Clinical manifestations

Presentation and course

Patients suspected of having a leukodystrophy require a thorough history (including family history), a thorough general and neurologic examination, brain MRI, and referrals to various subspecialists. Leukodystrophies are rare and clinically heterogeneous with various ages of disease onset. Some have more systemic involvement than others, and some have a more progressive course than others. Due to the clinical variability, it is difficult to create a set of symptoms common among all leukodystrophies. However, there are red flag neurologic features on history and examination that should alert a clinician to initiate a workup for leukodystrophy.

Clinical history. A clinical history or a family history of developmental regression or stagnation, especially in motor development is often the first symptom in many demyelinating leukodystrophies (53). Additionally, a delay in acquisition of milestones can be seen in the hypomyelinating leukodystrophies. Though many of the leukodystrophies are heritable, some have been observed as sporadic cases, especially in adult-onset leukodystrophies (33). Age of onset is also an important factor that may guide diagnosis as some leukodystrophies are more common in adults, such as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Most patients with ALSP will present with cognitive and frontal lobe-based behavioral symptoms and signs months before motor deficits develop (28). With many leukodystrophies, such as X-linked adrenoleukodystrophy, a patient may present at any age; however, presenting symptoms may be different in each age group. For example, childhood cerebral adrenoleukodystrophy is most common between the ages of 3 and 11 years, whereas adrenomyeloneuropathy is more common among males in their third decade (52).

Examination. Neurologic examination can be revealing and aid in diagnosis. Neurologic signs concerning for a central nervous system pathology, such as appendicular hypertonicity and axial hypotonicity, would indicate the need for neuroimaging. Patients with Aicardi-Goutières syndrome can have axial hypotonia and appendicular hypertonia, along with abnormal eye movements, persistence of the tonic neck reflex, and difficulty with vision (12). Other common neurologic abnormalities seen in patients with leukodystrophies are a combination of spasticity and cerebellar ataxia, as in Krabbe disease and 4H syndrome (41). This can affect all 4 extremities or only the lower extremities with delays of independent walking. Dystonia may be present when the basal ganglia are involved as in hypomyelination with atrophy of basal ganglia and cerebellum and in RNA polymerase III-related leukodystrophy (47; 42; 03). Tendon reflexes are usually increased, but decreased ankle reflexes compared to knee jerks suggest the presence of a peripheral neuropathy, for example, as seen in metachromatic leukodystrophy (08). The presence of peripheral nerve involvement can be subtle with normal nerve conduction velocity (50). Sensory examination is typically grossly normal, but vibration perception is often reduced, especially when the disease process also affects peripheral nerves (37).

As many of these leukodystrophies cause systemic symptoms, a general examination is also important. Growth is often delayed in systemic disorders, such as mitochondrial diseases; head circumference may be small in patients with Krabbe disease or megalencephalic in those with Canavan disease, Alexander disease, or megalencephalic leukoencephalopathy with subcortical cysts. A complete eye examination is important as findings can help narrow diagnosis. Patients with peroxisomal biogenesis disorders commonly have cataracts, corneal clouding, and findings consistent with glaucoma. Hepatomegaly can also be seen in patients with peroxisomal biogenesis disorders (27). Examination of the mouth can reveal a variety of teeth abnormalities, such as hypodontia, suggesting 4H syndrome (50). Examination of the extremities may reveal xanthomas, indicating cerebrotendinous xanthomatosis (36). Examination of the skin may show increased skin pigmentation, suggesting adrenal insufficiency and X-linked adrenoleukodystrophy (41); ichthyosis would suggest the diagnosis of Sjögren-Larsson syndrome (23).

Neuroimaging. Neuroimaging is key to the diagnosis of a leukodystrophy. By definition, in leukodystrophies, T2-weighted MRI signal hyperintensity in the white matter must be present, but T1-weighted signal may be variable (44; 59). Isointense or hyperintense T1 signal is consistent with a hypomyelinating leukodystrophy. It is also important to note that individual MRIs are generally not sufficient to determine delayed or hypomyelination, especially when done before 1 year of age. Therefore, serial MRIs, at least 6 months apart, are generally recommended (41). Other myelin pathologies, including demyelinating leukodystrophies, cause hypointense T1 signal (44; 58).

