Leukodystrophies

Overview

The leukodystrophies are a group of more than 30 inherited conditions in which the white matter of the brain is abnormal due to altered development, decreased amount, or degeneration of the lipid insulation covering neuronal processes in the brain. Although the type of leukodystrophy, age at presentation, and severity of the condition will affect presentation, most children present with a decline in developmental milestones during infancy or toddlerhood, or with a decline in cognitive and motor abilities during childhood. Some individuals will present as adults.

Diagnosis of leukodystrophy is based on characteristic white matter abnormalities seen on brain MRI; a specific leukodystrophy can be diagnosed in approximately half of these children. [Bonkowsky: 2010] Suggested diagnostic algorithms are available ([Richards: 2015]), and consultation with a specialist is suggested. Timely diagnosis is critical because curative treatments for a few of these conditions are available (see [Rosenberg: 2016]); however, treatment for most leukodystrophies is supportive.

Other Names & Coding

ICD-10 coding

E75.29, Other sphingolipidoses

Further coding details can be found by using the search feature at ICD10Data.com.

Prevalence

Incidence of the leukodystrophies, which is likely an underestimate, is 1:7,663 live births. [Bonkowsky: 2010] It should be noted that there is no agreement regarding the definition of leukodystrophy. [Vanderver: 2015]

Genetics

Leukodystrophies can be inherited in X-linked, recessive or dominant form, or they may occur spontaneously. For more information about mode of inheritance and genes involved, see Leukodystrophies, Genes, & Testing (GeneReviews).

Prognosis

Some leukodystrophies present with impairment from birth and do not progress, yet others have progressive deterioration in neurologic function. In general, leukodystrophies are severe diseases. In a large cohort, only 51% of children walked and 28% achieved the ability to track visually. [Bonkowsky: 2010] In a few leukodystrophies, primary disease manifestations can be prevented by hematopoietic stem cell transplantation (bone marrow transplantation) if performed early in the disease course. [Pagon: 2014]

Practice Guidelines

Parikh S, Bernard G, Leventer RJ, van der Knaap MS, van Hove J, Pizzino A, McNeill NH, Helman G, Simons C, Schmidt JL, Rizzo WB, Patterson MC, Taft RJ, Vanderver A.
A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies.
Mol Genet Metab. 2015;114(4):501-15. PubMed abstract / Full Text

Adang LA, Sherbini O, Ball L, Bloom M, Darbari A, Amartino H, DiVito D, Eichler F, Escolar M, Evans SH, Fatemi A, Fraser J, Hollowell L, Jaffe N, Joseph C, Karpinski M, Keller S, Maddock R, Mancilla E, McClary B, Mertz J, Morgart K, Langan T, Leventer R, Parikh S, Pizzino A, Prange E, Renaud DL, Rizzo W, Shapiro J, Suhr D, Suhr T, Tonduti D, Waggoner J, Waldman A, Wolf NI, Zerem A, Bonkowsky JL, Bernard G, van Haren K, Vanderver A.
Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.
Mol Genet Metab. 2017;122(1-2):18-32. PubMed abstract

Roles of the Medical Home

Quality of life for the family and child with leukodystrophy is enhanced by easy access to a medical home clinician for acute illnesses and preventive care. The benefit of subspecialist involvement may increase as the child becomes progressively more affected. Balance the benefit of subspecialty help with the family's wishes and convenience of services. Coordination of care among subspecialists, therapists, school, and community services will help optimize outcomes, minimize duplication of services, and ensure the family's goals are addressed. The medical home clinician may need to be involved with the individual education plan (IEP) to ensure the child receives needed school services. A teacher coming to the home to work with the child may be helpful in some cases.

Clinical Assessment

Overview

Consider a leukodystrophy in any child who shows developmental delay, global regression, or stops meeting developmental milestones. The diagnosis of a leukodystrophy requires an MRI and biochemical and/or genetic testing; there are no pathognomonic clinical findings. Vigilance for potential complications (growth problems, feeding problems, spasticity, and seizures) permits early intervention. If available, a social worker can help the family with finances and emotional functioning.

