Genetic and Metabolic Disorders of the White Matter

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Chapter 71 Genetic and Metabolic Disorders of the White Matter


Over the past two decades, an increasing number of novel heritable disorders affecting the white matter of the brain, or leukodystrophies, have been described, often with identification of a causative gene (Table 71-1). Pathognomonic magnetic resonance imaging (MRI) patterns (see Figure 71-1) or clinical characteristics permit identification in a number of these disorders, and should guide the clinician’s molecular diagnosis for many conditions (see Figures 71-3, 71-5, and 71-6 for MRI features). Challenges remain, however, for the neurologist, geneticist, or primary-care provider evaluating patients with suspected genetic or metabolic disorders of the white matter. In many settings, over half of subjects with suspected heritable white-matter disease do not receive a diagnosis, and therefore the focus of this chapter is on assisting the treating neurologist in the diagnosis of inherited disorders of the white matter.

Table 71-1 Molecular Causes of Leukodystrophies and Leukoencephalopathies (a Nonexhaustive List)

Disorder Gene
Acyl-coenzyme A (acyl-CoA) oxidase deficiency ACOX
Adenylosuccinate lyase deficiency ADSL
Aicardi–Goutières syndrome (AGS) TREX1, SMHD1, RNAseH2A, B, C
Alexander’s disease (AxD)* GFAP
Autosomal-dominant leukodystrophy with autonomic dysfunction* Duplication LaminB1
Canavan’s disease ASPA
Cerebrotendinous xanthomatosis (CTX) CYP27A1
D-bifunctional protein deficiency HSD17B4
eIF2B-related disorder/VWM disease* EIF2B1-5
Glutaric aciduria type II/multiple acylCoA dehydrogenase deficiency (MADD) ETFA, ETFB, ETFDH
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase deficiency HMGCR
Hypomyelination with congenital cataracts (HCC) * FAM126A
Infantile sialic acid storage disease (ISSD) SLC17A5
Krabbe’s disease GALC
Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL)* DARS2
Lowe’s syndrome (oculocerebrorenal syndrome of Lowe, OCRL) OCRL
Megalencephalic leukoencephalopathy with subcortical cysts (MLC)* MLC1
Metachromatic leukodystrophy (MLD) ARSA
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) TYMP
Mucolipidosis IV MCOLN1
Oculodental digital dysplasia (ODDD)* GJA1
Pelizaeus–Merzbacher disease (PMD)* PLP1
Pelizaeus–Merzbacher-like disease (PMLD)* GJC2
Peroxisomal thiolase deficiency ACAA
Polymerase gamma 1 (POLG1)* POLG1
Polyglucosan body disease (PGBD) GBE1
RNAse T2-deficient leukoencephalopathy* RNASET2
Sjögren–Larsson syndrome ALDH3A2
X-linked adrenoleukodystrophy (XALD) ABCD1
18q minus syndrome Deletion of short arm chromosome 18

VWM, vanishing white matter

* No specific biochemical marker clinically available, and molecular testing is primary diagnostic tool.


Fig. 71-1 Diagnostic algorithm for use in patients with abnormal myelination by MRI.

HIV, human immunodeficiency virus; PNS, peripheral nervous system; WM, white matter.

(Used with permission from Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 2009;72:750–759.)


Fig. 71-3 Hypomyelinating leukodystrophies and their differential diagnosis.

A, MRI of a 23-month-old child with Pelizaeus–Merzbacher disease and a duplication of PLP1. The supratentorial axial T2-weighted images show homogeneous hyperintense white-matter signal, indicating profound hypomyelination. There is also lack of myelin in the cerebellum. B, MRI of a 5-year-old child with Pelizaeus–Merzbacher-like disease due to a missense mutation in GJC2. The brainstem is less well myelinated, and the signal of the pyramidal tracts is slightly elevated. In the supratentorial structures, signal of the white matter is too high in the T2-weighted image. The sagittal T1-weighted image shows a normal cerebellar volume, but a thin corpus callosum. C, MRI of a 3-year-old child with 4H syndrome. White matter shows diffusely elevated signal with sparing only of a part of the posterior limb of the internal capsule and of the optic radiation. The coronal and sagittal images demonstrate the cerebellar atrophy. D, MRI of an 8-year-old child with Salla disease. Note diffuse increased signal of the supratentorial white matter, with relatively better myelination of the corpus callosum and posterior limb of the internal capsule. E, MRI of a child with hypomyelination with congenital cataracts or Hyccin deficiency. The white-matter signal in the T2-weighted image is slightly higher than in other hypomyelinating disorders. In the corresponding T1-weighted image, there are hypointense areas. Both indicate elevated water content. F, MRI of a 20-month-old child with GM1 disease. Note the delayed myelination, accompanied by globus pallidus signal abnormality. G, MRI of a 15-month-old child with POLG1 deficiency. Note the delayed myelination and atrophy in this child with a gray-matter disorder. H, Axial T2-weighted image of a 12-month-old child with infantile neuronal ceroid-lipofuscinosis; the signal of the white matter is also elevated compared to healthy children. Note the severe atrophy in the child with this gray-matter disease.


Fig. 71-5 Dysmyelinating and demyelinating leukodystrophies and pathognomonic MRI features, part I.

A, MRI of a child with juvenile-onset Alexander’s disease shows frontal predominance of white-matter abnormalities on fluid-attenuated inversion recovery (FLAIR) imaging. Other features not demonstrated here include brainstem and basal ganglia abnormalities, contrast enhancement of various intracranial structures, T1-high and T2-low periventricular rim, ventricular garlands, and characteristic capping of the frontal horns of the lateral ventricles. B, MRI of a 20-month-old male with metachromatic leukodystrophy shows the butterfly pattern of involvement in the cerebral white matter, sparing the U fibers. Note the prominent involvement of the corpus callosum. Within the affected white matter the presence of radiating stripes can be seen that are low-signal on T2 and high-signal on T1. C, MRI of a child with eIF2B4 mutations and vanishing white-matter disease, demonstrating (image to the left) rarefaction of affected white matter on FLAIR images, and typical appearance of radiating strips on sagittal T1 images (image to the right). D, MRI images of a 10-year-old male with X-linked adrenoleukodystrophy, demonstrating (top image) posterior predominance of white-matter involvement and involvement of the corpus callosum on FLAIR images, as well as the pathognomonic contrast enhancement of the border of the demyelinating lesion on postcontrast images (lower image). E, Neuroimaging from a child with TREX1 mutations resulting in Aicardi–Goutières syndrome. MRI at 2 and 4 months (left and middle images) shows the swollen appearance of subcortical white matter, in particular in the temporal lobes, and the rapid atrophy that occurred over a period of weeks. CT imaging of the head shows the sometimes limited calcifications in periventricular white matter, not visualized on standard MRI. F, MRI of a 3-year-old child with megalencephalic leukoencephalopathy with subcortical cysts. Sagittal T1-weighted images demonstrate subcortical swelling and cystic degeneration of the white matter, in particular in the temporal lobes (image to the left). FLAIR imaging clearly demonstrates cystic degeneration of affected white matter (image to the right). G, MRI of a 9-month-old female with Krabbe’s disease, demonstrating increased signal in the hilus of the dentate. This infant also had thickening of the optic chiasm, and diffuse white-matter involvement.


Fig. 71-6 Dysmyelinating and demyelinating leukodystrophies and pathognomonic MRI features, part II.