It should be stressed that although the pattern on MRI is an extremely valuable diagnostic tool, it does not always necessarily represent the actual pathological process; that is, a hypomyelinating pattern on the MRI may not imply actual hypomyelination. For example, in Pelizaeus-Merzbacher disease, despite the common MRI pattern being concerns for hypomyelination, the actual neuropathology is highly specific to the mutation (22; 30).

Prognosis and complications

The vast majority of leukodystrophies are progressive, eventually leading to complete dependency for everyday activities and premature death. Supportive care has extended the lives of many patients with progressive diseases, making it important to ensure appropriate management of the complications associated with many of the leukodystrophies, such as spasticity, seizures, musculoskeletal issues like scoliosis, skin care, urinary incontinence, and lack of ability to verbally communicate (01). It is important to note that some leukodystrophies, such as megalencephalic leukoencephalopathy with subcortical cysts and leukoencephalopathy, with thalamus and brainstem involvement and high lactate have an improving phenotype; therefore, progressive disease is no longer part of the definition of a leukodystrophy (31; 26). In adult forms of leukodystrophy, behavioral disturbances and psychiatric manifestations often cause loss of employment and conflicts in the family (21). Slowly progressive or even sometimes static psychiatric or cognitive symptoms frequently occur in adults with metachromatic leukodystrophy (61).

Biological basis

Etiology and pathogenesis

Leukodystrophies, though all with variable underlying etiology, are heritable disorders with glial cell or myelin sheath abnormalities leading to pathology of the white matter of the CNS and, at times, the PNS (57). What is striking is the wide range of etiologies representing a variety of cellular processes and functions. They include lysosomal enzyme deficiencies, inborn errors of intermediate metabolism (lipids or sugars, defects in transport of small molecules across lysosomes and peroxisomes, defects of innate immunity, control of protein translation initiation, and abnormalities of certain structural proteins of cells), and mutations of glial fibrillary acidic protein in Alexander disease.

The pathogenesis of a leukodystrophy varies according to its etiology; therefore, one cannot generalize across the various genetic entities. One approach is to divide the leukodystrophies according to the cell type that is predominantly affected (53). Initially, it was thought that oligodendrocytes are always the type of cell primarily affected; though true in some disorders, such as Pelizaeus-Merzbacher disease, metachromatic leukodystrophy, and Krabbe disease (15), we now know that numerous cell types in the brain can be involved, including oligodendrocytes, astrocytes, and microglia (25). For example, in Alexander disease, the mutated protein, glial fibrillary acidic protein (18), is expressed only in astrocytes. Astrocytes are also prominently involved in megalencephalic leukodystrophy with subcortical cysts and in CACH/VWM (14; 34). Immune cells, including microglia, are dysfunctional in X-linked adrenoleukodystrophy (45), ALSP (29; 28), and likely in Aicardi-Goutières syndrome as well (43). Defects in mitochondrial and cytoplasmic tRNA synthetases have been identified (49; 13; 64), though how these defects cause a leukodystrophy is not yet known. Consequently, in the majority of cases, the complete mechanism is not obvious, but it clearly involves more than one cell type. Axonal dysfunction and death occur in all leukodystrophies and are the main causes of the clinical neurologic dysfunction.

Epidemiology

Leukodystrophies are panethnic. There are limited epidemiologic data on the frequency of leukodystrophies, but their overall incidence is estimated to be 1:7500 live births (19). The incidence of individual leukodystrophies varies from 1:17,000 in X-linked adrenoleukodystrophy (17) to 1:40,000-1:100,000 in metachromatic leukodystrophy (32) and 1:500,000 and less in the rarest of these genetic diseases. The lifetime risk for leukodystrophies and genetic leukoencephalopathies in the United Kingdom is 31 per million live births (48).

Prevention

Reproductive planning in conjunction with genetic counseling is currently the primary method for the prevention of leukodystrophies. For families in whom the molecular defects have been identified in affected members, mutation analysis provides the most accurate method for prenatal diagnosis and carrier identification. When mutation analysis is available, pre-implantation genetic diagnosis is possible.

