Revised Consensus Statement on the Preventive and

Symptomatic Care of Patients with Leukodystrophies

Laura A. Adang, MD, PhD1, Omar Sherbini, MPH1, Laura Ball, PhD2, Miriam Bloom, MD3, Anil Darbari,
MD, MBA4, Hernan Amartino, MD5, Donna DiVito, RD1, Florian Eichler, MD6, Maria Escolar, MD7,
Sarah Evans, MD8, Ali Fatemi, MD, MBA9, Jamie Fraser, MD, PhD10, Leslie Hollowell, MSN11, Nicole
Jaffe, MD12, Christopher Joseph, MSPT9, Mary Karpinski, MSW13, Stephanie Keller, MD14, Ryan
Maddock, MSW3, Edna Mancilla, MD15, Bruce McClary, MSW9,Jana Mertz, MBA16, Kiley Morgart,
MSW17, Thomas Langan, MD18, Richard Leventer, MD19, Sumit Parikh, MD20, Amy Pizzino, MS, CGC3,
Erin Prange, MSN, CRNP1, Deborah L. Renaud, MD21, William Rizzo, MD22, Jay Shapiro, MD9, Dean
Suhr23, Teryn Suhr23, Davide Tonduti, MD, PhD24, Jacque Waggoner25, Amy Waldman, MD, MSCE1,
Nicole I. Wolf, MD, PhD26, Ayelet Zerem, MD27, Joshua L. Bonkowsky, MD, PhD28, Genevieve Bernard,
MD, MSc29, Keith van Haren, MD30, Adeline Vanderver, MD1 on behalf of the Global Leukodystrophy
Initiative (GLIA)

1. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA

2. Department of Physical Medicine and Rehabilitation and Center for Translational Science, Children’s National Medical
Center, Washington, DC, USA
3. Department of Pediatrics, Children's National Medical Center, Washington, DC, USA
4. Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's National Medical Center, Washington,
DC, USA
5. Servicio de Neurología Infantil, Hospital Universitario Austral, Buenos Aires, Argentina
6. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
7. Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA,
USA
8. Department of Physical Medicine and Rehabilitation, Children's National Medical Center, Washington, DC, USA
9. The Hugo W. Moser Research Institute, The Kennedy Krieger Institute, Baltimore, MD, USA
10. Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA
11. Complex Care Program, Children's National Medical Center, Washington, DC, USA
12. Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
13. Pediatric Multiple Sclerosis Center, Women and Children’s Hospital, Buffalo, NY, USA
14. Division of Pediatric Neurology, Emory University, Atlanta, GA, USA
15. Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
16. Autism Spectrum Disorders Center, Women and Children’s Hospital, Buffalo, NY, USA
17. Psychiatric Social Work Program, The Kennedy Krieger Institute, Baltimore, MD, USA
18. Hunter James Kelly Research Institute, Buffalo, NY, USA
19. Department of Paediatrics, Murdoch Children's Research Institute, University of Melbourne. Melbourne, Australia
20. Neurogenetics, Neurologic Institute, Cleveland Clinic, Cleveland, OH, USA
21. Division of Child and Adolescent Neurology, Departments of Neurology and Pediatrics, Mayo Clinic, Rochester, MN,
USA
22. Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA.
23. MLD Foundation, West Linn, OR, USA
24. Department of Child Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
25. Hunter’s Hope Foundation, Orchard Park, NY, USA
26. Department of Child Neurology, VU University Medical Centre and Amsterdam Neuroscience, Amsterdam, The
Netherlands
27. E. Wolfson Medical Center, Tel Aviv, Israel
28. Department of Pediatrics, Division of Pediatric Neurology, University of Utah School of Medicine, Salt Lake City, UT,
USA
29. Departments of Neurology and Neurosurgery, and Pediatrics McGill University, Montreal, Canada; Department of Medical
Genetics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Canada; Child Health and Human
Development Program, Research Institute of the McGill University Health Center, Montreal, Canada
30. Department of Neurology, Lucile Packard Children's Hospital and Stanford University School of Medicine, Stanford, CA,
USA
Corresponding Author:
Name: Laura Adang, MD, PhD
Email: adangl@email.chop.edu
Address: Children’s Hospital of Philadelphia
Colket Translational Research Building, 10th Floor
3501 Civic Center Blvd.
Philadelphia, PA 19104

Abbreviations
4H, hypomyelination, hypogonadotropic hypogonadism and hypodontia syndrome
ACC, augmentative and alternative communication
ACTH, adrenocorticotropic hormone
ADLD, adult onset autosomal dominant leukodystrophy
AGS, Aicardi–Goutières syndrome
AxD, Alexander disease
BiPAP, bilevel positive airway pressure
CPAP, continuous positive airway pressure
CRIES, Cry, Requires O2, Increased Vital Signs, Expression, Sleeplessness scale
CT, computed tomography
CTX, cerebrotendinous xanthomatosis
DBS, deep brain stimulation
DEXA or DXA, dual-energy X-ray absorptiometry
EEG, electroencephalogram
FEES, fiberoptic endoscopic study
FLACC, Face, Legs, Activity, Cry, Consolability scale
FSH, follicular stimulating hormone
G-tube, gastrostomy tube
GER, gastroesophageal reflux
GJ-tube, gastrojejunostomy tube
GLIA, Global Leukodystrophy Initiative
GMFCS, Gross Motor Functional Classification System
LH, luteinizing hormone
MBS, modified barium swallow
MLC, megalencephalic leukoencephalopathy
MLD, metachromatic leukodystrophy
MRI, magnetic resonance imaging
ODDD, oculodentodigital dysplasia
OSA, obstructive sleep apnea
PedsQL, Pediatric Quality of Life Inventory
PTH, parathyroid hormone
QoL, quality of life
SLE, systemic lupus erythematosus
SLP, speech-language pathology
UTI, urinary tract infections
VWM, vanishing white matter disease
X-ALD, X-linked adrenoleukodystrophy

Keywords: Leukodystrophy; Consensus; Therapy; Care; Outcomes; Prevention

Abstract
Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of

central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are

many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality

of life of these children is a primary goal that can complement efforts directed at curative therapies.

Contained within this report is a systems-based approach to management of complications that result from

leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and

management options to establish a comprehensive, standardized care approach. We will also address

clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency.

The recommendations within this review rely on existing studies and consensus opinions and underscore

the need for future research on evidence-based outcomes to better treat the manifestations of this unique set

of genetic disorders.
1. Introduction
Leukodystrophies are a heterogeneous collection of genetic disorders that, while individually rare,

collectively affect as many as 1 in 7500 individuals (1). Patients with leukodystrophies, and their families,

encounter a wide range of health problems and unique challenges to their care. These patients have a wide

variety of issues, ranging from behavioral and sleeping difficulties, to requirements for assisted ventilation,

to potential surgical interventions (2, 3). Hospitalizations and related health-care needs account for more

than $59 million of health care costs each year in total (4). For a minority of leukodystrophies, there are

curative options, such as hematopoietic stem cell transplantation (5). However, even in the absence of

curative treatment, evidence supports a comprehensive treatment and care plan for all patients with

leukodystrophies (6-8). In addition to significant morbidity, one third of children with a leukodystrophy

will succumb to the underlining disease and its complications by the age of 8 years (9).

The general tenets of our approach to the care of children with leukodystrophies are that there are

common core symptoms shared among these disorders, that it is important to have a comprehensive

approach that encompasses all relevant organ systems and includes the health of the care providers, and,

importantly, that all leukodystrophies are treatable.

In this review, we will discuss specific management options for each affected system. We will also

address disease-specific concerns, for example the adrenal insufficiency associated with

adrenoleukodystrophy and the need for intracranial arteriopathy screening in a subset of patients with

Aicardi-Goutières Syndrome. As leukodystrophy-related clinical studies are an area of active need, these

recommendations rely primarily on clinical consensus and extrapolated data regarding the management

described for other neurologic disorders.

2. Musculoskeletal and Skin issues

Dysfunction of the musculoskeletal system is one of the most universal concerns among patients

with leukodystrophies. Abnormalities in muscle tone such as spasticity and dystonia can result in secondary

medical complications and negatively impact respiratory status, mobility, hygiene, self-care, sleeping

patterns, and sexual function. Furthermore, the importance of ambulation for independence, bone and joint

health, and emotional well-being cannot be overstated.

2.1. Spasticity

Spasticity is defined as velocity-dependent hypertonia with hyperreflexia that is typically

accompanied by weakness (10). It occurs as the result of injury to the myelin and/or axons of the primary

motor pathways (i.e. corticospinal tracts) of the central nervous system and is, anecdotally, one of the most

common symptoms reported in patients with leukodystrophies. Patients often have a combination of tone

abnormalities, including truncal hypotonia mixed with appendicular hypertonia, dystonia, and other

movement disorders, which may change over time (11). Of importance, a sudden and persistent change in

tone should prompt an in-depth assessment to determine the etiology. An acute increase in tone is

commonly the result of an intercurrent illness or pain, although it may also be due to new central nervous

system pathology.

