguished by demonstration of deficient activity of arylsulfatase B and C, in addition to the defect of arylsulfatase A. Patients with saposin B deficiency have normal arylsulfatase A activity, but their sulfatide loading value and urinary sulfatide excretion are increased. Mutation analysis is of great value for the identification of persons heterozygous for the MLD-causing mutation. It detects the pseudodeficiency. However, it must be kept in mind that alleles bearing the relatively common pseudodeficiency polymorphism may, in addition, contain an MLD-causing mutation.

Pathogenesis

The accumulation of sulfatide, secondary to the deficiency arylsulfatase A, is the principal biochemical abnormality in MLD. The sulfatides accumulate mainly within the lysosome. The sulfatide accumulation is noted in several extraneural tissues, such as the gallbladder, liver, kidneys, pancreas, adrenal cortex, and sweat glands, but it leads to pathological changes only in the gallbladder.

The demyelination that occurs in MLD appears to be secondary to sulfatide-induced changes within the cells responsible for myelin maintenance: namely, the oligodendrocytes in the CNS and the Schwann cells in the peripheral nervous system.¹²⁹ Changes in the subcellular organelles of these cells are observed before any morphological abnormalities in the myelin sheaths associated with them are detectable.¹¹⁵ Investigators who used immunocytochemical techniques have demonstrated the accumulation of sulfatides in neurons and glial cells in arylsulfatase A-deficient mice.¹¹⁸ The degeneration of neurons and glia is enhanced and accelerated by the secretion of proinflammatory cytokines by monocytes.¹³⁰

Other pathogenetic mechanisms that may contribute are impaired myelin stability secondary to its abnormal biochemical composition¹³¹ and the abnormal accumulation of sulfogalactosylsphingosine (lysosulfatide).¹³² Lysosulfatide has been shown to inhibit the activity of protein kinase C and cytochrome oxidase at concentrations far below those found in tissues of patients with MLD.^132,133

Therapy

Bone marrow transplantation is under investigation as a therapy for MLD. It has not been effective in symptomatic patients with the late infantile form of the disease and may even accelerate the progression of the disease.¹³⁴ Several reports suggest that bone marrow transplantation arrests the progression in patients with the juvenile or adultonset MLD phenotype.^135–137 Evaluation of these results is difficult because of the relatively short follow-up and the variability of progression in untreated patients. Several presymptomatic patients have undergone transplantation.^138,139 Longer follow-up is necessary to assess effectiveness.

Therapeutic studies in the mouse model of MLD are highly encouraging. Ex vivo administration of genetic modification of hematopoietic stem cells led to a remarkable correction of neuropathological changes.¹⁴⁰ Matzner and coauthors reported the unexpected and surprising findings that intravenous administration of purified arylsulfatase A improved nervous system pathology and function.¹⁴¹

Clinical Features

The infantile form of the disease is most common. Hagberg and associates subdivided the course of the disease into three stages.¹⁴² In stage I, the child, apparently normal during the first few months after birth, becomes hyperirritable and hypersensitive to auditory and tactile stimuli, and there is some stiffness of the limbs. Slight regression of psychomotor development, feeding difficulties, and vomiting may be observed. Early peripheral nervous system manifestations are common.¹⁴³ In stage II, there is rapid deterioration. There is marked hypertonicity, with extended and crossed legs, flexed arms, and arched back. Optic atrophy and sluggish pupillary reflexes are common. Stage III is the “burnt-out” stage, sometimes reached within few weeks or months. The child is in a decerebrate state, is blind, and has no contact with his or her surroundings. Patients rarely survive for more than 2 years.

Juvenile- and adultonset cases are well documented. The juvenile cases have been subdivided into the late infantile (early childhood)-onset form, which begins at ages 6 months to 3 years, and the late childhood-onset form, which begins at ages 3 to 8 years.¹⁴⁴ The early childhood form progresses rapidly, with death approximately 2 years after onset. The late childhood cases manifest with loss of vision and with hemiparesis, ataxia, and psychomotor regression; death occurs 10 months to 7 years after onset. The number of reports of adultonset cases is increasing. Progressive paraparesis and tetraparesis with demyelination in the spinal cord are often the main abnormalities. One female patient developed slowly progressive paraparesis at 38 years of age.¹⁴⁵ Other cases were misdiagnosed as amyotrophic lateral sclerosis.¹⁴⁶

Pathology

The pathology is confined mainly to the nervous system.¹⁴⁷ Postmortem examination reveals that the brain is small and atrophic, with shrunken gyri and widened sulci. The major histopathological changes are demyelination, gliosis, and the presence of unique macrophages, the globoid cells in the white matter. The subarcuate fibers tend to be spared. The phylogenetically newer fiber tracts are usually more involved in the demyelinating process. In the spinal cord, the pyramidal tracts are more affected than are the dorsal columns. The oligodendroglial cell population is severely diminished in the areas of demyelination. Globoid cells are clustered around blood vessels and may be multinucleated. They contain tubular inclusions that have morphological similarities to the inclusions of pure galactosylceramide.¹⁴⁸ Secondary axonal degeneration is a consistent finding. The peripheral nerves are commonly affected. They show endoneurial fibrosis, proliferation of fibroblasts, and segmental demyelination. Inclusions similar to those in the globoid cells in the brain are found in the cytoplasm of histiocytes, macrophages, and Schwann cells.

Neuroimaging

In the early stages, computed tomographic changes may be more evident than MRI changes. In stage I, computed tomographic scans may be normal or exhibit symmetrical increased density in the thalami, the corona radiata, and the posterior limb of the internal capsule and basal ganglia.¹⁴⁹ MRI confirms the presence of white matter abnormalities with relative sparing of arcuate fibers in infantile-onset GLD (Fig. 80-1). The posterior limb of the internal capsule, corpus callosum, cerebellar white matter, and brain tracts are also involved. In cases of adultonset GLD, both computed tomography and MRI reveal predominant involvement of the occipital periventricular white matter with extension in the parietal and temporal direction and associated involvement of the splenium of the corpus callosum, a pattern that resembles that seen in X-ALD. In adultonset cases, symmetrical high-signal intensity lesions may be evident on T2-weighted MRI in frontoparietal white matter, the centrum semiovale, and the posterior limb of the internal capsule, with sparing of the periventricular white matter (see Fig. 80-1).¹⁴⁵ MRS in patients with infantile-onset GLD revealed pronounced elevation of myoinositol- and choline-containing compounds, which reflected gliosis and demyelination. N-acetyl aspartate levels were decreased, which reflected neuroaxonal loss.¹⁵⁰

Figure 80-1 Globoid leukodystrophy. Classic disease is shown, with posterior occipital white matter abnormalities that may be mistaken for adrenoleukodystrophy (A). Adultonset isolated corticospinal tract involvement (B) can be traced to the lower brainstem (D to F). Corpus callosal involvement can also been seen (C).

