Genetic White Matter Disorders Research Articles

Spectrum of Leukodystrophy and Genetic Leukoencephalopathy in Indian Population Diagnosed by Clinical Exome Sequencing and Clinical Utility.

Next-generation sequencing (NGS) has expedited the diagnostic process and unearthed many rare disorders in leukodystrophy (LD) and genetic leukoencephalopathy (gLE). Despite the progress in genomics, there is a paucity of data on the distribution of genetic white matter disorders (WMDs) and the diagnostic utility of NGS-based assays in a clinical setting. This study was initiated to explore the clinical, radiologic, and genetic spectrum of LD and gLE in the Indian population and also to estimate the diagnostic yield of clinical exome sequencing (CES). This is a retrospective descriptive analysis of patients with a diagnosis of genetic WMDs from a single tertiary referral center who had CES performed as part of the diagnostic evaluation between January 2016 and December 2021. The demographic, clinical, radiologic, and genetic data were collected. The variants were classified using the American College of Medical Genetics and Genomics criteria. Pathogenic and likely pathogenic variants were included in the calculation of the diagnostic yield. In the study period, 138 patients were clinically diagnosed with either LD or gLE, of which 86 patients underwent CES. Pathogenic variants, likely pathogenic variants, and variants of uncertain significance with phenotype match were seen in 40 (41.8%), 13 (29.1%), and 15 (15.2%) patients, respectively. The mean age at onset in these 68 patients was 6.35 years (range 1 month-39 years), and 38 (55.9%) were male. LDs and gLE were diagnosed in 31 and 37 patients, respectively. 56 patients (71.8%) had autosomal recessive inheritance. The common clinical presentations were developmental delay (23.5%), psychomotor regression (20.6%), progressive myoclonic epilepsy syndrome (19.1%), and spastic ataxia (14.7%). Myelin disorders (48.5%) and leuko-axonopathies (41.2%) were the commonest type of disorders. The most frequently identified genes were ARSA, CLN5, ABCD1, CLN6, TPP1, HEXA, and L2HGDH. The diagnostic yield of the study was 61.6% (53/86), which increased to 79.1% when VUS with phenotype match were included. This study demonstrated a high diagnostic yield from proband-only CES in the evaluation of genetic WMDs and should be considered as a first-line investigation for genetic diagnosis. This study provides Class IV evidence that proband-only clinical exome sequencing is a useful "first-line investigation" for patients with genetic white matter disorders.

Anything is better than nothing’: exploring attitudes towards novel therapies in leukodystrophy clinical trials

Background/AimLeukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers.MethodsAdults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts.Results5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options.ConclusionsInterviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes.

Dominant CST3 variants cause adult onset leukodystrophy without amyloid angiopathy.

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level.

Genotypic and phenotypic heterogeneity among Chinese pediatric genetic white matter disorders

BackgroundThe pediatric genetic white matter disorders are characterized by a broad disease spectrum. Genetic testing is valuable in the diagnosis. However, there are few studies on the clinical and genetic spectrum of Chinese pediatric genetic white matter disorders.MethodsThe participants were enrolled from the cohort of Peking Union Medical College Hospital. They all received history collection, brain MRI and gene sequencing. Their neurologic complaints which were related to white matter disorders occurred before 18. Brain MRI indicated periventricular and/or deep white matter lesions, fazekas grade 2–3.ResultsAmong the 13 subjects, there were 11 males and two females. The average age of onset was 10.0 ± 5.5 years old. The potential genetic variants were found in 84.6% (11/13) subjects. The ABCD1 showed the greatest mutation frequency (30.8%, 4/13). The EIF2B3 A151fs, EIF2B4 c.885 + 2T > G, EIF2B5 R129X and MPV17 Q142X were novel pathogenic/likely pathogenic variants. 100% (4/4) ABCD1 carriers were accompanied by visual impairment, whereas 100% (3/3) EIF2B carriers developed dysuria. 100% (4/4) ABCD1 carriers exhibited diffuse white matter hyperintensities mainly in the posterior cortical regions, while the EIF2B4 and EIF2B5 carriers were accompanied by cystic degeneration.ConclusionThere is genotypic and phenotypic heterogeneity among Chinese subjects with pediatric genetic white matter disorders. The knowledge of these clinical and genetic characteristics facilitates an accurate diagnosis of these diseases.