Clinical assessment of spasticity should include an evaluation by a physical therapist, ideally

employing standardized scoring systems to produce quantifiable metrics that can be tracked longitudinally

(Table 1). Although these particular scoring systems have not been validated in children with

leukodystrophies, they can be applied with caution in this population. In addition to specific scales to

measure the severity of the motor dysfunction, the impact of altered tone on quality of life (QoL) can be

assessed using standardized scales such as the Pediatric Quality of Life Inventory (PedsQL) (12). The

PedsQL is a self-reported assessment of health-related QoL. The Vineland Scales of Adaptive Behavior

Screener can be useful for children that are young or with relatively low functional levels (13). An

important area of future research should be the validation of these scales within the leukodystrophy
population, as these unique disorders are typically progressive (unlike cerebral palsy) and may affect a

younger population than was used to design the currently available assessment tools.

Abnormal tone can have significant medical complications and often patients necessitate medical

intervention (Table 2). In milder cases of spasticity without significant axial hypotonia, oral medications

such as baclofen or diazepam in combination with physical therapy and daily stretching routines are usually

sufficient (14-17). Chemodenervation with botulinum toxin or intramuscular neural lysis with phenol can

be useful to target focal areas of spasticity that impede functional tasks (e.g. adductor muscles to facilitate

hygiene, gastrocnemius muscles to improve ambulation) (14-18). The assessment and administration of

chemodenervation can be performed by a variety of specialists, but requires an experienced medical

provider with specialized training in this technique. Further guidance, as needed, can be provided by

physiatry or orthopedics.

If these initial medical interventions are not effective, or if oral medications are not suitable or tolerated,
consideration can be given to more invasive approaches. Intrathecal baclofen enables the use of higher
doses of medication with fewer systemic side effects as compared to oral baclofen, but requires an
implanted medical device that poses the added risk of infection or a mechanical failure that can lead to
drug withdrawal (14, 15, 19-21). Selective dorsal rhizotomy is a potentially effective treatment for
severe lower extremity spasticity, although it has not been studied for safety or efficacy in this patient
population in which tone abnormalities are complex (14, 22-24). However, as this surgical intervention
is permanent, particular care should be taken in patient selection. Weakness and underlying dystonia
can become more apparent after selective dorsal rhizotomy (23). In select cases, surgical interventions
to lengthen or sever tendons or nerve pathways can facilitate mobility, prevent joint deformity,
contractures, and fractures (14, 22, 24, 25). Consideration should be taken to the underlying risk of the
procedure and for the use of anesthesia in this fragile population. Perioperative complications in a study
of children with cerebral palsy undergoing scoliosis repair for example correlated with the number of
pre-operative medical issues (26).Table 1: Assessment tools for tone abnormalities and movement
disorders
 Differentiates between dystonia, spasticity, and
Hypertonia Assessment Tool (HAT) (27)
rigidity
 Measures passive resistance in the joint as
Modified Ashworth Scale (MAS) (14) perceived by the examiner
 Grades muscle resistance on a 6-point scale
Modified Tardieu Scale (MTS) (15, 28)  Accounts for velocity
Global Dystonia Rating Scale (GDS)  Rates dystonia in 14 body regions by 10-point
(27) scale
 Measures the impact of a movement disorder on
Movement Disorder Childhood Rating activities of daily living, overall motor function,
Scale (MD-CRS) (29) and attention/alertness level
 Able to detect small changes over time

Table 2: Complications of abnormal tone

  Discomfort or pain
 Interference with key functional activities
o e.g. ambulation, communication, and self-care
 Joint dislocation
 Pressure sores
 Contractures

2.2. Dystonia

Dystonias are hyperkinetic movement disorders characterized by generalized or focal involuntary

muscle contractions, frequently resulting in twisting and repetitive movements or abnormal postures (10).

Despite their prevalence in leukodystrophies, dystonias are often under-diagnosed and can worsen with

physical discomfort or voluntary movement.

One of the most efficient treatments for generalized dystonia is the anticholinergic medication

trihexyphenidyl (Artane), which is typically well tolerated in this patient population (3, 17-22). As

trihexyphenidyl can result in constipation, it is important to manage this side effect as clinically indicated.

Other options are dopaminergic drugs, such as L-dopa, and the dopamine-depleting drug tetrabenazine (14,

30-32). Oral baclofen and benzodiazepines can also be also effective, but require higher doses than are

typically used in the management of spasticity (14, 30). In patients with leukodystrophies, D2 receptors

blockers should be avoided because of the risk for tardive movement disorders (33). Although rarely

observed in this population, focal dystonias can be treated with botulinum toxin injection, which is

typically preferable to oral medications (14, 30, 31, 34). More invasive treatments include intrathecal

baclofen and, in rare cases, deep brain stimulation (DBS) (14, 30, 31, 34, 35).

2.3. Low Bone Mass/Density and Fractures

Patients with neurologic disorders are at high risk for low bone mass and fractures due to lack of

mobility, decreased sun exposure, and nutritional deficiencies (36). Additionally, some leukodystrophies

carry inherently higher risk for bony complications: vanishing white matter disease (VWM), AARS2-

related disorder, and POLR3-related leukodystrophy are associated with endocrine dysfunction and

secondary osteoporosis, and patients with cerebrotendinous xanthomatosis are at increased risk for
granulomatous lesions of the bones and fractures (2, 37, 38). Bone health should be actively monitored in

most patients with leukodystrophies, with particular attention paid to patients with steroid exposure,

epilepsy, a history of prior fractures, nutritional deficiencies, and those who are non-ambulatory (39-41).

Some anticonvulsants, including phenobarbital, phenytoin, carbamazepine, and valproic acid all have been

reported to have detrimental effects on bone mineralization (41). Long-term use of proton pump inhibitors

for reflux can also result in increased bone fractures, possibly through decreased calcium absorption (42).

In general, increased PTH levels can be interpreted as an initial marker of poor calcium intake or

absorption. Calcium level alone is not a sufficiently sensitive marker of low calcium reserves. Patients

should also have at least yearly monitoring of vitamin D levels (25-OH-D), as poor nutrition and limited

sun exposure can contribute to the risk of low bone density for age (Table 3 and 4).

Table 3: Vitamin D status definitions as per the Endocrine Society (43)

Deficiency 25(OH)D below 20 ng/mL (50 nmol/liter)

Insufficiency 21-29 ng/mL (52.5-72.5 nmol/liter)
Sufficiency 30-100 ng/mL

Table 4: Guidelines for the treatment of Vitamin D deficiency from the Endocrine Society (43):

 2,000 IU/day (vitamin D2 or D3) for 6 weeks

 Maintenance therapy of 400-1,000 IU/day after the serum
Infants and Toddlers 0-1 Year
25(OH)D level is above 30 ng/mL
 Follow levels in 4 weeks

 2,000 IU/day (vitamin D2 or D3) for 6 weeks or 50,000 IU

once weekly (vitamin D2) for at least 6 weeks
Children 1-18 Years
 Maintenance therapy of 600-1,000 IU/d after the serum
25(OH)D level is above 30 ng/mL

 50,000 IU once weekly (vitamin D2 or D3) for 8 weeks or

6,000 IU/day (vitamin D2 or D3)
Adults
 Maintenance therapy of 1,500-2,000 IU/d after the serum
25(OH)D level is above 30 ng/mL

Unique dosing needs for obesity,  Minimum initial treatment with 6,000-10,000 IU/day of
malabsorption, abnormal vitamin D vitamin D
metabolism (e.g. secondary to  Maintenance therapy of 3,000-6,000 IU/d after the serum
medications) 25(OH)D level is above 30 ng/mL
 As a complement to laboratory testing, imaging studies can useful in the diagnosis of bony

disease. Basal bone density scans, typically dual-energy X-ray absorptiometry (DEXA or DXA, L–spine

and Whole Body Less Head) scans are useful screening tools for demineralization in patients who are at

risk for fractures (39, 40, 44). After the initial study, DEXA scans should be repeated at a frequency

concordant with the initial results and evolving risk factors. Standard X-rays are not recommended as a

screening tool for bone demineralization, although for patients who are immobilized or have a history of

fracture, lateral spine X-rays can be used to screen for vertebral fractures.

If contractures or scoliosis prohibit standard bone imaging, a forearm or distal lateral femur scan

can be obtained (44). As with other complex areas of care, a consultation with a bone specialist or

endocrinologist is recommended at an early stage of the clinical course.

2.4. Scoliosis and Hip Dislocation

Although the true prevalence of scoliosis and hip dislocation in this unique patient population is

unknown, clinical experience suggests that it is common, particularly in advanced stages of disease (2)

(Figure 1). One epidemiological study on orthopedic and neurologic manifestations in the leukodystrophy

population found that scoliosis occurs in 70% and hip dysplasia in 89% of patients (45). Some individuals

may develop a progressive “windswept” appearance as a result of unequal tone in the lower extremities

causing asymmetric hip dislocation. Unfortunately, no natural history studies of the leukodystrophy

population have been performed to characterize relationship between scoliosis and hip dislocation. Studies

in neuromuscular diseases suggest that the scoliosis may accompany or precede pelvic obliquity, although

spinal deformity can also be a compensation for pelvic malalignment (46).