Genetics

The mode of inheritance is autosomal recessive. The gene has been mapped to loci 14q24.3-32.1. It codes for galactocerebroside (psychosine) β-galactosidase. The incidence is estimated to be 1 per 100,000 in the United States but appears to be higher in the Scandinavian countries. More than 60 mutations have been identified.^147,151 Although there is no consistent correlation between genotype and phenotype,¹⁵² some associations have been identified. The 502T/del mutation accounts for 50% of mutant alleles in The Netherlands and 75% in Scandinavian countries. The mutation probably occurred initially in Sweden and traveled from there throughout Europe, Asia, and the United States. This 30-kilobase deletion eliminates all of the coding region of one of the subunits of the enzyme, and patients who are homozygous for this deletion have the severe infantile-onset phenotype. Two other mutations, C1538T and A1652T, account for about 10% to 15% of mutant alleles of infant patients with European ancestry. The G809A mutation is common in patients with adultonset GLD. One copy of the G809A mutation is probably enough to explain a mild phenotype in heterozygous patients whose other allele has a mutation that usually is associated with a severe phenotype.¹⁴⁷ A series of polymorphic changes in the gene that occur on the same allele as disease-causing mutations have been identified; they influence the enzyme activity and clinical manifestations in persons who are heterozygous for GLD-causing mutations.¹⁵³

Diagnosis

Assays of GalC activity in peripheral leukocytes or cultured fibroblasts is the most reliable method for diagnosis.¹⁵⁴ Leukocyte and cultured fibroblast results are equally reliable. Wenger and colleagues¹⁴⁷ listed citations for validated techniques that use natural substrates. The same assay in cultured amniotic cells or in biopsy specimens of chorionic villi is used for prenatal diagnosis, but it is valuable for measuring the GalC enzyme activity in the carrier parents beforehand, because some carriers have enzyme levels that are sufficiently low to characterize them as homozygous affected. When this is the case, special care must be taken in the interpretation of the results of the prenatal study, and the results can be complemented by mutation analysis. The wide range of enzyme activity in normal individuals and in carriers, which results mainly from polymorphic amino acid changes that cause a wide range in the values tested, limits the reliability of the enzyme assay for carrier identification. In families in which the mutations have been defined, carrier status is determined by mutation analysis. An important diagnostic development is the progress that has been made toward mass neonatal screening for lysosomal disorders, including GLD,^155–157 Neurophysiological studies, such as motor conduction velocity and visual and auditory evoked responses are abnormal in most patients with GLD,¹⁵⁸ but it is important to realize that they may be normal in patients with the adultonset phenotypes.¹⁵⁹

Pathogenesis

The globoid cell, the hallmark pathological feature of GLD, is the consequence of the accumulation of galactosylceramide. Galactosylceramide is unique among sphingolipids in its ability to elicit the globoid cell reaction when injected into normal rat brain.¹⁶⁰ Even though the galactosylceramide thus plays a role in some aspects of the pathogenesis of GLD, there is increasingly compelling evidence that it is the accumulation of psychosine (sphingosine-galactose) that is the principal pathogenetic factor. This pathogenetic mechanism, now referred to as the psychosine hypothesis, was first proposed by Miyatake and Suzuki¹⁶¹ and reexamined in detail 25 years later by Suzuki.¹⁶² GalC, the gene product that is deficient in GLD, catalyzes the degradation of both galactosylceramide and psychosine. Psychosine is present in very low concentration in normal brain tissue, but its concentration in GLD white matter is increased 100-fold.¹⁴⁷

Psychosine with its free amino group is highly cytotoxic. Its effect is mediated by caspase activation.¹⁶³ Psychosine-induced apoptosis is a mouse oligodendrocyte precursor line mediated by caspase activity. Oligodendrocytes are selectively destroyed because psychosine formation occurs primarily in these cells. The molecular mechanisms of psychosine-induced cell death have been clarified.¹⁶⁴ Psychosine-induced apoptosis in human oligodendrocyte cell line studies in animal models, particularly the canine model and the twitcher mouse, have been of great value for the studies of pathogenesis of GLD and its therapy.¹⁶⁵

Therapy

HCT and bone marrow transplantation for GLD are under intense investigation. HCT was of benefit in four patients with adultonset GLD: CNS deterioration was reversed, MRI findings improved in three patients, and levels in cerebrospinal fluid (CSF) diminished.¹⁶⁶ The effect of HCT in patients with infantile-onset GLD and in asymptomatic infants with GLD has been evaluated.¹⁶⁷ Although the symptomatic boys with infantile GLD experienced no benefit, there was strong evidence of a beneficial effect in 11 asymptomatic newborns who received umbilical cord blood transplants at 12 to 44 days after birth. At the time of follow-up (median age, 3.0 years) they had age-appropriate cognitive function and receptive language skills, and serial MRI studies demonstrated progressive central myelination. There is no doubt the procedure has a profound effect with regard to mortality and early development, but there were mild-to-moderate delays in expressive language and gross motor function. Additional follow-up is needed to assess the long-range outcome. Ethical aspects of this therapeutic approach were discussed in an editorial.¹⁶⁸

Another approach, therapy aimed to reduce the concentrations of substrate, is being tested in experimental animals.¹⁶⁹ Studies of transplantation of neural cells and direct infection of the brain with viral vector containing GalC, are in progress in experimental animals.

