Leukodystrophies

Guidance for primary care clinicians diagnosing and managing children with leukodystrophies

The leukodystrophies are a group of more than 400 genetic conditions in which the brain's white matter is abnormal due to altered development, decreased amount, or degeneration of the lipid insulation covering neuronal processes in the brain.

Consider a leukodystrophy in any child with 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. Diagnosis is important and potentially urgent because effective treatments are available within a time-sensitive window.

Other Names

Key Points

Delay or regression in multiple abilities
Children with leukodystrophy may have delays in their development or may regress in some combination of language, interaction, 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.

Swallowing issues 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. See Feeding Tubes & Gastrostomies in Children.

Poor weight gain
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. See Boosting Calories for Babies, Toddlers, and Older Children.

Development (Cognitive, Motor, Language, Social-Emotional)
Collaborate with teachers and school personnel to advocate for services such as an IEP and 504 Plan. School Accommodations: IEPs & 504s provides ideas for facilitating this type of communication.

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

Bonkowsky JL, Keller S.
Leukodystrophies in Children: Diagnosis, Care, and Treatment.
Pediatrics. 2021. PubMed abstract

Diagnosis

The leukodystrophies are a group of more than 400 genetic 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, many 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 some of these children. [Bonkowsky: 2010] Suggested diagnostic algorithms are available at [Richards: 2015], and consultation with a specialist is suggested. Timely diagnosis is critical because curative treatments for some conditions are available and may only be effective within a narrow timeframe (see [Rosenberg: 2016]). However, treatment for most leukodystrophies is supportive.

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. Common findings include hypotonia progressing to spasticity, visual and/or hearing problems, and irritability. Manifestations may progress more slowly in individuals who present as adolescents or adults.

Diagnostic Criteria and Classifications

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

Diagnostic Testing & Screening

Laboratory Testing

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

Once abnormalities consistent with a leukodystrophy are identified on brain MRI, leukocyte lysosomal enzyme testing, tissue biopsy, genetic testing or other molecular DNA analyses can sometimes help pinpoint diagnose a specific leukodystrophy. This information may be important in guiding therapy,

Imaging

Brain MRI is important for diagnosis; MRI spectroscopy can be useful in some instances to provide further diagnostic understanding. Perform EEG if clinically indicated; seizures occur in about 50% of children with leukodystrophies. See MRI Images of Leukodystrophies (RadioGraphics). Not all white matter changes on MRI represent leukodystrophies; some examples are those seen in CNS immune disorders such as multiple sclerosis or following trauma or chemotherapy.

Other

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

Nerve conduction velocity testing and electromyography may be useful in the evaluation of certain leukodystrophies.

Testing for 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.

Genetics

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

Incidence & Prevalence

The incidence of leukodystrophies, which is likely an underestimate, is 1:4,500 live births [Soderholm: 2020]. Also, minority patients tend to be underdiagnosed. [Bonkowsky: 2018] It should be noted that there are several different terminologies and definitions for leukodystrophies. [Soderholm: 2020] [Urbik: 2020] The Diagnosis Prevalence List can give clinicians an idea of prevalence by clinical practice size.

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. For example, the CP Spectrum Disorders Panel (Invitae Labs) analyzes a broad panel of genes to identify a possible genetic origin for cerebral palsy. Cerebral Palsy has further details.
Demyelinating diseases
Consider demyelinating diseases (primarily multiple sclerosis and neuromyelitis optica) as differential diagnoses.

Comorbid Conditions

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

Prognosis

Some leukodystrophies present with impairment from birth and do not progress, while 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, hematopoietic stem cell transplantation (bone marrow transplantation) can prevent primary disease manifestations if performed early in the disease course. [Pagon: 2014]

Treatment & Management

When a leukodystrophy is identified, the possibility of an existing treatment should be considered with the child’s geneticist/neurologist. There are multiple existing treatments, and more are expected in the near future. Some treatments only work in pre-symptomatic or early symptomatic stages, so rapid diagnosis is important.

Next, existing abilities should be evaluated, and rehabilitation should be provided to help regain function or to prevent further deterioration as much as possible. Psychiatric symptoms may be the first to present in older children, adolescents, and adults. Seizures may occur as presenting or early symptoms. Endocrine abnormalities (hypothyroidism, diabetes, and others) are also observed and should be looked for on diagnosis. Spasticity may limit movement and cause pain in some children and should be monitored for over time.

Neurology

The Intellectual Disability & Global Developmental Delay and Seizures/Epilepsy can be helpful since these are often manifestations of many leukodystrophies. The Cerebral Palsy is also relevant for spasticity management.
There are clinical treatments that are standard of care as well as FDA approved for several leukodystrophies. In addition, there are multiple treatments for leukodystrophies in clinical trials. Different treatment approaches include medicines, 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] Clinical trials are listed at Leukodystrophy (clinicaltrials.gov).
In addition to developmental delay or regression, neurological signs and symptoms of leukodystrophies may include spasticity and/or hypotonia. Depending on local expertise, a neurologist or physiatrist may monitor the neurological exam and intervene when necessary. See the Cerebral Palsy for more information.
Seizures may be present in up to 50% of children with leukodystrophies. See the Seizures/Epilepsy for management information.

Dental

Optimal dental care is important for individuals with leukodystrophy, especially because reflux, swallowing problems, and contractures of the jaw may affect tooth brushing/flossing. Most individuals will require sedation for cleaning and other procedures. See Dental and Oral Health Screening and Dental and Oral Health Screening.

Referrals & Services

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.