A, T2-weighted MR images of a 16-year-old with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) demonstrate partly confluent hyperintense patches in the centrum semiovale and in the frontal white matter adjacent to the ventricles (left image). Infratentorially, the cerebellar white matter is abnormal. Within the brainstem (middle image), the internal intraparenchymal trajectories of the trigeminal nerves, the middle cerebellar peduncles, the inferior cerebellar peduncles, and the pyramidal tracts are involved. The sagittal image demonstrates high signal of the posterior columns and the pyramidal tracts (right image). B, MRI of a 50-year-old woman with adult polyglucosan body disease, demonstrating increased signal encircling the pons and extending into the brainstem on sagittal fluid-attenuated inversion recovery (FLAIR; image to the left). On T2-weighted axial imaging (image to the right), diffuse involvement of the cerebral white matter, with relative sparing of the U fibers, is seen. C, MRI of a 40-year-old male with lamin B1 duplication and autosomal-dominant leukodystrophy with autonomic disease (ADLD) demonstrates the significant brainstem signal abnormality that can be seen in these patients. Supratentorial white-matter changes are less characteristic. D, MRI of a patient with L2-hydroxyglutaric aciduria (L2HGA) demonstrates the predominantly subcortical cerebral white-matter abnormalities with preservation of periventricular white-matter tissue and abnormalities of the dentate nucleus, globus pallidus, putamen, and caudate nucleus. E, MRI of an infant with SURF1 mutations and a resulting mitochondrial cytopathy. In addition to nonspecific central white-matter involvement, this patient had striking signal abnormalities of the brainstem. F, MRI of a 10-year-old female with a peroxisomal biogenesis defect, demonstrating signal abnormality in the hilus of the dentate nucleus, the cerebellum, and the posterior parietal white matter on T2-weighted images. G, MRI of a 48-year-old woman with hereditary diffuse leukoencephalopathy with spheroids, demonstrating frontal predominance of patchy, slightly asymmetric white-matter abnormalities. Note the severe frontal atrophy and involvement of the frontal portions of the corpus callosum.

The first challenge is distinguishing inherited disorders from acquired white-matter pathologies, such as acute disseminating encephalomyelitis (ADEM), multiple sclerosis (MS), or neuromyelitis optica (NMO), vasculitis, toxins, or infectious processes. This distinction is critical to patient management and genetic counseling, and acquired etiologies should be excluded by clinical history, examination, and laboratory testing before pursuing differential diagnosis of the heritable white-matter disorders. Special consideration should be given to endocrine dysfunction, as both congenital and acquired thyroid and adrenal dysfunction have been associated with white-matter disorders, as have nutritional factors such as vitamin B12 deficiency.

Furthermore, many inherited disorders, such as inborn errors of metabolism, or disorders with primarily neuronal dysfunction, can show central nervous system (CNS) white-matter abnormalities on neuroimaging, but are not considered classic leukodystrophies. This chapter will cover the classic leukodystrophies, as well as inborn errors of metabolism and neuronal disorders relevant to differential diagnosis of the leukodystrophies. A number will not be included in this review, but should be mentioned briefly as having a component of white-matter involvement. These include, but are not limited to, hypomelanosis of Ito, incontinentia pigmenti, monocarboxylate transporter-8 (MCT8) deficiency, spastic paraplegia type 11 (SPG 11), and giant axonal neuropathy.

While history and clinical examination are critical to excluding acquired leukoencephalopathies or disorders with secondary white-matter manifestations, many classic leukodystrophies share clinical manifestations with these other disorders. The hallmarks of CNS white-matter disorders are progressive spasticity, often associated with rigidity or ataxia, bulbar symptoms, and preserved cognitive function. Cranial nerve abnormalities, such as optic nerve atrophy, strabismus or nystagmus, and hearing loss, can be seen. Peripheral nerve function may be preserved or lost to varying degrees, depending on the disorder. Seizures are less commonly seen and should alert the clinician to the possibility of an underlying neuronal disorder, as should prominent dementia. These features do not, however, exclude a leukodystrophy. Seizures, for example, are a prominent feature of infantile Alexander’s disease.

Given the heterogeneity and limited specificity in clinical findings, MRI pattern recognition is the most useful tool for evaluating suspected leukodystrophy patients [Schiffmann and van der Knaap, 2009] (Figure 71-1). MRIs should be reviewed comprehensively, with attention to changes over time, expected myelin development for the patient’s age, and characteristics of T1- and T2-weighted signal abnormalities. Broadly, there are two groups of leukodystrophies. Hypomyelinating leukodystrophies show increased white-matter signal on T2 relative to age, and often isointense or hyperintense white-matter signal on T1. Conversely, demyelinating leukodystrophies show increased white-matter signal on T2 relative to age, and hypointense white-matter signal on T1. Additional radiologic features should be examined, such as white-matter vacuolization or cysts, best seen on fluid-attenuated inversion recovery (FLAIR) or similar imaging paradigms; involvement of the basal ganglia, brainstem, cerebellum, or spinal cord; and abnormalities of cortical gray matter. Finally, findings consistent with calcifications should be noted, and if clinically indicated, a computed tomography (CT) scan or calcium-sensitive MRI sequences should be acquired to exclude the presence of calcifications that might be missed on standard MRI.

The following chapter details a series of disorders for consideration in the differential diagnosis of patients with white-matter signal abnormality on neuroimaging. For each disorder, genetic etiology, clinical features, mechanism of disease, and diagnostic strategies are reviewed. As this chapter’s focus is diagnosis of heritable white-matter disorders, histopathologic markers are discussed where relevant to diagnostic evaluation and pathophysiology. Symptomatic management remains the mainstay of care for the majority of these conditions, and specific treatments are described only when disease-modifying therapies are available or actively being researched.

Hypomyelinating White-Matter Disorders

White-matter disorders with hypomyelination are relatively frequent; hypomyelinating leukodystrophies comprise 20 percent of leukodystrophies. They are characterized by a significant and permanent deficit of myelin [Schiffmann and van der Knaap, 2009]. Even with thorough genetic investigation, at least half of these hypomyelinating disorders lack definitive diagnosis, prognostic information, and potential for prenatal diagnosis. While most of these disorders show autosomal-recessive inheritance, both X-linked inheritance and de novo mutations are possible. Clinical manifestations common to hypomyelinating disorders are ataxia, spasticity, and nystagmus. Other non-neurological features can be valuable in diagnosis, such as hypodontia in 4H syndrome and cataracts in hypomyelination with congenital cataracts.

The diagnosis of hypomyelination may be made if two MRIs at least 6 months apart after the age of 12 months show little or no myelin development. Images in hypomyelinating leukodystrophies demonstrate diffusely hyperintense signal of the supratentorial white matter in T2-weighted images, and iso- or hyperintense white-matter signal on T1-weighted images. Certain areas, such as the posterior internal capsule, may have more normal-appearing myelin signal. Myelin deposition in infratentorial structures is usually higher. A definitive diagnosis of hypomyelination is not possible in young infants, as myelination is incomplete. If no myelin deposition is visible on the first MRI of a child older than 24 months, however, hypomyelination is highly probable [Schiffmann and van der Knaap, 2009].

Delayed myelination is sometimes misdiagnosed as hypomyelination. In contrast to hypomyelination, in delayed myelination, myelination progresses on serial MRI images to near-normal myelin development (Figure 71-2). Gray-matter disorders with early onset often show hypomyelination, presumably a result of defective axonal function. Features such as early atrophy and signal changes of cortex and basal ganglia may help distinguish between primary hypomyelination and hypomyelination secondary to neuronal dysfunction (see Figure 71-3F, G, and H below).

In cases of primary hypomyelination, the disorders described below should be considered.

Pelizaeus–Merzbacher Disease

Pelizaeus–Merzbacher disease (PMD, OMIM 312080) is the prototypic hypomyelinating disorder, and is caused by alterations in the proteolipid 1 (PLP1) gene [Hudson et al., 1989; Trofatter et al., 1989]. Located on Xq22.2, this gene encodes the PLP1 protein, which constitutes roughly half of all myelin protein. The most common abnormality is a duplication of the entire gene, found in 60–70 percent of PMD cases and associated with the classic form of the disease [Ellis and Malcolm, 1994; Sistermans et al., 1998]. The lack of common breakpoints in these duplications results in varying sizes of the duplicated area between patients. Missense mutations account for 10–15 percent of cases. Several missense mutations affecting splicing or putative regulation of expression have also been described. Deletions are also seen in a smaller number of cases. Triplications are present in 1–2 percent of cases; higher copy numbers have been described in one child. More complex chromosomal rearrangements involving PLP1 or its promoter region have been described in individual cases [Muncke et al., 2004]. Deletions or null mutations are rare. Roughly 15 percent of cases fulfilling diagnostic criteria for PMD do not possess identifiable PLP1 mutations, suggesting the possibility of mutations in regulatory regions beyond genetic assays.