Decreased RNA polymerase III Expression Leads to Several Defects in Oligodendrocyte-Lineage Development (P12-9.009)

<h3>Objective:</h3> To characterize the role of RNA polymerase III (Pol III) in oligodendrocyte development. <h3>Background:</h3> Hypomyelinating leukodystrophies are a heterogeneous group of rare, genetic white matter disorders characterized by insufficient myelin deposition in development. They typically present in early development and lead to progressive neurodegeneration and premature death in the months to years following onset. RNA polymerase III-related hypomyelinating leukodystrophy (POLR3-HLD) is one of the most common hypomyelinating leukodystrophies and arises from biallelic pathogenic variants in genes encoding subunits of Pol III, a ubiquitous enzymatic complex. Myelin, produced by oligodendrocytes (OLs) in the central nervous system, insulates axons, enabling efficient propagation of action potentials. As the constitutive nature of Pol III would suggest a multi-system organ disease, it is unclear why OLs are particularly vulnerable to reduced Pol III activity to explain the devastating hypomyelination seen in POLR3-HLD. <h3>Design/Methods:</h3> Oligodendrocyte precursor cells (OPCs) undergo a complex developmental process to become OLs. Therefore, we hypothesized that reduced Pol III activity would lead to defective OL-lineage development, either in the 1) migration and proliferation of OPCs, 2) maturation of OPCs into OLs and/or 3) myelination. To investigate this, primary murine OPCs were isolated and transfected with siRNA targeting <i>Polr3a, Polr3b</i> or <i>Polr1c</i> and subjected to various <i>in vitro</i> assays. <h3>Results:</h3> Our data shows that reducing Pol III activity leads to a maturation defect, as evidenced by reduced morphological complexity and decreased expression of late-stage OL markers. Apoptotic marker staining indicates these cells remain alive. Analysis of the OPC stage demonstrated abnormal proliferation, while migration was unaffected. Ongoing myelination assays suggest this altered oligodendrogenesis impacts myelination. <h3>Conclusions:</h3> Our results suggest a role for Pol III in normal OL development, providing valuable insight into the cellular mechanisms underlying myelination failure in POLR3-HLD. <b>Disclosure:</b> Ms. Macintosh has nothing to disclose. Mackenzie A. Michell-Robinson has nothing to disclose. Dr. Chen has nothing to disclose. Geneviève Bernard has nothing to disclose.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services

BackgroundNext generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AimThis study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. MethodsTwenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. ResultsCausative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DiscussionThese results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. ConclusionsGenetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.

Background and ObjectivesGenetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes.MethodsA case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient.ResultsWe evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD.DiscussionOur strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.

Epidemiological, clinical, and genetic characteristics of paediatric genetic white matter disorders in Northern Finland.

To examine the epidemiological, clinical, and genetic characteristics of paediatric patients with genetic white matter disorders (GWMDs) in Northern Finland. A longitudinal population-based cohort study was conducted in the tertiary catchment area of Oulu University Hospital from 1990 to 2019. Patients were identified retrospectively by International Statistical Classification of Diseases and Related Health Problems codes in hospital records and prospectively by attending physicians. Inclusion criteria were children younger than 18 years with defined GWMDs or genetic disorders associated with white matter abnormalities (WMAs) on brain magnetic resonance imaging. Eighty patients (mean age [SD] at the end of the study 11y [8y 6mo], range 0-35y; 45 males, 35 females) were diagnosed with a defined GWMD. The cumulative childhood incidence was 30 per 100000 live births. Regarding those patients with 49 distinct GWMDs, 20% had classic leukodystrophies and 80% had genetic leukoencephalopathies. The most common leukodystrophies were cerebral adrenoleukodystrophy, Krabbe disease, and Salla disease. Additionally, 29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders. Aetiology was mitochondrial in 21% of patients. The most common clinical findings were motor developmental delay, intellectual disability, hypotonia, and spasticity. The cumulative childhood incidence of childhood-onset GWMDs was higher than previously described. Comprehensive epidemiological and natural history data are needed before future clinical trials are undertaken. What this paper adds Forty-nine distinct genetic white matter disorders (GWMDs) were identified, with 20% of cases being classic leukodystrophies. The cumulative childhood incidence of GWMDs was higher than described previously. A considerable proportion (36%) of GWMDs were previously undefined or recently characterised GWMDs. Mitochondrial aetiology was more common (21%) than previously reported.

New insights into genetic white matter disorders.

This commentary is on the original article by Knuutinen et al. on pages 1066–1074 of this issue.

Hypomyelinating leukodystrophies - unravelling myelin biology.