Pearls & Alerts for Assessment

Regression in multiple abilities

Children with leukodystrophy not only regress in language and interaction, as might be seen in a child with autism, but also in some combination of motor, fine motor, and visual abilities.

Myelin varies by age

Because the appearance of myelin in children of different ages varies, MRIs should be performed in a facility where pediatric neuroradiologists are available to interpret the scans.

Poor weight gain

Problems swallowing, high metabolic need, difficulty with positioning, and other issues can lead to poor weight gain. A feeding tube (nasogastric, nasojejunal, or gastrostomy) may be helpful. See Feeding Tubes and Gastrostomies.

Screening

For the Condition

Newborn screening for some leukodystrophies is performed in certain states. Routine developmental screening will identify many children affected by leukodystrophies.

Of Family Members

Screening of family members is recommended for some leukodystrophies and should be guided by a geneticist or neurologist. Genetic counseling is appropriate for parents who wish to have more children and siblings of the child with leukodystrophy.

For Complications

Screening for complications and comorbidities (e.g., spasticity, seizures, developmental delays) can occur during physical therapy sessions, well-child checks, and subspecialist visits.

Presentations

Leukodystrophies present in many ways. A typical presentation is an infant or child with developmental delay who stops achieving milestones or has developmental regression. Hypotonia progressing to spasticity, visual and/or hearing problems, and irritability are common findings. Manifestations may progress more slowly in individuals who present as adolescents or adults.

Diagnostic Criteria

Leukodystrophies are diagnosed by characteristic white matter abnormalities on an MRI, but definitive diagnosis requires further biochemical and/or genetic testing.

Differential Diagnosis

Cerebral Palsy (CP): Leukodystrophy should be suspected if a child thought to have CP is experiencing a progression of disability or a slowing of developmental achievement, particularly when there is no apparent antecedent for the CP.

Demyelinating diseases: Consider demyelinating diseases (primarily multiple sclerosis and neuromyelitis optica) as differential diagnoses.

History & Examination

Current & Past Medical History

Children may be otherwise healthy - psychiatric symptoms may be the first presenting symptoms in older children, teens, and adults. Seizures may occur as presenting or early symptoms. Endocrine abnormalities (hypothyroidism, diabetes, and others) are also observed. Ask about lung and urinary tract infections, which may occur due to physical limitations.

Family History

A family history can provide clues to diagnosis of certain leukodystrophies. A 3-generation pedigree should be performed if possible.

Pregnancy/Perinatal History

The history is usually normal or with mild, nonspecific problems.

Developmental & Educational Progress

Failure to achieve or regression in developmental milestones for infants and toddlers, or motor and cognitive abilities for children, are typical.

Social & Family Functioning

Identify family needs at diagnosis and then periodically. Parental grief, marital problems, and challenges for unaffected siblings are a few of the problems that many families will face.

Physical Exam

General

A child with leukodystrophy may have reduced interaction with the environment or may be irritable.

Growth Parameters

Weight and height may be impaired; follow weight closely. Increased calories or alternative feeding methods may be needed.

Extremities/Musculoskeletal

If contractures develop, they may respond to bracing or other therapies.

Neurologic Exam

Spasticity, hypertonic reflexes, and up-going toes may be noted. Evaluate for increasing spasticity that may be causing discomfort and pain.

Testing

Sensory Testing

Initial and periodic evaluation of vision and hearing can help guide management. Specialists may need to be involved.

Laboratory Testing

Leukocyte lysosomal enzyme testing, tissue biopsy, or other molecular DNA analyses can sometimes help pinpoint a diagnosis. Consider testing as clinically indicated for hypothyroidism, diabetes, and abnormalities in growth hormone and sex hormones. In addition to guiding therapy, abnormal results may also help diagnose a specific leukodystrophy.

Imaging

Brain MRI is important for diagnosis. MRI spectroscopy may help delineate a specific white matter disease. Perform EEG if clinically indicated; seizures are present in about 50% of children with leukodystrophies. See MRI Images of Leukodystrophies (RadioGraphics).

Genetic Testing

Testing guided by a neurologist or geneticist can help diagnose some specific leukodystrophies. Testing might be considered if clinical findings are consistent with a newly described type.

Other Testing

Nerve conduction velocity testing and electromyography may help identify a specific leukodystrophy type.