Clinical Features

Pathology

Features include lack of myelin in all parts of the CNS. Islets of preserved myelin around blood vessels in deeper parts of brain produce the so-called tigroid pattern. Axons are relatively preserved. Oligodendrocytes are reduced in number, as is the number of cytoplasmic processes. A length-dependent axonal degeneration is also present.¹⁷³

Neuroimaging

MRI reveals an arrest of myelination. In some cases, no myelin appears to be present; in other cases, myelin is present in parts of the brainstem, cerebellar white matter, the posterior limb of the internal capsule, the thalamus, and the globus pallidus. The pattern described is normal for a neonate or an infant in the first few months of life, although not normal at the age of the patient. The white matter may appear speckled, reflecting the tigroid pattern seen pathologically. There also is evidence of neuroaxonal injury, based on the demonstration of significant and widespread reduction in brain N-acetyl aspartate levels.¹⁷⁶

Genetics

The mode of inheritance is X-linked recessive. Some women heterozygous for Pelizaeus-Merzbacher disease develop neurological progressive paraparesis.^175,177,178 The gene maps to locus Xq22 and codes for PLP. This protein makes up approximately 50% of myelin protein weight. It is composed of four helices that span the cell membrane. Portions of the protein chain extend into the extracellular space, where they have a homophilic interaction with PLP molecules in adjacent spirals of the cell membrane.¹⁷⁹ This region is visualized as the intraperiod line on electron microscopy.¹⁸⁰

Duplication of the region surrounding locus Xq22 accounts for the majority, perhaps up to 70%, of the mutations in PLP.¹⁸¹ These duplications arise from sister chromatid exchange. Striking variations in the breakpoints and in the size of the duplication occur.^182,183 Most patients with mutations have the classic phenotype¹⁸²; some have the connatal form,¹⁸⁴ and others have the mild SPG2 phenotype. Deletions of the PLP locus occur only rarely.^185,186 Patients in whom no PLP protein product is formed, referred to as null mutations, tend to have a mild phenotype with relatively mild spastic paraparesis, which progressed during adolescence and (unlike that in classic Pelizaeus-Merzbacher disease) was associated with demyelinating peripheral neuropathy.¹⁷³ About 20% of patients have point mutations at the PLP locus that alter the amino acid sequence of the PLP/DM20 proteins. Approximately 100 distinct mutations have been discovered to date. The majority of abnormal PLP/DM20 proteins result in severe phenotypes through a toxic gain of function, whereas the remainder result in a milder form that is associated with loss of function.

Diagnosis

Although the classic phenotype has a relatively distinct clinical manifestation,¹⁷⁰ the connatal form can be confused with motor neuron disease or spinal muscular atrophy. The mildest forms merge clinically with the syndromes of SPG2. MRI is essential for the evaluation of individuals with clinical signs and symptoms of classic Pelizaeus-Merzbacher disease or SPG2. Virtually all patients with Pelizaeus-Merzbacher disease eventually have MRI findings consistent with a leukodystrophy.^187,188

A search for proteolipid protein 1 (PLP1) gene duplication is the most efficient initial screening test. Both interphase fluorescent in situ hybridization and quantitative polymerase chain reaction should be used.¹⁸² If neither method yields a positive result, direct sequencing of the PLP1 gene should be performed.¹⁸⁹ Prenatal diagnosis has been accomplished.¹⁹⁰

Pathogenesis

Because mutations in which no PLP1 protein is synthesized lead to the mildest disease, it has been postulated that toxic effects are caused either by overexpression of the gene in patients with duplications of the normal gene or by the presence of mutant genes. In patients with the gene duplications, excessive amounts of PLP1 have been shown to accumulate in the late endosomal and lysosomal compartments. PLP1 normally is associated with cholesterol and other lipids to form “lipid rafts” that traffic through the Golgi compartment. In rodent models of Pelizaeus-Merzbacher disease in which there is an excess of PLP1, these lipid rafts are shunted to the late endosomal and lysosomal compartments, effectively draining myelin lipids from the Golgi compartment.¹⁹¹ In patients with mutations in the PLP1 coding region, the differences in clinical severity appear to be related to differential effects of the mutation on protein folding and trafficking.¹⁹² These unfolded proteins accumulate in the endoplasmic reticulum, and this leads to the unfolded protein response.^193,194 This response, which involves the increased expression of unfolded protein response effector genes, protects the cell against metabolic stress to preserve or reestablish homeostasis. In cells in which homeostasis cannot be maintained, there often is apoptosis by activation of caspase cascades.¹⁹⁵ This pathogenetic mechanism is presumed to be operative in oligodendrocytes and neurons. The understanding of the pathogenesis of Pelizaeus-Merzbacher disease has been aided greatly by studies in animal models of the disease.¹⁹⁶ These include the “jimpy” mouse and the “jimpy-msd” mouse, in which the disorder resembles classic Pelizaeus-Merzbacher disease; the “jimpy-4j” mouse, in which the disorder resembles connatal Pelizaeus-Merzbacher disease; and the “rumpshaker” mouse, which is a model of SPG2. The myelin-deficient rat also provides a model of connatal Pelizaeus-Merzbacher disease. Because rats are larger animals, this model is well suited for neurophysiological studies of pathogenesis and for the study of therapeutic interventions.^197,198

Therapy

At this time, there is no specific therapy for Pelizaeus-Merzbacher disease.

Clinical Features

Age at onset is most commonly between 3 and 6 months. In the patients with early onset, mental changes are severe, and the clinical phenomena of nervous system maturation are not observed.^199–203 Instead, there is increasing difficulty in feeding, progressive lethargy, and increasing stiffness of the limbs. When the disease begins later in infancy, normal development of social, motor, and visual responses is seen at first, but this is lost as the disease advances. Hypotonia is present early in the course of the disease and is followed by increased tone that begins in the legs and produces a posture of extension. Optic atrophy occurs in a large proportion of cases. Macrocephaly (>90th percentile) was documented in 54 of 59 children; 51 of 58 had nystagmus, 38 of 60 had epilepsy, and optic atrophy was present in 17 of 60.²⁰² Although cases with later onset have been reported,^204,205 only two cases have been biochemically confirmed,²⁰⁶ and in these patients, onset of symptoms occurred by 2 years of age. Although most patients die during the first decade, 14 of the 60 patients in Traeger and Rapin’s series²⁰² were alive in the second or third decade, albeit all severely disabled.

