Rudolph's Pediatrics, 22nd Ed.

CHAPTER 576. Leukoencephalopathies

Mark P. Gorman

Leukoencephalopathies comprise a clinical and radiographic heterogeneous group of disorders. All these disorders share the common features of neurologic dysfunction and preferential involvement of CNS white matter. Although white matter can be affected by many different processes, the term leukodystrophy is generally reserved for those with an identified or presumed genetic basis that is associated with a loss of previously formed myelin. Acquired causes of white matter dysfunction include infectious (such as encephalitis), inflammatory (such as acute disseminated encephalomyelitis and multiple sclerosis; see Chapter 556, nutritional (such as vitamin B12 deficiency), and neoplastic (such as astrocytoma) etiologies. When evaluating a patient with a suspected leukoencephalopathy, these acquired disorders should be considered and excluded with specific testing when clinically indicated.

MRI can help to distinguish genetic from acquired white matter disorders. Normal myelination starts prenatally and continues for decades, generally proceeding in a caudalto-rostral and central-to-peripheral pattern.1 Depending on a patient’s age, specific areas are expected to be myelinated, and others are unmyelinated. With myelination, the brain MRI appearance changes, with increasing T1 signal and decreasing T2 signal in the myelinated areas. In general, brain MRI in acquired white matter disorders shows asymmetric disturbances in this process, whereas the leukodys-trophies produce a symmetric pattern of abnormalities (see Fig. 556-2).

In the past, treatment of genetic leukoencephalopathies was largely restricted to supportive measures. However, hematopoietic stem cell transplantation (HSCT) has been increasingly used for some of these leukoencephalopathies. For most of these disorders, replacement of the deficient enzyme from donor cells, especially monocytes that can cross the blood-brain barrier, serves as the underlying therapeutic mechanism. This process is slow and inefficient, typically leading to an approximate 6- to 12-month period before CNS symptoms stabilize, and does not typically reverse existing deficits.2 Therefore, although useful in certain disorders, HSCT has also been disappointingly ineffective for patients with advanced symptoms and/or one of the more rapidly progressing leukoencephalopathies. In addition, HSCT is associated with significant potential morbidity and mortality. Thus, as the genetic and molecular bases for the leukoencephalopathy become increasingly delineated, it is hoped that more specific treatments, such as enzyme replacement therapy or gene therapy, will become available. At the time of the writing of this chapter, such therapies have been implemented on a small scale for few of the disorders.

There is a very long list of leukoencephalopathies, which can be broadly divided into disorders in which there is a permanent deficit in myelin deposition (hypomyelinating), disturbances of myelin formation (dysmyelinating), or loss of existing white matter (demyelinating).1 Although useful for defining disease mechanisms, these categories do not readily translate clinically. Therefore, this chapter will use a clinical approach, dividing the leukoencephalopathies primarily based on age of onset, associated symptoms, and MRI appearance (Figs. 576-1576-2). Given the frequent heterogeneity within some of the leukoencephalopathies and the ever-expanding list of disorders, this algorithm is an oversimplification, but can nonetheless be a clinically useful initial guide to testing.

With the list narrowed, clinicians can then use the MRI appearance to support or refute their clinical impression, and biochemical and genetic testing to confirm a specific diagnosis. With this approach, the clinician can avoid testing for every leukodystrophy, a costly endeavor that is becoming rapidly impractical due to the growing number of identified leukodystrophies. This chapter will focus on the more common and clinically important leukodystrophies, as well as those whose genetic basis has been recently identified. For an exhaustive review of all white matter disorders, with an emphasis on the radiographic findings, the reader is referred elsewhere.1

X-LINKED ADRENOLEUKODYSTROPHY

X-linked adrenoleukodystrophy (ALD) is an X-linked recessive disorder that affects approximately 1 in 21,000 males and has an overall frequency (male hemizygotes plus female heterozygotes) of approximately 1 in 16,800 in the United States.3 It affects all racial and ethnic groups.

 PATHOPHYSIOLOGY AND GENETICS

Mutations in the gene ABCD1 on Xq28 cause ALD. ABCD1 encodes ALD protein, a peroxisomal transmembrane protein that is a member of the ATP-binding cassette transporter family. Most mutations are missense (61%), frameshift (23%), or nonsense (10%) mutations, with less than 10% due to deletions or insertions.4 Ninety-three percent of mutations are inherited, with only 7% forming de novo.4 As of May 2008, nearly 500 unique mutations had been reported to the X-Linked Adrenoleukodystrophy Database (www.x-ald.nl).

FIGURE 576-1. Algorithm for the differential diagnosis of leukodystrophies with onset in the first year of life. MRS, magnetic resonance spectroscopy; NAA, N-acetyl aspartate; MLC, megalencephalic leukoencephalopathy with subcortical cysts; PLP22, proteolipid protein 22; PMD, Pelizaeus-Merzbacher disease.

Although its precise activity is unknown, Adrenoleukodystrophy protein (ALDP) plays an essential, although indirect, role in the β-oxidation of very-long-chain fatty acids (VLCFA).5 Its dysfunction in patients with ALD leads to the accumulation of VLCFA in most tissues, particularly the CNS, adrenal cortex, and testes.