Figure 1: Examples of orthopedic disorders in children with leukodystrophies. Pelvic tilt in a patient
with Krabbe disease is shown by hip radiograph (a). Bilateral coxa valga with bilateral dislocated
femoral heads is demonstrated in a patient with Pelizaeus-Merzbacher (b). Severe thoracolumbar
scoliosis and pelvic tilt is shown in a patient with X-linked Adrenoleukodystrophy (c).

2.4.1. Hip Dislocation

Hip issues are common in the leukodystrophy population as a consequence of spasticity, dystonia,

and decreased mobility. Dislocation at the hip joints may impair mobility and bone mass. In patients with

cerebral palsy, regular hip surveillance programs have been effective in improving long term outcomes and

reducing rates of hip dislocation (47) and scoliosis (48). These programs include physical examinations

every six months and regular X-rays starting at 2 years of age and recurring annually until skeletal maturity

(73). With any clinical concerns, patients should have further imaging studies of the hips and/or spine and

be referred to specialists in orthopedics, physiatry, and physical therapy. Physiatry and orthopedics can help

to guide discussions about appropriate management options, which should take into consideration the

overall health of the patient and the family’s goals of care. Not all hip dislocations require surgical

intervention. Surgery should be considered if the dislocation is painful, impairs mobility, or poses other

risks to the patient’s well-being. Conservative approaches, including adductor releases and tone

management, are preferable in patients under five years of age. After six years of age, reconstructive

surgery may be considered.

2.4.2. Scoliosis

Scoliosis in patients with leukodystrophies may be progressive and can seriously impact health

and quality of life, posing particular risks to respiratory and cardiac function. Progressive scoliosis may

diminish lung function, a relationship referred to as “thoracic insufficiency syndrome” (49). Scoliosis

management guidelines for other neurodegenerative disorders recommend a brief spinal exam by clinical

observation at each clinic visit (76-78). If scoliosis is suspected, anterior-posterior and lateral spine X-rays

can be obtained, with referral to an orthopedic surgeon as clinically indicated. Based on general

recommendations, braces and external frames may be appropriate in milder cases. Garches braces can

maximize chest expansion capacity by optimizing seating position, though these will not affect the rate of

scoliosis progression (49). Spinal surgery is often considered if the curve exceeds a Cobb angle of 40-50°

(50).

2.5. Ambulation

While some patients with leukodystrophies are able to achieve independent ambulation, most will

eventually experience some degree of impairment in their mobility. Preserving and optimizing ambulation

or, at a minimum, maintaining weight-bearing exercises, is widely considered important for the overall

health and quality of life. Without this, patients may experience secondary complications including

contractures and joint dislocation, and impaired bone health.

Patients should be screened for any treatable conditions that may impact ambulation and weight-

bearing ability, including abnormal tone or pain (Table 5). Among patients with impaired ambulation, falls

potentially pose a serious health risk. During clinical encounters, physical therapists and/or physiatrists can

help to assess fall risk and the degree of mobility independence. Although they have only been validated in

other patient populations, standardized tools such as the Gross Motor Functional Classification System

(GMFCS) can be helpful for these assessments (51, 52). Other simple tools, such as the 10-meter walk test,

can be used to monitor ambulation at various stages of disease.

 Physical therapists can help to guide the options for age-appropriate devices to assist mobility and

maximize independence. These devices include orthotics, braces, gait trainers, walkers, lifts, and standers.

Outpatient physical therapy can also help to preserve motor skills.

Table 5: Barriers to Ambulation

 Spasticity
 Weakness
 Rigidity
 Dislocation or contractures of joints
 Ill-fitting or inappropriate adaptive equipment
 Pain
 Injury
 Poor balance
 Abnormal sensation
 Involuntary movement disorders such as dystonia
and chorea

2.6. Skin Care

Most skin infections are readily amenable to simple prevention strategies, such as daily skin

surveys by the primary caregiver. With each clinical evaluation, we recommend a full head-to-toe

assessment – with clothes removed – to examine for areas of skin breakdown and pressure, with particular

attention placed on areas where orthotic devices, braces or other medical equipment comes in contact with

skin and the diaper area for incontinent patients. Families should be educated about skin wounds and

provided with educational handouts (Table 6). Non-blanching erythema or indurated skin may indicate an

emerging skin abrasion or decubitus ulcer and might necessitate a change in hardware, bed care, or

behavioral strategies. Physical therapy can help to review seating and orthotic devices at each visit, as an

ill-fitting adaptive device can result in preventable skin breakdown.

Table 6: Challenges to skin integrity in the leukodystrophy population

  Limited mobility
 Orthotic devices or adaptive hardware
 Peripheral neuropathies
 Urinary or fecal incontinence
 Disease-specific predispositions to skin lesions (Aicardi-Goutières Syndrome and Sjogren-
Larsson Syndrome)

2.6.1. Leukodystrophy-specific Skin Issues

Uniquely, patients with Aicardi-Goutières Syndrome (AGS) have several skin manifestations such

as chilblains, which require specialized wound care. Chilblains are necrotic lesions typically found on the

hands, feet, elbows, and the pinna of the ears (53). Children with AGS can also experience acrocyanosis

and periungual skin infections. Ichthyosis can be associated with several leukoencephalopathies, including

multiple sulfatase deficiency and Sjogren-Larsson syndrome (54, 55).

3. Nutrition, Bowel, and Urinary Tract Guidelines

3.1. Hypersalivation

Sialorrhea or excessive drooling is a common problem in children with neurodevelopmental

disabilities (56, 57). Importantly, it can be associated with physical, social, and psychological distress. It

can result in skin maceration, and in severe cases, secondary respiratory problems. Sialorrhea can be due to

a variety of medical issues, including dental problems (gingivitis, dental caries, and malocclusion),

gastroesophageal reflux, obstructive sleep apnea, and dysphagia leading to excess pooling of oral secretions

(57, 58). Speech-language pathologists and physical therapists can evaluate patients and help to optimize

adaptive equipment. First-line interventions to help with excessive drooling include oromotor or behavioral

exercises, positioning, replacing medications that stimulate saliva secretion, as well as optimization of

constipation, scoliosis, and gastroesophageal reflux (57, 59, 60).

Medications for hypersalivation, particularly anticholinergic agents, should be used cautiously in

this patient population because of thickening of secretions and central sedative effects. Anticholinergics,

which include hyoscine (oral/transdermal Scopolamine) and trihexyphenidyl (Artane), decrease mucus

secretions (37). Sublingual 1% atropine ophthalmic solution has also been used with success (61).

Glycopyrrolate successfully reduces the production of saliva with fewer central nervous system side effects

and is approved for use in children older than 3 years of age (59). More intense or invasive treatments for

intractable aspiration of saliva, such as, targeted botulinum toxin A injections and salivary gland surgery,

can be administered by a trained provider (57, 60, 62).

3.2. Upper Gastrointestinal Complications

Swallowing dysfunction, gastroesophageal reflux, and feeding issues are common among

individuals with leukodystrophies. Chronic malnutrition and limited fluid intake can have various adverse

effects on growth, brain development, immune function, bowel/bladder health, and overall quality of life

(63). Malnutrition in the context of leukodystrophy is often polyfactorial, influenced by dietary intake and

basal metabolic needs, as well as non-nutritional factors such as dysphagia and gastroesophageal reflux
(63-65). Patients at highest risk for nutritional issues include those with impaired communication, impaired

mobility, and dysphagia, the latter of which is a risk factor for aspiration pneumonia (65-68).

Particular attention should be paid to making sure that the diet is nutritionally complete. This is

especially important if food aversions, such as texture, temperature, or consistency preferences, are present

due to behavioral or swallowing dysfunction. Even children who gain weight adequately are at risk for

micronutrient deficiency if they are too selective in their food choices. If there is any question, a dietician

can be consulted.

We encourage each clinical visit to include a comprehensive assessment of feeding-related risk

factors, including dental issues, oral/pharyngeal dysphagia, gastroesophageal reflux, and constipation.

These regular feeding and nutrition assessments can occur at time of diagnosis and regularly every 3-6

months. The goal of these visits is to optimize oral feeding and continually assess the need for nutritional

interventions (64). Speech-language pathologists, occupational therapists, and physical therapists are

equipped to assess oral sensorimotor function, swallowing and feeding-related issues. They can suggest

appropriate adaptations, including proper positioning, adjustment of food consistency, pacing of feeding,

and equipment (40, 42, 43, 54, 55). It can be particularly helpful for a speech-language therapist or

occupational therapist to observe the child eating and evaluate oral-facial structures and function,

performance on various food types, efficiency (volume and timing), and oral-pharyngeal status (e.g., bolus

cohesion, oral residue, pharyngeal response). The general physical examination should include assessment

for malnutrition, as indicated by hydration status, skin color, and subcutaneous fat distribution. The child

should also be examined for signs of oromotor dysfunction, coughing, a change in growth parameters, and

the efficiency or duration/ease of feeding (40, 45, 54, 56). Primary caregivers may be able to provide

additional information about day-to-day feeding issues at home.

