Diagnosis Of Leukodystrophy Research Articles

Leukodytrophy in Children: 12 Cases

Introduction: Leukodystrophies are a rare geneLc disease characterized by damage of the myelin sheath. They represent a large number of diseases that are heterogeneous by their clinical and physiopathological aspects. Material and Methods: We report 12 cases of leukodystrophies collected at the Neuropediatric Unit of Abderrahim Harouchi Mother and Child Hospital CHU Ibn Rochd, Casablanca, Morocco. Results: The average age of diagnosis was 2 years and 9 months, with a predominance of females (sex raLo:0.33). Consanguinity was found in 5 cases. The onset symptomatology was dominated by psychomotor regression, found in 8 paLents, and seizures in 4 paLents. Motor signs were in the foreground: pyramidal syndrome in 5 cases, hypotonia in 4 cases, tetraparesis in 1 case, dysarthria in 1 case. The lumbar puncture, carried out in 4 paLents, revealed hyperproteinorachy in 3 cases, glycorachy and cytological study were normal. We noLced a decreased level of Aryllsulfatase A in 6 cases. Imaging was performed in all paLents and showed diffuse white ma]er demyelinaLon. MRI allowed us to classify our cases and showed 7 cases of metachromaLc leukodystrophy, 1 case of cavitary leukodystrophy, 1 case of Refsum disease, 1 case of Canavan disease, 1 case of Cockaynes syndrome and 1 case of adrenoleukodystrophy. The electroneuromyogram showed a decrease in nerve conducLon velociLes in 2 cases. Molecular study was performed in one paLent finding a hyccin mutaLon. Conclusion: The diagnosis of leukodystrophies is o_en difficult because of their clinical heterogeneity. The partnership of clinicians with geneLcists may be the key point to improve diagnosis and therapeuLc management.

A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies

ObjectiveMitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. MethodsThis study summarizes the clinical, imaging, and molecular data of these patients for five years. ResultsThe three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. ConclusionsThe findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

Clinical and Neurophysiological Features of Epilepsy in Pediatric Patients with Vanishing White Matter Disease-A single institute experience and literature review (P12-9.006)

<h3>Objective:</h3> Refractory epilepsy is a common presentation in Vanishing white matter disease (VWMD) patients. However, there is little literature describing the nature and evolution of seizures. We aim to study the electroencephalograpic findings in patients with a genetically confirmed diagnosis of VWMD, and their correlation with MRI progression and clinical status longitudinally. <h3>Background:</h3> Vanishing White Matter Disease (VWMD) is one of the most prevalent leukodystrophies in pediatric patients with unique clinical, pathological, and molecular features. It mostly affects children, but may develop at all ages, from birth to senescence. Incidence in one study is reported to be 1 in 80,000 live births. The molecular basis of the disease has been shown to be due to mutations in subunits of Eukaryotic Translation Initiation Factor 2B (eIF2B) ie eIF2B 1–5. <h3>Design/Methods:</h3> An IRB approved retrospective chart review was conducted at Children’s Medical Center, Dallas TX. The initial search pulled up 42 patients that had an associated diagnosis of leukodystrophy. Four of these 42 patients were found to have a genetically confirmed diagnosis of VWMD. <h3>Results:</h3> In our cohort, there were 3males and 1female. Age of diagnosis ranged between 2–10 years and mutations in EIF2B5 was the most common. The earliest seizure onset was noted at 2 years of age at the time of diagnosis. Patients that presented with intractable seizures were noted to have significant MRI changes. Average time of seizure onset from time of diagnosis was 1.6 years. Our patient that was diagnosed with VWMD at 10 years of age did not go on to develop seizures and his EEG did not have any epileptiform discharges. His MRI did not show significant white matter changes and clinically patient had mild to moderate deficits. <h3>Conclusions:</h3> We observe that there is a wide range of severity of epilepsy in these patients &amp; not all patients with a diagnosis of VWMD go on to develop seizures. <b>Disclosure:</b> Dr. Laheji has nothing to disclose. Dr. Lowden has nothing to disclose.

Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1.