The presence of VLCFA in biologic membranes appears to alter their structure and function and may particularly impair myelin stability.6 White matter lesions in patients with ALD contain 3 zones: an outer layer with destruction of myelin but no inflammation, a central layer with demyelination and perivascular inflammation, and an inner layer with gliosis and little inflammation.5 Thus immune responses, particularly CD8+ cytotoxic T lymphocytes targeting oligodendrocytes, are important in ALD pathogenesis.7 Although the levels of VLCFA and the degree of inflammation appears to correlate in postmortem brain tissues of patients with ALD, the mechanisms linking these 2 processes are undefined.6

 CLINICAL PRESENTATION

Although many different phenotypes have been reported, most male patients with ALD present with the childhood cerebral (35% of all affected individuals), adrenomyeloneuropathy (40–45%), or “Addison disease only” (10%) forms.4 The cerebral form can also affect adolescents and adults. Persons with the ALD mutation may also be detected in an asymptomatic or presymptomatic stage during screening of at-risk family members.

The cerebral form is the most common subtype in children and begins between ages 4 and 8, with a mean age of onset of 7.2 years.4 Affected children first develop symptoms suggestive of attention deficit hyperactivity disorder, which are followed by signs of impaired auditory discrimination, cognitive dysfunction, visual abnormalities, ataxia, and, later, signs of corticospinal tract involvement. Seizures occasionally may be the heralding event. Adrenal function is abnormal in 90% of patients.4 After the initial onset, the illness advances rapidly to a vegetative state within a mean of 1.9 years, with death occurring at a mean age of 9.4 years.8

Adrenomyeloneuropathy (AMN) is the most common adult form, with a mean age of onset of 27 years. The main clinical findings are a slowly progressive spastic paraparesis, with sensory disturbances most severe in the distal aspects of the lower extremities and sphincter disturbances. These symptoms reflect the predominant involvement of the spinal cord and peripheral nerves in these patients. Impotence develops in the later stages, although many of these male patients have fathered children. Brain involvement occurs in 40% to 45% of patients with AMN based on clinical exam or MRI and is clinically severe in 10% to 20%.4 The AMN subtype also affects 20% of heterozygote females who develop milder symptoms in the third to fifth decades.

FIGURE 576-2. Algorithm for the differential diagnosis of leukodystrophies in childhood with onset after the first year of life.

 DIAGNOSIS

The initial differential diagnosis of the childhood cerebral form of adrenoleukodystrophy (ALD) mainly includes distinguishing it from primary attention deficit hyperactivity disorder. As symptoms progress, ALD should be distinguished from other childhood-onset leukodystrophies, such as juvenile-onset metachromatic leukodystrophy, on the basis of clinical and MRI findings, with laboratory confirmation. Patients with ALD who present acutely with gadolinium enhancement may be thought to have acquired demyelinating disorders, such as acute disseminated encephalomyelitis or multiple sclerosis; these disorders tend to have much more asymmetric MRI abnormalities. Disorders that can mimic the AMN subtype include multiple sclerosis, vitamin B12 deficiency, and hereditary spastic paraparesis.

The diagnosis of ALD can be confirmed by the detection of elevated levels of very long chain fatty acids (VLCFA) in plasma, particularly C26:0 (hexacosanoic acid), the ratio of C24:0 to C22:0, and the ratio of C26:0 to C22:0. These values are elevated in 99.9% of affected males and 85% of carrier females.4 Although sequencing of the ABCD1 gene can be performed, it is clinically useful only in rare male patients with nondiagnostic VLCFA values and carrier females with normal VLCFA levels.

Gadolinium-enhanced brain MRI should be performed in all patients. Brain MRI shows preferential, symmetric involvement of the parieto-occipital white matter and/or splenium of the corpus callosum in 66% of patients overall and 80% of patients under 10 years of age (Fig. 576-3).9 When present, gadolinium enhancement is typically curvilinear and close to the advancing margin, correlating with the middle zone on neuropathology specimens. Enhancement is found in approximately 45% of patients overall and predicts faster clinical and radiographic progression.9

 MANAGEMENT

All patients should undergo an assessment of their adrenal function with measurement of plasma adrenocorticotropin hormone (ACTH) levels or cortisol response in an ACTH stimulation test with the assistance of an endocrinologist. Patients with initially normal results should be reevaluated regularly. The first priority of treatment in ALD is to provide adrenal hormone supplementation, if adrenal insufficiency is identified, in order to avoid the morbidity and mortality associated with adrenal crises.

Additional treatment of ALD may include Lorenzo’s oil, a 4:1 mixture of glycerol trioleate and glycerol trierucate that lowers plasma VLCFA levels by approximately 50% in patients with ALD, likely via competitive inhibition of VLCFA synthesis.6 Although it is ineffective in significantly altering clinical progression in patients with cerebral ALD with established neurologic symptoms, it may have a role in disease prevention. In an open-label, single-arm trial involving 89 boys with ALD, no neurologic symptoms, and a normal brain MRI, Lorenzo’s oil therapy appeared to reduce the risk of developing the childhood cerebral form of the disease by twofold over a mean follow-up of 6.9 years. In 30% to 40% of treated patients, Lorenzo’s oil reduces platelet counts, which should be followed regularly. Very close nutritional and biochemical monitoring must also be carried out.