Pediatric Neurology (see NV providers [5])
Involve in the diagnosis and periodic assessments. Consider referral for monitoring developmental progress. 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.

Medical Genetics (see NV providers [5])
Consider for specific genetic diagnosis.

Pediatric Ophthalmology (see NV providers [6])
Consider involving to diagnose certain forms of leukodystrophy.

Developmental - Behavioral Pediatrics (see NV providers [3])
Refer for help monitoring developmental progress and academic achievement and suggesting or coordinating interventions when necessary.

Pediatric Ophthalmology (see NV providers [6])
Consider involving to diagnose certain forms of leukodystrophy.

Pediatric Physical Medicine & Rehabilitation (see NV providers [3])
Consider for help in managing spasticity, impairments in walking, and the activities of daily living.

Pediatric Dentistry (see NV providers [25])
Refer to monitor dental health and treat as necessary. Some issues that affect dental care are problems handling saliva, reflux, mouths that do not open well, and the need for sedation for cleaning and other procedures.

CSHCN Clinics (see NV providers [5])
In some locales, children may be able to receive care from a specialty clinic.

ICD-10 Coding

E75.29, Other sphingolipidoses

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

Resources

Information & Support

Related Portal Content

For Professionals

Leukodystrophies (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

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

For Parents and Patients

United Leukodystrophy Foundation (ULF)
A non-profit organization dedicated to funding cutting-edge research and providing patients and their families with disease information and medical referrals.

Leukodystrophies (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Leukodystrophy (NORD)
Information for families that includes synonyms, signs & symptoms, causes, affected populations, related disorders, diagnosis, therapies (both standard and investigational), and support organizations; National Organization of Rare Disorders.

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

Services for Patients & Families in Nevada (NV)

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.

Studies

Leukodystrophy (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Helpful Articles

Adang L.
Leukodystrophies.
Continuum (Minneap Minn). 2022;28(4):1194-1216. PubMed abstract

Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR.
An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.
Expert Rev Neurother. 2020;20(1):65-84. PubMed abstract

Keller SR, Mallack EJ, Rubin JP, Accardo JA, Brault JA, Corre CS, Elizondo C, Garafola J, Jackson-Garcia AC, Rhee J, Seeger E, Shullanberger KC, Tourjee A, Trovato MK, Waldman AT, Wallace JL, Wallace MR, Werner K, White A, Ess KC, Becker C, Eichler FS.
Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies.
J Child Neurol. 2021;36(1):65-78. PubMed abstract / Full Text

Page KM, Stenger EO, Connelly JA, Shyr D, West T, Wood S, Case L, Kester M, Shim S, Hammond L, Hammond M, Webb C, Biffi A, Bambach B, Fatemi A, Kurtzberg J.
Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network.
Biol Blood Marrow Transplant. 2019;25(12):e363-e374. PubMed abstract

Authors & Reviewers

Initial publication: May 2011; last update/revision: August 2023
Current Authors and Reviewers:
Author: Lynne M. Kerr, MD, PhD
Reviewer: Joshua L Bonkowsky, MD, PhD
Authoring history
2019: update: Lynne M. Kerr, MD, PhDA; Joshua L Bonkowsky, MD, PhDR
2015: update: Joshua L Bonkowsky, MD, PhDA; Meghan S Candee, MD, MScR
2011: first version: Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Adang L.
Leukodystrophies.
Continuum (Minneap Minn). 2022;28(4):1194-1216. PubMed abstract

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

Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR.
An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.
Expert Rev Neurother. 2020;20(1):65-84. PubMed abstract

Bonkowsky JL, Keller S.
Leukodystrophies in Children: Diagnosis, Care, and Treatment.
Pediatrics. 2021. 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

Bonkowsky JL, Wilkes J, Bardsley T, Urbik VM, Stoddard G.
Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients.
JAMA Netw Open. 2018;1(7):e185031. PubMed abstract / Full Text

Keller SR, Mallack EJ, Rubin JP, Accardo JA, Brault JA, Corre CS, Elizondo C, Garafola J, Jackson-Garcia AC, Rhee J, Seeger E, Shullanberger KC, Tourjee A, Trovato MK, Waldman AT, Wallace JL, Wallace MR, Werner K, White A, Ess KC, Becker C, Eichler FS.
Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies.
J Child Neurol. 2021;36(1):65-78. PubMed abstract / Full Text

Page KM, Stenger EO, Connelly JA, Shyr D, West T, Wood S, Case L, Kester M, Shim S, Hammond L, Hammond M, Webb C, Biffi A, Bambach B, Fatemi A, Kurtzberg J.
Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network.
Biol Blood Marrow Transplant. 2019;25(12):e363-e374. PubMed abstract

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

Soderholm HE, Chapin AB, Bayrak-Toydemir P, Bonkowsky JL.
Elevated Leukodystrophy Incidence Predicted From Genomics Databases.
Pediatr Neurol. 2020;111:66-69. PubMed abstract / Full Text

Soderholm HE, Chapin AB, Bayrak-Toydemir P, Bonkowsky JL.
Elevated Leukodystrophy Incidence Predicted From Genomics Databases.
Pediatr Neurol. 2020;111:66-69. PubMed abstract / Full Text

Urbik VM, Schmiedel M, Soderholm H, Bonkowsky JL.
Expanded Phenotypic Definition Identifies Hundreds of Potential Causative Genes for Leukodystrophies and Leukoencephalopathies.
Child Neurol Open. 2020;7:2329048X20939003. PubMed abstract / Full Text