Differential diagnosis

A number of leukoencephalopathies (diseases that predominantly affect the white matter of the brain) may be confused with and initially diagnosed as leukodystrophies. Therefore, it is important to consider other acquired and genetic disorders that may result in white matter disease on neuroimaging when evaluating a patient for leukodystrophy (Table 2) (57).

Acquired disorders. Acquired disorders can affect the white matter of the brain. Postinfectious, infectious, and autoimmune disorders can result in demyelination without a primary genetic basis. Disorders such as acute disseminated encephalomyelitis, multiple sclerosis, and neuromyelitis optica typically differentiate themselves from the heritable disorders of the white matter by abrupt onset and multiphasic presentations (59). In addition, MRI abnormalities are more likely to be multifocal and patchy (44), with variation or even improvement over time and with treatment. Nevertheless, when evaluating a child with a suspected leukodystrophy, it is always important to exclude potentially treatable or reversible acquired disorders. Central nervous system injury, particularly in the perinatal period, can result in significant white matter signal abnormalities but will typically also be irregular in appearance and may result in a loss of white matter volume, characteristics to help differentiate it from a leukodystrophy (59).

Primary neuronal disorders. Primary neuronal disorders are often associated with significant white matter abnormalities (51). The infantile variants of disorders like GM1 gangliosidosis, GM2 gangliosidosis, and neuronal ceroid lipofuscinosis may have significant white matter abnormalities because the primarily neuronal disease disrupts the normal myelination process. Later onset variants of these disorders eventually affect the cerebral white matter, and mild signal abnormalities arise related to Wallerian degeneration with loss of axons and myelin. In other disorders, such as MCT8-related disorder (62), myelination can be extremely delayed but progress over time to become almost complete. These are not considered primary white matter disorders. Primary neuronal disorders may, thus, be confused with leukodystrophies (44). When features such as significant encephalopathy and seizures are present in a child with leukoencephalopathy, primary neuronal disorders should be considered along with leukodystrophies.

Disorders affecting white and gray matter. Some disorders affect the white and gray matter indiscriminately and are not leukodystrophies. When evaluating a patient with abnormal white matter on neuroimaging, it is important to carefully evaluate for associated cortical lesions. Examples include mitochondrial disorders, such as MELAS (mitochondrial encephalopathy with lactic acidosis and seizures) and POLG1-associated mitochondrial encephalopathy, or familial hemophagocytic lymphohistiocytosis, which results in both white and gray matter injury (66).

Vasculopathies. Vasculopathies can result in white matter signal abnormalities but are not leukodystrophies. Genetic abnormalities of the vessel wall, such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infants), and defects in COL4A1, such as in autosomal dominant porencephaly, can give multifocal and, in the end, confluent signal abnormalities in the periventricular and deep white matter, typically with multifocal abnormalities in the central gray matter structures and brainstem (06). Cathepsin A-related arteriopathy with strokes and leukoencephalopathy also has been described in adult patients to show extensive white matter disease (11; 20). However, because they are not primary glial cell disorders, they are arbitrarily not considered leukodystrophies.

Table 2. Heritable Disorders with Significant White Matter Involvement That Are Not Leukodystrophies

For further information and assistance in unsolved leukodystrophies, please also see the Myelin Disorders Bioregistry Project at www.myelindisorders.org.

Diagnostic workup

The approach to diagnosis is heavily based on clinical features, advanced neuroimaging, and laboratory testing, including ancillary biochemical tests and genetic testing. Pattern recognition in advanced imaging plays an important role in diagnosis, and the diagnostic algorithm based on imaging is an important tool for clinicians (Schiffman and van der Knaap 2009; 41).

Clinical and laboratory tests that can aid in further narrowing the diagnosis are: ophthalmologic examination; biochemical tests – very long chain fatty acids (plasma), lactate (blood), pyruvate (blood), amino acids (blood), sulfatides (urine), organic acids (urine), lysosomal enzymes; CSF analysis; neurophysiologic testing, such as visual evoked potentials and nerve conduction studies; and genetic testing.