FIGURE 576-3. Brain MRI of an 8-year-old boy who developed declining school performance, clumsiness, and visual impairment at age 5 years. His symptoms became progressively worse over time. Physical exam showed cognitive impairment and hyperreflexia. Plasma levels of very-long-chain fatty acids were increased, confirming a diagnosis of X-linked adrenoleukodystrophy. A: Axial T2-weighted image showing symmetric, posterior-predominant hyperintense signal. B: Axial, postgadolinium T1-weighted image showing T1 hypointensity in the region of T2 hyperintensity. Contrast enhancement is present at the peripheral margin. (Courtesy of Dr. Omar Khwaja, Department of Neurology, Children’s Hospital, Boston, MA.)

Hematopoietic stem cell transplantation (HSCT) improves survival and neurologic function in patients with childhood cerebral ALD, particularly those early in the disease course. Although overall 5-year survival was 56% in 94 patients with ALD who received HSCT and 66% in a historical cohort of non-transplanted patients, this figure was significantly higher in patients with mild neurologic deficits and/or MRI findings at the time of HSCT.10,11 In a subgroup of 19 patients with 0 or 1 neurologic deficits and MRI severity score less than 9 on a standardized scale, the 5-year survival rate was 95% compared to 54% in a historical cohort of 30 nontransplanted patients with a similarly mild degree of neurologic deficits.10,11 In addition, 53% of the surviving transplanted patients in this subgroup were neurologically stable at 5 years, compared to only 6% in the historical control group.11 Patients with more significant clinical and MRI disease burden are at high risk of death following HSCT, which is therefore not recommended for this group of patients. In addition, as only 35% to 40% of boys younger than 10 years old with biochemical evidence of ALD will develop childhood cerebral ALD and there are substantial risks associated with HSCT, this treatment is not recommended for patients without MRI evidence of demyelination.2 Therefore, the challenge is to identify the patients who have minimal, but not more advanced, neurologic involvement and to successfully perform HSCT in them quickly. The mechanism by which HSCT affects ALD is uncertain, but probably involves alterations in the immune system, rather than replacement of the defective gene product.

 OUTCOME AND PREVENTION

As described above, the prognosis for ALD depends on the specific clinical phenotype. Within the childhood cerebral subtype, the overall prognosis is poor in the absence of timely HSCT. Unfortunately, plasma levels of VLCFA and specific mutations in ABCD1 do not correlate well with the clinical phenotype, making prognostication difficult. Patients with the same mutation within the same family can have different clinical expression.  Early age of onset is also associated with a worse prognosis.9

The diagnosis of ALD can now be made via analysis of newborn blood spots, thus making newborn screening a possibility. It is estimated that at least 50 presymptomatic boys with ALD would be identified each year in the United States.6 Importantly, 92% of boys with ALD with normal brain MRI have normal cognition on detailed neuropsychological testing.12 This finding, combined with the potential efficacy of Lorenzo’s oil in delaying disease expression and the proven efficacy of HSCT in early-stage patients, makes newborn screening an attractive, although challenging, possibility. Early diagnosis would substantially increase the currently narrow therapeutic window of opportunity by allowing advanced preparation for HSCT should it be needed. In families in which the specific mutation is known, prenatal diagnosis is also available.

AICARDI-GOUTIERES SYNDROME

Patients with Aicardi-Goutieres syndrome develop a subacute, severe encephalopathy within the first year of life, with irritability, developmental regression, and slowing of head growth. This phase usually lasts several months, after which the patient has severe cognitive impairment, spasticity, and microcephaly, but does not continue to regress.13 More than 50% also have seizures and 40% have chilblain lesions on the digits or ears. Fever in the absence of infection is also common. Computerized tomography of the head shows calcification of the basal ganglia and periventricular white matter. Brain MRI reveals hyperintense signal in the periventricular white matter with a frontal predominance on T2-weighted images. Cerebrospinal fluid contains elevated levels of white blood cells, interferon-α, and neopterin, which gradually decline over several years. Mutations in AGS1, 2, 3, or 4 cause approximately 80% of cases of the syndrome, with nearly all patients having homozygous recessive or compound heterozygote mutations.13AGS1 encodes for 3 prime repair exonuclease 1 (TREX1). Mutations in this gene can produce the syndrome at birth, with associated hepatosplenomegaly, transaminitis, and thrombocytopenia. AGS2, 3, and 4 encode for subunits of ribonuclease H. Due to the presence of neurologic abnormalities, microcephaly, and intracranial calcifications, congenital toxoplasmosis, rubella, CMV, and herpes simplex (TORCH) infections should be ruled out with appropriate serologic and virologic studies in patients suspected of having Aicardi-Goutieres syndrome.

ALEXANDER DISEASE

Alexander disease is a rare, autosomal dominant leukodystrophy that has been reported in many different racial and ethnic groups. Its exact incidence is uknown.14

Prior to 2001, the definitive diagnosis of Alexander disease required the demonstration of Rosenthal fibers, eosinophilic rodlike intracellular inclusions composed of aggregates of glial fibrillary acidic protein (GFAP) and other proteins, on brain biopsy specimens of affected patients. In 2001, Brenner and colleagues discovered mutations in GFAP on chromosome 17q21 in 10 of 11 patients with Alexander disease.15 Subsequent studies have shown that GFAP mutations account for more than 90% of all cases of Alexander disease.16 Nearly all of the identified mutations are missense mutations involving exons 1, 4, or 6, with hotspots at residues R79 and R239.17 GFAP is the major intermediate filament protein in CNS astrocytes. The exact mechanisms by which alterations in GFAP in astrocytes lead to the myelin abnormalities seen in Alexander disease are unknown.

