Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies

Adang, Laura; Sherbini, Omar; Ball, Laura J.; Bloom, Miriam; Darbari, Anil; Amartino, Hernán; DiVito, Donna; Eichler, Florian; Escolar, Maria L.; Evans, Sarah Helen; Fatemi, Ali; Fraser, Jamie L.; Hollowell, Leslie; Jaffe, Nicole; Joseph, Christopher; Karpinski, Mary; Keller, Stephanie; Maddock, Ryan M.; Mancilla, Edna E.; B, McClary; Mertz, Jana; Morgart, Kiley; Langan, Thomas J.; Leventer, Richard J.; Parikh, Sumit; Pizzino, Amy; Prange, Erin O'Connor; Renaud, Deborah L.; Rizzo, William B.; Shapiro, Jay R.; Suhr, Dean; Suhr, Teryn; Tonduti, Davide; Waggoner, Jacque; Waldman, Amy; Wolf, Nicole I.; Zerem, Ayelet; Bonkowsky, Joshua L.; Bernard, Geneviève; Haren, Keith Van; Vanderver, Adeline

doi:10.1016/j.ymgme.2017.08.006

Cited by 55 publications

(47 citation statements)

References 105 publications

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“…Pain related to neuropathy, dystonia, and spasticity is typically observed across the leukodystrophies. 5,54,57 Patients may begin to experience gastrointestinal symptoms including gastroesophageal reflux and chronic constipation resulting from autonomic dysfunction. Pain resulting from feeding intolerance is common as dysphagia develops during the course of the disease.…”

Section: Screening: Pediatric Pain Intensity Scalesmentioning

confidence: 99%

“…Gastrointestinal dysmotility 5 Pain and spasticity 6 Dysautonomia 5 Circadian rhythm disorders 20 Exaggerated myoclonic jerks 6,21 Environmental factors: nighttime nursing care, feedings, and suctioning 22…”

Section: Common Etiologies To Considermentioning

confidence: 99%

“…Reflux 56 Spasticity, dystonia 5,54,57 Contractures 6 Scoliosis 6 Joint dislocation 6 Pressure injuries 6 Compression fractures 58 Constipation, feeding intolerance ,60 Urinary retention 6 Urinary tract infections 6 Corneal abrasions 5…”

Section: Language and Cognitionmentioning

confidence: 99%

“…Children with any form of symptomatic leukodystrophy may benefit from physical, occupational, and/or speech therapy services. 5 These services are often provided through early intervention to children younger than 3 years. Among children older than 3 years with a disability, services may in part be provided through the US school system.…”

Section: Treatment: Speech Therapy and Communication Devicesmentioning

confidence: 99%

“…5 In the evaluation of a patient's individual communication needs, cognition, language, vision, hearing, and physical skills should all be considered. 5 For children with anticipated hearing or vision impairment, initiation of sign language and Braille education should begin early if cognitively appropriate. Social workers or education advocates may help families work with the school system to obtain an individualized education plan and appropriate therapies.…”

Section: Treatment: Speech Therapy and Communication Devicesmentioning

confidence: 99%

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Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies

et al. 2020

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Leukodystrophies are a group of neurodegenerative genetic disorders that affect approximately 1 in 7500 individuals. Despite therapeutic progress in individual leukodystrophies, guidelines in neurologic care are sparse and consensus among physicians and caregivers remains a challenge. At patient advocacy meetings hosted by Hunter’s Hope from 2016-2018, multidisciplinary experts and caregivers met to conduct a literature review, identify knowledge gaps and summarize best practices regarding neurologic care. Stages of severity in leukodystrophies guided recommendations to address different levels of need based on a newly defined system of disease severity. Four core neurologic domains prioritized by families were identified and became the focus of this guideline: sleep, pain, seizures/epilepsy, and language/cognition. Based on clinical severity, the following categories were used: presymptomatic, early symptomatic, intermediate symptomatic, and advanced symptomatic. Across the leukodystrophies, neurologic care should be tailored to stages of severity while accounting for unique aspects of every disease and multiple knowledge gaps present. Standardized tools and surveys can help guide treatment but should not overburden families.

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Section: Screening: Pediatric Pain Intensity Scalesmentioning

confidence: 99%

Section: Common Etiologies To Considermentioning

confidence: 99%

Section: Language and Cognitionmentioning

confidence: 99%

Section: Treatment: Speech Therapy and Communication Devicesmentioning

confidence: 99%

Section: Treatment: Speech Therapy and Communication Devicesmentioning

confidence: 99%

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Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies

et al. 2020

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Randomized Clinical Trial ofFirst‐LineGenome Sequencing in Pediatric White Matter Disorders

Vanderver

Bernard

Helman

et al. 2020

Annals of Neurology

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Objective Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. Methods A prospective time‐delayed crossover design trial of GS to assess the efficacy of GS as a first‐line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. Results Thirty‐four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed‐GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild–Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild–Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate‐GS group (log‐rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8–89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single‐arm observational study. Interpretation In this study, first‐line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence‐based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264–273.

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Oligodendrocytes are susceptible to Zika virus infection in a mouse model of perinatal exposure: Implications for CNS complications

Schultz

Barrie

Donald

et al. 2021

Glia

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Some children with proven intrauterine Zika virus (ZIKV) infection who were born asymptomatic subsequently manifested neurodevelopmental delays, pointing to impairment of development perinatally and postnatally. To model this, we infected postnatal day (P) 5–6 (equivalent to the perinatal period in humans) susceptible mice with a mammalian cell‐propagated ZIKV clinical isolate from the Brazilian outbreak in 2015. All infected mice appeared normal up to 4 days post‐intraperitoneal inoculation (dpi), but rapidly developed severe clinical signs at 5–6 dpi. All nervous tissue examined at 5/6 dpi appeared grossly normal. However, anti‐ZIKV positive cells were observed in the optic nerve, brain, and spinal cord; predominantly in white matter. Co‐labeling with cell type specific markers demonstrated oligodendrocytes and astrocytes support productive infection. Rarely, ZIKV positive neurons were observed. In spinal cord white matter, which we examined in detail, apoptotic cells were evident; the density of oligodendrocytes was significantly reduced; and there was localized microglial reactivity including expression of the NLRP3 inflammasome. Together, our observations demonstrate that a clinically relevant ZIKV isolate can directly impact oligodendrocytes. As primary oligodendrocyte cell death can lead later to secondary autoimmune demyelination, our observations may help explain neurodevelopmental delays in infants appearing asymptomatic at birth and commend lifetime surveillance.

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Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies

Cited by 55 publications

References 105 publications

Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies

Practical Approaches and Knowledge Gaps in the Care for Children With Leukodystrophies

Randomized Clinical Trial ofFirst‐LineGenome Sequencing in Pediatric White Matter Disorders

Oligodendrocytes are susceptible to Zika virus infection in a mouse model of perinatal exposure: Implications for CNS complications

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