Leukodystrophies

Description

Other Names

Known Leukodystrophies (ULF) lists 40 types.

Diagnosis Coding

ICD-10

E75.23, krabbe disease

E75.25, metachromatic leukodystrophy

E75.29, other sphingolipidoses

Search icd10data.com with the name of a specific leukodystrophy to find coding details.

Description

The leukodystrophies are a group of 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] Though bone marrow transplantation is being performed for a few of these conditions; current treatment for most leukodystrophies is supportive. A list of leukodystrophies can be found at Known Leukodystrophies (ULF).

Prevalence

Incidence of the leukodystrophies, which is likely an underestimate, is 1:7,663 live births. [Bonkowsky: 2010]

Genetics

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

Prognosis

Outcomes vary by condition, but, with some leukodystrophies, there is progressive deterioration in neurologic function. In general, leukodystrophies are severe diseases - only 51% of children in a large cohort walked, and only 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) early in the disease course. [Pagon: 2014]

Roles Of The Medical Home

For a child with leukodystrophy and his or her family, quality of life 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. Balancing the benefit of subspecialty help with the wishes of, and convenience for, the family is essential. Coordination of care among subspecialists, therapists, and school and community services will help in optimizing outcomes, minimizing duplication of services, and assuring that 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 gets the needed school services. A teacher coming to the home to work with the child may be helpful in some cases.

Practice Guidelines

There are no published practice guidelines. Consensus guidelines include:

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

Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC.
Consensus statement on preventive and symptomatic care of leukodystrophy patients.
Mol Genet Metab. 2015;114(4):516-526. PubMed abstract

Helpful Articles

PubMed search for leukodystrophies in children, last 2 years.

Costello DJ, Eichler AF, Eichler FS.
Leukodystrophies: classification, diagnosis, and treatment.
Neurologist. 2009;15(6):319-28. PubMed abstract

Lyon G, Fattal-Valevski A, Kolodny EH.
Leukodystrophies: clinical and genetic aspects.
Top Magn Reson Imaging. 2006;17(4):219-42. PubMed abstract

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

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

Clinical Assessment

Overview

Consider a leukodystrophy in any child who shows a global regression or stops meeting developmental milestones. The diagnosis of a leukodystrophy requires 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 should work with the family for help with finances and emotional functioning.

Screening

For The Condition

Routine developmental screening will identify most 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 for siblings.

For Complications

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

Presentations

Leukodystrophies may present in various ways, but the most common presentation is an infant or child who stops achieving milestones or who has a 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.

Pearls & Alerts

Regression in multiple abilities

The regression in children with leukodystrophy is not only in language and in interaction, as might be seen in a child with autism, but involves regression 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.

History & Examination

Family History

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

Pregnancy Or Perinatal History

Usually normal, or with mild, nonspecific problems.

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.

Developmental & Educational Progress

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

Social & Family Functioning

Identify family needs at diagnosis and periodically through the child's course. 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

Both weight and height growth may be impaired. Weight should be followed closely; increased calories or alternative feeding methods may be needed.

Extremities/Musculoskeletal

Contractures may develop over time and 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 in pinpointing 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. EEG should be performed if clinically indicated; seizures are present in about 50% of children with leukodystrophies. See MRI Images of Leukodystrophies (RadioGraphics).

Genetic Testing

Testing can be helpful in diagnosing some specific leukodystrophies; it should be guided by neurology or genetics specialists. 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.

Subspecialist Collaborations & Other Resources

Pediatric Neurology (see Services below for relevant providers)

Involve in the diagnosis and periodic assessments.

Pediatric Genetics (see Services below for relevant providers)

Consider for specific genetic diagnosis.

Pediatric Ophthalmology (see Services below for relevant providers)

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 with respect to spasticity management.

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)

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

Pearls & Alerts

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.

Systems

Development (general)

Often a plateau, or regression in development, is what leads to a brain MRI and a diagnosis of leukodystrophy. Development should be closely monitored, and children should be referred to early intervention programs, physical, occupational, and speech therapy, and special education as necessary.

Subspecialist Collaborations & Other Resources

Developmental Pediatrics (see Services below for relevant providers)

Can help monitor developmental progress and academic achievement, and suggest or coordinate interventions when necessary

Pediatric Neurology (see Services below for relevant providers)

May be helpful in monitoring developmental progress

Pediatric Physical Medicine & Rehab (see Services below for relevant providers)

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

Neurology

Neurological signs and symptoms of leukodystrophies may include spasticity and/or hypotonia, in addition to developmental delay or regression. 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.

