Clinical characteristics.

Leukodystrophies are heritable myelin disorders affecting the white matter of the central nervous system with or without peripheral nervous system myelin involvement. Involvement of the white matter tracts almost universally leads to motor involvement that manifests as hypotonia in early childhood and progresses to spasticity over time. This may lead to variable motor impairment, from mild spastic diplegia to severe spastic quadriplegia that limits purposeful movement. In addition, motor dysfunction is likely to significantly impair vital functions including swallowing, chewing, and (in some cases) respiration. Other findings that vary by disorder include extrapyramidal movement disorders (e.g., dystonia and/or dyskinesias), ataxia, seizures, and delay in cognitive development or change in cognitive function over time.

Diagnosis/testing.

Establishing the specific leukodystrophy present in a given individual usually involves:

• Obtaining a medical history and detailed family history
• Performing a physical examination and neurologic examination
• Review of brain MRI findings:
  • T₂-weighted hyperintensity in the white matter is the MRI finding required for diagnosis of a leukodystrophy.
  • T₁-weighted signal may be variable: iso- or hyperintense T₁-weighted signal is consistent with a hypomyelinating leukodystrophy; hypointense T₁-weighted signal is consistent with a demyelinating leukodystrophy.
• Performing specialized laboratory testing, often including molecular genetic testing (either stepwise single-gene testing or use of a multigene panel targeted to the leukodystrophies).

Genetic counseling.

Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Prenatal testing for pregnancies at increased risk is possible for some types of leukodystrophy if the pathogenic variant(s) in the family are known. Many leukodystrophies are still without an identified genetic cause; once a genetic cause is identified, other inheritance patterns may emerge.

Management.

Treatment of manifestations: Treatment is symptomatic and ideally occurs in a multidisciplinary setting by specialists experienced in the care of persons with a leukodystrophy. Pharmacologic agents are used to manage muscle tone and block neuronal signaling to muscle (chemodenervation). Intensive physical therapy is used to improve mobility and function. Pharmacologic treatment of dystonia and dyskinesias may result in significant functional improvement. Treatment of ataxia, seizures, and cognitive issues is provided in the usual manner, depending on the needs of the individual.

Prevention of primary manifestations: In a few leukodystrophies primary disease manifestations can be prevented by hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) early in the disease course.

Surveillance: Routine assessment of growth and nutritional status; physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications; and routine history regarding signs and symptoms of seizures.

Agents/circumstances to avoid: Mild head injuries and infection as these may exacerbate disease manifestations.

Evaluation of relatives at risk: When primary prevention of a leukodystrophy is possible (e.g., by HSCT or BMT), it is appropriate to offer testing to asymptomatic at-risk relatives who would benefit from early diagnosis and consideration of early treatment.

Medical History

A history of certain clinical features may be helpful in identifying a specific leukodystrophy; however, in the majority of cases, only nonspecific loss of function (primarily motor) occurs and medical history alone does not provide insight into a specific diagnosis.

In the hypomyelinating leukodystrophies helpful diagnostic clues may, for example, be the following:

• Congenital cataract: hypomyelination and congenital cataract (HCC)
• Hypodontia and/or hypogonadotropic hypogonadism: POLR3-related leukodystrophy
• Severe seizures: sialic acid storage disorders

In the demyelinating leukodystrophies helpful diagnostic clues may, for example, be the following:

• Recurrent vomiting: Alexander disease
• Adrenal dysfunction: X-linked adrenoleukodystrophy (X-ALD)
• Early-onset autonomic dysfunction: AD adult-onset leukodystrophy (ADLD)
• Chronic cerebrospinal fluid lymphocytosis or (more often) recurrent "aseptic meningitis": Aicardi-Goutières syndrome
• Abrupt loss of function after a fever or fall: childhood ataxia with central nervous system hypomyelination/vanishing white matter (and possibly other leukodystrophies)

Family History

A detailed three-generation family history should be compiled, focusing on individuals with hypotonia, spasticity, dystonia, seizures, ataxia, and/or delay in cognitive development or change in cognitive function over time.

• Because most leukodystrophies are autosomal recessive, special attention to parental consanguinity and medical problems in sibs is warranted.
• Evaluation of relatives and/or review of their medical records may be needed.

Physical Examination and Neurologic Examination

In most instances physical findings do not suggest a specific diagnosis; however, certain findings may direct the reader to further explore specific underlying etiologies:

• Macrocephaly; see Table 6 (pdf)
• Abnormal dentition: POLR3-related leukodystrophy or oculodentodigital dysplasia (ODDD)
• Palatal myoclonus in adults: Alexander disease
• Xanthomas: cerebrotendinous xanthomatosis (CTX)
• Abnormalities of skin pigmentation: X-linked adrenoleukodystrophy (X-ALD)
• Ichthyosis: Sjögren-Larsson syndrome
• Vascular retinal abnormalities: cerebroretinal microangiopathy w/calcifications & cysts (CRMCC)
• Cherry red spot on retinal examination: disorders such as GM1 and GM2 gangliosidosis

Brain MRI Findings

Step 2

Within the hypomyelinating and demyelinating leukodystrophies, determine if patterns of involvement suggest specific diagnoses.