Pathology

The majority of affected infants show an increase in brain size and weight. In formalin-fixed sections, the white matter is soft, gelatinous, and darker than normal; enlargement of ventricles increases as the disease advances. The most striking microscopic change is the widespread vacuolization, which characteristically involves the lower layer of the cerebral cortex and the subcortical white matter; the more central zones are relatively or entirely spared. There is a widespread lack of myelin, which involves the area of spongy degeneration and extends far beyond them. In the areas of spongy degeneration, as well as in the demyelinated zones, oligodendrocytes are preserved. Axis cylinders in the areas of demyelination are diminished but not absent. Throughout the cerebral cortex and basal ganglia, there are conspicuous increases in the number and size of protoplasmic astrocytes.²⁰¹ Ultrastructural studies have shown that the vacuoles in the subcortical white matter lie within the myelin sheaths, between split lamellae of the myelin spirals. The split was noted between the major dense lines.²⁰⁷ Some of the membranes were focally ruptured. The vacuoles communicated through these ruptured membranes into the widened extracellular spaces. Cell membranes of protoplasmic astrocytes were also disrupted. The mitochondria within the astrocytes displayed enormous elongations and contained distended and distorted cristae.

Neuroimaging

In all stages of the disease, MRI shows the most severe abnormalities in the subcortical white matter of the cerebrum and cerebellum. Central white matter structures such as the periventricular rim of white matter, internal capsule, corpus callosum, and brainstem are preserved longer. After several years, cerebral atrophy with enlargement of the ventricles ensues.²⁰⁸ The most characteristic neuroimaging abnormality is the accumulation of N-acetyl aspartic acid, demonstrable by proton spectroscopy.²⁰⁹

Genetics

The mode of inheritance is autosomal recessive. The defective gene maps to chromosome 17pter and has been isolated.²¹⁰ It codes for aspartyl acylase, which hydrolyzes N-acetyl aspartate to aspartate and acetate. Canavan’s disease occurs most frequently in the Ashkenazi Jewish population, in which carrier frequency is 1 per 38.²¹¹ Two mutations are most common among Jewish patients: a missense mutation in codon 285 with substitution of glutamic acid to alanine, which accounted for 86.3% of mutations in 104 alleles, and a nonsense mutation on codon 231, tyrosine to stop codon, which was found in 13.4%. Together, these two mutations accounted for 97% of all the alleles in Jewish patients with Canavan’s disease. In non-Jewish patients, the mutations are different and more diverse: the most common is in codon 305, a missense mutation substituting alanine to glutamic acid. This mutation was observed in 35.7% of 70 alleles from 35 unrelated non-Jewish patients. Fifteen other mutations accounted for 24 mutant alleles.

Diagnosis

Definitive diagnosis is achieved by measurement of levels of N-acetyl aspartic acid in urine. It is essential that the isotope dilution assay procedure be used.^212,213 N-acetylneuraminic acid (NANA) levels in Canavan’s disease are 80 to 120 times higher than control levels. NANA assay in amniotic fluid enables prenatal diagnosis.²¹⁴ Further studies of this assay showed that although significantly increased levels of amniotic fluid NANA were reliable markers, moderate increases should be interpreted with caution and could lead to false-negative results.²¹⁵ Measurement of aspartoacylase activity is not reliable for postnatal or prenatal diagnosis.^214,216 It is recommended strongly that, whenever possible, it be combined with mutation analysis in amniocytes or trophoblasts.^217,218 Mutation analysis is a key diagnostic procedure.²¹¹ It is particularly so in the Ashkenazi Jewish populations, in which two common mutations account for all the mutations that have been encountered. The American College of Obstetrics and Gynecology has recommended that molecular carrier screening be offered to Ashkenazi Jewish couples.²¹⁹

Pathogenesis

The key defect in Canavan’s disease is the deficiency of N-acyl-L-aspartate aminohydrolase,²²⁰ which hydrolyses NANA to L-aspartate and acetate. NANA is found only in the nervous system, in which its normal concentration, 6 to 7μmol/g, is second only to that of glutamic acid in the free amino acid pool. NANA is synthesized in neuronal mitochondria by the enzyme aspartate N-acyltransferase, whereas the catabolic enzyme N-acyl-L-aspartate is present mainly in oligodendrocytes,²²¹ and its concentration is even higher in Canavan’s disease.

Three pathogenetic mechanisms for Canavan’s disease have been proposed: (1) Madhavarao and colleagues²²¹ demonstrated that levels of acetate in the brain and the synthesis of myelin lipids are reduced significantly in the mouse model of Canavan’s disease and also in a patient with Canavan’s disease, and they proposed that this is a consequence of an impaired acetate supply in the oligodendrocyte secondary to the N-acyl-L-aspartate deficiency. (2) Levels of N-acetyl aspartate glutamate may be increased in Canavan’s disease and may interfere with the function of the N-methyl-D-aspartate receptor.²²² (3) Because of its high concentration, NANA may act as an organic osmolyte that normally removes excess water from neurons by acting as a molecular water pump, and this function may be deficient in Canavan’s disease.²²³

Two animal models of Canavan’s disease have been developed. Aspartoacylase gene knockout in the mouse leads to reproduction of the clinical, pathological, radiological, and biochemical defects of Canavan’s disease in humans.^224,225

Therapy

There is no specific therapy for Canavan’s disease. It was the first neurodegenerative disorder to be treated by gene therapy.²²⁶ A nonviral lipid-entrapped, polycation-condensed delivery system in conjunction with adeno-associated virus-based plasmid containing recombinant N-acyl-L-aspartate was administered by intraventricular injection to two patients with Canavan’s disease. The procedure was well tolerated. Fifteen additional patients were treated.²²⁷ There were no definitive changes in clinical course.