Specialty Collaborations & Other Services

Pediatric Neurology (see NM providers [33])

Involve in the diagnosis and periodic assessments.

Pediatric Genetics (see NM providers [3])

Consider for specific genetic diagnosis.

Pediatric Ophthalmology (see NM providers [9])

Consider involving to diagnose certain forms of leukodystrophy.

Treatment & Management

Overview

The Portal's modules on Intellectual Disability and Seizures/Epilepsy can be helpful since these are often manifestations of many leukodystrophies. The Cerebral Palsy module is also relevant for spasticity management.

Treatments for several leukodystrophies are in clinical trials. Different approaches to treatment include adeno-associated virus-mediated CNS gene therapy, enzyme replacement therapy, bone marrow and umbilical cord blood transplantation, and bone marrow transplantation of genetically modified autologous hematopoietic stem cells. ([Rosenberg: 2016] Trials are in progress or planned for metachromatic leukodystrophy, adrenoleukodystorphy, and LINCL, but they are still in the early stages. Trials are listed at (Leukodystrophy (clinicaltrials.gov)).

Pearls & Alerts for Treatment & Management

Swallowing may become a problem

Swallowing difficulty may lead to long feeding times, weight loss, and aspiration pneumonias. If suspected, swallowing difficulty should be evaluated by periodic swallow studies. Treatment consists of alternative feeding approaches, such as a gastrostomy tube. Feeding Tubes and Gastrostomies provides further details.

How should common problems be managed differently in children with Leukodystrophies?

Growth or Weight Gain

Consider nutrition and/or GI involvement early. Screen for caloric insufficiency and/or feeding impairment/dysmotility.

Development (cognitive, Motor, Language, Social-Emotional)

Collaborate with teachers and school personnel to advocate for school services such as an IEP and 504 plan. Education & Schools provides ideas for facilitating this type of communication.

Systems

Development (general)

Often a plateau or regression in development is what leads to a brain MRI and a diagnosis of leukodystrophy. Monitor development closely and refer children early to Early Intervention programs, physical, occupational, and speech therapy, and special education as necessary.

Specialty Collaborations & Other Services

Developmental - Behavioral Pediatrics (see NM providers [5])

Refer for help monitoring developmental progress and academic achievement and suggesting or coordinating interventions when necessary.

Pediatric Neurology (see NM providers [33])

Consider referral for monitoring developmental progress.

Pediatric Physical Medicine & Rehabilitation (see NM providers [3])

Consider for help in managing impairments in walking and the activities of daily living.

Neurology

In addition to developmental delay or regression, neurological signs and symptoms of leukodystrophies may include spasticity and/or hypotonia. A neurologist or physiatrist, depending on local expertise, may monitor the neurological exam and intervene when necessary. See the Cerebral Palsy module for more information.

Seizures may be present in up to 50% of children with leukodystrophies. See the Seizures/Epilepsy, Treatment & Management for more information about management.

Specialty Collaborations & Other Services

Pediatric Neurology (see NM providers [33])

Depending on the frequency of seizures and the response to medications, consider consultative or co-management care. Neurologists can also monitor neurological changes and suggest or manage interventions.

CSHCN Clinics (see NM providers [0])

In some locales, children may be able to receive care from a specialty clinic.

Pediatric Physical Medicine & Rehabilitation (see NM providers [3])

Consider for help monitoring children periodically and treating spasticity and related conditions as clinically indicated.

Dental

Some issues that affect dental care are problems handling saliva, reflux, mouths that don't open well, and the need for sedation for cleaning and other procedures.

Specialty Collaborations & Other Services

Pediatric Dentistry (see NM providers [66])

Refer to monitor dental health and treat as necessary.

Issues Related to Leukodystrophies

Funding & Access to Care

Writing Letters of Medical Necessity

Ask the Specialist

One of my patients with some unknown kind of leukodystrophy based on MRI findings came to see me for a respiratory infection. Mom wanted to know what his prognosis is. The last time he saw genetics was about 3 years ago when they weren’t able to give the family much information. Are there advances since then that would make another visit worthwhile?