If the clinical bedside speech-language pathology or occupational therapy assessment is suggestive

of dysphagia or a risk for aspiration, further instrumental diagnostic studies may be indicated. These

include videofluoroscopic swallow study (VFSS), modified barium swallow study (MBS), or fiberoptic

endoscopic study examination of swallow (FEES). Instrumental swallow assessment is useful in

determining specific areas of concern (e.g., oral, pharyngeal) and safety of swallowing various food
consistencies (e.g., aspiration, laryngeal penetration, airway protective reflexes). If these initial studies are

unrevealing, the patient can be clinically re-evaluated, typically at 3-6 month intervals. With any significant

change in clinical status, the swallow assessment can be repeated sooner.

If there is concern for aspiration risk as suggested by coughing, choking, wet or gurgly voice,

oromotor dysfunction (e.g., effortful, food escaping lips, food residue in mouth after swallow), difficulty

maintaining weight, or general feeding difficulties (e.g., food refusals, emesis), a further investigation may

be warranted. With documented aspiration, difficulty maintaining weight, and marked inefficiency of oral

nutritional intake, an expedited consultation with gastroenterology or general surgery for consideration of

gastrostomy (G-tube) or jejunostomy (J-tube) tube placement may be indicated.

3.2.1 Gastroesophageal Reflux

Gastroesophageal reflux (GER) is common among individuals with neurologic dysfunction (7,

69). Pathologic GER can have adverse effects on feeding and sleep, and can cause vomiting, esophagitis,

respiratory compromise, dental issues, and malnutrition (70). Aspiration of oral-pharyngeal matter or

secondary aspiration of refluxed pharyngeal-esophageal matter may lead to lung disease and secondary

respiratory-related death among children with neurological impairments (71).

Importantly, GER is a clinical diagnosis that does not necessitate confirmatory studies. For

children with reflux, speech and physical therapy can help to optimize position and food consistency during

feeding (70, 72). Adjunctive medications, such as acid buffering agents, antisecretory agents, and

prokinetic agents can be helpful as well (70). Ranitidine, lansoprazole, and omeprazole are also effective

options (7, 73). Of note, proton pump inhibitors can be associated with decreased absorption of calcium,

magnesium, iron, and vitamin B12, and therefore patients on long-term treatment with these agents should

be monitored for these deficiencies (42). If medical approaches fail to manage pathologic GER and its

secondary medical complications, surgical interventions should be considered. Nissen fundoplication is

often offered in conjunction with a gastrostomy or gastrojejunal tube placement (7, 70, 71). Evidence

supports effectiveness of these procedures for reducing esophagitis, GER, aspiration pneumonia,
respiratory illness, failure to thrive, reflux-related hospitalization, and death (71). As such, local expertise

and family preference should be considered in decision-making process.

3.3. Gastrostomy tubes

Gastrostomy tubes are widely considered a safe and effective way to maintain the nutritional

needs of neurologically impaired individuals, although no formal studies have directly assessed this

important topic in patients with leukodystrophies (74-76). G-tube placement should be considered in the

context of persistently poor weight gain despite optimization of nutrition or in the presence of oromotor

dysfunction that impacts safe and efficient swallowing (74, 77-79). Unfortunately, the first encounter with a

gastroenterologist and/or general surgeon is often delayed until after a child is no longer orally feeding,

losing weight, and/or declining, at which point G-tube placement carries an inherently higher risk (76).

Ideally, the G-tube can be a tool to keep the child healthy, reduce the frequency of

hospitalizations, facilitate safe and easy administration of medications, and prevent serious respiratory

complications (74). Children with leukodystrophies may benefit from G-tube placement even as oral feeds

continue. Specifically, a G-tube can be employed to deliver unpalatable supplemental nutrition or

medications; to provide safe intake of thin liquids when aspiration is observed on only that consistency; and

to provide supplemental nutrition when the child does not meet nutritional needs in a timely manner due to

inefficiency or rapid fatigue. While there are benefits to tube placement, parents report that children with

nasogastric (NG) tubes vomit frequently (particularly in patients younger than 1 year of age) and children

with G-tube experience nausea, loss of hunger, as well as skin issues including granulation tissue and

irritation (80). Little evidence exists to support a specific type of feeding tube, however anecdotal clinical

evidence indicates greater difficulty transitioning to oral feeds, greater difficulty managing oral secretions,

and higher levels of food aversions associated with NG versus G-tube. Also, in the absence of clinically

significant gastroesophageal reflux, there is no evidence to guide choice of a Nissen fundoplication with G-
tube placement compared to G-tube alone (70, 74, 75). Endoscopic placement versus surgical placement

should be based on the patient’s overall health status, anesthesia risk, and available resources and expertise.

The decision to place a gastrostomy is often complicated by psychosocial factors , including

perceived parental culpability for child’s feeding difficulty, implied deterioration of the child’s condition,

impact of the feeding tube on social relationships, child’s enjoyment of feeding (e.g., tastes, smells) and

maintaining feeding skills for later oral intake (81). This many explain why some families may agree to a

nasogastric tube, but are hesitant about use of a gastrostomy tube or jejunostomy tube.

Additional education, counseling, and time can be helpful to families making these decisions (81).

Furthermore, G-tube placement is often misinterpreted as a permanent step. When addressing interventions,

it can be helpful to emphasize “quality of life care” rather than “end of life care” (73). From the family’s

perspective, this language alone contributes to emotional distress and may discourage them to pursue G-

tube placement, even though it could significantly improve the family’s quality of life. Encouraging

families to meet with a specialist early in the clinical course can work to avoid such misconceptions. This

conversation should ideally occur in an outpatient setting during an anticipatory conversation as part of a

broader care plan.

3.4. Bowel Motility

Impaired bowel motility is a common problem in many patients with neurologic impairment (7,

73). Constipation is an easily treated, yet frequently overlooked source of chronic pain that can

significantly impact quality of life and lead to serious secondary complications, such as urinary retention.

While there is no standard definition for constipation, it is generally considered as two or fewer bowel

movements per week. The diagnosis is made clinically by obtaining a patient history and/or rectal exam.

Assessment of fluid intake should also be made at time of examination, as chronic dehydration is a risk

factor for constipation. Families can provide additional information on frequency of stooling, as well as

appearance based on the Bristol Stool Chart (82). A plain abdominal X-ray is only indicated if impaction is

suspected and is not needed for the diagnosis of constipation.

 Education of primary caregivers and implementation of appropriate prevention strategies, such as

simple dietary changes, increased hydration, and supplemental dietary fiber or adding enteral formula with

fiber if the child is G-tube fed, are the key elements in the management of constipation (Table 7) (83). If

symptoms persist, polyethylene glycol or lactulose can be used as stool softeners (73). Sodium phosphate

enemas are particularly effective at managing constipation in children with limited mobility. Stool

stimulants such as Senna or bisacodyl can be helpful as well. While these may lead to dependency, priority

should be given to optimization of quality of life. Finally, if the treatment of acute constipation necessitates

disimpaction, the medical team should consider consulting a gastroenterologist or general surgeon.

Table 7: Family Education on Constipation

 The GI tract is an organ with many nerve cells important for its normal function,
 A neurodegenerative disease is expected to cause some degree of constipation
secondary to the underlying disease process
 Constipation can be painful and can result in other serious complications such as urinary
tract infections
 Mobility and hydration are important factors in constipation
 It is better to be proactive: to prevent rather than treat
 Education on the logistics of toileting
 Education on toileting adaptive equipment and clothing modifications

3.5. Bladder Health

Urinary dysfunction is a common and important complication seen in the leukodystrophy

population. Dysautonomia, neurogenic bowel and bladder, and constipation are risk factors for secondary

urinary dysfunction. Urinary incontinence represents a significant source of embarrassment and

stigmatization. From a psychosocial perspective, it is important to destigmatize the issue and shift the focus

to improving patient quality of life.

Symptoms may manifest as urinary incontinence, urgency, or retention, all of which increase the

risk of a bacterial infection of the bladder and kidney. In non-verbal patients, untreated urinary tract
infections (UTIs) may result in serious pain and discomfort, and may contribute to life threatening illness or

hospitalization, or seizures (8). Of note, pediatric patients with neurologic impairment may be either

hyperthermic or hypothermic at times of infections. Diagnostic tests for urinary tract infections should be

ordered urgently, as delays can increase the severity of UTI and decrease quality of life. This evaluation

should include a urinalysis with urine culture, with isolation of more than 100,000 colonies per milliliter

considered a reasonable threshold for clinically significant bacteriuria. Urinalysis with urine culture is not

appropriate for patients with a history of intermittent or chronic catheterization, as often the bladder is

colonized.