The availability of animal models of Canavan’s disease has made it possible to test gene transfer therapy in these models. Stereotactic delivery of adeno-associated virus 2-mediated N-acyl-L-aspartate to “tremor rats” reduced brain NANA levels and was associated with some improvement in motor function.²²⁸ On the basis of the hypothesis that acetate deficiency in Canavan’s disease limits synthesis of myelin lipids,²²¹ a trial of dietary supplementation with acetate or acetate precursors has been proposed.²²¹

Clinical Features

Early infantile, juvenile, and adultonset forms have been described. The early infantile-onset form manifests at approximately 6 months with rapidly progressive neurological and mental retardation, in association with macrocephaly spasticity and seizure, and leads to death in the second or third year.^229,230 Among patients with the juvenile-onset form, macrocephaly was present in only 27%, and progressive cognitive defects occurred in 60%. In the adultonset form, ataxia, eye movement disturbances, and bulbar and pseudobulbar symptoms²³¹ predominate. Palatal myoclonus,²³² autonomic disturbances, and sleep disturbances have also been reported.²³³

Pathology

In the early infantile-onset form, the brain is enlarged with a normal convolutional pattern. The white matter is discolored, soft, and swollen in the frontal region. Light microscopy reveals that the main abnormalities are the abundance of Rosenthal fibers and demyelination of the white matter (Rosenthal fibers are eosinophilic intracytoplasm filamentous cytoplasmic fibers within astrocytes).²³⁴ The major chemical components of Rosenthal fibers are glial fibrillary acidic protein, the small heat-shock proteins α-crystalline and hsp27, and ubiquitin.²³⁵ Rosenthal fibers have a tendency to accumulate at interfaces with mesodermal tissue that is underneath the pia mater and around the blood vessels. They are most prominent in the frontal and parietal regions and much less so in the occipital lobes. The basal ganglia are also involved. The tracts and nuclei of the brainstem nuclei are involved heavily from the midbrain to lower medulla; the cerebellar hemispheres, only slightly.^229,236

Neuroimaging

On the basis of the study of 5 patients with the infantile-onset form and 14 with the juvenile-onset form, van der Knaap and colleagues²³⁷ proposed five MRI criteria for the diagnosis of Alexander disease: (1) extensive cerebral white matter T2-weighted abnormalities with a frontal preponderance; (2) the presence of a periventricular rim of decreased T2-weighted signal intensity but with increased T1-weighted signal intensity in the same region; (3) abnormalities in the basal ganglia and thalami, in the form of either elevated signal intensity or atrophy and either elevated or decreased signal intensity on T2-weighted images; (4) brainstem abnormalities, particularly those involving the midbrain and medulla; and (5) contrast enhancement involving 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, and brainstem structures (Fig. 80-2).

Figure 80-2 Alexander’s disease. Frontal preponderance of frontal white matter lesions (A) and abnormality in the basal ganglia that may sometimes be enhanced (B). In juvenile and adultonset forms, lesions are more often localized in the brainstem and cerebellum with demarcation of the dentate nucleus (C). Cerebellar pathways and pontine lesions may get mistaken for glial tumors (D).

The authors concluded that the imaging pattern in infantile and juvenile-onset cases was sufficiently specific to allow the in vivo MRI diagnosis of Alexander’s disease and that brain biopsy is necessary only in atypical cases. However, in a later study of 10 patients with later onset and atypical features, the same group of investigators reported that this typical pattern was not found.²³⁸ In these patients, late-onset disease, ataxia, bulbar symptoms, and eye movement disturbances dominated the clinical findings.^231,233 The MRI revealed predominantly posterior lesions, including multiple tumor-like brainstem lesions.

Genetics

The mode of inheritance is autosomal dominant. The abnormal gene has been mapped to locus 17q21. It codes for the glial fibrillary acid protein. One hundred and two pathogenic mutations have been identified.^239–241 In one study, 72 patients had the infantile-onset phenotype, 22 had the juvenile-onset phenotype, 7 had the adultonset phenotype, and 1 was asymptomatic. All of the cases of the infantile phenotype, 21 of those with the juvenile phenotype, and 4 of those with the adult phenotype were sporadic. Five pedigrees with more than one affected member have been reported. All of the 16 affected persons in these pedigrees had the adult or the juvenile phenotype.

Diagnosis

In the patients with the typical infantile phenotype, the clinical features, combined with brain MRI findings,²³⁷ are sufficiently specific to establish the diagnosis. However, in juvenile and adultonset cases, mutation analysis²³⁹ is required for diagnosis. In these cases, the range of phenotypical expression and MRI abnormalities is wider than had been recognized in the past. It is recommended that mutation analysis be performed not only in the affected persons but also in their parents. This makes it possible to distinguish between sporadic cases (the majority) and familial cases. In familial cases, mutation analysis should be performed in at-risk members. Most of the familial cases have the adultonset phenotype, and their identification is required for genetic counseling.

Pathogenesis

Glial fibrillary acidic protein is one of the intermediate filament proteins, which also includes the keratins, vimentin, desmin, peripherin, and nestin.²⁴² Intermediate filament contains α-helical polypeptides that are linked and intertwined to form protofilaments. There is a great deal of evidence that the mutations in Alexander’s disease have a dominant negative effect: namely, that the abnormal glial fibrillary acidic protein allele product in astrocytes causes secondary dysfunction of oligodendrocytes and neurons.²⁴³ In support of this is the fact that no null mutations have been identified in patients with Alexander’s disease (which suggests that these would be lethal) and that glial fibrillary acidic protein knockout genes in mice cause only subtle pathological changes.²⁴³

Therapy

There is currently no specific therapy. Because the abnormal allele probably acts in a dominant negative manner, techniques such as RNA interference²⁴⁴ may offer hope for the future.

Clinical Features

Clinical features develop slowly and may manifest irregularly in varying combinations. The most common features are xanthomas in the Achilles tendon, neurological dysfunction, and cataracts. As patients grow older, they develop progressive coronary arteriosclerosis and osteoporosis that predisposes to bone fractures.²⁴⁶ The CNS manifestations are gradual deterioration of intellectual function, which progresses to dementia; behavior and psychiatric manifestations; pyramidal tract signs; spastic paraplegia; ataxia; dysarthria; and nystagmus. Epileptic seizures occur in half of the symptomatic subjects. Peripheral neuropathy is also present. Chronic diarrhea is a frequent symptom. Some specific clinical points have been highlighted; for example, the spinal phenotype (without xanthomas) may be misdiagnosed as multiple sclerosis.²⁴⁷ In children, cataracts may be the first manifestation of cerebrotendinous xanthomatosis,²⁴⁸ and xanthomata may be absent in patients with severe neurological involvement.²⁴⁹

Pathology

In the nervous system, the most conspicuous abnormalities are found in the cerebellum. Xanthomatous tissue, with large amounts of neutral fat, needle-like clefts, and cystic spaces, may replace the white matter. The outflow tracts of the dentate nucleus and the superior cerebellar peduncles are most severely involved. In the brainstem, the pyramidal tracts, transverse pontine fibers, and fiber tracts emanating from the inferior olive are demyelinated. The cerebral cortex and hemispherical white matter usually appear normal. Smaller areas of demyelination are found in the optic tract, the internal capsule, and the periventricular region.