The clinical features of PMD were well described by Pelizaeus and Merzbacher. Typically, affected boys develop a pendular nystagmus at the age of several weeks, similar to infants with congenital nystagmus. Shortly thereafter, delayed psychomotor development becomes apparent. These infants show axial hypotonia with difficult head control, titubation, exaggerated tendon reflexes, and a combination of ataxia and extrapyramidal features. Nystagmus may improve or even disappear over time. Optic atrophy is common. In classic PMD, patients are unable to walk, and often unable to sit without support. If they develop active speech, it is difficult to understand because of dysarthria and scanning speech. A learning problem or cognitive impairment is common, although motor impairment tends to be more pronounced than cognitive disability. In connatal PMD, symptoms are evident shortly after birth and often include congenital stridor, feeding difficulties, and profound hypotonia. Development is more impaired than in the classic form; connatal PMD patients do not learn to talk or sit without support, and make very little developmental progress. Microcephaly is common. Transitional PMD is intermediate in severity between the connatal and classic variants. These three subtypes likely form a continuous spectrum. Epilepsy is rare in PMD, even in the severe connatal form, and has only been described in exceptional cases.

Clinical course in PMD is chronic. Until late childhood or early adolescence, patients may improve and make definite, albeit slow, developmental progress. From this age, however, slow deterioration begins, with insidious progression of neurologic symptoms and slow cognitive decline. Optic atrophy, if not yet present, develops. While difficult to predict for individual patients, life expectancy is reduced, and depends on severity of neurologic deficits and additional complications. Connatal PMD patients often die within the first decade of life, classic PMD patients in the second or third decade.

PMD is allelic with a relatively mild disorder, X-linked spastic paraplegia type 2 (SPG2), also caused by PLP1 mutations [Saugier-Veber et al., 1994]. In its pure form, the sole symptom associated with SPG2 is slowly increasing spasticity, more of the legs than of the arms, which begins during childhood or adolescence. In the complicated forms, additional symptoms, such as nystagmus, ataxia, dysarthria, and mild cognitive impairment, are present. Life expectancy in this form is normal. Peripheral neuropathy is another possible finding with certain PLP1 mutations. Altogether, alterations of PLP1 mutations give rise to a spectrum of disorders, ranging from the very severe connatal phenotype to mild spastic paraplegia with adolescent onset.

Genotype–phenotype correlations have been established for most PLP1 alterations, although clinical heterogeneity among patients with common genetic alterations makes definitive characterization difficult. Symptoms do not correlate with duplication size, but high copy number appears to predict increased clinical severity. Severe epilepsy has been reported in children with triplications, an otherwise uncommon feature of PMD [Wolf et al., 2005]. Point mutations are associated with the full spectrum of PLP1-connected disorders [Cailloux et al., 2000]. Demyelinating neuropathy is associated with either null mutations or mutations in PLP-specific regions. Patients with functional null mutations show relatively mild clinical course; they usually achieve independent, albeit clumsy, ambulation, and show mild cognitive impairment and demyelinating neuropathy. As spasticity increases after the first decade, patients become wheelchair-bound and develop pseudobulbar palsy. Histopathologic investigations show evidence of length-dependent axonal degeneration in these patients and in corresponding mouse models [Garbern et al., 2002].

PLP1 is a highly conserved, hydrophobic membrane protein with four transmembrane domains and a large cytosolic loop between the second and third transmembrane domains. The N- and C-termini are located in the cytoplasm. Different splicing of PLP1 yields a second, smaller isoform, DM20. Both isoforms are primarily expressed within the CNS. While the function of PLP1 and DM20 remains poorly understood, mutations that leave DM20 intact are associated with relatively mild phenotype. Mutations associated with severe phenotype likely cause protein misfolding, which activates compensatory oligodendrocytic responses that ultimately cause oligodendrocyte apoptosis. The pathogenicity of PLP1 duplications is less well understood, although it has been speculated that overexpressed PLP1 in endosomal and lysosomal compartments depletes myelin rafts of lipids necessary for the production of functional myelin compounds [Garbern, 2007].

Interestingly, female heterozygotes may develop symptoms. In cases of PLP1 duplications, symptoms are rare and include transient, PMD-like symptoms in young girls. Symptom development in females tends to be associated with mutations causing mild phenotypes in males. It has been suggested that severe mutations and duplications cause early apoptosis in oligodendrocytes expressing the mutated allele in females. Oligodendrocytes expressing the wild-type allele proliferate to compensate for the loss of mutant cells. Mild mutations, however, do not elicit oligodendrocytic apoptosis, and surviving mutant cells cause impaired myelin formation and ultimate axonal degeneration. Female carriers of these mutations develop slowly progressive spastic paraplegia and cognitive decline later in life.

MRI in PMD shows hypomyelination, indicated by diffusely elevated white-matter signal on T2 (Figure 71-3A). Myelination is arrested and fails to progress on repeated scans. Some patients show a more mottled, “tigroid” signal, perhaps due to small myelinated areas surrounding blood vessels. In some patients, myelin deposition is seen in the posterior limb of the internal capsule or the optic radiations. Myelination is usually present in the brainstem and sometimes in the cerebellar hemispheres. Often – but not always – the pyramidal tracts in the brainstem show high T2 signal. At a young age, atrophy is not considerable, especially in the cerebellum, although white-matter volume may be decreased. The corpus callosum is thin, reflecting lack of myelinated axons. As children grow older, generalized atrophy develops. Proton MR spectroscopy reveals low choline, due to reduced membrane turnover in the absence of myelinating oligodendrocytes, and normal to elevated N-acetylaspartate (NAA), due to more densely packed axons. Patients with null mutations or deletions show more advanced supratentorial myelination. In SPG2 patients, MRI abnormalities are variable, ranging from diffuse mild hypomyelination to mild periventricular signal changes. Carrier females sometimes display small areas of elevated white-matter signal, but MRI is usually normal.

Diagnosis of PMD is based on typical clinical presentation, radiologic evidence of hypomyelination, and detection of PLP1 alterations. Routine laboratory and metabolic tests, including cerebrospinal fluid (CSF), are normal. As most PLP1 alterations are duplications, simple sequencing must also be accompanied by gene dose quantification by Southern blot, quantitative polymerase chain reaction (PCR), or, more recently, multiple ligation-dependent probe amplification (MLPA). Recently, elevation of the dipeptide N-acetylaspartylglutamate (NAAG) has been described in several PMD cases, with NAAG level appearing to predict clinical severity [Burlina et al., 2006]. The mechanism of NAAG elevation, however, remains unknown, and it is neither specific to PMD, nor a marker of hypomyelination.

Pelizaeus–Merzbacher-Like Disease

Pelizaeus-Merzbacher-like disease (PMLD, OMIM 608804) is phenotypically similar to PMD, although its inheritance is autosomal-recessive instead of X-linked. Children with hypomyelination on MRI, but without the PMD phenotype, are often mischaracterized as PMLD. The primary clinical features include early nystagmus, ataxia, and spasticity.

PMLD is a genetically heterogeneous disease. In most cases, no gene has been identified. In a small subset of PMLD patients (fewer than 10 percent), mutations in GJC2 (also called GJA12), coding for connexin 46.6 (Cx47), have been found (OMIM 608804) [Henneke et al., 2008]. Located on chromosome 1q41–q42, this gene was identified using a homozygosity mapping approach in a large consanguineous family [Uhlenberg et al., 2004]. Mutations were subsequently found in other, unrelated, patients, confirming GJC2 as the responsible gene. It remains the only gene identified in PMLD; other approaches to identify PMLD genes, such as sequencing candidate genes for structural myelin proteins, have so far been unsuccessful.

Connexins (Cx) are integral to intercellular junctions. In the CNS, there are gap junctions that are an essential component of the large glial syncytium among astrocytes and oligodendrocytes. Oligodendrocytes express two connexins, Cx32 and Cx47, and GJC2 mutations cause loss of Cx47 function, disturbing gap-junction properties between oligodendrocytes and astrocytes. The mechanistic link between these molecular genetic insults and hypomyelinating phenotype remains unclear. Interestingly, other connexin genes have been implicated in white-matter disorders. GJA1 (Cx43) mutations are associated with oculodentodigital dysplasia, which is also characterized by hypomyelination. GJB1 (Cx32) mutations lead to Charcot–Marie–Tooth disease type I. Transient, sometimes fluctuating, central neurological symptoms may occur in this disorder, often associated with mild infections. MRI reveals mild cerebral white-matter hyperintensities, likely reflecting myelin splitting and intramyelinic oedema.