It is our general recommendation that a urology consultation should be considered if a female

patient presents with two or more UTIs annually, or if a male patient presents with one or more UTIs

annually. Consultation can also be helpful in the context of symptoms such as delayed urinary stream,

urgency, or secondary enuresis. Renal and bladder ultrasounds with voiding studies may be helpful to

assess for neurogenic bladder, and urodynamic studies can help identify issues related to sphincter or

bladder control. Prophylactic anti-microbial agents may be used on a case-by-case basis under the guidance

of a urologist or infectious disease specialist. Patients taking anti-seizure medications should be monitored

closely for urinary dysfunction, as some of these medications can predispose to nephrolithiasis. With

bladder retention, consideration should be given to urinary catheterization as guided by urology (7, 8). A

delay in catheterization can increase the risk of UTI recurrence and lead to serious infectious complications

and potential renal dysfunction.

3.6. Gastrointestinal and Urinary Health: Leukodystrophy-Specific Guidelines

As gallbladder involvement has been detected in more than half of patients with metachromatic

leukodystrophy (MLD), we recommend that patients with MLD are followed by a gastroenterologist with

scheduled gallbladder ultrasounds (84, 85). Abdominal computed tomography (CT) can be used if reliable

gallbladder ultrasounds are not available (84). The most common abnormalities include wall thickening and

polyps (84). Gallbladder dysfunction can present as abdominal pain, which can be difficult to distinguish

from other issues, such as spasticity. Polyps smaller than 5mm may be followed annually. As determined
by gastroenterology, laparoscopic cholecystectomy should be considered for polyps larger than 5mm.

Gallstones have been reported in patients with cerebrotendinous xanthomatosis as well, although the true

incidence of this complication warrants formal study (37, 86).

Metachromatic leukodystrophy can also be associated with acid-base disturbances in

approximately one quarter of patients (87). This is likely secondary to renal sulfatide accumulation and can

result in a significant metabolic acidosis, particularly in the context of clinical stressors (87). Patients with

Aicardi Goutieres syndrome can sustain inflammatory complications to the kidneys, including a lupus-like

glomerulonephritis, and these patients should have regular urinanalysis to assess for proteinuria.
4. Respiratory Health, Sleep, and Communication

4.1. Progressive Respiratory Insufficiency

Respiratory complications such as aspiration pneumonia and community-acquired pneumonia are

a common source of serious morbidity and mortality among individuals with neurodegenerative disorders

(Table 8) (88). Importantly, many potentially life-threatening complications are amenable to preventive

strategies. Primary respiratory failure may occur in the late stages of some leukodystrophies, particularly

those associated with peripheral nerve dysfunction, such as MLD. Bulbar dysfunction, such as seen in Type

II Alexander disease, is associated with central apneas. Finally, dystonic dysphonia, such as that seen in H-

ABC and 4H syndrome, and obstructive symptoms seen in many leukodystrophies with hypotonia can

result in intermittent obstructive apnea.

Table 8: Concerning Features for Respiratory Insufficiency and/or Aspiration

 Frequent coughing
 Coughing with feeds
 Drooling
 Snoring
 Apnea during sleep or wakefulness
 Persistent drowsiness
 Diminished Cough and/or Pneumonia
 Prolonged Recovery from Respiratory Illness
 Prolonged supine positioning
 Neck flexor weakness
 Tachypnea or increased work of breathing
 Stridor

Dysphagia, as discussed in detail in the Upper Gastrointestinal section, can contribute to acute or

chronic lung disease. A clinical swallow assessment by a speech-language or occupational therapist in

combination with instrumental diagnostic studies (e.g. VFSS, MBS, or FEES) is helpful in the

identification of aspiration risk (38, 72). After the initial evaluation, we recommend that re-assessment

recurs every 3–12 months as guided by disease progression or appearance of new signs, symptoms or risk

factors (Table 6). More frequent swallow assessments are indicated in high-risk patients, including those

with clinical signs of oropharyngeal weakness, oral coordination issues, or sialorrhea, a clinical history of

pneumonia, or coughing during meals (31, 34, 35).

 It is important to identify the cause of respiratory insufficiency (e.g. weakness, obstruction,

chronic injury, severe scoliosis), as this information can guide the options for intervention. Clinical

recommendations and goals of care should encompass the family’s quality of life considerations, as well as

cultural and religious beliefs. Consultation with pulmonology, gastroenterology, and/or otolaryngology

should be considered early in the disease course to guide preventive strategies, foster therapeutic

relationships, and enable anticipatory discussions of future supportive interventions such as G-tube,

tracheostomy, and mechanical ventilation. Pulmonary care ideally should be preventative more than

reactive.

A comprehensive interventional strategy for respiratory insufficiency should include infection

prevention, airway maintenance, and mechanical support. Infection prevention includes annual influenza

vaccination, positioning and feeding modifications, regular hand washing, and avoidance of sick contacts

when possible (8). Palivizumab, which targets respiratory syncytial virus (RSV), may have a role in select

cases. Key airway maintenance strategies include repositioning, ambulation, physical therapy, as well as

targeted interventions such as chest physical therapy, vest therapy, or cough-assist devices (7). Some

patients may benefit from regular use of a suction aspirator machine at home. Additional medical and

surgical options are available to treat persistent sialorrhea, as discussed above. Salivary Botox injections

may help to reduce aspiration pneumonia risk, although this option has not yet been formally studied (56).

Because of progressive respiratory insufficiency, a discussion regarding the possibility of using

mechanical ventilation will be required in most cases. Available options, which should be considered in

consultation with a qualified pulmonologist, include invasive mechanical ventilation, continuous positive

airway pressure (CPAP), bilevel positive airway pressures (BiPAP), or supplemental oxygen. In contrast to

neuromuscular disorders, primary respiratory failure in the leukodystrophy population typically occurs in

the context of severe cognitive impairment. The family, patient, and leukodystrophy provider should have

anticipatory discussions of mechanical ventilation in the context of ongoing goals of care discussions (73).
4.2. Communication

Maintaining communication between the affected individual and caregivers is among the most

important and underappreciated goals of a comprehensive care strategy (68, 89, 90). Simplistically, a

language disorder is an impairment in the comprehension and/or the use of spoken, written, or symbol

systems involving form (e.g. grammar, syntax), content (e.g. vocabulary and meaning) and functional use

(e.g. pragmatics) of language (91). The array of language impairments in an individual patient with

leukodystrophy depends largely on the specific regions of the brain impacted by abnormal myelin

development, abnormal myelin homeostasis, and secondary neuronal injury. The progressive loss of

language in children with leukodystrophies is an area needing further formal study.

Children with leukodystrophies, like others affected by neurological impairments, often present

with neuromotor speech disorders (i.e., dysarthria, apraxia of speech) (69, 89, 92). Dysarthria is used to

describe a group of speech disorders that are caused by abnormal strength, speed, range, steadiness, tone or

accuracy of speech movements (93). Features of dysarthria include spastic, flaccid, hypokinetic,

hyperkinetic, or ataxic speech. Unlike dysarthria, apraxia of speech is caused by difficulty planning or

programming commands that direct speech movements in sequence (93). A child with neuromotor speech

impairments, including dysarthria or apraxia, has difficulty with sound production, and this is often

accompanied by reduced intelligibility and comprehensibility of speech. As a result, these children are

isolated socially, exhibit maladaptive behaviors for communication, and have limited communication

partners.

Speech-language pathology (SLP) evaluation should be considered for any patient with

communication difficulties or bulbar neuromotor features. A comprehensive exam will assess motor speech

function, language skills (verbal and written expression and comprehension), communication effectiveness,

and evaluation for communication tools (68, 89, 90, 92, 94-96). In order to best guide the individual family,

the speech-language pathologist should ask primary caregivers how they communicate with the child. This

often serves as a good introduction to a broader “goals of care” conversation, but also provides valuable

insight into the communication abilities of the patient at home.

 A comprehensive augmentative and alternative communication (AAC) evaluation should be

consider for any child whose current methods of communication are not effective in meeting the child’s

daily communication needs (97). For some children, AAC may be used in specific situations identified as

problematic, while others may use AAC as a primary means of communication. During the AAC

assessment, the family and child work with a SLP to identify appropriate symbolic representations (e.g.,

photos, symbols, text), message types (e.g., full utterance, word-by-word, spelling), voice output (e.g.,

recorded digitized, synthesized speech), technology level (e.g., no tech, low tech, high tech), and access

(e.g., direct with hand or eye gaze, indirect scanning) options (89, 90). In order to meet a patient’s

individual communication needs, cognition, language, vision, hearing, and physical skills should all be

considered. It is important to adapt to a child’s evolving communication needs, which include new

communication environments and changes in physical, cognitive, and language skills associated with

typical development as well as disease progression.