Three forms of Alexander disease are recognized based on age of onset. The infantile-onset form manifests within the first 2 years of life and comprises approximately 65% of cases.14 Typical symptoms include developmental delay, megalencephaly, and seizures. As the disease progresses, cognitive decline, feeding problems, and spastic quadriparesis become apparent. Some infants present acutely in the first year with hydrocephalus and increased intracranial pressure due to aqueductal stenosis. Death usually occurs between the ages of 2 and 10 years. A more fulminant neonatal form with onset in the first month of life and very rapid progression has also been proposed.

Juvenile-onset Alexander disease (25%) usually begins between the ages of 4 and 10 years. The most common symptoms consist of bulbar or pseudobulbar dysfunction, especially dysphagia. Spasticity, ataxia, and cognitive regression may also occur. Megalencephaly may occur, but is less common than in the infantile-onset form. These children may survive for up to 10 years and frequently longer. Adult-onset forms comprise 10% of all cases with marked variability in presentation.14

The combination of macrocephaly and leukodystrophy in the first 2 years of life is suggestive of Alexander disease. MRI findings and biochemical and genetic testing help to differentiate it from other disorders such as Canavan disease and megalencephalic leukoencephalopathy with subcortical cysts. Juvenile-onset cases can be distinguished from other leukodystrophies with a similar age of onset, such as the juvenile-onset forms of metachromatic leukodystrophy and Krabbe disease, by the lack of peripheral nervous system involvement, as well as MRI features.

MRI in Alexander disease demonstrates extensive, symmetric T2 hyperintense signal in the cerebral white matter with predominant involvement of the frontal lobes (Fig. 576-4). Additional common findings include (1) a periventricular rim of T1 hyper-intensity and T2 hypointensity, (2) swelling and later atrophy of the basal ganglia and thalamus, (3) brainstem abnormalities, and (4) contrast enhancement involving various locations. The presence of 4 of 5 of these common findings makes the diagnosis of Alexander disease likely, based on a large, multicenter study.18 However, although frontal-predominant white matter T2 hyperintensities remains the most classic finding, recent studies have demonstrated significant heterogeneity in the MRI appearance.19 Thus, patients suspected of having Alexander disease should undergo sequencing of the GFAP gene, even in the presence of atypical MRI findings.

There is no specific treatment for Alexander disease, although supportive treatment may improve symptoms. The overall prognosis is poor, although significant differences in rates of progression and age at death exist between the different subtypes. Due to its relative rarity, predictive genotype-phenotype correlations do not exist. Prenatal diagnosis is possible in families in which the disease-causing mutation is known.

CANAVAN DISEASE

Canavan disease is an autosomal-recessive neurologic disorder that affects all ethnic groups, but has its highest rate in Ashkenazi Jews. In this group, the carrier rates have been estimated between 1:40 and 1:60.20

Mutations in the ASPA gene on chromosome 17p cause Canavan disease. This gene encodes aspartoacylase, an enzyme that is responsible for hydrolyzing N-acetylaspartic acid to aspartic acid and acetate. Two mutations (E285A and Y231X) account for 98% of alleles in Ashkenazi Jewish patients, while 1 mutation (A305E) is found in approximately 50% of non-Jewish patients.20 Deficiency of the enzyme leads to accumulation of N-acetylaspartic acid in the brain, which in turn causes spongiform degeneration of the white matter via unknown mechanisms.

Following normal initial development, patients with Canavan disease develop the classic triad of macrocephaly, hypotonia, and poor head control.23 Delayed development is apparent by 3 months of age. Macrocephaly may not be apparent within the first few months, but the head enlarges to above the 90th percentile within 6 months to a year of life. Affected children never develop the ability to support the head, sit, or stand independently. Seizures and optic atrophy frequently develop in the second year of life. Over time, hypotonia evolves into spasticity, gastroesophageal reflux becomes prominent, and swallowing deteriorates, leading to feeding difficulties, poor weight gain, and need for gastrostomy tube feeding.20 The rate of overall disease progression is variable.23

FIGURE 576-4. Brain MRI of a 5-month-old boy who presented with seizures. He then developed developmental delay and progressive macrocephaly. Sequencing of the GFAP gene revealed a G-to-A mutation at nucleotide 730, changing residue 239 from arginine to histidine, and confirming a diagnosis of Alexander disease. This axial T2-weighted image shows hyperintense signal in the cerebral white matter with a frontal predominance. There is also T2 hyperintense signal in the caudate heads bilaterally. (Courtesy of Dr. Magdi Sobeih, Department of Neurology, Children’s Hospital, Boston.)

The combination of macrocephaly and leukodystrophy with onset at less than 12 months of age raises Canavan disease and Alexander disease as the 2 most likely possibilities, which can be distinguished with magnetic resonance spectroscopy (MRS) and biochemical testing. MRI demonstrates diffuse symmetric white matter changes consisting of increased signal on T2-weighted images (Fig. 576-5A). MRS reveals the characteristic elevation in N-acetylaspartic acid (Fig. 576-5B), which can also be detected in very high levels in urine samples. The diagnosis can be confirmed with analysis of the ASPA gene, starting with targeted mutation screening followed by full sequencing if needed.

Treatment of Canavan disease is supportive. Two patients have undergone intraventricular injection of a liposome/adeno-associated virus–based plasmid in attempt to deliver the ASPA gene.24 A larger trial of such gene therapy is reportedly ongoing, but clinical results have not been published to date.