As in PMD, patients typically present with nystagmus apparent after the first few weeks of life. Motor development is delayed and children display ataxia during the first few years. Pyramidal signs and frank spasticity often develop later. Compared with boys with classic PMD, motor and cognitive performance in PMLD is better, especially during the first years of life, and children are often able to walk, some without support. However, patients show a more precipitous decline, with progressive spasticity, prominent pseudobulbar signs, and facial weakness reminiscent of myopathic face. Patients become wheelchair-bound in their teens. Epilepsy starting in late school age has been reported in a substantial proportion of cases, and may be more severe in isolated cases, a very unusual feature for boys with PMD. Mild demyelinating peripheral neuropathy revealed by nerve conduction studies has been described in some patients, although it does not influence the overall clinical manifestation. A recently described family carrying a homozygote missense mutation in GJC2 showed a phenotype of almost pure spastic paraplegia and minor cerebellar signs [Orthmann-Murphy et al., 2008]. There are no histopathological data on PMLD.

MRI shows hypomyelination, and prominent signal abnormalities of the pyramidal tract of the brainstem have been described (Figure 71-3B). Cerebellar atrophy is mild or absent, at least in the early stages; supratentorial atrophy with considerable white-matter loss is prominent in older patients [Wolf et al., 2007]. Brainstem atrophy is often seen in later stages. Routine metabolic investigations are normal. In CSF, NAAG is elevated, as it is in PMD [Sartori et al., 2008].

4H Syndrome

This recently described leukoencephalopathy (OMIM 612440) is also characterized by hypomyelination. Its name is derived from its three main clinical findings: hypomyelination, hypodontia, and hypogonadotropic hypogonadism [Wolf et al., 2005, 2007; Timmons et al., 2006]. The disorder is rare and a genetic locus has not yet been identified. As affected siblings of both sexes have been reported, inheritance is presumed to be autosomal-recessive.

Initial development is normal, and affected children often start to walk without support before 18 months. Their gait, however, does not improve, as in healthy children, and by the age of 2–3 years, parents note that their children walk clumsily and frequently fall. Fine motor skills are also poor. Neurologic examination reveals pronounced ataxic gait, mild intention tremor, and dysmetria. Cerebellar eye movement disorder with saccadic pursuit and gaze-evoked nystagmus is seen. Clinical course remains more or less stable, although many parents describe episodic deterioration with infections. Ataxia progresses towards the end of the first decade, and pyramidal signs develop. Children lose independent ambulation, and are ultimately almost unable to move, despite largely intact cognitive function. A considerable spectrum of severity exists; some children never gain independent ambulation, while others develop into adulthood with only minor ataxia. Cognition is less impaired than motor skills, as often seen in pediatric white-matter disorders, but is not normal. Most children show mild to moderate learning disability. Many have a language disorder with dysarthria. Peripheral neuropathy is an inconstant finding.

Besides these neurological symptoms, hypodontia is the most prominent diagnostic sign (Figure 71-4). Eruption of deciduous teeth is delayed, and its order disturbed. Normally, the lower median deciduous incisors erupt first, followed by the upper median incisors. In 4H syndrome, the deciduous molars erupt first, followed by the incisors, and finally by the upper median incisors. Despite this delayed and disorganized eruption, the deciduous teeth are usually complete. In the permanent dentition, however, some teeth are missing. The incisors have an abnormal shape and often also a yellowish color. About 10 percent of patients show natal teeth, an otherwise very rare finding occurring only in 1 in 1000–3000 newborns.


Fig. 71-4 Dental phenotype of children with 4H syndrome.

The upper median incisors erupt late. A, Child aged 5 years. The typical situation in a younger child with lacking upper median (and in this case also lateral) incisors. The left lower median incisor [Schiffmann et al., 1994] has not erupted yet. B, Child aged 8 years. No deciduous incisors have erupted. The right permanent upper median incisor [Paznekas et al., 2003] shows yellowish discoloration. The left median incisors have not erupted yet.

Hypogonadotropic hypogonadism can only be diagnosed in adolescence when patients fail to enter puberty. Low luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels indicate central hypogonadism, although the cause of reduced LH and FSH is unknown. Other common symptoms include myopia, which may be high, and small stature, which becomes evident around school age.

As the name of the disease suggests, MRI shows hypomyelinated white matter (see Figure 71-3C). T2 signal in the supratentorial white matter is diffusely elevated, with the exception of aspects of the posterior limb of the internal capsule and optic radiation. T1 white-matter signal varies from hypointense to hyperintense, depending on the amount of myelin deposited. Cerebellar white matter is usually myelinated on T2. Corpus callosum is thin. There is also early and considerable cerebellar atrophy, more of the vermis than of the hemispheres, in virtually all patients. Whether clinical severity correlates with amount of myelin deposited or degree of initial cerebellar atrophy has not yet been elucidated. Proton MR spectroscopy reveals low choline, as is usual in hypomyelination, and often also elevation of myo-inositol compatible with gliosis. In the later stages, considerable cortical atrophy and white-matter loss develop, indicating on-going myelin loss.

Metabolic investigations are all normal. In some children, a muscle biopsy, with assessment of respiratory chain enzymes, has been performed in the context of deterioration of symptoms with infections, but showed normal results. Analysis of the known genes involved in hypomyelination, including GJA1, in which mutations lead to oculodentodigital dysplasia, did not reveal abnormalities [Wolf et al., 2007].

Oculodentodigital Dysplasia

Oculodentodigital dysplasia (ODDD, OMIM 164200) is another hypomyelinating disorder characterized by dental abnormalities. Its inheritance is autosomal-dominant. Dominant mutations in another connexin gene on chromosome 6q21–23.2, GJA1, coding for connexin 43 (Cx43), cause ODDD. There is one family described with autosomal-recessive mutations leading to the same phenotype. Cx43 is expressed in the developing brain and teeth, and also in hands and feet [Paznekas et al., 2003].

ODDD is likely not as common as 4H syndrome. Affected children are usually regarded as neurologically normal, and are primarily diagnosed based on the typical dysmorphic signs. These consist of ocular anomalies (microphthalmus, microcornea, iris abnormalities, short palpebral fissures, epicanthus), facial dysmorphic signs (especially a thin nose with hypoplastic alae, small anteverted nares, and a prominent columella), hand and foot abnormalities (syndactyly of third, fourth, and fifth fingers and second, third, and fourth toes, clinodactyly of fifth fingers), thin and brittle hair, and sometimes microcephaly. Dental abnormalities have not been described in detail but are present in all patients. Teeth are brittle and prone to decay. They show early discoloration, probably due to a defect in dentine. Microdontia and hypodontia are other common findings.

Neurologic symptoms are common, although no large case series has been reported, so little is known about the exact time course and development of neurologic abnormalities. In childhood and adolescence, coordination problems and mild ataxia are common. In adulthood, slow neurologic deterioration is seen, with development of pyramidal tract lesions, ataxia, dysarthria, loss of bladder control, and finally, frank spasticity. Unsupported gait may become impossible in late stages. Optic atrophy and deafness are possible. Cognition is preserved in most patients, although learning disabilities have been reported. Whether and to what extent early cognitive deterioration occurs awaits further study. Peripheral nervous system appears unaffected [Loddenkemper et al., 2002].

MRI shows mild to moderate hypomyelination, supratentorial atrophy, and mild cerebellar atrophy. Some authors describe hypointense signal of the basal ganglia and thalami.

Hypomyelination with Congenital Cataract

Hypomyelination with congenital cataract (HCC, OMIM 610532) is a recently described disorder with CNS hypomyelination, reported in five families. The genetic locus of HCC is FAM126A, earlier called DRCTNNB1A, on chromosome 7p15.3. It encodes the Hyccin membrane protein. Missense mutations, mutations affecting splice sites, and a deletion of the entire gene have been identified, but the gene’s role in myelination remains obscure.