He should have genetic testing again. Over the past few years, many more specific leukodystrophies/genetic mutations causing leukodystrophies have been discovered. In addition, gene therapy is becoming available for some of these conditions. On average, a followup genetics evaluation should be performed about every 2 years. [Willemsen: 2016]

Are there treatments for leukodystrophies?

Gene therapy is slowly becoming possible for some children with leukodystrophies. For example, Lenti-D gene therapy may be able to replace allogeneic stem-cell transplantation in boys with cerebral adrenoleukodystrophy. Most of the gene therapies are still in clinical trials, but there is hope for more to come. [Eichler: 2017]

Are all changes in the white matter of the brain a leukodystrophy?

No, there are many mimics of leukodystrophies. For example, multiple sclerosis can look like a leukodystrophy (and vice versa). Also, certain things, such as post-traumatic or post-chemotherapy, can cause changes in the brain that look like a leukodystrophy.

Resources for Clinicians

On the Web

Leukodystrophies Overview (GeneReviews)
An expert-authored, peer-reviewed, current description that applies genetic testing to diagnosis and management information for the condition. Table 1 has links to diagnosis criteria for specific leukodystrophies; US National Library of Medicine.

MRI Images of Leukodystrophies (RadioGraphics)
Examples of MRIs of common leukodystrophies; Radiological Society of North America.

Leukodystrophies (OMIM)
Extensive review of literature, with emphasis on the gene-phenotype relationship; Online Mendelian Inheritance in Man site, hosted by Johns Hopkins University.

Helpful Articles

PubMed search for leukodystrophies in children, last 2 years.

Ferreira CR, Gahl WA.
Lysosomal storage diseases.
Transl Sci Rare Dis. 2017;2(1-2):1-71. PubMed abstract / Full Text

Helman G, Van Haren K, Bonkowsky JL, Bernard G, Pizzino A, Braverman N, Suhr D, Patterson MC, Ali Fatemi S, Leonard J, van der Knaap MS, Back SA, Damiani S, Goldman SA, Takanohashi A, Petryniak M, Rowitch D, Messing A, Wrabetz L, Schiffmann R, Eichler F, Escolar ML, Vanderver A.
Disease specific therapies in leukodystrophies and leukoencephalopathies.
Mol Genet Metab. 2015;114(4):527-536. PubMed abstract

Helman G, Van Haren K, Escolar ML, Vanderver A.
Emerging treatments for pediatric leukodystrophies.
Pediatr Clin North Am. 2015;62(3):649-66. PubMed abstract / Full Text

Yang E, Prabhu SP.
Imaging manifestations of the leukodystrophies, inherited disorders of white matter.
Radiol Clin North Am. 2014;52(2):279-319. PubMed abstract

van der Knaap MS, Bugiani M.
Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.
Acta Neuropathol. 2017;134(3):351-382. PubMed abstract / Full Text

Resources for Patients & Families

Information on the Web

United Leukodystrophy Foundation (ULF)
Non-profit organization that offers information, lists of resources, and notices of conferences and other events.

Leukodystrophies (MedlinePlus)
Offers a brief description of leukodystrophies and numerous links to general information about specific leukodystrophies; from the National Library of Medicine.

Known Leukodystrophies (ULF)
A listing of known leukodystrophies, many with links to additional information; United Leukodystrophy Foundation.

Leukodystrophies (Genetics Home Reference)
A list of leukodystrophies with links to a detailed review of the specific condition; sponsored by the U.S. National Library of Medicine.

Leukodystrophy (NORD)
Overview of information on leukodystrophy. If registered, you will have access to detailed reports (a limited number of reports are free to those who register); National Organization for Rare Disorders.

National & Local Support

United Leukodystrophy Foundation Support Community
An online support community providing opportunities to connect with other families of children with leukodystrophies; free sign-up required.

Metachromatic Leukodystrophy (MLD Foundation)
Provides information and support to families of children diagnosed with metachromatic leukodystrophy.