Neuroimaging

The most important and earliest MRI abnormalities occur in the cerebellum. On T2-weighted images, there are high-intensity lesions in the dentate nuclei and cerebellar hemispheres.^4,214 Atrophy of cerebellar folia and symmetrical lesions in the corticospinal tracts, the medial lemniscus in the brainstem, and the inferior olive may occur. In the supratentorial region, ill-defined slight signal changes are seen in the periventricular region.

Genetics

The mode of inheritance is autosomal recessive. Several hundred cases have been reported from many countries, particularly The Netherlands, Italy, Israel, and Japan. The gene maps to locus 2q33ter. It codes for a sterol 27-hydroxylase (CYP27A).²⁵⁰ More than 20 mutations have been defined.²⁵¹

Diagnosis

Although the clinical manifestations and MRI findings of cerebrotendinous xanthomatosis are rather characteristic, laboratory diagnosis is required for definitive diagnosis. Laboratory techniques also enable presymptomatic diagnosis and early initiation of therapy. Demonstration of abnormally increased levels of cholestanol through precise methods such as selected ion monitoring²⁵² is a key diagnostic step.²⁵¹ A screening method that detects increased levels of 7α-hydroxylated bile acids in urine is a valuable technique.²⁵³ Mutation analysis in at-risk relatives²⁵⁰ of known patients is recommended highly for presymptomatic identification of affected persons and for genetic counseling.

Pathogenesis

The primary defect in cerebrotendinous xanthomatosis is the deficiency of C27-steroid hydroxylase, which leads to defective bile acid synthesis and the accumulation of a variety of metabolites with the C27-steroid side chains. There are series of complex metabolic and pathological consequences.²⁵¹ The major clinical manifestations are caused by generalized accumulation of cholestanol and cholesterol in nearly every tissue, including the CNS. Menkes and associates demonstrated the accumulation of cholestanol in the brains of patients with cerebrotendinous xanthomatosis in 1968.²⁵⁴ Cholesterol synthesis is greatly increased, because in the absence of bile acids, the normal bile acid feedback inhibition does not take place. Cholestanol is normally produced from cholesterol in small quantities by a four-step pathway. In cerebrotendinous xanthomatosis, C27-steroids that cannot be converted into bile acids may be shunted into this pathway.²⁵¹ The C27-steroid hydroxylase that is deficient in cerebrotendinous xanthomatosis normally may also act on the C25-steroid hydroxylase that is involved in vitamin D metabolism, and this may contribute to osteoporosis. C27-steroid hydroxylase also functions to transport steroids out of cells, and a defect in this mechanism may contribute to the premature atherosclerosis in cerebrotendinous xanthomatosis.

Therapy

There is compelling evidence that oral administration of chenodeoxycholic acid in a dosage of 750 mg/day benefits patients with cerebrotendinous xanthomatosis. Chenodeoxycholic acid is one of the bile acids produced in normal persons, but it is not produced in patients with cerebrotendinous xanthomatosis because of the enzymatic defect. Chenodeoxycholic acid administration reduces the levels of cholestanol in plasma and CSF^255,256 and was shown to reduce the excretion of urinary bile alcohols²⁵⁷ and bile alcohol glucuronides.²⁵⁸ It has been reported to improve somatosensory and motor evoked potentials,²⁵⁹ visual and brainstem auditory evoked responses,²⁶⁰ brain MRI abnormalities,²⁶¹ and osteoporosis.^262,263 There are several reports that it stopped or slowed neurological progression.^256,264 Berginer and coauthors²⁵⁵ reported improvements in cerebellar function, behavioral disturbances, and seizure control after 1 year of chenodeoxycholic acid therapy. Beneficial effects are most evident if therapy is started when deficits are slight. Biochemical and DNA screening of at-risk relatives now enables identification of asymptomatic persons with cerebrotendinous xanthomatosis. It is possible that chenodeoxycholic acid therapy will reduce or prevent later disability.

Addition of lovastatin or simvastatin to the chenodeoxycholic acid regimen may further decrease cholestanol levels,^265–267 but additional clinical benefits have not been demonstrated.²⁶⁸ Reduction of cholestanol levels can also be achieved with low-density lipoprotein apheresis,²⁶⁹ but this relatively invasive therapy, which would need to be administered repeatedly and is the subject of controversy,^270,271 should be considered only in patients who have not responded to pharmacological therapy.

Clinical Features

The three cardinal features are ichthyosis, mental retardation, and spastic diplegia or tetraplegia.²⁷² The ichthyosis is already present at birth or in the neonatal period. It is mild to moderate in severity and generalized in distribution. The face is mildly involved or spared. Neurological symptoms vary considerably but become evident within the first 3 years of life. Spastic diplegia is much more common than tetraplegia. Many patients never gain the ability to walk, and many who do walk require leg braces. The degree of mental retardation tends to be correlated with the severity of spasticity. In a study of Swedish patients, two thirds had an IQ of less than 50. Of enzymatically confirmed cases, 13% showed no mental retardation.²⁷³ Most patients have speech deficits of various types, including delayed speech and dysarthria. Two thirds have an associated seizure disorder. Patients with Sjögren-Larsson syndrome generally do not show neurological regression, and most survive well into adulthood. Abnormalities of the retina are frequent. The most consistent findings are glistening white dots in the foveal and perifoveal regions.²⁷⁴

Pathology

The nervous system shows a widely distributed loss of myelin, most prominent in the centrum semiovale, pyramidal tracts, and frontal lobes.²⁷⁵ There is considerable variation in the degree of myelin deficiency. Ballooning of myelin sheaths has been noted in the areas of myelin loss and near blood vessels. There is significant gliosis and proliferation of astrocytes. Gray matter is much less affected. The loss of neurons and axons tends to occur in areas where myelin loss has become extensive and appears to be secondary to myelin loss.