Cerebral adrenoleukodystrophy (CALD) is a fatal genetic disease characterized by rapid, devastating neurological decline, with a narrow curative treatment window in the early stage. Non-canonical splice-site (NCSS) variants can easily be missed during genomic DNA analyses, and only a few of them in ABCD1 have been explored. Here, we studied a Chinese patient with clinical features similar to those of early-stage CALD but with a negative molecular diagnosis and a sibling who had presumably died of CALD. Trio-based whole-exome sequencing (trio-WES) and RNA sequencing (RNA-Seq) revealed a novel hemizygote NCSS variant c.901-25_901-9 del in ABCD1 intron 1, resulting in a complex splicing pattern. The in vitro minigene assay revealed that the c.901-25_901-9 del construct contained two aberrant transcripts that caused skipping of exon 2 and a small 48-bp deletion on left of the same exon. We identified a novel NCSS variant, that extends the spectrum of the known ABCD1 variants, and demonstrated the pathogenicity of this gene variant. Our findings highlight the importance of combining RNA-Seq and WES techniques for prompt diagnosis of leukodystrophy with NCSS variants.

Reliability of the Telemedicine Application of the Gross Motor Function Measure-88 in Patients With Leukodystrophy

BackgroundLeukodystrophies are a rare class of disorders characterized by severe neuromotor disability. There is a strong need for research regarding the functional status of people with leukodystrophy which is limited by the need for in-person assessments of mobility. The purpose of this study is to assess the reliability of the Gross Motor Function Measure-88 (GMFM-88) using telemedicine compared with standard in-person assessments in patients with leukodystrophy. MethodsA total of 21 subjects with a diagnosis of leukodystrophy (age range = 1.79-52.82 years) were evaluated by in-person and by telemedicine evaluations with the GMFM-88 by physical therapists. Inter-rater reliability was assessed through evaluation of the same subject by two independent raters within a three-week period (n = 10 encounters), and intrarater reliability was assessed through blinded rescoring of video-recorded assessments after a one-week time interval (n = 6 encounters). ResultsRemote assessments were performed by caregivers in all 21 subjects using resources found in the home with remote guidance. There was agreement between all paired in-person and remote measurements (Lin's concordance correlation ≥0.995). The Bland-Altman analysis indicated that the paired differences were within ±5%. Intrarater and inter-rater reliability demonstrated an intraclass correlation coefficient of >0.90. ConclusionsThese results support that remote application of the GMFM-88 is a feasible and reliable approach to assess individuals with leukodystrophy. Telemedicine application of outcome measures may be of particular value in rare diseases and those with severe neurologic disability that impacts the ability to travel.

Leukodystrophies and Genetic Leukoencephalopathies in Children Specified by Exome Sequencing in an Expanded Gene Panel.

The overlapping clinical and neuroimaging phenotypes of leukodystrophies pose a diagnostic challenge to both clinicians and researchers alike. Studies on the application of exome sequencing in the diagnosis of leukodystrophies are emerging. We used targeted gene panel sequencing of 6440 genes to investigate the genetic etiology in a cohort of 50 children with neuroimaging diagnosis of leukodystrophy/genetic leukoencephalopathy of unknown etiology. These 50 patients without a definite biochemical or genetic diagnosis were derived from a cohort of 88 patients seen during a 2.5-year period (2015 January-2017 June). Patients who had diagnosis by biochemical or biopsy confirmation (n = 17) and patients with incomplete data or lack of follow-up (n = 21) were excluded. Exome sequencing identified variants in 30 (60%) patients, which included pathogenic or likely pathogenic variants in 28 and variants of unknown significance in 2. Among the patients with pathogenic or likely pathogenic variants, classic leukodystrophies constituted 13 (26%) and genetic leukoencephalopathies 15 (30%). The clinical and magnetic resonance imaging (MRI) findings and genetic features of the identified disorders are discussed.