Services for Patients & Families in New Mexico (NM)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: September 2011; last update/revision: April 2019
Current Authors and Reviewers:
Author: Lynne M. Kerr, MD, PhD
Reviewer: Joshua Bonkowsky, MD, Ph.D.
Authoring history
2015: update: Joshua Bonkowsky, MD, Ph.D.A; Meghan Candee, MDR
2011: first version: Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Adang LA, Sherbini O, Ball L, Bloom M, Darbari A, Amartino H, DiVito D, Eichler F, Escolar M, Evans SH, Fatemi A, Fraser J, Hollowell L, Jaffe N, Joseph C, Karpinski M, Keller S, Maddock R, Mancilla E, McClary B, Mertz J, Morgart K, Langan T, Leventer R, Parikh S, Pizzino A, Prange E, Renaud DL, Rizzo W, Shapiro J, Suhr D, Suhr T, Tonduti D, Waggoner J, Waldman A, Wolf NI, Zerem A, Bonkowsky JL, Bernard G, van Haren K, Vanderver A.
Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.
Mol Genet Metab. 2017;122(1-2):18-32. PubMed abstract

Bonkowsky JL, Nelson C, Kingston JL, Filloux FM, Mundorff MB, Srivastava R.
The burden of inherited leukodystrophies in children.
Neurology. 2010;75(8):718-25. PubMed abstract / Full Text

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA.
Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy.
N Engl J Med. 2017;377(17):1630-1638. PubMed abstract / Full Text

Ferreira CR, Gahl WA.
Lysosomal storage diseases.
Transl Sci Rare Dis. 2017;2(1-2):1-71. PubMed abstract / Full Text

Helman G, Van Haren K, Bonkowsky JL, Bernard G, Pizzino A, Braverman N, Suhr D, Patterson MC, Ali Fatemi S, Leonard J, van der Knaap MS, Back SA, Damiani S, Goldman SA, Takanohashi A, Petryniak M, Rowitch D, Messing A, Wrabetz L, Schiffmann R, Eichler F, Escolar ML, Vanderver A.
Disease specific therapies in leukodystrophies and leukoencephalopathies.
Mol Genet Metab. 2015;114(4):527-536. PubMed abstract

Helman G, Van Haren K, Escolar ML, Vanderver A.
Emerging treatments for pediatric leukodystrophies.
Pediatr Clin North Am. 2015;62(3):649-66. PubMed abstract / Full Text

Pagon RA, Adam MP, Ardinger HH, et al.
Leukodystrophy Overview.
GeneReviews® ; (2014) http://www.ncbi.nlm.nih.gov/books/NBK184570/. Accessed on October 2015.

Parikh S, Bernard G, Leventer RJ, van der Knaap MS, van Hove J, Pizzino A, McNeill NH, Helman G, Simons C, Schmidt JL, Rizzo WB, Patterson MC, Taft RJ, Vanderver A.
A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies.
Mol Genet Metab. 2015;114(4):501-15. PubMed abstract / Full Text

Richards J, Korgenski EK, Taft RJ, Vanderver A, Bonkowsky JL.
Targeted leukodystrophy diagnosis based on charges and yields for testing.
Am J Med Genet A. 2015;167A(11):2541-3. PubMed abstract / Full Text

Rosenberg JB, Kaminsky SM, Aubourg P, Crystal RG, Sondhi D.
Gene therapy for metachromatic leukodystrophy.
J Neurosci Res. 2016;94(11):1169-79. PubMed abstract / Full Text

Vanderver A, Prust M, Tonduti D, Mochel F, Hussey HM, Helman G, Garbern J, Eichler F, Labauge P, Aubourg P, Rodriguez D, Patterson MC, Van Hove JL, Schmidt J, Wolf NI, Boespflug-Tanguy O, Schiffmann R, van der Knaap MS.
Case definition and classification of leukodystrophies and leukoencephalopathies.
Mol Genet Metab. 2015;114(4):494-500. PubMed abstract / Full Text

Willemsen MA, Harting I, Wevers RA.
Neurometabolic disorders: Five new things.
Neurol Clin Pract. 2016;6(4):348-357. PubMed abstract / Full Text

Yang E, Prabhu SP.
Imaging manifestations of the leukodystrophies, inherited disorders of white matter.
Radiol Clin North Am. 2014;52(2):279-319. PubMed abstract

van der Knaap MS, Bugiani M.
Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.
Acta Neuropathol. 2017;134(3):351-382. PubMed abstract / Full Text