The value of communication cannot be overstated; the difference between complete absence of

communication and the simple ability to communicate “yes” or “no” represents an extreme change in

quality of life. Perhaps the most extreme version of this scenario is poignantly illustrated by accounts of

individuals suffering from “locked-in-syndrome” where the body and mind continue to experience the

pains and pleasures of the physical world but are unable to communicate (98).

4.3. Sleep

Sleep dysregulation, characterized by recurring episodes of difficulty initiating and/or maintaining

sleep, is a common feature in the leukodystrophy population that can negatively affect quality of life of

both patients and caregivers (99). While the specific incidence of sleep disorders in the leukodystrophy

population is unknown, sleep disorders occur in over half of all children with severe multi-system disability

(100). Common sleep problems include difficulty with sleep onset or maintenance, sleep-related breathing

disorders, abnormal circadian rhythms, and hypersomnolence (100). Obstructive and central sleep apneas

are also common in children with leukodystrophies and may necessitate specialist care and interventions
Untreated obstructive sleep apnea (OSA) can result in a variety of medical issues, including excessive

daytime sleepiness, headaches, and even serious secondary cardiac complications.

Neurologic irritability, such as that seen in early onset disorders such as infantile Krabbe and

Aicardi Goutieres Syndrome, can in some cases severely impact sleep as well. Sleep dysfunction can also

be the result of other medical issues, including gastroesophageal reflux, pain, and spasticity that interrupt

sleep. Each of these causes should be managed accordingly.

An important first step in managing sleep disorders is optimizing sleep hygiene, with an emphasis

on a consistent sleep schedule, avoiding screen time 1-2 hours prior to bedtime, and minimizing

unnecessary medical interventions at night (99). Primary caregivers can record a sleep diary to help

characterize the patient’s sleep patterns and identify problem areas. While there are no FDA-approved

medications for the treatment of insomnia in children, off-label options include clonidine, tricyclic

antidepressants, and benzodiazepines (99, 100). In clinical practice, melatonin is often used to help with

sleep initiation. Referral to a sleep medicine provider should be considered, particularly if OSA is

suspected.

5. Neurologic Issues

Many patients with a leukodystrophy experience a wide range of neurologic complaints, including

pain, irritability, and cognitive impairment, all of which may negatively impact the quality of life of the

patient and primary caregivers. The degree of cognitive impairment is largely dictated by the extent of the

neural networks affected and the severity of the underlying injury. Even within a family, each affected

child may demonstrate variable rates of cognitive decline. As the typical course of a leukodystrophy is

progressive, school and home accommodations should be continually re-assessed and adjusted to the

child’s evolving needs. In addition to the medical team, social workers can help families navigate these

complex issues.

5.1. Pain

Pain, irritability, and sleep are central to maintaining quality of life, but are often under-recognized

and undertreated (37). Validated pain assessment tools are categorized by age and cognitive ability (73). In
very young children, the CRIES (Cry, Requires O2, Increased Vital Signs, Expression, Sleeplessness) or

FLACC (Face, Legs, Activity, Cry, Consolability) scales can be used.

Older children may be able to use numerical or illustrated pain scales, such as the Wong-Baker

FACES® Pain Rating Scale, to describe pain levels.

A child with an AAC system for communication may use alternative methods for describing

discomfort or pain, such as a gesture dictionary or photographic body representations.

After the child is determined to be in pain, the caregivers and clinical team should investigate

common triggers for discomfort. The list of potential occult causes is extensive, but includes dental

abscesses, bowel obstruction and constipation, pancreatitis, bone fractures, acute joint dislocation, tone

issues, respiratory compromise, skin breakdown, and urinary tract infections (101). In addition, current

medications should be reviewed for agents that may be contributing to pain or worsen existing neurologic

symptoms (101). Peripheral neuropathies are common in select leukodystrophies, such as Krabbe (globoid

cell) and MLD, and can result in neuromuscular dysfunction as well as discomfort.

The World Health Organization has published guidelines for pain management for pediatric

oncology, which can be adapted to children with chronic neurologic disease (73, 102). According to these

guidelines, the basic tenets of pediatric pain management include (73): treating by ladder (standardized

escalation plan), treating by clock (scheduled timing), treating by mouth (using the least invasive route

possible), and treating by child (individualized therapies). Gabapentin can be particularly helpful for

managing neuroirritability and neuropathic pain, though this approach has not been formally studied in the

leukodystrophy population (7, 101). Benzodiazepines and neuroleptics may also be effective for managing

agitation (101).

5.2. Seizures

Not just a manifestation of late-stage neurodegeneration, seizures affect almost 50% of patients

with leukodystrophies (9). In rare cases, seizures may be the presenting symptom, such as in Alexander

Disease (90). Epilepsy is common feature of Krabbe disease, megalencephalic leukoencephalopathy

(MLC), sialic acid storage disorders, peroxisomal disorders, and L-2-hydroxyglutaric aciduria. Epilepsy is

defined as two or more unprovoked seizures, a single seizure with a high risk for a second seizure, or the

presence of a known epilepsy syndrome (103, 104). Seizure mimics are common and should be considered

during the evaluation of any potential epileptic event (Table 9) (105).

Table 9: Common seizure mimics

 Gastroesophageal reflux (Sandifer syndrome)

 Breath holding spells
 Syncope and dysautonomia
 Movement disorders (including tics and dystonias)
 Behavioral events
 Pain crises
 Sleep disorders (including parasomnias such as
periodic limb movements and night terrors)
 Metabolic disturbances (including hypoglycemia)
 Staring spells or inattention

A careful clinical history will allow providers to determine whether a child has had a clinical

seizure (104), and clinical history alone is often sufficient for the diagnosis of epilepsy (101). Features such

as focality at onset, duration, and context are important in the evaluation of seizures. A routine

electroencephalogram (EEG) may help establish a formal diagnosis of seizures and guide subsequent

medication selection, and video EEG monitoring can be useful to distinguish between seizures and non-

epileptic events. Following a clinical seizure, we recommend that patients are referred to a neurologist, who

will guide the need for and selection of prophylactic medication (104). There is no evidence to support the

use of anti-seizure medications prior to the onset of clinical seizures, as these medications do not prevent

the development of epilepsy and the majority of leukodystrophy patients will not develop seizures (92). As

such, the first step after resolution of a seizure should be an assessment for provoking factors, such as fever,

electrolyte dysregulation, medication withdrawal, and infection. Urinary tract infections are an especially

common risk factor for seizure in the leukodystrophy population because of underlying issues with urinary

retention and voiding (8). For provoked seizures, the patient is unlikely to require a daily prophylactic
anticonvulsant medication. Regardless of daily prevention needs, abortive anti-seizure options, such as

rectal diazepam and buccal or intranasal midazolam, can be provided for patients with prolonged or

clustered seizures (101).

5.3. Autonomic Nervous System Dysfunction

Autonomic dysfunction affects many patients with leukodystrophies and, given the autonomic

nervous system’s role in maintaining global homeostasis, can result in diverse symptomatology (Table 10)

(100, 106, 107). Autonomic symptoms are a particularly prominent feature of several leukodystrophies,

including later-onset (type II) Alexander disease and adult-onset autosomal dominant leukodystrophy

(ADLD) (108, 109).

Autonomic dysfunction can be inherent to the neurodegenerative process or can be triggered

acutely by pain or infection. The acute onset of a cluster of dysautonomic symptoms is referred to as an

“autonomic storm”. Potential triggers should be evaluated in patients who are at risk for autonomic

dysfunction. Medications that may be helpful in the preventative management of dysautonomia include

gabapentin, cyproheptadine, baclofen, beta-blockers, and clonidine (100). For acute attacks,

diphenhydramine, acetaminophen, or ibuprofen can be useful.

Table 10: Autonomic Dysfunction (106, 107, 110)

System Examples of Dysfunction Potential Evaluation and Management
 Evaluation by urology
 Management of urinary retention by
 Urinary retention
Genital-urinary bladder training, catheterization,
 Urinary incontinence
system and/or medications
 Nocturia
 Routine assessment for urinary tract
infections
Gastrointestinal  Feeding difficulties  Speech/occupational therapy
system  Dysphagia evaluation of feeding
 Esophageal dysmotility  Assessment of nutritional status
 Delayed gastric emptying  Assessment for aspiration risk
  Dietary management: optimize
 Recurrent abdominal pain
hydration and dietary fiber for
 Intestinal dysmotility
constipation
 Incontinence or
 Medical management (e.g. stool
constipation
softeners and laxatives) for
constipation
 Arrhythmias  Evaluation by cardiology
 Tachycardia  Optimization of environmental
Cardiac and
 Hypertension factors for acrocyanosis
vascular systems
 Postural hypotension  Optimization of hydration and salt
 Acrocyanosis intake for postural hypotension
 Temperature regulation
(Hyperthermia or
Sudomotor  Optimization of environmental
Hypothermia)
function factors
 Flushing
 Sweating issues
 Alacrima  Evaluation by ophthalmology
Ophthalmology  Pupillary changes  Eye lubrication or eye patching at
 Ptosis night to prevent cornea abrasions
 Apneas
 Evaluation by pulmonology
Pulmonary  Disordered breathing
 Consider sleep study for diagnosis
 Respiratory insufficiency
 Pain
 Sleep cycle dysregulation
 Spasticity  Pain management medications
Neurology
 Dystonia  Sleep management interventions
 Seizures
 Irritability

5.4. Additional Neurologic Considerations

Several leukodystrophies are associated with significant behavior issues, including inattention,

irritability, hyperactivity, and aggression. Infantile Krabbe disease classically is characterized by

hyperirritability. Although not evaluated by controlled clinical studies, gabapentin is typically chosen as the

first line medication given its safety profile. It is reasonable to start at 15-20 mg/kg/d divided 2-3 times

daily and to escalate as needed to 60 mg/kg/d. Non-validated alternatives include pregabalin, topiramate,

tricyclic antidepressants, and valproic acid. In refractory cases, benzodiazepines can be used with caution.

