Expanded Phenotypic Definition Identifies Hundreds of Potential Causative Genes for Leukodystrophies and Leukoencephalopathies

Urbik, Veronica M.; Schmiedel, Marilyn; Soderholm, Haille E.; Bonkowsky, Joshua L.

doi:10.1177/2329048x20939003

Cited by 7 publications

(7 citation statements)

References 21 publications

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“…Very few of them can improve over time [ 44 ]. To date, about 30 diseases have been classified as LDs [ 43 ] but in the last decade the number of LDs linked to specific gene mutations has consistently increased thanks to the improvements of the DNA sequencing technologies and the definition of effective imaging criteria for their diagnosis [ 42 , 43 , 47 ]. Currently, LD diagnosis follows a consequential step process encompassing a first supposed diagnosis, based on clinical and imaging evidence (by magnetic resonance imaging (MRI)), then a genetic test for confirmation [ 42 ].…”

Section: Leukodystrophies: Rare Disease Of the Cns Affecting Myelin Structure And Functionalitymentioning

confidence: 99%

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Lanciotti

Brignone

Macioce

et al. 2021

IJMS

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Astrocytes are very versatile cells, endowed with multitasking capacities to ensure brain homeostasis maintenance from brain development to adult life. It has become increasingly evident that astrocytes play a central role in many central nervous system pathologies, not only as regulators of defensive responses against brain insults but also as primary culprits of the disease onset and progression. This is particularly evident in some rare leukodystrophies (LDs) where white matter/myelin deterioration is due to primary astrocyte dysfunctions. Understanding the molecular defects causing these LDs may help clarify astrocyte contribution to myelin formation/maintenance and favor the identification of possible therapeutic targets for LDs and other CNS demyelinating diseases. To date, the pathogenic mechanisms of these LDs are poorly known due to the rarity of the pathological tissue and the failure of the animal models to fully recapitulate the human diseases. Thus, the development of human induced pluripotent stem cells (hiPSC) from patient fibroblasts and their differentiation into astrocytes is a promising approach to overcome these issues. In this review, we discuss the primary role of astrocytes in LD pathogenesis, the experimental models currently available and the advantages, future evolutions, perspectives, and limitations of hiPSC to study pathologies implying astrocyte dysfunctions.

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Section: Leukodystrophies: Rare Disease Of the Cns Affecting Myelin Structure And Functionalitymentioning

confidence: 99%

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Lanciotti

Brignone

Macioce

et al. 2021

IJMS

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“…Although genetic sequencing technologies have drastically evolved in recent years, identification and interpretation of rare variants associated with phenotypically similar but genetically heterogeneous diseases remains a challenge. Rare inherited white matter disorders, or leukodystrophies, can be especially difficult to genetically diagnose, given the growing number of causal genes associated with different disease subtypes ( 1 , 2 ). Clinical presentation can be similar between patients, involving typically progressive neurological manifestations such as cerebellar, pyramidal, and extrapyramidal features, with or without cognitive involvement ( 3 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing

et al. 2023

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IntroductionRare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.MethodsEach of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease.ResultsFollowing different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including TMEM106B, GJA1, AGA, POLR3A, and TUBB4A. We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas.DiscussionThis study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies.

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“…Most proposals for new ICD code development are only for a single code or a single disease, although we proposed more than 30 different new codes for leukodystrophies. There are now more than hundreds of distinct genetic diseases of the white matter, depending on the definition criteria used, 14,15 but only six unique ICD codes represent only four diseases. Because of the rapid advances in therapeutic development and in clinical trials, new specific ICD codes for different leukodystrophies were critically needed.…”

Section: Introductionmentioning

confidence: 99%

An introduction to ICD code development for pediatric neurology

Baker

Bonkowsky

2023

Annals of the Child Neurology Society

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ObjectiveQuerying large data sets in the United States is challenging due to limitations of International Classification of Diseases 10th edition Clinical Modification (ICD‐10‐CM) codes. ICD codes were developed for tracking mortality and for billing purposes but are also the most widely used data structure to represent clinically significant and distinct disorders. We report an approach for developing new ICD codes based on our work creating new codes for leukodystrophies.MethodsImportant steps in ICD‐10‐CM code development include working with the ICD‐10‐CM Coordination and Maintenance Committee, a subset of the National Center of Health Statistics (NCHS); working to ensure the code has the best placement and is appropriate for submission; presenting the code and accompanying proposal (rationale) at a Coordination and Maintenance Committee Meeting; and requesting letters of support and addressing concerns raised by various groups.ResultsWe describe the historical development of ICD codes as well as their current hierarchical structure. Important features for successful code development included consulting future ICD‐11‐CM code structure; determining which codes are most important to the community; having a multidisciplinary approach; and obtaining organizational and institutional support.ConclusionFocusing on the clinical importance of leukodystrophy codes was important for their approval. Although challenging, there is a route for new code development, and we were ultimately successful in obtaining approval for 10 new leukodystrophy ICD‐10‐CM codes. Understanding ICD codes and their structure, considering their usage for clinical and research work, and appreciating how new codes can be developed is important for the pediatric neurology community.

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Expanded Phenotypic Definition Identifies Hundreds of Potential Causative Genes for Leukodystrophies and Leukoencephalopathies

Cited by 7 publications

References 21 publications

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Human iPSC-Derived Astrocytes: A Powerful Tool to Study Primary Astrocyte Dysfunction in the Pathogenesis of Rare Leukodystrophies

Solving inherited white matter disorder etiologies in the neurology clinic: Challenges and lessons learned using next-generation sequencing

An introduction to ICD code development for pediatric neurology

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