Hypomyelinating leukodystrophies constitute a subset of genetic white matter disorders characterized by a primary lack of myelin deposition. Most patients with severe hypomyelination present in infancy or early childhood and develop severe neurological deficits, but the clinical presentation can also be mild with onset of symptoms in adolescence or adulthood. MRI can be used to visualize the process of myelination in detail, and MRI pattern recognition can provide a clinical diagnosis in many patients. Next-generation sequencing provides a definitive diagnosis in 80-90% of patients. Genes associated with hypomyelination include those that encode structural myelin proteins but also many that encode proteins involved in RNA translation and some lysosomal proteins. The precise pathomechanisms remain to be elucidated. Improved understanding of the process of myelination, the metabolic axonal support functions of myelin and the proposed contribution of myelin to CNS plasticity provide possible explanations as to why almost all patients with hypomyelination experience slow clinical decline after a long phase of stability. In this Review, we provide an overview of the hypomyelinating leukodystrophies, the advances in our understanding of myelin biology and of the genes involved in these disorders, and the insights these advances have provided into their clinical presentations and evolution.

Neurogenic Bladder and Acute Kidney Injury in Leukodystrophy

Leukodystrophies are genetic white matter disorders. In the young, they represent an important cause of progressive neurological disability. Impairment of the bladder function may be part of the clinical picture of leukodystrophies. A neurogenic bladder is a dysfunctional urinary bladder caused by a disease of the central or peripheral nervous system involved in the control of micturition. In our patient, leukodystrophy-induced neurogenic bladder and acute kidney injury were revealed. If untreated, a neurogenic bladder can cause renal failure and urinary incontinence. Patients with a neurogenic bladder should be monitored, and management should aim to preserve renal function and achieve social continence.

Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders.

Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. 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. 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. 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.

Genome sequencing in persistently unsolved white matter disorders.

Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease‐associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.

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

Background:The genes responsible for genetic white matter disorders (GWMD; leukodystrophies and leukoencephalopathies) are incompletely known. Our goal was to revise the list of genes considered to cause GWMD. We considered a GWMD to consist of any genetic disease causing T2 signal white matter changes in magnetic resonance images.Methods and Results:Using a systematic review of PubMed, Google, published literature reviews, and commercial gene panels, we identified 399 unique genes meeting the GWMD definition. Of this, 87 (22%) genes were hypomyelinating. Only 3 genes had contrast enhancement on magnetic resonance imaging (MRI): ABCD1, GFAP, and UNC13D.Conclusions:A significantly greater number of genes than previously recognized, 399, are associated with white matter signal changes on T2 MRI. This expansion of GWMD genes can be useful in analysis and interpretation of next-generation sequencing results for GWMD diagnosis, and for understanding shared pathophysiological mechanisms of GWMDs.

Neuroimmunology-the past, present and future.

SummaryNeuroimmunology as a separate discipline has its roots in the fields of neurology, neuroscience and immunology. Early studies of the brain by Golgi and Cajal, the detailed clinical and neuropathology studies of Charcot and Thompson’s seminal paper on graft acceptance in the central nervous system, kindled a now rapidly expanding research area, with the aim of understanding pathological mechanisms of inflammatory components of neurological disorders. While neuroimmunologists originally focused on classical neuroinflammatory disorders, such as multiple sclerosis and infections, there is strong evidence to suggest that the immune response contributes to genetic white matter disorders, epilepsy, neurodegenerative diseases, neuropsychiatric disorders, peripheral nervous system and neuro‐oncological conditions, as well as ageing. Technological advances have greatly aided our knowledge of how the immune system influences the nervous system during development and ageing, and how such responses contribute to disease as well as regeneration and repair. Here, we highlight historical aspects and milestones in the field of neuroimmunology and discuss the paradigm shifts that have helped provide novel insights into disease mechanisms. We propose future perspectives including molecular biological studies and experimental models that may have the potential to push many areas of neuroimmunology. Such an understanding of neuroimmunology will open up new avenues for therapeutic approaches to manipulate neuroinflammation.

Astroglia in Leukodystrophies.

Leukodystrophies are genetically determined disorders affecting the white matter of the central nervous system. The combination of MRI pattern recognition and next-generation sequencing for the definition of novel disease entities has recently demonstrated that many leukodystrophies are due to the primary involvement and/or mutations in genes selectively expressed by cell types other than the oligodendrocytes, the myelin-forming cells in the brain. This has led to a new definition of leukodystrophies as genetic white matter disorders resulting from the involvement of any white matter structural component. As a result, the research has shifted its main focus from oligodendrocytes to other types of neuroglia. Astrocytes are the housekeeping cells of the nervous system, responsible for maintaining homeostasis and normal brain physiology and to orchestrate repair upon injury. Several lines of evidence show that astrocytic interactions with the other white matter cellular constituents play a primary pathophysiologic role in many leukodystrophies. These are thus now classified as astrocytopathies. This chapter addresses how the crosstalk between astrocytes, other glial cells, axons and non-neural cells are essential for the integrity and maintenance of the white matter in health. It also addresses the current knowledge of the cellular pathomechanisms of astrocytic leukodystrophies, and specifically Alexander disease, vanishing white matter, megalencephalic leukoencephalopathy with subcortical cysts and Aicardi-Goutière Syndrome.

