Leukodystrophies

Patricia L. Musolino

Florian Eichler

GENERAL CONCEPTS

Leukodystrophies are inherited disorders that affect the white matter of the central nervous system with or without involvement of the peripheral nerve. Collectively leukodystrophies represent an important cause of progressive neurological disability in children. All disorders share glial cell or myelin sheath involvement. Brain MRI plays a large role in detection and diagnosis. Patterns of white matter involvement can be pathognomonic (Fig. 9.1). Diagnosis is important for palliative or experimental therapies that may offer benefits, as well as for reproductive counseling and family screening of currently unaffected individuals. Since the few treatments available are more effective in the early stages, timely referral to an expert is crucial.¹

CLINICAL FEATURES

Age of Onset

First symptoms are usually neurological and appear, with few exceptions, in previously healthy children. Most leukodystrophies occur within a particular age group and can range in onset from early infancy to late adulthood. Within a leukodystrophy the phenotypes can vary, with more severe phenotypes usually starting in early childhood. Symptoms usually progress
slowly, with possible periods of stagnation. Phenotypes are variable depending on the severity of mutations. Starting from the age of the patient at onset of symptoms, certain types can be considered (Tables 9.1 and 9.2).

FIGURE 9.1 Algorithm for the Use of MRI Patterns in Distinguishing Disorders with White Matter Involvement (Reproduced with permission from Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15:319-328.)

TABLE 9.1 Most Common Leukodystrophies by Age of Onset of Symptoms

Leukodystrophies to Consider in Relation to Age of Patient at Onset
Patient age at onset of symptoms	Leukodystrophies (in order of probability)
Infantile (1st y of life)	Globoid cell leukodystrophy Pelizaeus-Merzbacher disease Canavan disease Vanishing white matter disease Megalencephalic leukodystrophy with cysts Aicardi-Goutières syndrome Hypomyelination with atrophy of the basal ganglia and cerebellum
Late infantile (1-5 y)	Metachromatic leukodystrophy Alexander disease Vanishing white matter disease Megalencephalic leukodystrophy with cysts Hypomyelination with atrophy of the basal ganglia and cerebellum Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate Giant axonal neuropathy type I
Juvenile	X-linked adrenoleukodystrophy Metachromatic leukodystrophy Vanishing white matter disease Megalencephalic leukodystrophy with cysts Alexander disease Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate
Adolescence, young adulthood	Metachromatic leukodystrophy Vanishing white matter disease Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate
Adapted from Kohlschutter A, Eichler F. Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother. 2011;11:1485-1496.

Neuroimaging

MRI of the head is the most important ancillary test. Standard investigation is T1- and T2-weighted and fluid-attenuated inversion-recovery (FLAIR) images. The distribution of white matter abnormalities (see Fig. 9.1) and certain specific patterns (Table 9.3) can assist in the differentiation of leukodystrophies. A systematic assessment of lesion location, presence of hypomyelination, cystic lesions, calcifications, contrast enhancement, and abnormalities on proton MR spectroscopy (MRS) is crucial. A rough classification of leukodystrophies according to their presentation on neuroimaging is shown in Table 9.3.¹^,²

TABLE 9.2 Differential Diagnosis of Leukodystrophies by Age of Onset

Childhood Onset

Primary CNS inflammation (ADEM, MS)

Primary CNS infection (encephalitis)

CNS neoplasia (glial tumors, lymphoma)

Toxic leukoencephalopathy (radiation, chemotherapy, biologic therapies)

Perinatal injury (hypoxic ischemic encephalopathy, periventricular leukomalacia)

Adult Onset

Infiltrative tumors (gliomas, gliomatosis cerebri, primary CNS lymphoma)

Toxic leukoencephalopathy (radiation, chemotherapy, organic solvents, biologic therapies, drugs of abuse)

Metabolic leukoencephalopathy (anoxia, carbon monoxide, mitochondrial)

Infection (encephalitis, HIV encephalopathy, progressive multifocal leukoencephalopathy)

Trauma (diffuse axonal injury) vasculopathies (ischemic, inflammatory, CADASIL), CNS inflammation (MS, ADEM, systemic disorders with CNS involvement)

CNS indicates central nervous system; ADEM, acute demyelinating encephalomyelitis; MS, multiple sclerosis, HIV, human immunodeficiency virus; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Adapted from Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: classification, diagnosis, and treatment. Neurologist. 2009;15:319-328.