Many adult presentations of leukodystrophies, including MLD, Krabbe, Alexander disease, and Hereditary

Diffuse Leukodystrophy with Spheroids, can be associated with significant psychiatric symptoms.

The cerebral demyelinating lesions associated with X-linked adrenoleukodystrophy (X-ALD) may

manifest symptoms that mimic of attention-deficit hyperactivity disorder. This can be immediately

differentiated through the imaging findings. The presence of brain lesions may qualify boys with X-ALD
for bone marrow transplantation, but only if detected at an early stage. Patients with more advanced

cerebral X-ALD may experience significant behavior disturbances. Clinical experience suggests that

risperidone and valproic acid may be helpful mood and behavior stabilizers in this population.

Certain leukodystrophies can result in significant peripheral nerve involvement and pain, and may

include Krabbe, MLD, AARS2 related leukodystrophy, Polyglucosan body disease and Pelizaeus

Merzbacher disease, among others. Since the signs of peripheral neuropathy may be overshadowed by

central neurologic signs, and patients may be unable to communicate the symptoms of neuropathy, careful

attention should be given to detect the presence of peripheral nerve involvement.

Eliciting symptoms of dysesthesia should be included in routine neurologic examinations, in

particular for early onset disorders such as infantile Krabbe and late infantile MLD. When peripheral

neuropathy is identified, consideration of appropriate treatment to manage these sometimes painful

symptoms should be given utmost attention.

After genetic diagnosis, most patients with leukodystrophies do not require subsequent imaging

outside of clinical trials. Exceptions include patients affected by L-2-hydroxyglutaric aciduria who are at

increased risk for brain malignancy and therefore necessitate serial brain imaging. Patients with SAMHD1-

associated Aicardi-Goutières Syndrome (AGS) are at increased risk for cerebrovascular accidents, and may

benefit from annual brain MRI and MR angiograms. The evidence behind the frequency of testing remains

to be established through future formal studies.

6. Endocrine Guidelines

6.1. Adrenal Insufficiency

Up to 90% of male patients affected by X-ALD will ultimately develop adrenal insufficiency at

any point between infancy and adulthood (94, 95). Adrenal insufficiency should be considered in any

patient with malaise and fatigue and signs including hypotension, hyponatremia, hyperpigmentation,

weight loss, vomiting, and poor growth. A simple and reliable screening test, very long chain fatty acids

(VLCFA), can help to diagnose X-ALD and should be considered for all boys with suspected adrenal

insufficiency. Although potentially fatal, adrenal insufficiency can be treated with corticosteroid

supplementation. Once present, adrenal insufficiency in X-ALD is usually chronic, requiring daily oral

steroid administration with increased dosing at times of clinical stress.

 Adrenal insufficiency is assessed through laboratory measurements of adrenocorticotropic

hormone (ACTH) and morning cortisol levels. We recommend that patients with X-ALD should be

screened for adrenal insufficiency every 6 months beginning at the time of diagnosis, although the

frequency of this testing has yet to be validated. Additional testing can be considered in the context of

illness requiring any escalation of medical care. An endocrinologist may also recommend additional studies

such as aldosterone, plasma renin activity, and ACTH stimulation tests when biochemical values are

equivocal.

Boys undergoing stem cell transplantation for X-ALD should be closely monitored for adrenal

function. It is important to provide families with a letter of instruction on steroid stress dosing and testing to

be given to outside providers and emergency rooms.

6.2. Ovarian Failure

Primary ovarian failure may arise as a complication of a number of leukodystrophies, including

AARS2-related diseases, as well as some mitochondrial and chromosomal (ex.18q-) disorders. Females

diagnosed with vanishing white mater (VWM) disease may experience primary or secondary ovarian

failure. These patients may need screening measurements of estradiol, luteinizing hormone (LH), and

follicular stimulating hormone (FSH) as guided by endocrinology or gynecology.

6.3. Other Leukodystrophy-specific Endocrine Issues

Patients with hypomyelination, hypogonadotropic hypogonadism and hypodontia (4H syndrome)

typically experience a variety of endocrine abnormalities, including hypogonadotropic hypogonadism,

hypothyroidism, and, less commonly, growth hormone deficiency (111). Although there is no clinical

evidence, we recommend that patients be screened at diagnosis and then annually for growth failure.

Additionally, testing of testosterone, luteinizing hormone, and follicular stimulating hormone levels should

be considered at the age of expected puberty (by 13 years old for females and by 14 years old for males). A

slow or flat rate of growth as plotted on a growth chart may be indicative of growth hormone failure.

Thyroid stimulating hormone (TSH) and T4 can be used as marker of hypothyroidism, with hormone

replacement therapy administered as needed. For cases of hypogonadotropic hypogonadism, the benefits
and risks of sex steroid replacement should be discussed thoroughly with the patient and family.

Hypothyroidism has also been reported in patients with cerebrotendinous xanthomatosis (37, 112) and in

patients with Aicardi Goutieres syndrome and these patient populations should be specifically screened for

this condition.

6.4. Post-transplantation Endocrine Considerations

Patients who have undergone therapeutic stem cell transplantation are at increased risk for

endocrinopathy secondary to medication, irradiation, and the transplant itself. These patients should be

considered for referral to endocrinology for regular growth evaluation or for growth hormone screening if

growth failure is observed. These patients also may benefit from regular monitoring of thyroid function,

with clinical follow-up for thyroid nodules. After transplant, patients are also at risk for gonadal failure,

which can present as delayed puberty. Post-transplant osteoporosis should also be assessed and treated as

clinically indicated.

7. Additional System-Specific Concerns

7.1. Autoimmune Disorders

In general, autoimmune disorders are overrepresented in patients with Aicardi-Goutières

Syndrome (AGS) and include thyroid dysfunction, systemic lupus erythematosus (SLE), celiac disease, and

gastrointestinal inflammatory diseases (113). Patients affected by AGS may benefit from annual testing of

TSH levels, as well as clinical screening for other autoimmune diseases. With any concerns, we

recommend an evaluation by endocrinology or rheumatology.

7.2. Cardiac Issues

Some leukodystrophies are known to be associated with cardiac issues, in addition to

dysautonomia, and require regular visits with cardiology. These most notably include Aicardi-Goutières

Syndrome, 18q- syndrome, infantile sialic acid storage disorders, and fucosidosis. Mitochondrial
leukoencephalopathies can also be associated with cardiomyopathy and cardiac rhythm abnormalities. Due

to the underlying abnormalities in cholesterol metabolism, cerebrotendinous xanthomatosis may be

associated with accelerated coronary heart disease and hypertrophy of the atrial septum (37, 114).

Additionally, respiratory complications such as obstructive sleep apnea can cause secondary cardiac

abnormalities. If suspected, prompt referral to a cardiologist is recommended.

7.3. Ophthalmologic Issues

Regular ophthalmological monitoring can prevent many of the ocular complications associated

with leukodystrophies. Potential problems range from glaucoma, which is observed in patients with

Aicardi-Goutières Syndrome (AGS) and peroxisomal disorders, to the ocular malformations found in

oculodentodigital dysplasia (ODDD) (Table 11) (113). Progressive myopia is a common manifestation of

4H or POLR3-related leukodystrophy and require regular ophthalmological assessments. Optic atrophy is a

common feature in a number of leukodystrophies. Eye movement abnormalities, including the nystagmus

common to many hypomyelinating leukodystrophies including Pelizaeus Merzbacher disease, can impair

function and academic activities such as reading. Macular degeneration with perifoveal crystalline

inclusions is common in Sjogren-Larsson syndrome, a disorder of lipid metabolism. With any ocular

concerns, we recommend evaluation with ophthalmology, and vision services as appropriate. Finally, facial

weakness and decreased blinking can result in significant risk of ocular dryness with subsequent injury to

the cornea. Careful observation and questioning to elicit this complication should be included in general

health maintenance. Where appropriate, ocular lubricants should be used.

