Dataset Information

The burden of inherited leukodystrophies in children.

ABSTRACT:

Objectives

Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies.

Methods

We conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional children's hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates.

Results

A total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were $22,579. Population incidence was 1 in 7,663 live births.

Conclusions

Inherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.

SUBMITTER: Bonkowsky JL

PROVIDER: S-EPMC2931652 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Publications

The burden of inherited leukodystrophies in children.

Bonkowsky J L JL Nelson C C Kingston J L JL Filloux F M FM Mundorff M B MB Srivastava R R

Neurology 20100721 8

<h4>Objectives</h4>Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies.<h4>Methods</h4>We conducted a retrospective, hospi ...[more]

PMID: 20660364

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Project description:IMPORTANCE:The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE:To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN:Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING:Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS:A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS:Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES:Mutations in CSF1R. RESULTS:We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE:These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.

Project description:Background and purposeAchieving a specific diagnosis in leukodystrophies is often difficult due to clinical and genetic heterogeneity. Mitochondrial defects cause 5%-10% of leukodystrophies. Our objective was to define MR imaging features commonly shared by mitochondrial leukodystrophies and to distinguish MR imaging patterns related to specific genetic defects.Materials and methodsOne hundred thirty-two patients with a mitochondrial leukodystrophy with known genetic defects were identified in the data base of the Amsterdam Leukodystrophy Center. Numerous anatomic structures were systematically assessed on brain MR imaging. Additionally, lesion characteristics were scored. Statistical group analysis was performed for 57 MR imaging features by hierarchic testing on clustered genetic subgroups.ResultsMR imaging features indicative of mitochondrial disease that were frequently found included white matter rarefaction (n = 50 patients), well-delineated cysts (n = 20 patients), T2 hyperintensity of the middle blade of the corpus callosum (n = 85 patients), and symmetric abnormalities in deep gray matter structures (n = 42 patients). Several disorders or clusters of disorders had characteristic features. The combination of T2 hyperintensity in the brain stem, middle cerebellar peduncles, and thalami was associated with complex 2 deficiency. Predominantly periventricular localization of T2 hyperintensities and cystic lesions with a distinct border was associated with defects in complexes 3 and 4. T2-hyperintense signal of the cerebellar cortex was specifically associated with variants in the gene NUBPL. T2 hyperintensities predominantly affecting the directly subcortical cerebral white matter, globus pallidus, and substantia nigra were associated with Kearns-Sayre syndrome.ConclusionsIn a large group of patients with a mitochondrial leukodystrophy, general MR imaging features suggestive of mitochondrial disease were found. Additionally, we identified several MR imaging patterns correlating with specific genotypes. Recognition of these patterns facilitates the diagnosis in future patients.

Project description:BACKGROUND: The concept of individual burden, associated with disease, has been introduced recently to determine the "disability" caused by the pathology in the broadest sense of the word (psychological, social, economic, physical). Inherited ichthyosis belong to a large heterogeneous group of Mendelian Disorders of Cornification. Skin symptoms have a major impact on patients' Quality of Life but little is known about the burden of the disease on the families of patients. OBJECTIVES: To develop and validate a specific burden questionnaire for the families of patients affected by ichthyosis. METHODS: Two steps were required. First, the creation of the questionnaire which followed a strict methodological process involving a multidisciplinary team and families. Secondarily, the validation of the questionnaire, including the assessment of its reliability, external validity, reproducibility and sensitivity, was carried out on a population of patients affected by autosomal recessive congenital ichthyosis. A population of parents of patients affected by ichthyosis was enrolled to answer the new questionnaire in association with the Short Form Q12 questionnaire (SF-12) and a clinical severity score was filled for each patient. RESULTS: Ninety four families were interviewed to construct the verbatim in order to create the questionnaire and a cognitive debriefing was realized. The concept of burden could be structured around five components: "economic", "daily life", "familial and personal relationship", "work", and "psychological impact". As a result, "Family Burden Ichthyosis" (FBI) reproducible questionnaire of 25 items was created.Forty two questionnaires were analyzable for psychometric validation. Reliability (Cronbach's alpha coefficient?=?0.89), reflected the good homogeneity of the questionnaire. The correlation between mental dimensions of the SF-12 and the FBI questionnaire was statistically significant which confirmed the external validity. The mean FBI score was 71.7?±?18.8 and a significant difference in the FBI score was shown between two groups of severity underlining a good sensitivity of the questionnaire. CONCLUSIONS: The internal and external validity of the "FBI" questionnaire was confirmed and it is correlated to the severity of ichtyosis. Ichthyoses, and other chronic pathologies, are difficult to assess by clinical or Quality of Life aspects alone as their impact can be multidimensional. "FBI" takes them all into consideration in order to explain every angle of the handicap generated.

Dataset Information

The burden of inherited leukodystrophies in children.

Objectives

Methods

Results

Conclusions

Publications

The burden of inherited leukodystrophies in children.

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