Case definition and classification of leukodystrophies and leukoencephalopathies.

An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders.

Relative Incidence of Inherited White Matter Disorders in Childhood to Acquired Pediatric Demyelinating Disorders

Epidemiologic frequencies of pediatric white matter disorders as a class have not been well defined. This is particularly true of genetic disorders of the white matter of the brain. In this study, ICD-9 codes were used to estimate relative incidence rates and descriptive statistics of leukodystrophies, other genetic leukoencephalopathies and acquired demyelinating disease among children residing in the Washington, D.C. metropolitan area. Children being treated at US children's hospitals between January 1, 2004, and December 31, 2009, for acquired demyelinating disease or genetic white matter disorders were captured using the Pediatric Health Information System and the Physician Practice Management system and validated with local electronic medical records. Comparisons were made between genetic white matter disorders and acquired demyelinating disorders, to determine differences in incidence, age, gender, ethnicity, and mortality. Genetic causes of white matter disease identified with ICD-9 codes had an estimated incidence of 1.2/100,000 children in the Washington, DC area. What was of interest was nearly 5 out of 10 cases of pediatric white matter disease of any etiology were attributable to genetic causes. When only progressive white matter diseases were considered, 7 out of 10 cases were attributable to genetic causes, and only 3 out of 10 to progressive acquired demyelinating disease such as multiple sclerosis. These findings signify the important contribution of heritable white matter disorders to pediatric neurologic disease in the Washington, DC, metro area as well as throughout the United States. Continued research of these understudied disorders should compare disease incidence and determinants to validate these findings in different populations.

Unraveling the Leukodystrophies: Clinical, Biochemical and Molecular Studies of Sixty Brazilian Patients with Genetic White Matter Disorders

Method: All patients were evaluated in neurogenetics clinics. A full medical history was taken and the following were performed: neuroimaging studies (CT, MRI with spectroscopy), ophthalmologic and auditory evaluations, neurophysiologic studies (EEG, ERG, EMG/ NCV), hormone and biochemical tests, muscle biopsy with OXPHOS analysis, screening for IEMs (lysosomal studies; peroxisomal/sterol panels; cholestanol dosage; organic acids, sulfatides and aminoacid chromatography; analysis of GAG) and, when indicated, nerve/skin biopsy for EM studies, karyotype and molecular tests. Results: In forty patients it was possible to establish a diagnosis for the leukodystrophy. X-ALD, metachromatic leukodystrophy and Krabbe disease were the commonest inborn errors of metabolism implicated in the pathophysiological of the “metabolic leukodystrophies”. Infantile Refsum disease, Canavan disease, AMACR deficiency, Niemann-Pick type C were other rare IEMs diagnosed. It was worthy of note the fact that Vanishing White Matter disease was a leading cause of leukodystrophies in our patients (eight patients). Conclusion: Almost 50% of patients with white matter abnormalities remain without a specific diagnosis even after an exhaustive investigation. Therefore a specific protocol for investigation is crucial. Treatment options are becoming a reality for some disorders, so reaching a specific diagnosis is important so that patients can be offered appropriate therapeutics.

Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases

Background: In order to identify biomarkers useful for the diagnosis of genetic white matter disorders we compared the metabolic profile of patients with leukodystrophies with a hypomyelinating or a non-hypomyelinating MRI pattern. Methods: We used a non-a priori method of in vitro 1H-NMR spectroscopy on CSF samples of 74 patients with leukodystrophies. Results: We found an elevation of CSF N-acetylaspartylglutamate (NAAG) in patients with Pelizaeus–Merzbacher disease (PMD)— PLP1 gene, Pelizaeus–Merzbacher-like disease— GJC2 gene and Canavan disease— ASPA gene. In the PMD group, NAAG was significantly elevated in the CSF of all patients with PLP1 duplication (19/19) but was strictly normal in 6 out of 7 patients with PLP1 point mutations. Additionally, we previously reported increased CSF NAAG in patients with SLC17A5 mutations. Conclusions: Elevated CSF NAAG is a biomarker that suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Our findings also point to unique pathological functions of the overexpressed PLP in PMD patients with duplication of this gene.