Table 11: Ophthalmologic Complications of Leukodystrophies

Leukodystrophy Potential Issues

4H or POLR3-related leukodystrophy  Severe myopia

(111)  Retinal detachment
Aicardi-Goutières Syndrome (AGS)
 Glaucoma
(113)
  Glaucoma
Peroxisome biogenesis disorders (113)  Cataracts
 Pigmentary retinopathy
 Glaucoma
Oculodentodigital dysplasia (ODDD)  Microophthalmia
 Microcornea
(113)
 Iris malformations
 Optic atrophy

Cerebroretinal microangiopathy with

 Bilateral retinal telangiectasia
calcifications and cysts disease
 Retinal exudates
(CRMCC, Coats plus syndrome)

Leukoencephalopathy, brain  Bilateral retinal telangiectasia

calcifications, and cysts disease (LCC)  Retinal exudates

Retinal vasculopathy with cerebral  Bilateral retinal telangiectasia

leukodystrophy (RVCL)  Retinal exudates
 Macular degeneration with perifoveal crystalline
Sjogren-Larsson Syndrome (SLS)
inclusions
Hypomyelination and congenital
 Cataracts
cataracts (HCC)
 Nystagmus
Pelizaeus-Merzbacher disease
 Dysfunctional smooth pursuits

Cerebrotendinous xanthomatosis (37)  Cataracts

7.4. Dental Guidelines

In addition to the regular dental care needed for all patients, children affected by select

leukodystrophies require regular dental evaluations, preferably by specialists who are aware of the disease-

specific considerations. Patients affected by Cockayne syndrome have predisposition to develop cavities.

4H syndrome, or POLR3-related leukodystrophy, is associated with variety of teeth abnormalities,

including delayed eruption of teeth or natal teeth. Patients with Aicardi-Goutieres syndrome and

cerebrotendinous xanthomatosis are at increased risk for tooth loss. Strong consideration should be given to

finding a specialist in pediatric special-needs dentistry.

8. Coordination of Care

8.1. Biopsychosocial Assessment

The biopsychosocial assessment should paint a picture of “where the family is coming from” and

will begin to set a “compass” to guide care (73).This might include questions to address the medical
condition of the patient and the patient’s and/or family’s understanding of the diagnosis. In order to fully

care for a child, it is important to understand living arrangements of the patient, the accessibility of those

living arrangements based on patient’s degree of disability, and the access to transportation services.

Additional considerations include the access to support programs, the family’s composition and challenges,

the support system for the parents and family, and parental health and coping mechanisms. A social worker

often guides these discussions and allows the team to start to building trust with the family and positions

the team in a better position to help as important end-of-life decisions need to be discussed with the family.

The ultimate goal is to develop or adopt a standardized intake form that can be used across GLIA

and leukodystrophy care network clinical sites. This form would address clinical, research, and quality of

life elements. The clinical team of physicians and social work should have evolving discussions about goals

of care with the family.

8.2. Clinical Care Plan

As demonstrated by the extensive and complex medical issues outlined in this article,

leukodystrophy clinical care and encounters can be overwhelming for families and challenging to medical

and allied health care providers. To help families understand the process, a member of the care team should

help to outline a longitudinal clinical care plan: starting at diagnosis and continuing over the course of their

medical care. This will improve the relationship between family and clinical care team by increasing

transparency and communication. In writing, basic disease information and a summary of the key areas of

clinical focus should also be provided to families. The handout should list each provider and their specific

recommendations for follow up visits, studies, and medications (Table 12).

In order to facilitate communication, “red flags” that may warrant consultation with a specialty

care center should be detailed, such as the symptoms of adrenal failure in boys with adrenoleukodystrophy.

Additionally, to empower families, the documents should also include space for patients/families to

independently keep track of their local care team visits, medication changes, lab results, and medical

treatments. All patients with leukodystrophies should have the opportunity to be involved in clinical

research, including natural history studies.

 Table 12: Example Clinical Care Plan
Today your child saw the following
providers:
Prescribes X medication (dosage and schedule) for
seizures
Neurology (Dr. X, contact information) Prescribes X medication (dosage and schedule) for
behavioral issues
Recommends X study to be completed

Prescribes X medication (dosage and schedule) for

Physiatry (Dr. X, contact information)
spasticity

Physical Therapy (X, contact information) Recommends the following exercises and stretches

Nutrition (X, contact information) Recommends the following changes to your child’s diet

8.3. Transitions in Care

There are several key transitions of care that occur during the life of patients with

leukodystrophies: inpatient versus outpatient; pediatric to adult care; home to group care, insurance

coverage changes, changes in access to services; and end of life care. Conversations on transitions of care

should be started early to familiarize the family with the concepts and the idea that with most patients with

leukodystrophies have evolving needs. Earlier access to palliative care can guide the families with difficult

decision-making and work to set the “compass”. As a whole, our health care systems need to dedicate more

effort to educating families in order to overcome longstanding stigmas associated with palliative care and

help distinguish it from hospice care. The primary goal of palliative care is the treatment of suffering and

improvement of quality of life (73). Hospice can be a valuable resource for end of life care (73).

8.4. Strengthening Family Supports

There are many aspects of quality of life relevant to both patients and families that should be

addressed in addition to the clinical visit (73). This can include access to care, billing and insurance issues,

continuing education, and family counseling. Social workers, essential members of the core team, can help

families to access resources outside of their immediate support group. Database-linked surveys could

identify key quality of life issues not fully addressed during clinical encounters. This can be in turn used to

determine, revise, and optimize resources and approaches used to support the family at home and between
visits. Existing metrics for assessing quality of life, including PedsQL and other questionnaires have not yet

been validated in this population.

Leukodystrophy centers should develop a resource-categorized central web resource (e.g. the

GLIA Website) that will allow families to access information on more specific disease-oriented sites such

as advocacy groups on social media. In general, online resources are able to quickly report on relevant

innovations, changes in care strategies and resources, to communicate about research and therapeutic

opportunities, and allow a more active role as parents, clients, and patient advocates.
9. Conclusions

Our goal with this document is to provide a framework to address the multi-faceted needs of

patients with leukodystrophies, maximizing their quality of life. A dedicated leukodystrophy center is only

one part of the important network of providers and may not be accessible to all patients and their families.

A primary goal is to create a wider network of physicians who are qualified to accommodate patients who

do not have regular access to sites within formal leukodystrophy care centers. Efforts are underway to

develop a system that allows more experienced specialists to train providers beyond the geographical reach

of the clinical sites and have specialized physicians actively communicate with local physicians and help

them access the resources they need.

The ultimate goal of care for a patient with leukodystrophy is to enhance both the quality and

duration of life. While a definitive diagnosis may inform disease-specific therapies and research eligibility,

and represents a major milestone in the patient’s clinical odyssey, the lack of a diagnosis should not

preclude comprehensive preventative and symptomatic care. All patients deserve, at a minimum, a

comprehensive prevention and symptom management plan. Delivery of such care requires the involvement

of a multidisciplinary team, ideally in the context of a dedicated leukodystrophy center, working in

collaboration with local pediatricians and health care providers. As guided by the patient’s changing needs,

the team may include geneticists and genetic counselors, neurologists, complex care pediatricians,

pulmonologists and respiratory therapists, gastroenterologists, speech therapists, endocrinologists,

physiatrists, orthopedic surgeons and physical/occupational therapists, specialists in palliative and hospice

care, and social workers.

9.1. About the Global Leukodystrophy Initiative

The Global Leukodystrophy Initiative (GLIA), a consortium of leukodystrophy experts and patient

advocates, was founded in 2013 with the aim of standardizing guidelines for the diagnosis and management

of leukodystrophies. For more information, or to join our organization, please visit us at theglia.org or

contact the GLIA Coordinator, Omar Sherbini, at (215) 590-3068.

Conflicts of Interest

As members of GLIA, we participate in clinical and research programs dedicated to the care of

leukodystrophy patients. DS President and Chair of the Board at the MLD Foundation. DH is a member of

GLIA and is the President and Chair of the Board of the PMD Foundation, and the Leukodystrophy

Alliance. Otherwise, there are no reports of conflicts of interest.

Funding Sources

The GLIA consensus meeting was funded in part by a grant from the Departments of Neurology

and Genetics at Children's National Medical Center and the members of the Leukodystrophy Alliance.

Additional funding includes, KV: Supported by grants from the Lucile Packard Foundation (salary support)

and the Child Neurology Foundation (research and salary support). JLB: Supported by the PCMC

Foundation, NIH DP2 MH100008, March of Dimes Foundation research grant, and the Vanishing White

Matter Foundation. GB: Research Scholar Junior 1 award from the Fonds de Recherche du Québec en

Santé (FRQS) (2012-2016) and the New Investigator Salary Award from the Canadian Institutes for Health

Research (2017-2022). AV: Supported by grants from the National Institutes of Health, National Institute

of Neurologic Disorders and Stroke (1K08NS060695) and the Myelin Disorders Bioregistry Project.
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