The prognosis for Canavan disease is poor, with patients not achieving independent sitting. With improved medical and nursing care, the average life expectancy is into the teens.20 Accurate genotype-phenotype correlations are lacking. Given the high carrier rate in Ashkenazi Jews, population screening has been proposed. Prenatal detection is also available in families in which the pathogenic mutation is known.

GLOBOID CELL LEUKODYSTROPHY (KRABBE DISEASE)

Globoid cell leukodystrophy is an autosomal recessive inherited glycosphingolipid storage disorder primarily causing a leukodystrophy. It has an estimated incidence of 1:100,000 in the United States and affects all ethnic groups.28

 PATHOPHYSIOLOGY AND GENETICS

Globoid cell leukodystrophy is caused by mutations in the GALC gene on chromosome 14q31 encoding the lysosomal enzyme galactosylceramide β-galactosidase (galactocerebrosidase). Many different mutations affecting each of the 17 exons have been detected. In patients of European ancestry with infantile onset, a 30-kb deletion starting in exon 10 comprises approximately 45% of mutant alleles.28 This deletion typically results in the classic infantile form, unless it is inherited with the G-to-A mutation at position 809 on the other allele, which invariably results in the late-onset form.

Galactocerebrosidase is required to degrade galactosylceramide, an important glycolipid in myelin structure. Most mutations lead to the production of an unstable, rapidly degraded form of the protein, with residual enzyme activity at 0% to 5% of normal levels.28 The protein is also responsible for the degradation of galactosylsphingosine (pyschosine); resulting elevated levels appear to be toxic to oligodendrocytes.29 Neuropathologic specimens show the accumulation of globoid cells, perivascular multinucleated macrophages with inclusion bodies, as well as loss of oligodendrocytes, white matter rarefaction, and gliosis. The disorder also affects the peripheral nervous system in the form of a diffuse demyelinating sensorimotor polyneuropathy.

FIGURE 576-5. Brain magnetic resonance imaging (MRI) (A) and magnetic resonance spectroscopy (MRS) (B) of a 6-month-old girl with poor head control, hypotonia, and macrocephaly. Axial T2-weighted image (A) shows hyperintense signal in all of the white matter. MRS (B) reveals a markedly elevated N-acetyl aspartate peak (white arrow) consistent with Canavan disease. (Courtesy of Dr. David Urion, Department of Neurology, Children’s Hospital, Boston.)

 CLINICAL PRESENTATION

The classic infantile form with onset in the first 6 months of life accounts for 90% of all cases.28 This form frequently consists of extreme irritability followed by rigidity, tonic spasms, and progressive neurologic deterioration. Three stages have been proposed. Following a period of a few months of apparently normal development, stage I ensues with irritability, fever in the absence of infection, hypersensitivity to stimuli, and developmental arrest. Although it may not be apparent clinically, peripheral neuropathy is detectable by nerve conduction studies in nearly all patients at this stage.30Cerebrospinal fluid examination is remarkable for the elevation of protein, typically above 70 mg/dL. Stage II consists of rapid, global deterioration, with severe spasticity resulting in opisthotonic posturing. Epileptic seizures also occur. Finally, the patient is left in a decerebrate state with blindness and immobility in stage III. Death occurs at an average age of 13 months in untreated patients.28

Onset after 6 months of life has been designated as late-onset, which has a variable presentation and subsequent course. This form has been generally divided into late-infantile (onset at 6 months to 4 years of age), juvenile (4 years to 19 years), and adult-onset (> 20 years) subtypes. Common presenting symptoms include weakness and vision loss, followed by progressive deterioration of motor and then cognitive function. In general, patients with onset at a younger age within the late-onset group have a more rapidly progressive course.29

The clinical features described above, although nonspecific, should raise suspicion for globoid cell leukodystrophy. The initial presentation will typically lead to a brain MRI that focuses the differential diagnosis on leukodystrophies. Due to the involvement of the peripheral nervous system, late-onset globoid cell leukodystrophy can be confused with metachromatic leukodystrophy. In order to confirm the diagnosis, galactocerebrosidase enzyme activity should be measured in an experienced laboratory. Mutation analysis can be subsequently performed.

More than 95% of patients with the early infantile form have slowed sensory and motor conduction velocities on nerve conduction studies, detectable as early as 1 day of life.30 Although they may be present, nerve conduction study abnormalities are significantly milder in late-onset patients. Nerve conduction studies are more sensitive than other electrophysiologic tests. In the early onset group, abnormal brainstem auditory evoked potentials, electroencephalograms, and visual evoked potential are present in approximately 90%, 65%, and 50% of patients, respectively.31 Such abnormalities are less frequent in the late-onset group.

The CT scan may initially demonstrate nonspecific increased density in the brainstem, thalami, caudate nuclei, corona radiata, cerebellar cortex, and periventricular and capsular white matter (Fig. 576-6A). In patients with the infantile-onset form, MRI reveals large, symmetric, nonenhancing T2 hyperintensities in the brainstem, cerebellum, and centrum semiovale, initially sparing the subcortical fibers.29 Areas of low signal on T2-weighted images, particularly in the thalamus and dentate, may also be present (Fig. 576-6B).29 Patients with later-onset forms often have discrete T2 hyper-intense lesions in the corticospinal tracts in the internal capsules and brainstem.29 Over time, the white matter changes become more diffuse in both groups. Rare symptomatic infants have had apparently normal brain MRIs.