Neuroimaging

A study of 18 patients with Sjögren-Larsson syndrome demonstrated characteristic changes.²⁷⁶ MRI revealed a zone of abnormally high signal intensity in the periventricular high matter on T2-weighted images. The abnormality was present already at 2 years of age and remained relatively stable after that. The subarcuate fibers, cerebellum, and corpus callosum were relatively spared. The gray matter was normal. Mild cerebral atrophy was found in most patients older than 10 years. MRS revealed a prominent and narrow resonance at 1.3ppm, at which protons of methylene groups resonate. The nature of the lipids that give rise to this peak has not been defined. This peak was present in the white matter but not in the gray matter. The total N-acetyl aspartate level was normal, which was consistent with the relative preservation of neurons; creatine, choline, and inositol levels were increased, which was consistent with the gliosis and myelin damage.

Genetics

The mode of inheritance is autosomal recessive. Sjögren-Larsson syndrome is a rare disorder, first reported and apparently most common in Sweden, where the frequency is 0.4 per 100,000. By 2001,²⁷³ more than 200 patients had been recognized in all parts of the world. The gene maps to locus 17p11.2. It codes for fatty aldehyde dehydrogenase.²⁷⁷ Mutations of the gene were first identified by De Laurenzi and associates.²⁷⁸ Seventy-two mutations in the gene have been defined.²⁷⁹

Diagnosis

Diagnosis is suggested by the clinical triad of ichthyosis, mental retardation, and spasticity and is aided by brain MRI and MRS studies²⁷⁶ and the presence of glistening spots in the retina.²⁷⁴ Definitive diagnosis depends on demonstration of fatty aldehyde dehydrogenase deficiency in cultured skin fibroblasts.^280,281 This assay also enables prenatal diagnosis.²⁸² Van den Brink and associates reported an alternative enzymatic assay based on demonstration of impaired phytol degradation in cultured fibroblasts of Sjögren-Larsson syndrome patients.²⁸³ DNA-based diagnosis is feasible²⁷⁸ and is being applied increasingly for heterozygote identification and prenatal diagnosis.

Pathogenesis

The deficiency of fatty aldehyde dehydrogenase leads to a large number of biochemical derangements, but it is not yet clear which contributes to pathogenesis. These derangements include the following:

The levels of essential polyunsaturated fatty acids in plasma are reduced.²⁸⁵

Treatment

Treatment is symptomatic. Topical administration of keratolytic agents and the systemic administration of short-acting retinoids has ameliorated the ichthyosis. A variety of fat-modified diets, such as those in which long-chain fatty acids are replaced by medium-chain fatty acids, and the administration of polyunsaturated fatty acids have been used without definitive favorable effects.²⁷³ Haug and Braun-Falco²⁸⁶ reported that adeno-associated virus vectors restored fatty aldehyde dehydrogenase deficiency in fibroblast cell lines from patients with Sjögren-Larsson syndrome, which suggests that gene therapy may eventually become an option.

Clinical Features

Pathology

Extensive degeneration of white matter with cystic degeneration is a feature. The cortex is preserved. There is increased density and apoptosis of oligodendrocytes.²⁹⁵ Astrocyte structure is abnormal.²⁸⁸

Neuroimaging

Three imaging findings are characteristic: (1) Cerebral hemispherical white matter is symmetrically and diffusely abnormal; (2) part or all of the abnormal white matter has a signal intensity close to or the same as CSF in both T2-weighted and either proton density or fluid-attenuated inversion recovery images; and (3) a fine meshwork of remaining tissue strands is visible within the areas of CSF-like white matter.

Genetics

The mode of inheritance is autosomal recessive. The distribution is panethnic, possibly more common in white persons from Western Europe and North America. The incidence is 1 per 40,000 in certain parts of The Netherlands. This disease is probably more common than had been recognized.

The basic defect involves the eukaryotic translation initiation factor eIF2β. eIF2β is a complex consisting of five subunits, eIF2β1 to eIF2β5, encoded on loci 3q27, 14q24, 1q34.1, 2q23.3, and 12q24.3. Mutations of eIF2β5 (3q27) are most common. In one series, 14 of 16 mutations were missense,⁸ and most involved nonconserved amino acids. The R113H mutations in eIF2β5 and the E213G mutations in eIF2β2 appear to be associated with milder phenotypes.^296,297

Diagnosis

The wide range of phenotypical expression is a challenge to clinical diagnosis. The episodic worsening or coma in association with minor injuries, fever, or fright provides a clue. Provisional diagnosis is based on the characteristic brain MRI and MRS findings.

Mutation analysis is required for definitive diagnosis.

Pathogenesis

eIF2β plays a fundamental role in the initiation of translation and was summarized by van der Knaap and colleagues.⁸ The first step of the translation process is that a complex of eIf2-guanosine triphosphate (GTP) and methionyl-transfer RNA binds to the ribosome; eIf2 leaves the ribosome as eIF-guanosine diphosphate. In order to bind another methionyl-transfer RNA, eIf2 must be reactivated by exchange of guanosine diphosphate for guanosine triphosphate. This reaction is catalyzed by eIF2β. Under a variety of stress conditions, protein synthesis is decreased. This response is a protective mechanism. The down regulation is induced by the rapid expression of a specific set of proteins called heat shock proteins. In the absence or impaired function of eIF2β, these key regulatory mechanisms cannot take place. The processes that lead to the specific defects in vanishing white matter disease are not yet clear. Apoptosis of oligodendrocytes²⁹⁵ and impairment of astrocyte generation²⁸⁸ have been demonstrated. The nearly instantaneous neurological worsening after a frightful event that has been reported by Vermeulen and associates²⁹⁰ provided hints about the speed and complexity of these control mechanisms.

Therapy

There is no specific therapy for vanishing white matter disease. Prompt treatment of fever and reasonable steps to prevent injuries and other forms of stress may help reduce the risk for rapid stepwise neurological progression.