Vanderver and colleagues showed that genomic sequencing (of patients and both parents) as a first-line test in patients with pediatric white matter disease not only decreases the time to diagnosis but also increases the overall diagnostic yield from 21% to 56% when compared to standard-of-care diagnostic testing. With this in mind, a revised diagnostic algorithm was proposed. It is important to note that biochemical testing is still the cornerstone of testing to identify treatable entities in a timely manner(56).

It is important to note that earlier interventions, when available, lead to improved outcomes. Hence, newborn screening can potentially play a crucial role in early diagnosis and management of certain leukodystrophies. Through the Secretary of Health and Human Services, the federal government recommended that X-linked adrenoleukodystrophy be added to the Recommended Uniform Screening Panel (RUSP) (24). Of note, while the RUSP is federally recommended, the implementation of newborn screening is state-based. Therefore, not all states are currently screening for X-linked adrenoleukodystrophy. On the other hand, Krabbe disease has been added to the RUSP, with New York State initiating screening since 2006 (63). The challenges of balancing the need for early diagnoses as new therapeutics evolve with the challenge of addressing pseudodeficiency alleles, variants of uncertain significance in genetic screening, and long-term financial and ethical considerations will need to be assessed, discussed, and evaluated as conditions are added to the newborn screening process.

Management

In patients with advanced neurologic signs, there is no disease-specific therapy; therefore, the main management procedures remain symptomatic and supportive and consist of the following (01):

In general, once a patient has been diagnosed with a leukodystrophy, the patient should be referred to a center with expertise in managing patients with leukodystrophies.

In select leukodystrophies, therapies exist to slow disease progression and perhaps change the natural history of the disease. In cerebrotendinous xanthomatosis, early treatment with chenodeoxycholic acid has shown to slow the progression of both the neurologic and non-neurologic disease (38). Additionally, in X-linked adrenoleukodystrophy, and typically in those who have not yet developed neurologic signs, bone marrow transplantation or hematopoietic stem cell transplantation is effective and may also be partially effective in patients with metachromatic leukodystrophy and Krabbe disease (10; 60). It is not clear how transplant prevents progression of X-linked adrenoleukodystrophy, but the effect is likely related to immunological modification. However, in lysosomal disease, the therapeutic efficacy of transplantation relies on the migration of donor bone marrow-derived cells of the monocyte-macrophage lineage into diseased target organs, where they replace the resident enzyme-deficient population and become a local and steady source of the missing enzyme (40). On the other hand, in metachromatic leukodystrophy, there is no enzymatic cross-correction; rather, inflammatory and immune modulation likely explains the therapeutic effect (65). In select metachromatic leukodystrophy patients, such as in the very early stage of the juvenile and adult forms of leukodystrophy, transplantation has been reported to delay onset and slow progression of the disease (10). Clinical experience has shown no efficacy of transplantation if performed in symptomatic patients with early-onset disease or in advanced stages for patients with late-onset disease. Unfortunately, considering these selection criteria, only a minority of metachromatic leukodystrophy patients can benefit from transplantation, which can be further limited by the availability of HLA-compatible donors (40). In addition, transplantation is associated with fairly high morbidity and mortality due to conditioning regimens, rejection, failure of engraftment, and graft-versus-host disease. However, with the advent of reduced-intensity conditioning and availability of umbilical cord blood, mortality and morbidity have been reduced, and the umbilical cord blood allows for a more readily available stem cell source (55). Ex-vivo gene therapy, which negates the need for a matched donor and the risk of rejection altogether, has been attempted for patients with X-linked adrenoleukodystrophy and metachromatic leukodystrophy (46; 16); thus far, the results are promising.

Currently, leukodystrophies thought to have disease modifying therapies are X-linked adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, and cerebrotendinous xanthomatosis; however, early detection is imperative to make a meaningful difference in outcomes (41).

Special considerations

Anesthesia

Children with leukodystrophy often require anesthesia during imaging procedures or for surgical procedures (35; 07). These children are at special risk of airway complications with sedation and anesthesia because of poor pharyngeal muscle control, copious oral secretions, and the prevalence of gastroesophageal reflux and seizure disorders. Therefore, it is recommended that when needed, these patients be referred to centers with expertise in treating children with leukodystrophies.