Hypomyelinating leukodystrophy. Note specific patterns on neuroimaging that include the following (Figure 2):

Figure 2.

Hypomyelinating leukodystrophy – patterns on MRI A→B. Improvement of myelination over time in MCT8-specific thyroid hormone cell transporter deficiency seen in a male with documented SLC16A2 (MCT8) pathogenic variants at age two years (more...)

• Improvement of myelination over time (e.g., as seen in MCT8-specific thyroid hormone cell transporter deficiency; see Figure 2A→B)
• Severe atrophy of cortical gray matter (variably seen in primary neuronal disorders as well as a limited number of classic leukodystrophies; see Figure 2C)
• Persistent hypomyelination without atrophy of cortical gray matter (e.g., in Pelizaeus-Merzbacher disease; see Figure 2D)
• Cerebellar atrophy (e.g., in POLR3-related leukodystrophy [4H syndrome]; see Figure 2E)
• Basal ganglia involvement (e.g., in HABC syndrome; see Figure 2F)

Demyelinating leukodystrophy

• Identify the region in which white matter abnormalities predominate.
• Distinguish confluent from multifocal lesions (Figure 3):
  • Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically.
  • Multifocal white matter lesions are more discrete, often asymmetric and involving a limited area. Multifocal abnormalities have a specific differential diagnosis.

Figure 3.

Confluent white matter lesions are extensive white matter abnormalities in significant portions of the brain, often affecting specific regions or tracts, although not necessarily perfectly symmetrically. Multifocal white matter lesions are more discrete, (more...)

Specific patterns on neuroimaging in confluent disorders include (Figure 4):

Figure 4.

Demyelinating leukodystrophy – patterns on MRI A. Diffuse cerebral involvement in an individual with megalencephalic leukodystrophy with subcortical cysts

• Diffuse cerebral involvement (e.g., as seen in megalencephalic leukodystrophy with subcortical cysts; see Figure 4A)
• Frontal involvement (e.g., in Alexander disease; see Figure 4B)
• Parieto-occipital involvement (e.g. in X-linked adrenoleukodystrophy; see Figure 4C)
• Temporal involvement (e.g., in Aicardi-Goutières syndrome; see Figure 4D)
• Subcortical involvement (e.g., in Kearns-Sayre syndrome; see Figure 4E)
• Periventricular involvement (e.g., in metachromatic leukodystrophy; see Figure 4F)
• Brain stem involvement (e.g., in adult polyglucosan body disease with heterogeneous involvement of the brain stem; see Figure 4G)
• Cerebellar/cerebellar peduncle involvement (e.g., in AD adult-onset leukodystrophy (ADLD) with involvement of the middle cerebellar peduncles; see Figure 4H)
• Large, asymmetric lesions (e.g., in hereditary diffuse leukoencephalopathy with spheroids [HDLS]; Figure 4I)

Diagnostic algorithm. For algorithms based on MRI findings, see Figure 5 (demyelinating and other conditions) and Figure 6 (hypomyelinating conditions) [Schiffmann & van der Knaap 2009].

Figure 5.

Algorithm Part 1: Demyelinating and other conditions Adapted from Schiffmann & van der Knaap [2009]

Figure 6.

Algorithm Part 2: Hypomyelinating conditions Adapted from Schiffmann & van der Knaap [2009]

Step 3

Look for the following associated features which, in addition to the pattern of findings on brain MRI, can assist in recognition of a specific leukodystrophy:

• White matter rarefaction and cysts (Table 3) seen on FLAIR imaging (e.g., in vanishing white matter disease: childhood ataxia with central nervous system hypomyelination/vanishing white matter; Figure 7A)
• Calcium deposits and hemosiderin deposits (Table 4) visible on CT, and not easily distinguishable on MRI (e.g., in Aicardi-Goutières syndrome; see Figure 7B)
• Contrast enhancement (Table 5) on T₁-weighted imaging within the abnormal white matter (e.g., in X-linked adrenoleukodystrophy; see Figure 7C)
• Leukoencephalopathy with macrocephaly(Table 6)
• Cortical gray matter lesions (Table 7) (e.g., in POLG-related disorders; see Figure 7D)
• Cerebellar abnormalities (Table 8) seen in the dentate nucleus (e.g., in L-2-hydroxyglutaric aciduria; see Figure 7E)
• Thinning of the corpus callosum (Table 9), in particular, of the genu (e.g., in hereditary spastic paraplegia 11; see Figure 7F)
• Non-calcifying basal ganglia lesions (Table 10) (e.g., in Alexander disease; see Figure 7G, signal abnormality of the basal ganglia and frontal white matter)
• Brain stem involvement (Table 11) (e.g., in AD adult-onset leukodystrophy (ADLD); see Figure 7H)
• Spinal cord involvement (Table 12) (seen in many disorders, including LBSL; see Figure 7I, an example of involvement of tracts within the spinal cord)

Figure 7.