 TREATMENT AND OUTCOMES

Hematopoietic stem cell transplantation in the presymptomatic state or in late-onset patients with mild symptoms may be beneficial. The differing rates of progression in the early versus late-onset forms may partially explain the discrepant benefits of stem cell transplantation in these 2 groups.

FIGURE 576-6. Computed tomography (A) and axial T2-weighted MRI (B) of a 2-month-old girl who presented with irritability and developmental arrest. Cerebrospinal fluid protein was markedly elevated at 216 mg/dL. CT shows symmetric hyperdensities in the bilateral lateral thalami, putamen, and adjacent white matter. MRI shows hypointense signal in the corresponding regions (arrows). Galactocerebrosidase enzyme activity was undetectable. The patient was homozygous for the common 30-kb deletion, consistent with Krabbe disease. (Courtesy of Dr. Eugenia Ho, Department of Neurology, Children’s Hospital, Boston.)

In 4 patients with late-onset disease, resolution or stabilization of established neurologic deficits, and improvement in electrophysio-logic and MRI findings have been reported following bone marrow transplantation.32 Beneficial effects were also reported in 11 “asymptomatic” infants who were diagnosed prenatally or at birth due to prior family history and received umbilical cord blood transplantation at a median age of 28 days.33 These benefits included a survival rate of 100%, developmental progress in cognition and language, and improvements or normalization in brain MRI and electrophysiologic studies. However, these benefits in mortality and morbidity were not observed in 14 symptomatic infants in the same study, and the procedure is therefore not recommend in early-infantile onset patients with established symptoms.33 Umbilical cord blood is preferred over bone marrow as the source of stem cells in the infantile group in order to speed the matching process and time to transplantation.

The prognosis of untreated patients with the early-infantile onset form is poor, with an average age of death of 13 months.28 The prognosis for patients with later-onset forms is variable; in general, those with earlier onset within this group have severe neurologic deficits and death by age 10 years.29

Tandem mass spectrometry can measure galactocerebrosidase enzyme activity in dried newborn blood spots, thus allowing for newborn screening, which has been implemented in New York State.28 This earliest detection may allow for very rapid stem cell transplantation, even in patients without a family history. In addition, prenatal diagnosis via measurement of GALC enzyme activity or gene sequencing in affected families is available.

METACHROMATIC LEUKODYSTROPHY (MLD)

Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease involving glycosphingolipid metabolism that causes a leukoencephalopathy with an estimated frequency of 1 in 40,000.37Although the incidence is higher in select small population groups with high rates of consanguinity, it affects all ethnic groups.

 PATHOPHYSIOLOGY AND GENETICS

The major cause for metachromatic leukodystrophy (MLD) is mutations in the gene on chromosome 22q13.3 encoding the lysosomal enzyme arylsulfatase A (ASA), which catalyzes cerebroside 3-sulphate (sulfatide). Sulfatide normally composes approximately 5% of myelin lipids. Over 100 mutations have been identified in the ASA gene.38 Mutations have been broadly classified as I alleles, which result in no functional enzyme activity, or A alleles, which retain some activity. Inheritance of 2 I alleles usually causes infantile-onset MLD, and 2 A alleles leads to adult-onset MLD; the combination results in the juvenile-onset form. Most mutations are found in individual patients, but 3 mutations are fairly common among patients of European ancestry: (1) a splice donor-site I type mutation at the exon 2/intron 2 border (25%), (2) a Pro426Leu A type substitution (25%), and (3) an Ile179Ser A type substitution (12%).38 Patients with homozygous P426L mutations typically present with gait disturbance, whereas patients with I179S heterozygous mutations present with neuropsychiatric symptoms.39 However, the overall poor genotype-phenotype correlation in MLD impedes accurate prediction in individual patients and suggests additional, undefined genetic or environmental factors.

Approximately 10% of the normal population carries the so-called arylsulfatase A-pseudodeficiency (ASA-PD) alleles. These alleles result in 5% to 20% of normal ASA enzyme activity but no clinical manifestations, even when inherited in a homozygous state or when inherited with a single MLD allele. If moderate reductions in ASA activity are found, gene sequencing can be performed to differentiate the disease, carrier and pseudodeficiency states.

Rarely, patients with normal ASA gene structure and enzyme activity have a clinical phenotype compatible with metachromatic leukodystrophy. This situation is caused by mutations in the gene on chromosome 10 encoding the cerebroside sulfate activator protein known as saposin B. This protein is required to solubilize sulfatides so that arylsulfatase A can then hydrolyze them.37 Other rare patients have multiple sulfatase deficiency that combines features of metachromatic leukodystrophy and the mucopolysaccharidoses, including coarse facial features and skeletal abnormalities. Mutations in the gene encoding the formylglycine-generating enzyme, which is needed to activate several sulfatases, cause this disorder.

Regardless of the specific genetic cause, sulfatide accumulation in the liver, kidney, and central and peripheral nervous systems occurs in each of these disorders. When such tissues are stained with cresyl violet or toluidine blue, the excess sulfatides produce a brownish or reddish color compared to the blue color of cell nuclei, leading to the name metachromatic. In the nervous system, sulfatides particularly accumulate in oligodendrocytes and Schwann cells, leading to demyelination via unknown mechanisms. Postulated mechanisms include myelin instability, impaired signaling, and inflammation.40 Psychosine sulfate is also elevated and may have a toxic effect on myelin.