Affected patients present early with delayed motor development. Cognitive development is mildly to moderately delayed. Most HCC children learn to walk with support before their second birthday. Neurological examination reveals dysarthria, moderate to severe spasticity with elevated muscle tone, brisk reflexes, extensor plantar response, and cerebellar signs such as intention tremor and dysmetria. Nystagmus is rare. As in other hypomyelinating disorders, progression of secondary neurologic symptoms occurs, and children may be unable to walk, even with support, by the end of the first decade. An additional pathognomonic finding is congenital cataract [Zara et al., 2006]. Several HCC cases have been published, and one patient failed to develop cataract until age 9. A small subset of HCC patients suffers from occasional seizures. Peripheral neuropathy is seen in almost all patients, leading to loss of previously exaggerated tendon reflexes and distal muscle wasting. It is not yet known whether a broad phenotypic spectrum exists in HCC, and clinical presentation is heretofore remarkably homogeneous, with the exception of cataract and peripheral neuropathy, which are not present in all patients. There are no data yet about CNS pathology, nor experimental models to elucidate Hyccin function.

Electrophysiological studies show evidence of demyelinating neuropathy. Sural nerve biopsy in several patients revealed lack of myelinated nerve fibres, thin, noncompacted myelin surrounding the few myelinated axons, and, in some cases, formation of small onion bulbs near Schwann cell processes.

MRI shows hypomyelination, as evident from the diffusely elevated T2 white-matter signal. In contrast to those with other hypomyelinating disorders, HCC patients show additional areas of higher T2 white-matter signal and decreased signal intensity on corresponding T1-weighted images, indicating elevated water content in these areas, particularly in periventricular regions [Rossi et al., 2007] (Figure 71-3E). Cerebellar atrophy is not seen. In the early stages, normal myelin signal may be apparent in subcortical fibres and corpus callosum. In the late stages, white matter appears shrunken, with increased apparent diffusion quotients. Proton MR spectroscopy gives variable results, depending on the disease stage. Choline may even be slightly elevated in the early stages, which is unusual for a hypomyelinating disorder, and decreased in later stages.

Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC, OMIM 612438) is a rare disorder of unknown genetic origin [van der Knaap et al., 2002]. As no affected siblings of children with HABC have been reported, it is possible that this entity arises from a dominant de novo mutation, although autosomal-recessive inheritance remains possible. Disease severity ranges from severely affected infants presenting shortly after birth to more mildly affected children with initially normal development. In severe cases, children fail to achieve motor milestones and linguistic development, and show profound axial hypotonia. Some have nystagmus, and optic atrophy is possible. Spasticity is common. Extrapyramidal symptoms, comprising dystonia, rigidity, and choreoathetosis, are uniquely common to HABC relative to other white-matter disorders. Failure to thrive and microcephaly are common. In mildly affected children, unsupported walking is achieved within the first few years of life, sometimes on time, but is later lost. There is a combination of spasticity, extrapyramidal symptoms, and ataxia. cognitive impairment is mild, although patients tend to show cognitive decline in addition to deteriorating motor functions.

Recently published neuropathologic findings from one HABC patient detail slightly reduced white-matter volume, reduced oligodendrocytes, severe myelin deficiency, especially of deep white matter, and some white-matter loss, as indicated by the presence of macrophages in perivascular regions [van der Knaap et al., 2007]. Axons appeared relatively preserved. There was mild astrocytosis and a strong presence of microglia. The putamen was visible only as a small streak, and microscopy revealed substantial neuronal loss. Cerebral cortex was normal, both macroscopically and microscopically. In the atrophic cerebellum, there was loss of granule cells. Pyramidal tracts appeared degenerated in the brainstem and spinal cord. Metabolic investigations are normal in these children.

MRI shows hypomyelination. In some children, T2 white-matter signal is less hyperintense, indicating some myelin deposition. The cerebellum is atrophic, the vermis more so than the cerebellar hemispheres. Characteristic MRI features are atrophy or absence (in the later stages) of the putamen, apparent within the first year of life. The caudate is reduced, and in some patients, disappears entirely. Thalamic and pallidal volume remains normal. Over time, white-matter loss leads to supratentorial atrophy. The extent of basal ganglia and white-matter atrophy predicts clinical severity. These MRI features are considered diagnostic at this time.

Sialic Acid Storage Disorders

Salla disease (OMIM 604369) and infantile sialic acid storage disease (ISSD, OMIM 269920) are both caused by autosomal-recessive mutations in SLC17A5, coding for Sialin, a lysosomal membrane protein transporting sialic acid from lysosomes [Verheijen et al., 1999]. The gene is located on chromosome 6q14/15. Recently, it was shown that Sialin also functions as a shuttle for aspartate and glutamate in synaptic vesicles [Miyaji et al., 2008]. Free sialic acid accumulates in lysosomes of many cell types, including liver and kidney cells and cultured fibroblasts. In leukocytes, this accumulation causes vacuoles visible at light microscopic examination. Electron microscopy reveals membrane-bound vacuoles filled with fibrillogranular amorphous material. The pathogenesis of free sialic acid storage disease and the role of sialic acid remain unclear.

Both diseases are characterized by elevated excretion of free sialic acid in urine. Sialic acid is also elevated in other fluids, such as CSF. Recently, two siblings have been described who lack the characteristic sialuria; sialic acid was elevated only in CSF [Mochel et al., 2009]. Prevalent in Finland, Salla disease is characterized by seemingly normal early development, followed by presentation with hypotonia and ataxia in the second half of the first year of life. Nystagmus is also common. It may be evident in the neonatal period and frequently disappears. Many children also show strabismus. Spasticity develops slowly, and mild extrapyramidal symptoms are common in later stages. Mean age at walking is 4 years, with roughly one-third of patients who do not develop independent ambulation. Language is severely affected and usually dysarthric; patients are, at best, able to produce short sentences. Epilepsy with short, complex focal seizures is relatively common. In some patients, there is evidence of peripheral hypomyelination with decreased nerve conduction velocities. The disease is stable over a long period of time, with ultimate late progression. Additional symptoms may include short stature or hypogonadotropic hypogonadism. Facial features become coarse in adulthood. Otherwise, there is no evidence for dysostosis multiplex or hepatosplenomegaly, despite the presence of free sialic acid storage in liver and spleen. Life expectancy is normal [Aula et al., 2000].

ISSD is a much more severe disease, with neonatal presentation and rapid progression. Hydrops fetalis is possible. Neonates may show hepatosplenomegaly and ascites. They have fair hair and coarse features. Milestones of normal development are not acquired, and death occurs within the first couple of years.

A phenotype with intermediate severity relative to Salla disease and ISSD has also been identified.

MRI in patients with Salla disease shows hypomyelination [Sonninen et al., 1999] (Figure 71-3D). There is white-matter volume loss. Corpus callosum may be stringlike, especially in severe cases. There is usually cerebellar atrophy, and supratentorial atrophy is found in older patients. Thickening of the calvarium is another common radiologic feature. Proton MR spectroscopy reveals a high NAA peak, likely due to elevated free sialic acid, whose N-acetyl peak co-resonates with the N-acetyl peak of NAA [Varho et al., 1999].

Serine Synthesis Defects

Serine is synthesized by a three-step biochemical pathway, and defects in any of the three enzymes in this pathway have been shown to cause serine biosynthesis defects: 3-phosphoglycerate dehydrogenase (OMIM 601815), phosphoserine phosphatase (OMIM 172480), and phosphoserine aminotransferase (OMIM 610992). The biochemical hallmark of these disorders is low serine and glycine concentration in CSF. In plasma, serine concentration is often also decreased but may be normal, making CSF investigations an essential diagnostic tool for this group of disorders.

Children with 3-phosphoglycerate dehydrogenase deficiency are born microcephalic, and their development is grossly delayed. Epilepsy develops in the second half of the first year of life; West’s syndrome is one possible manifestation. Supplementation with serine and glycine is effective in seizure management. If treatment is commenced prenatally, head circumference at birth and development are normal [de Koning et al., 2004]. In untreated children, MRI shows hypomyelination and white-matter volume loss [de Koning et al., 2000]. Corpus callosum is thin and short. Myelination improves under treatment.