Subspecialist Collaborations & Other Resources

Pediatric Neurology (see Services below for relevant providers)

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 Services below for relevant providers)

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

Pediatric Physical Medicine & Rehab (see Services below for relevant providers)

May monitor children periodically and treat spasticity and related conditions as clinically indicated.

Dental

Children may have several problems that affect dental care, including problems handling saliva, reflux, mouths that don't open well, and the need for sedation for dental procedures, such as cleaning.

Subspecialist Collaborations & Other Resources

Pediatric Dentistry (see Services below for relevant providers)

Refer to monitor dental health and treat as necessary.

Frequently Asked Questions

Do all leukodystrophies cause death?

No, different leukodystrophies have different courses- some are static or unchanging; some worsen very slowly with time; and others have a rapid worsening.

Are there any treatments for leukodystrophies?

For a few leukodystrophies there are treatments, and that is why it is very important to make a timely diagnosis and referral.

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.

Issues Related to Leukodystrophies

Funding & Access to Care

Writing Letters of Medical Necessity

Resources

Information for Clinicians

Leukodystrophies (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.

Metachromatic Leukodystrophy (GeneReviews)
An expert-authored, peer-reviewed, current description that applies genetic testing to diagnosis and management information for this common leukodystrophy; sponsored by the US National Library of Medicine.

Helpful Articles

PubMed search for leukodystrophies in children, last 2 years.

Costello DJ, Eichler AF, Eichler FS.
Leukodystrophies: classification, diagnosis, and treatment.
Neurologist. 2009;15(6):319-28. PubMed abstract

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

Lyon G, Fattal-Valevski A, Kolodny EH.
Leukodystrophies: clinical and genetic aspects.
Top Magn Reson Imaging. 2006;17(4):219-42. PubMed abstract

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

Information & Support for Families

Family Diagnosis Page

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)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

Leukodystrophy Information Page (NINDS)
Contains a brief overview and links to clinical trials and other organizations; National Institute of Neurological Disorders and Stroke.

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.

Support National & Local

United Leukodystrophy Foundation Support Community (inspire.com)
An online support community providing opportunities to connect and communicate 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

Adaptive Recreation

See all Adaptive Recreation services providers (64) in our database.

Assistive Technology

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CHIP, State Children's Health Insur Prog

See all CHIP, State Children's Health Insur Prog services providers (44) in our database.

CSHCN Clinics

See all CSHCN Clinics services providers (15) in our database.

Child Care, Special Needs

See all Child Care, Special Needs services providers (10) in our database.

Developmental Pediatrics

See all Developmental Pediatrics services providers (5) in our database.

Early Intervention Programs

See all Early Intervention Programs services providers (52) in our database.

Health Insurance/Funding, Transition

See all Health Insurance/Funding, Transition services providers (42) in our database.

Pediatric Dentistry

See all Pediatric Dentistry services providers (57) in our database.

Pediatric Genetics

See all Pediatric Genetics services providers (5) in our database.

Pediatric Neurology

See all Pediatric Neurology services providers (10) in our database.

Pediatric Ophthalmology

See all Pediatric Ophthalmology services providers (8) in our database.

Pediatric Physical Medicine & Rehab

See all Pediatric Physical Medicine & Rehab services providers (8) in our database.

Prescription Funding

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Schools for the Deaf & Blind

See all Schools for the Deaf & Blind services providers (12) in our database.

State Disability Agencies

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Wish Foundations

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For other services related to this condition, browse our Services categories or search our database.

Authors

Reviewing Author: Meghan Candee, MD - 11/2015
Content Last Updated: 11/2015

Bibliography

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

Costello DJ, Eichler AF, Eichler FS.
Leukodystrophies: classification, diagnosis, and treatment.
Neurologist. 2009;15(6):319-28. PubMed abstract

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

Lyon G, Fattal-Valevski A, Kolodny EH.
Leukodystrophies: clinical and genetic aspects.
Top Magn Reson Imaging. 2006;17(4):219-42. 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

Van Haren K, Bonkowsky JL, Bernard G, Murphy JL, Pizzino A, Helman G, Suhr D, Waggoner J, Hobson D, Vanderver A, Patterson MC.
Consensus statement on preventive and symptomatic care of leukodystrophy patients.
Mol Genet Metab. 2015;114(4):516-526. PubMed abstract

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