 CLINICAL PRESENTATION AND DIAGNOSIS

The clinical phenotype of metachromatic leukodystrophy has been divided based on the age of onset. The late-infantile form (50–60% of cases) manifests with difficulty walking, weakness, and hypotonia between ages 1 and 2, following initially normal development. Eventually, spasticity and loss of speech result in a quadriplegic state and death approximately 3.5 years after onset.37 Juvenile-onset cases (20–30%) develop between 4 and approximately 14 years of age. Within this range, younger patients often present with gait problems related to peripheral nerve involvement, whereas older children tend to initially have school problems and behavioral difficulties. The rate of progression of the disease varies, with survival typically 10 to 20 years after onset. Patients with the adult-onset form (15–20%) usually have psychiatric problems as the major initial feature of the disease.

FIGURE 576-7. Axial T2-weighted images showing T2 hyperintense signal in the white matter with sparing of the subcortical U fibers, characteristic of metachromatic leukodystrophy (MLD). A. MRI of a 2-year-old girl who initially had normal development but did not achieve walking. Examination showed absent reflexes, and nerve conduction studies were consistent with a generalized polyneuropathy. Urine sulfatides were elevated and arylsulfatase A activity was low, consistent with late-infantile MLD. B. The same MRI pattern is seen in a 7-year-old boy who developed declining school performance at age 6 followed by gait abnormalities. Arylsulfatase A activity was low. Sequencing of the ARSA gene revealed 1 copy of the common late-infantile mutation (G459+1A) and 1 copy of a common adult-onset mutation (P426L), leading to juvenile-onset MLD.

Some patients may initially present with features restricted to the peripheral nervous system and receive a diagnosis of an isolated peripheral neuropathy, such as chronic inflammatory demyelinating polyneuropathy. However, the eventual development of cerebral involvement should lead to a brain MRI, revealing the leukodystrophy. Patients with symptoms and signs referable to the CNS will undergo brain MRI at the onset. The differential diagnosis in such patients is focused on the leukodystrophies. In particular, given the involvement of the peripheral nervous system, metachromatic leukodystrophy should be distinguished from late-onset globoid cell leukodystrophy via biochemical and genetic testing.

Brain MRI in patients with metachromatic leukodystrophy reveals diffuse, symmetric hyperintense signal on T2-weighted images involving the cerebral white matter, characteristically sparing the immediate subcortical U fibers (Fig. 576-7). These abnormalities may initially start posteriorly and then spread anteriorly as the disease progresses. Atrophy often follows. Nerve conduction studies show diffusely slow motor and sensory conduction velocities indicative of a demyelinating polyneuropathy. Measurement of arylsulfatase A enzyme activity narrows the diagnosis to metachromatic leukodystrophy. Urinary excretion of sulfatides is also elevated. Sequencing of the arylsulfatase A gene confirms the diagnosis, with rare patients requiring analysis of the saposin B gene.

 TREATMENT AND OUTCOMES

Treatment for metachromatic leukodystrophy is primarily symptomatic, with treatments directed at spasticity and pain control. A phase I/II trial of enzyme replacement therapy is also underway, but results are currently unknown.38Bone marrow transplantation (BMT) may be effective to partially ameliorate symptoms if it is used early in the course of juvenile- and adult-onset forms. However, peripheral nervous system involvement is not improved by BMT and patients eventually develop significant motor impairment.42 BMT is not recommended for patients with symptomatic late-infantile MLD as the rapid progression of the disease outpaces any potential improvment.2 It is unclear if asymptomatic siblings of patients with late-infantile MLD benefit from BMT.

Untreated patients with metachromatic leukodystrophy eventually develop profound motor and cognitive dysfunction leading to early death. The age at which this process starts and the rate of subsequent deterioration depends on the specific subtype as described above. Prenatal diagnosis is available in families with a previously affected member. Tools for newborn screening are also available and may soon allow for very early diagnosis and consideration of BMT prior to symptom onset, even in patients without a family history.

PELIZAEUS-MERZBACHER DISEASE

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukoencephalopathy with a prevalence of approximately 1/200,000 to 1/500,000.45

 PATHOPHYSIOLOGY AND GENETICS

PMD is caused by abnormalities in the proteolipid protein 1 (PLP1) gene on chromosome Xq22. This gene encodes the transmembrane myelin proteolipid protein, which makes up 50% of the protein content of myelin. The full PLP1 transcript can also be alternatively spliced to form DM20, which lacks residues 117-151 encoded in a portion of exon 3. Mutations in PLP1 appear to cause aberrant folding of myelin proteolipid protein, which in turn triggers the unfolded protein response and oligodendrocyte apoptosis.46 Pathologic specimens show decreased or absent myelin in affected areas, with preservation of axons and scattered areas of preserved but abnormally thin myelin.47

Duplication of PLP1, which can be detected with interphase fluorescent in situ hybridization or quantitative polymerase chain reaction testing, accounts for 50% of all cases. It is usually associated with the classic phenotype described below. More than 100 reported point mutations comprise 15% to 20% of cases.45 Deletions and splice-site or regulatory region mutations account for a small percentage of patients. Mutations in PLP1 can also cause familial spastic paraplegia type 2 (SPG2), which forms a clinical continuum with PMD. Although exact genotype-phenotype correlations do not exist, mutations in the PLP1-specific region in exon 3, which therefore spare DM20, tend to cause SPG2 instead of PMD.48

Approximately 5% to 20% of patients with a PMD phenotype do not have detectable PLP1 mutations, suggesting the involvement of other genes. Such patients are labeled as having PMD-like disease. Mutations in one such gene, GJA12 on chromosome 1q41-42, which encodes gap junction protein α12 (connexin 46.6), account for less than 10% of such cases.49 The remaining genes are unidentified at present.