The first documented patient with phosphoserine aminotransferase deficiency presented in the neonatal period with severe epilepsy resistant to medical treatment and rapidly developing microcephaly. MRI showed supratentorial and brainstem atrophy. Supplementation with serine and glycine did not attenuate the seizures. The same treatment, if started before the development of symptoms, was shown to prevent epilepsy and enable normal development in the sibling of the proband [Hart et al., 2007].

Cockayne’s Syndrome and Trichothiodystrophy

Cockayne’s syndrome (CS) is a rare disease combining neurologic and non-neurologic features. This disorder and related disorders of DNA repair, such as cerebro-oculo-facial syndrome (COFS) and trichothiodystrophy (TTD), are genetically heterogeneous and are caused by mutations in CSA (CKN1 or DNA excision repair protein ERCC-8, responsible for 20 percent of CS cases), CSB (CKN2 or ERCC-6, responsible for most of the remainder of CS cases), XPB (ERCC3, OMIM 610651), XPD (ERCC2), XPG (ERCC5), ERCC1-XPF, TTDA and TTDN1 genes, and possibly others [Weidenheim et al., 2009].

The classic form, Cockayne’s syndrome type I, presents in the first year of life with failure to thrive; weight is more affected than length (“cachectic dwarfism”), and there is loss of subcutaneous fat, leading to a “wizened,” bird-like, progeroid face. Microcephaly also develops, usually by the end of the second year. Children develop contractures of the large joints, giving them a typical posture. Hands and feet are disproportionally large. Dental caries is prominent. Psychomotor development is also delayed, resulting in mild to severe cognitive impairment. Predominant neurologic features include ataxia and spasticity, which show slow progression. In late stages, peripheral neuropathy leads to muscle wasting and loss of the initially increased tendon reflexes. Over half of individuals develop sensorineural hearing loss. Most suffer from pigmentary retinal degeneration and cataracts. Autonomic dysfunction (hypolacrimia, hypohydrosis, miosis, acrocyanosis) is possible. In Cockayne’s syndrome type II, the clinical picture is much more severe, with growth failure already evident at birth. Loss or even absence of subcutaneous fat is striking. Joint contractures and kyphosis develop rapidly. Hypotonia is prominent initially, followed by development of spastic tetraparesis. Psychomotor development is absent or extremely delayed, with subsequent deterioration and early death. Subcutaneous fat loss has been treated in both types by early hypercaloric tube feeding, which allows reasonable growth in some children. Type III describes patients with milder forms of disease. Cutaneous photosensitivity is also characteristic of CS, occurring in 75 percent of all patients [Rapin et al., 2000].

In trichothiodystrophy (also called Tay’s syndrome), hair is dry, thin, and brittle. Polarization microscopy of affected hair reveals a typical tiger tail pattern. Structural hair abnormalities are due to a strong reduction in cysteine residues, which reduces disulfide cross-links in hair fibers. In some children, hair is lost after episodes with fever. Prominent cutaneous photosensitivity is also present and ichthyosis is possible. Nails are dystrophic. Neurologic symptoms are variable, and may include psychomotor delay, mild cognitive impairment, ataxia, pyramidal signs, frank spasticity, and nystagmus. As in CS, cataracts and retinal degeneration may also be seen.

Both syndromes are caused by defective nucleotide excision repair. Over 30 proteins are involved in this process. It eliminates DNA lesions induced by ultraviolet light. There are two major subpathways of nuclear excision repair: transcription-coupled repair, dealing with reparation of transcribed genes, and global genome repair, removing lesions in the entire genome. Defective DNA repair can be demonstrated by irradiating cultured skin fibroblasts with ultraviolet light and subsequently measuring unscheduled DNA synthesis. This unscheduled DNA synthesis is diminished in TTD and xeroderma pigmentosum patients. In CS, this unscheduled DNA synthesis is not significantly attenuated, but the otherwise rapid recovery of RNA and DNA synthesis after ultraviolet irradiation is adversely affected, indicating that the global genome repair is still functional. Additionally, reduction in basal transcription is also seen, an important signal for apoptosis. These defects of transcription, perhaps combined with activation of apoptosis, are thought to be mainly responsible for the neurologic symptoms in CS. Complementation assays in cultured cells could distinguish two different complementation groups, CS type I (OMIM 216400), caused by mutations in the gene coding for group 8 excision-repair cross-complementing protein (ERCC8), and type II (OMIM 133540), due to mutations in ERCC6. TTD is also heterogeneous, genetic defects having been identified in at least three different genes [Cleaver et al., 2009].

MRI of patients with CS shows hypomyelination, its degree corresponding to clinical severity. In severe cases with CS type II, hypoplasia of cerebellum and brainstem is possible. Basal ganglia calcifications are common. Similar features are seen in TTD, although calcifications are less common than in CS [Rapin et al., 2000; Adachi et al., 2006].

18q Minus Syndrome

In this disorder (OMIM 601808), the distal region of the long arm of chromosome 18 is deleted. It occurs de novo most commonly. The contiguous gene deletion usually involves the bands 18q22.3→qter. The gene for myelin basic protein (MBP), a component of healthy myelin, is located within this region. It has been postulated that haploinsufficiency for MBP leads to the myelin abnormalities observed in 18q minus syndrome. Heterogeneity in severity of clinical symptoms and hypomyelination between patients, despite consistent loss of MBP, is a focus of on-going inquiry. There is a well-investigated mouse model, the shiverer mouse, with homozygous rearrangements in the MBP gene [Nave, 1994], which lead to CNS, but no peripheral, hypomyelination. It is unknown why peripheral myelin is spared, despite MBP expression in peripheral nerves.

The disorder is stable, with a variety of dysmorphic features (microcephaly, hypertelorism, epicanthus, high or cleft palate, short neck, tapering fingers and clinodactyly, external ear anomalies, cardiac malformations, foot abnormalities) and neurologic abnormalities. Most patients show moderate to severe cognitive impairment, but cases with normal intelligence have been seen. Many suffer from sensorineural deafness. Patients may also show hypotonia in infancy, ataxia, nystagmus, and epilepsy. IgA deficiency and partial growth hormone deficiency are common.

MRI shows hypomyelination of variable, but usually mild, degree. The myelin signal in the cerebral hemispheres may be inhomogeneous, with patchy white matter abnormalities. Corpus callosum may be thin. There may be mild supratentorial atrophy [Linnankivi et al., 2006].

SOX10-Associated Disorders

These rare syndromes are caused by mutations in SOX10 on chromosome 22q13, which encodes a transcription factor for various genes, some involved in myelin formation and metabolism, such as GJB1 (connexin 32). These disorders are characterized by a white hair lock and hypomelanotic spots, sensorineural deafness, and Hirschsprung’s disease. Patients are affected with varying severity, ranging from antenatal onset with congenital arthrogryposis multiplex and severe neurologic abnormalities, to more mildly affected patients who lack neurologic manifestations (Waardenburg–Shah syndrome, WS4, OMIM 277580). The severe variant has been designated peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg’s syndrome, Hirschsprung’s disease, or PCWH (OMIM 609136). Consistent with a neurocristopathy, many features of this disease can be explained by defective differentiation or migration of neural crest cells. In the severe cases, MRI reveals hypomyelination [Touraine et al., 2000]. The milder phenotype of WS4 is explained by SOX10 haploinsufficiency, whereas the severe form, PCWH, is thought to be caused by a dominant negative mechanism. Mutations found in children with PCWH are all truncating and located in the last exon. These mutations, unlike SOX10 mutations leading to WS4, escape nonsense-mediated decay and can therefore exert their dominant negative effect on protein level [Inoue et al., 2004, 2007].

Neurologic symptoms of children with PCWH include delayed development, nystagmus, spasticity, and ataxia. In severe cases, neonates are already symptomatic, with profound hypotonia, seizures, or congenital arthrogryposis due to hypomyelinating neuropathy. Other possible symptoms are reduced tear and saliva production, anhidrosis, and severe failure to thrive, in addition to the classic syndromes of WS4. Neuropathologic investigations of a severely affected infant have shown absence of central and peripheral nervous system myelin at the age of 3 months [Inoue et al., 2002]. Detailed MRI features have not been reported for many patients, but preliminary cases suggest mild to severe hypomyelination, and possibly atrophic brainstem [Inoue et al., 1999].