TABLE 9.3 Childhood Leukodystrophies According to Major Neuroimaging Patterns

Disorders with Confluent MRI Lesions

Alexander disease¹

Canavan disease

Globoid cell leukodystrophy

Leukoencephalopathy with metaphyseal chondrodysplasia

Metachromatic leukodystrophy

Metachromatic leukodystrophy with multiple sulfatase deficiency

Mitochondrial disorders

X-linked adrenoleukodystrophy

Disorders with Cavitating MRI Lesions

Cystic leukoencephalopathy without megalencephaly

Glycine leukoencephalopathy

Leukoencephalopathy with calcifications and cysts

Megalencephalic leukodystrophy with cysts

Progressive cavitating leukoencephalopathy

Disorders with Hypomyelination

Fucosidosis

Folate receptor defect

Hypomyelination with atrophy of the basal ganglia and cerebellum

Hypomyelination and congenital cataract

Hypomyelination, hypodontia, hypogonadotropic hypogonadism

Hypomyelination with monocarboxylate transporter-8 deficiency

Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher-like disease

Sialic acid storage disorder

Tremor-ataxia with central hypomyelination

Disorders with Calcifications

Aicardi-Goutières syndrome

Cerebrotendinous xanthomatosis

Leukoencephalopathy with calcifications and cysts

¹Infantile type.

Adapted from Kohlschutter A, Eichler F. Childhood leukodystrophies: a clinical perspective. Expert Rev Neurother. 2011; 11:1485-1496.

Physical and Neurological Exams

Most patients with leukodystrophies do not have any physical abnormalities. Some have a large head (Alexander disease, Canavan disease, megalencephalic leukodystrophy with cysts, and vanishing white matter disease). Very rarely, they can have dysmorphic features and skeletal abnormalities that resemble those seen in mucopolysaccharidoses (fucosidosis and metachromatic leukodystrophy [MLD] with multiple sulfatase deficiency). Dental abnormalities are seen in some forms of hypomyelination, such as hypomyelination, hypodontia, and hypogonadotropic hypogonadism (4H syndrome).¹

MOST COMMON LEUKODYSTROPHIES (TABLE 9.4)

X-linked Adrenoleukodystrophy (ALD)

Defect: Mutations in the ABCD1 gene lead to defects in peroxisomal betaoxidation & very long chain fatty acid (VLCFA) accumulation. Locus Xq28.

Presentation: Cerebral ALD (only seen in males): Onset 4 to 8 y, 85% present initially with neurologic symptoms. Often begins with personality changes (resembles ADHD) and academic performance decline, followed by ataxia, spasticity, loss of vision and hearing. Dementia and seizures can occur later in the course. It often leads to total disability within 2 y. Adrenomyeloneuropathy (AMN) or adult form (males and some females): Onset after 20 y with spastic paraplegia, sensory peripheral neuropathy, sphincter disturbances, and impotence. Other si/sx: Adrenal insufficiency (mean onset 7.5 y, may be isolated). Prognosis: In cerebral ALD, there is progression to vegetative state and death by 3 y after onset (slower progression in adult cerebral ALD). FHx: X-linked, only males affected in cerebral form, up to 20% of female carriers will develop AMN.

Dx:

Imaging: Cerebral form: T2-hyperintense confluent lesion that starts in the splenium of the corpus callosum and spreads to the posterior periventricular white matter and corticospinal tracts. A garland of peripheral contrast enhancement (Fig. 9.2). Adult form: Normal MRI or T2-hyperintense lesions of lateral spinal cord columns without contrast enhancement.
Labs: High plasma VLCFA (concentration of C26:0, ratios of C24:0/C22:0 and C26:0/C22:0) is diagnostic in males (20% females have normal levels). Abnormal response to ACTH stimulation test. Low plasma Cortisol in advanced cases.
Biopsy: Skin for enzyme assay in cultured fibroblasts.
Definitive dx:

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