 CLINICAL PRESENTATION

PLP1-related disorders form a clinical continuum, with connatal PMD at the most severe end and pure SPG2 at the mildest end.45 The connatal form presents at, or shortly after, birth and includes nystagmus, hypotonia, and stridor. As the infant ages, severe spasticity, ataxia, and cognitive impairment develop, and walking is not achieved. Classic PMD manifests with nystagmus, typically in the first 2 months of life. Symptoms are similar to the connatal form, but are generally less severe and progress more slowly. Movement disorders may also be present. Following normal development in the first year of life, pure SPG2 usually starts between ages 2 and 5 with spastic paraparesis and bladder dysfunction. Complicated forms of SPG2 include nystagmus, ataxia, and cognitive dysfunction. Female carriers of PLP1mutations may develop mild to moderate symptoms later in life.

FIGURE 576-8. Axial fluid-attenuated inversion recovery MRI of a 2-year-old boy showing bilateral, symmetric increased signal throughout the white matter. He developed nystagmus at 1 month of life and had severe global developmental delay. Examination also revealed hypotonia. Fluorescent in situ hybridization analysis revealed duplication of the PLP1 gene, consistent with classic Pelizaeus-Merzbacher disease. (Courtesy of Dr. Caroline Robson, Department of Radiology, Children’s Hospital, Boston.)

 DIAGNOSIS AND TREATMENT

The combination of early-onset nystagmus and leukodystrophy narrows the differential diagnoses significantly, as other leukoencephalopathies such as adrenoleukodystrophy and metachromatic leukodystrophy, do not typically include this symptom. Patients with Salla disease (free sialic acid storage disorders) can also have nystagmus and a diffuse leukodystrophy. This disorder can be considered in patients with negative PLP1 and GLA12 testing.

The MRI appearance of PMD shows a diffuse increase in the signal of white matter on T2-weighted images that is characteristic for children over the age of 1 year (Fig. 576-8). In younger children, the MRI is less specific because the brain has yet to fully myelinate. Patients with spastic paraplegia type 2 may have patchy T2 hyperintensities in the cerebral white matter. Evoked potential studies are also abnormal, and EMG and nerve conduction velocities are usually normal. Patients suspected of having PMD should undergo testing of the PLP1 gene, looking first for duplications and proceeding to sequencing if needed. GJA12 sequencing should be considered in patients with the PMD phenotype and normal PLP1 testing.

Treatment of PMD is supportive, with attention to spasticity and seizures. The prognosis of the PLP1-related disorders depends on the specific phenotype as described above. Although there is some variation, presentations within a single family tend to be similar. Prenatal diagnosis is available if the disease-causing mutation is known in the family.

VANISHING WHITE MATTER DISEASE

Vanishing white matter (VWM) disease, also known as childhood ataxia with diffuse CNS hypomyelination, is an important cause of previously undiagnosed leukodystrophies, although its exact incidence is unknown. Mutations in any of the 5 genes (EIF2B1-5) encoding the 5 subunits (α, β, γ, δ and ) of eukaryotic translation initiation factor eIF2B cause the disease. Approximately two thirds of mutations are found in EIF2B5.50 eIF2B is involved in the initiation of translation of mRNAs into proteins. Pathologic specimens in patients with VWM disease show marked changes restricted to the white matter, often with frank cavitation, without inflammation. The mechanisms by which the mutations lead to selective, severe white matter injury are uncertain, but may involve the unfolded protein response.50

The most common form of VWM disease presents between ages 2 and 6 years, with chronic progressive ataxia and less severe spasticity and cognitive decline, punctuated by acute deteriorations in the setting of minor head trauma or fever with incomplete or no recovery. Mild epilepsy is also common. In addition to this classic phenotype, a wide spectrum of presentations, ranging from a severe antenatal form to mild adult-onset variants, have been described.50 In addition to brain involvement, primary or secondary ovarian failure can be an important clue in some patients. The acute episodes and white matter changes may prompt consideration of acute disseminated encephalomyelitis (ADEM). However, patients with ADEM typically have more asymmetric white matter lesions and marked or complete recovery from the acute episodes (see also Chapter 556). Encephalitis is also a consideration, but typically involves both gray and white matter on MRI.

MRI demonstrates diffuse confluent abnormality in all of the cerebral white matter early in the course of the disease and even in presymptomatic patients. As the disease progresses, the white matter is replaced by fluid, shown best as the conversion from high to low signal on fluid-attenuated inversion recovery sequences.50 Diagnostic MRI criteria have been developed by van der Knaap and are highly sensitive and specific for the identification of mutations in EIF2B genes.

There is no known treatment for VWM disease, but potential precipitating factors should be avoided and treated promptly if present. Many patients with the childhood onset form die within a few years, but there is overall considerable clinical heterogeneity. Prenatal diagnosis is available for families in which the disease-causing mutation is known.