White-Matter Disorders with Demyelination

If MRI is not consistent with hypomyelination, there is white-matter hypointensity on T1 instead of iso- or hyperintensity, and there is hyperintensity on T2, the imaging pattern fits the demyelinating leukodystrophies. They comprise the leukodystrophies with primary demyelination, leukodystrophies with white-matter vacuolization, calcifying leukoencephalopathies, cystic leukoencephalopathies, leukoencephalopathies with brainstem involvement, and most adult-onset leukoencephalopathies. In the assessment of patients with these leukodystrophies, careful attention should be paid to specific neuroimaging features, including basal ganglia or brainstem signal abnormalities, contrast enhancement, cysts, calcifications, contrast enhancement, or specific FLAIR imaging abnormalities (Figure 71-5 and Figure 71-6; see also Figure 71-3) to assist in the differential diagnosis.

Primary Demyelinating Leukodystrophies

These conditions comprise several of the “classic” leukodystrophies, and include Alexander’s disease, X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe’s disease.

Alexander’s Disease

Alexander’s disease (AxD, OMIM 203450)[Alexander, 1949] is associated with mutations in the gene encoding the glial fibrillary acidic protein (GFAP) [Brenner et al., 2001]. GFAP mutations are thought to confer gain-of-function mutations, and a mutation on a single allele is sufficient to cause disease. In most cases, mutations are sporadic, although familial cases are described in adult- or juvenile-onset cases. In familial cases, inheritance is autosomal-dominant. There is usually concordance in presentation within a family, such that a family with adult-onset presentation and subsequent infantile presentation has not been reported. There is no definite genotype–phenotype correlation, with the exception of the two most common mutations, R79 and R239. R239, in particular, is associated with earlier onset and poor prognosis.

AxD presents with two predominant clinical phenotypes. The infantile form typically presents before the second year of life. In very rare cases, patients present in the neonatal period with macrocephaly and delay in milestones, with both cognitive and motor deficits. Patients may present with seizures, often febrile, although these are rarely refractory to classic anticonvulsants. Pyramidal and sometimes extrapyramidal features develop, and children often lose motor skills in the first decade of life. Bulbar features, such as intractable vomiting, swallowing difficulties, and respiratory compromise, can be present early on or only develop over time. Hydrocephalus can become a significant clinical issue, and serial CT scans, in particular when abrupt clinical decompensation is noted, may help in clinical management. In some cases, surgical placement of a ventricular drainage system has provided clinical benefit. With aggressive supportive care, these children can enjoy periods of clinical stability, although the disease is relentless. Life span is variable.

The juvenile (2–12 years at onset) or adult (>12 years at onset) forms have historically been seen as distinct entities, but in reality are a continuum of very similar clinical features. These patients present with predominant motor dysfunction, often with progressive gait disturbance or fine motor difficulties, and clinically evident spasticity. Bulbar symptoms, in particular palatal myoclonus, can be very suggestive of the diagnosis. Over time, dysphonia and dysphagia can become increasingly debilitating. Dysautonomia is frequent. Sleep apnea is a commonly reported problem and sleep history should be monitored. In juvenile patients undergoing significant statural growth, scoliosis often evolves. In the older subjects, disease progression is slower than in the infantile cases, and many subjects continue to benefit from school and social activities for many years. In rare cases, juvenile and adult patients can present with atypical clinical manifestations, such as focal brainstem abnormalities that can be mistaken for brainstem gliomas.

Incidence and prevalence of AxD are not known. The infantile form was long assumed to be more common than the juvenile or adult variants, but an increasing number of adult cases are now being recognized, forcing clinicians to reconsider this characterization.

GFAP mutations are thought to result in decreased solubility of the glial fibrillary acidic protein, and accumulation of GFAP, along with vimentin, αβ-crystallin, and heat shock protein 27, result in Rosenthal fiber (RF) aggregation. RFs, accumulating in astrocytes, are thought to obstruct normal glial cell function and result in myelin destruction. RF accumulation in the ventricular collecting system is believed to cause the hydrocephalus seen in the clinical setting. Studies to improve pathophysiologic understanding of this disease and possible treatment strategies are on-going in an existing murine model of AxD. AxD is typically suspected from clinical presentation and characteristic MRI features. Typical AxD imaging features include frontal predominance of white-matter abnormalities, basal ganglia and or brainstem involvement, a periventricular rim of altered signal on T1- and T2-weighted imaging, and contrast enhancement of specific intracranial structures (see Figure 71-5A). The presence of four of five of these features makes diagnosis of AxD very likely and should prompt mutation testing [van der Knaap et al., 2001]. In very young infants and in the juvenile- or adult-onset cases, MRI may be less typical and involve only restricted brain regions. Additional features described in AxD imaging include predominant or isolated involvement of posterior fossa structures, multifocal tumor-like brainstem lesions, brainstem atrophy, and garland-like abnormalities along the ventricular wall [van der Knaap et al., 2005, 2006]. MR spectroscopy can be helpful in the diagnosis if it shows a lactate peak in affected tissues, but may also lead to inappropriate evaluations for mitochondrial cytopathies. There have been reports of findings of elevations of GFAP protein in CSF [Kyllerman et al., 2005], but this test is not used as a clinical tool.

X-Linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (XALD, OMIM 300100) is associated with mutations in the ABCD1 gene [Mosser et al., 1993] encoding a peroxisomal membrane transporter. This disorder follows X-linked inheritance, and often, when male children are diagnosed with the childhood-onset cerebral form, disease manifestations are recognized in obligate female carriers or male relatives of the proband. Differences in disease manifestations are known to occur with identical genotype, and even within a sibship, underscoring the likely effect of other genetic factors on clinical presentation. Genotype does not predict very long chain fatty acid levels or specific clinical prognosis. Genetic changes reported include missense mutations, nonsense mutations, frameshift mutations, small deletions/insertions, and large deletions.

XALD is characterized by three predominant phenotypes. The best known is the childhood-onset cerebral form (35 percent of affected individuals), in which male children of school age (usually 4–8 years) present with a prior history of behavioral or cognitive changes. These are often initially misdiagnosed as attention-deficit disorder or hyperactivity. The progressive nature of the symptoms, overlaid with progressive motor difficulties, deteriorating school function and handwriting, altered perception of speech, and worsening behavior problems, usually brings the child to medical attention, and neuroimaging frequently is highly suggestive of the diagnosis. Disease course is variable, but complete symptom development occurs over a range of 6 months to 2 years. Over time, significant motor involvement develops, with a spastic quadriplegia. In addition, bulbar dysfunction becomes problematic, and often necessitates gastrostomy tube feeding. Adrenal insufficiency is a life-threatening complication of XALD, and studies suggest that a large number of subjects with the childhood-onset cerebral form have adrenal insufficiency at time of diagnosis. Adrenal function should be tested at diagnosis and monitored thereafter to permit symptomatic management.

A second frequent type of presentation is adrenomyeloneuropathy (AMN; 40–45 percent of affected individuals), characterized by onset in young adult males (20s to middle age) of progressive gait abnormalities, sexual dysfunction, and abnormalities of sphincter control. In some cases, predominant spinal cord symptoms are associated with significant abnormalities on MRI of the brain, and in a subset of these, relentless neurologic deterioration will occur. In the remainder of the subjects, the disease appears slowly progressive. Adrenal insufficiency should be sought at diagnosis and at follow-up, although it is less frequent than in the cerebral childhood-onset form.

A third type is isolated adrenal insufficiency. On occasion, patients with adrenoleukodystrophy may first present with an Addisonian crisis, and no neurologic features or abnormalities on neuroimaging. XALD should be considered in the differential diagnosis of isolated adrenal insufficiency in a male subject. Finally, approximately 20 percent of female carriers may have symptoms of progressive gait disturbance and spastic paraparesis similar to what is seen in subjects with AMN. Onset is usually in middle age.