Features associated with specific leukodystrophies A. White matter rarefaction and cysts on FLAIR imaging in vanishing white matter disease; arrow indicates cystic rarefaction within abnormal white matter.

Specialized Laboratory Testing (Including Molecular Genetic Testing)

If the findings on brain MRI are consistent with a specific leukodystrophy, consider biochemical or molecular genetic testing for that disorder (Table 1). Note: Molecular genetic testing may be performed either as single-gene testing in a stepwise fashion based on the information gained during the evaluation or, if available, as a multigene panel.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Mode of Inheritance

Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner; other inheritance patterns may be identified as more genetic causes of leukodystrophy are discovered.

If a proband has a specific syndrome associated with a leukodystrophy, counseling for that condition is indicated.

Risk to Family Members

Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for leukodystrophy are possible.

Treatment of Manifestations

Although the underlying mechanisms of leukodystrophies are diverse, many manifestations are similar across this group of disorders. In the great majority of cases, primary treatment is not possible, but management of symptoms can improve the comfort and care of individuals with these complex disorders.

Ideally, the child or adult with a leukodystrophy is managed in a multidisciplinary setting by providers experienced in the care of persons with a leukodystrophy.

Spasticity. Pharmacologic agents are used to manage muscle tone and block neuronal signaling to muscle (chemodenervaton). Intensive physical therapy is used to improve mobility and function.

Extrapyramidal manifestations. Dystonia and dyskinesias may cause significant disability; pharmacologic treatment may result in significant functional improvement.

Ataxia. No specific treatment of ataxia exists, although rehabilitative measures can be of great assistance.

Seizures. Seizures should be treated with typical anticonvulsants and are rarely refractory, except on occasion at the end of life.

Cognitive developmental delay / encephalopathy. It is important to advocate for persons with a leukodystrophy in school or at work to avoid limitations related to their motor disabilities. Augmentative communication may be used to address speech deficits. Accommodations for cognitive delays and fine motor disabilities should be used as needed.

Orthopedic. Attention should be given to the prevention and treatment of orthopedic problems, such as hip dislocation and scoliosis.

Feeding. Swallowing dysfunction and pulmonary problems resulting from the increased risk of aspiration are common as the disease progresses. Decreased nutritional intake and failure to thrive may also occur. The decision to place a gastrostomy tube for nutrition is based on the overall health status of the individual, expected disease course, and family and patient wishes.

Prevention of Primary Manifestations

Primary disease manifestations can be prevented in a few of the leukodystrophies: in X-linked adrenoleukodystrophy, Krabbe disease, and metachromatic leukodystrophy, for example, hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) may be beneficial if performed early in the disease course. Patients with these disorders should be referred to specialized centers for consideration of HSCT or BMT [Eichler et al 2009].

Surveillance

Standard surveillance includes the following:

• Routine measurement of weight and height to assess growth and nutritional status
• Physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications
• Routine history regarding signs and symptoms of seizures

Certain disorders require specialized surveillance; for example, monitoring for the development of hydrocephalus in Alexander disease.

Agents/Circumstances to Avoid

In a number of leukodystrophies anecdotal evidence suggests episodic worsening of manifestations with mild head injuries and infection. While this has been clearly documented only for childhood ataxia with central nervous system hypomyelination/vanishing white matter, it appears prudent to avoid these triggers when possible.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Literature Cited

• Bezman L, Moser AB, Raymond GV, Rinaldo P, Watkins PA, Smith KD, Kass NE, Moser HW. Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening. Ann Neurol. 2001;49:512–7. [PubMed: 11310629]
• Bonkowsky JL, Nelson C, Kingston JL, Filloux FM, Mundorff MB, Srivastava R. The burden of inherited leukodystrophies in children. Neurology. 2010;75:718–25. [PMC free article: PMC2931652] [PubMed: 20660364]
• Eichler F, Grodd W, Grant E, Sessa M, Biffi A, Bley A, Kohlschuetter A, Loes DJ, Kraegeloh-Mann I. Metachromatic leukodystrophy: a scoring system for brain MR imaging observations. AJNR Am J Neuroradiol. 2009;30:1893–7. [PMC free article: PMC7051299] [PubMed: 19797797]
• Heim P, Claussen M, Hoffmann B, Conzelmann E, Gärtner J, Harzer K, Hunneman DH, Köhler W, Kurlemann G, Kohlschütter A. Leukodystrophy incidence in Germany. Am J Med Genet. 1997;71:475–8. [PubMed: 9286459]
• Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology. 2009;72:750–9. [PMC free article: PMC2677542] [PubMed: 19237705]
• van der Knaap MS, Breiter SN, Naidu S, Hart AA, Valk J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology. 1999;213:121–33. [PubMed: 10540652]
• van der Knaap MS, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. Berlin, Germany: Springer. 2005.

Revision History

• 30 January 2020 (ma) Retired chapter: Phenotype is too broad.
• 6 February 2014 (me) Review posted live
• 14 February 2012 (av) Original submission