Clinical Features

Macrocephaly is present at birth or, more frequently, develops during the first year of life.^7,298–301 After the first year of life, the head growth rate normalizes. The first clinical symptom is delay in walking. Walking is often unstable, and the child falls frequently.⁴ After an interval of several years, there is slow deterioration of motor function, with the development of ataxia. Signs of pyramidal tract dysfunction are late and minor. Most affected children become wheelchair dependent at the end of the first decade or during the second decade of life. Mental deterioration is late and mild. Speech becomes increasingly dysarthric, and dysphagia may develop. Some patients have dystonia and athetosis. Almost all patients have epilepsy from early on; it is usually controlled easily with medication.³⁰⁰ Minor head trauma may induce temporary degeneration.⁴

Pathology

The cerebral white matter exhibits status spongiosus with innumerable vacuoles.³⁰¹ The white matter shows intense fibrillary astrogliosis. Electron microscopy reveals splitting of the myelin sheaths at the intraperiod line with intramyelinic vacuole formation. There is no evidence of axonal degeneration or loss. The cerebral cortex is normal.

Neuroimaging

The cerebral hemispherical white matter is diffusely abnormal and swollen. The swelling is most marked during the first year of life, with obliteration of peripheral CSF spaces and narrowing of ventricles (Fig. 80-3). The external and extreme capsules are prominently involved. The central white matter structures are relatively spared.⁴ Cysts are present almost invariably in the anterior temporal regions and often also in the frontal and parietal subcortical regions (see Fig. 80-3). They enlarge with age and may become very large. Only a few infants and children with MLC lack cysts. MRS shows reduction of all signals, which is indicative of high water content.

Figure 80-3 Megalencephalic leukoencephalopathy in a 45-year-old patient with significant white matter involvement and progressive cortical atrophy. T1-weighted magnetic resonance image (A) shows involvement of diffuse white matter and a temporal lobe cyst. Fluid-attenuated inversion recovery image (B and C) show involvement of white matter involved with multiple cysts.

Genetics

The mode of inheritance is autosomal recessive. It is a rare disorder but relatively prevalent among Turkish people and in a certain Asian-Indian community, the Agrawal ethnic group. The defective gene has been mapped to locus 22qter.¹⁰ It encodes a protein of unknown function with eight transmembrane domains and is now referred to as MLC1. It is highly conserved throughout evolution. MLC1 mutations have been demonstrated in 70% of patients with MLC. Twelve mutations have been defined.^8–10

Diagnosis

Diagnosis of MLC is based on the characteristic clinical, MRI, and MRS findings. Mutations in the MLC1 gene have been identified in 70% of the patients.^4,8–10

Pathogenesis

Within the brain, MCL1 protein is expressed in astrocytic endfeet in the perivascular, subependymal, and subpial regions.^4,302 This localization suggests a possible role in a transport process across the blood-brain barrier.³⁰³ Of interest is that water transport proteins such as aquaporin-4 display a similar localization.³⁰⁴

Therapy

There is no specific therapy. Anticonvulsants are effective for seizure control. Even minor head trauma should be avoided.

Clinical Features

The clinical course is divided into four stages:³⁰⁵ (1) The latent stage extends into adulthood; (2) the osseous stage begins in the third decade and is characterized by fractures after minor injuries, cystic rarefaction, metaphyseal cysts, and replacement of cancellous bone by cysts; (3) The neuropsychiatric stage, which begins in the third or fourth decade, is characterized by progressive dementia with predominately frontal syndrome and by agnosia, apraxia, and loss of social inhibition; and (4) the dementia stage is characterized by cachexia, seizures, and death between 35 and 45 years of age.

Palatal myoclonus, dysarthria, nystagmus and ataxic gait have been reported in patients in stage 3.³⁰⁶ One 56-year-old patient had an unusually benign course, with bone lesions for 16 years but no neurological or psychiatric disturbances.³⁰⁷

Pathology

In the bone lesion, bone and hematopoietic tissue are replaced by cysts originating from adipocytes. They contain membrane membranes that are autofluorescent and carbohydrate, phospholipids, and fatty acid crystals. Periodic acid-Schiff stain of these cysts yields positive results.^305,308

Brain weight is reduced. There is atrophy of the superior frontal gyri. Deep frontal white matter is shrunken with grayish discoloration, and basal ganglia are reduced in size. Neocortical cytoarchitecture is generally preserved; there are no pathological inclusions. There is severe loss of axons and myelin, accompanied by scattered axonal spheroids and widespread activation of microglia. Vascular alterations are present in the deep frontal and white matter. These alterations affect scattered small arterioles and capillaries and consist of concentric thickening of the vascular wall with narrowing or obliteration of lumen.³⁰⁹

Neuroimaging

MRI shows bilateral T2-weighted hyperintensity and areas of cavitation in the periventricular region. Subarcuate fibers are spared. There is frontotemporal atrophy. Cerebellum and brainstem are atrophic. Computed tomography revealed calcification in the dentate nucleus and putamen.^306,310

Genetics

The mode of inheritance is autosomal recessive. The disorder is rare. By 1997, it had been observed in fewer than 150 patients.³⁰⁵ Most cases occur in two widely separated population groups: the Japanese population and the Finnish population in northern Scandinavia. The estimated population frequency in the Finns is 2 × 10⁻⁶. The defective gene maps to 19q13.1. It codes for TYRObp,³¹¹ a transmembrane protein that is a key activating signal in natural killer cells.³¹² Loss-of-function mutations have been identified in both Japanese and Finnish patients.

Diagnosis

Diagnosis is based on the characteristic combination of clinical findings and radiological skeletal changes and, in the past, brain biopsy findings. It is anticipated that DNA analysis will be of key importance for diagnosis, carrier identification, and prenatal diagnosis.

Pathogenesis

The defect of TYRObp is suggestive of a link between the bone and CNS lesions. This gene is expressed in microglial cells³¹³ and may also be expressed in osteoclasts. The detailed pathogenetic mechanisms are still unclear. The glial proliferation in white matter and the TYRObp expression patterns suggest that microglia contribute to the pathogenesis of CNS abnormalities. It is not known whether the abnormalities in small blood vessels in white matter play a primary role in pathogenesis or are a secondary event.³⁰⁹

Therapy

There is no specific therapy.