Of note, an allelic disorder, with a neonatal presentation of cholestasis, hypotonia, and developmental delay, is caused by a contiguous gene deletion syndrome involving the 5′ end of ABCD1. This disorder is called contiguous ABCD1 DXS1357E deletion syndrome (CADDS), and is clinically distinct from XALD [Corzo et al., 2002].

The estimated prevalence of XALD is estimated to be 1:20,000–1:50,000. The estimated prevalence of hemizygotes (affected males) and heterozygotes (carrier females) is estimated at 1:16,800 [Bezman et al., 2001].

The pathophysiology of XALD is believed to arise from accumulation of saturated very long chain fatty acids (SVLCFA) within the brain. This accumulation is thought to result from defective peroxisomal fatty acid oxidation of SVLCFA, caused by defective transport by the mutated ABCD1, possibly due to altered adenosine triphosphate (ATP) binding [Gartner et al., 2002; Roerig et al., 2001].

Diagnosis is based on characteristic clinical presentation and suggestive MRI features. MRI shows a predominance of occipital findings (see Figure 71-5D), although frontal and corpus callosum variants are recognized. The affected white matter appears hyperintense on T2 and hypointense on T1. Characteristically, there is a rim of enhancement around the abnormal tissue that can be very helpful in establishing the diagnosis, as few other leukodystrophies, with the exception of Alexander’s disease, show significant contrast enhancement. When XALD is suspected, appropriate clinical tests include fasting VLCFA testing on plasma, which shows an excess in SVLCFA with specific abnormalities in C26:0, C24:0/C22:0, and C26:0/C22:0 ratios [Moser et al., 1981]. Mutation testing of the ABCD1 gene provides molecular confirmation of the diagnosis, with attention to the 7 percent of cases with deletions or rearrangements.

Treatment with Lorenzo’s oil or diets rich in oleic and erucic acids, in addition to VLCFA restriction, can alter VLCFA levels. As treatment strategies for XALD evolve, interest in newborn screening is growing. This can be done using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test for the analyte 1-hexacosanoyl-2-lyso-sn-3-glycero-phosphorylcholine (26:0-lyso-PC)[Hubbard et al., 2009; Raymond et al., 2007]. As with many disorders now being considered for widespread newborn screening, the clinical benefit of early diagnosis remains to be established.

Treatment of XALD depends on the stage and type of disease manifestations, and is still research-based. Treatment with Lorenzo’s oil, which decreases hexacosanoic acid (C26:0), does not appear to stop or reverse cerebral disease once it has begun, although there are reports of improved long-term stability in presymptomatic patients in open-label studies with no placebo control [Moser et al., 2007]. The use of Lorenzo’s oil is investigational and should be performed in the context of a clinical research protocol. Bone marrow transplantation (BMT) is indicated in children with early-stage, cerebral-form XALD, as evidenced by active disease on MRI. Family members of an affected proband should be tested by VLCFA and monitored for early MRI evidence of cerebral involvement to identify candidates for BMT. These patients should be evaluated by clinicians with specific expertise in this disorder. Gene therapy is a potential future tool and research studies are under way. Supportive care can improve comfort and quality of life for XALD patients. Careful monitoring and treatment of adrenal insufficiency should be part of therapeutic management.

Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD, OMIM 250100) [Greenfield, 1933; Von Hirsch and Peiffer, 1955; Suzuki and Chen, 1966] is caused by mutations in the ARSA gene encoding arylsulfatase A [Stein et al., 1989; Austin et al., 1964] on chromosome 22q13.31, and is inherited in an autosomal-recessive manner. Homozygous or compound heterozygous ARSA mutations impair arylsulfatase A degradation of sulfatides, causing sulfatide accumulation within the brain and peripheral nervous system. Complete loss of arylsulfatase A activity (“I” or “O” alleles) is typically associated with early infantile MLD. Partial loss of arylsulfatase A activity (“R” or “A” alleles) is typically associated with juvenile- or adult-onset MLD. Compound heterozygosity with an I and A allele usually results in juvenile-onset MLD. Rarely, subjects with microdeletions of 22q13 and deletion of the ARSA gene with an MLD-causing mutation on the other allele have been diagnosed with MLD.

Additionally, there are common polymorphisms of ARSA (referred to as “PD” alleles), which result in sufficient residual activity to avoid sulfatide accumulation. These cause arylsulfatase pseudodeficiency, rather than MLD. These polymorphisms, either homozygous or compound heterozygous with MLD-causing ARSA mutations, do not cause MLD. Enzymatic evidence of low arylsulfatase activity must be accompanied by accumulation of sulfatides linked to pathogenic ARSA mutations before establishing a diagnosis of MLD.

MLD is characterized by three clinical subtypes, defined primarily by age at presentation. Late infantile MLD patients usually present by age 2, following a period of apparently normal development. Initial clinical manifestations include gait disturbance, ataxia, dysarthria, or cranial nerve features such as esotropia. Initially, symptoms may be slowly progressive or may plateau, sometimes followed by a rapid loss of motor skills over a few weeks, during which time the diagnosis is commonly made. Tonic spasms with pyramidal and extrapyramidal dysfunction, and loss of peripheral reflexes are striking. Eventually, disease progresses to severe motor impairment with loss of volitional movements, bulbar dysfunction, loss of vision and hearing, and seizures. The time course of deterioration is highly variable, and, with maximal supportive care, death often occurs much later than reported in older texts. The disease, however, is relentlessly progressive after the initial period.

Juvenile MLD patients present between age 4 and puberty (12–14 years). Patients presenting after this age are classified as having adult-onset MLD. Patients often present with cognitive and behavior difficulties. Younger juvenile-onset patients often show early motor involvement and may also show rapid decline. Clumsiness, gait problems, dysarthria, incontinence, and worsening behavioral problems occur later in the course, and often prompt etiologic evaluation and diagnosis. Patients may have seizures, most often complex partial seizures. Progression is similar in juvenile MLD to that described in infantile MLD, with a slower course.

Adult-onset MLD patients may present with motor symptoms common to earlier presentations. Alternatively, patients may develop severe neuropsychiatric symptoms, often leading to misdiagnosis until motor features evolve. Patients may initially present with predominant peripheral neuropathy or with seizures. Arylsulfatase A deficiency results in impaired breakdown of sulfatides (cerebroside sulfate or 3-0-sulfo-galactosylceramide). Sulfatides comprise approximately 5 percent of myelin within the central and peripheral nervous system. They are also found at high concentrations in the kidneys and testes. Sulfatide accumulation in glial cells is thought to lead eventually to myelin destruction, glial cell death, and the resultant neurologic phenotype. The only other organs known to show manifestations are the kidneys (with excretion of large amounts of sulfatides in urine but no clinical symptoms), the gallbladder, and the testes. Microscopic pathology is characterized by myelin loss, paucity of oligodendroglia, reactive astrogliosis, and metachromatically staining material in the white matter.

MLD diagnosis is often suspected based on clinical manifestations of motor impairment with a peripheral neuropathy. Typical MRI features include sparing of arcuate fibers and a rim of subcortical white matter, with involvement of periventricular and deep white matter in the supratentorial CNS (see Figure 71-5B). Involved white matter takes on the appearance of radiating stripes that can be highly suggestive of the disorder and reflects accumulation of sulfatides in perivascular macrophages. These radiating stripes are also present in other disorders, however, including Krabbe’s disease. In early stages or in adult cases, incomplete neurologic findings can complicate diagnosis, and early involvement of the corpus callosum may provide a clue. Occasionally, isolated involvement of cranial or peripheral nerves has been seen in the early stages of disease.

When the diagnosis is suspected, enzymatic assessment of peripheral leukocytes for arylsulfatase A activity is often performed. If abnormal, confirmatory evidence of disease, such as excess urinary sulfatides, should be sought to avoid the diagnostic pitfall of pseudodeficiency. To offer appropriate genetic counseling and carrier testing for family members, molecular confirmation should be sought by sequencing the ARSA gene. In view of evolving treatment studies, some states are now providing newborn screening that includes lysosomal disorders such as MLD. This practice is highly debated due to lack of evidence of complete penetrance and perfect genotype–phenotype correlation, and uncertainty regarding management of affected patients.

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