Geographic and Specialty Access Disparities in US Pediatric Leukodystrophy Diagnosis

To examine disparities in the diagnosis of leukodystrophies including geographic factors and access to specialty centers. Retrospective cohort study of pediatric patients admitted to Pediatric Health Information System hospitals. Patients with leukodystrophy were identified with International Classification of Diseases, Tenth Revision, Clinical Modification diagnostic codes for any of 4 leukodystrophies (X-linked adrenoleukodystrophy, Hurler disease, Krabbe disease, and metachromatic leukodystrophy). We used 3-level hierarchical generalized logistic modeling to predict diagnosis of a leukodystrophy based on distance traveled for hospital, neighborhood composition, urban/rural context, and access to specialty center. We identified 501 patients with leukodystrophy. Patients seen at a leukodystrophy center of excellence hospital were 1.73 times more likely to be diagnosed than patients at non-center of excellence hospitals. Patients who traveled farther were more likely to be diagnosed than those who traveled shorter. Patients living in a Health Professionals Shortage Area zip code were 0.86 times less likely to be diagnosed than those living in a non-Health Professionals Shortage Area zip code. Geographic factors affect the diagnosis of leukodystrophies in pediatric patients, particularly in regard to access to a center with expertise in leukodystrophies. Our findings suggest a need for improving access to pediatric specialists and possibly deploying specialists or diagnostic testing more broadly.

TSEN54 missense variant in Standard Schnauzers with leukodystrophy.

We report a hereditary leukodystrophy in Standard Schnauzer puppies. Clinical signs occurred shortly after birth or started at an age of under 4 weeks and included apathy, dysphoric vocalization, hypermetric ataxia, intension tremor, head tilt, circling, proprioceptive deficits, seizures and ventral strabismus consistent with a diffuse intracranial lesion. Magnetic resonance imaging revealed a diffuse white matter disease without mass effect. Macroscopically, the cerebral white matter showed a gelatinous texture in the centrum semiovale. A mild hydrocephalus internus was noted. Histopathologically, a severe multifocal reduction of myelin formation and moderate diffuse edema without inflammation was detected leading to the diagnosis of leukodystrophy. Combined linkage analysis and homozygosity mapping in two related families delineated critical intervals of approximately 29 Mb. The comparison of whole genome sequence data of one affected Standard Schnauzer to 221 control genomes revealed a single private homozygous protein changing variant in the critical intervals, TSEN54:c.371G>A or p.(Gly124Asp). TSEN54 encodes the tRNA splicing endonuclease subunit 54. In humans, several variants in TSEN54 were reported to cause different types of pontocerebellar hypoplasia. The genotypes at the c.371G>A variant were perfectly associated with the leukodystrophy phenotype in 12 affected Standard Schnauzers and almost 1000 control dogs from different breeds. These results suggest that TSEN54:c.371G>A causes the leukodystrophy. The identification of a candidate causative variant enables genetic testing so that the unintentional breeding of affected Standard Schnauzers can be avoided in the future. Our findings extend the known genotype-phenotype correlation for TSEN54 variants.

Association of Diagnosis of Leukodystrophy With Race and Ethnicity Among Pediatric and Adolescent Patients

Inherited leukodystrophies are a group of neurological diseases affecting myelin that cause significant morbidities and death. Timely and correct diagnosis is important for initiating treatment, designing disease screening, and offering care and guidance to patients and families. To determine whether there are disparities in leukodystrophy diagnosis in different racial backgrounds. This case-control study involved a retrospective review of patients aged 18 years or younger who were diagnosed with 1 of 4 leukodystrophies (metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe disease, and Hurler disease) in the US Children's Hospital Association's Pediatric Health Information System database from October 1, 2015, through September 30, 2017. Leukodystrophy diagnosis and racial background of the patients were analyzed. Adjusted prevalence estimates of leukodystrophies were obtained by controlling for sex, insurance type, urban or rural status, 2010 median household income for patient zip code, number of inpatient days, and age at first visit. Pathogenic leukodystrophy gene allele frequencies in different racial backgrounds for ABCD1, ARSA, GALC, and IDUA were determined using the gnomAD database. Of the 557 patients identified with a leukodystrophy (221 [40%] female; 321 [58%] white non-Hispanic, 54 [10%] black non-Hispanic, and 51 [9%] white Hispanic; median [range] age, 7 [0-18] years), nonwhite race, including black non-Hispanic, black Hispanic, and white Hispanic, was associated with not having a leukodystrophy diagnosis. The adjusted prevalence for a leukodystrophy diagnosis in white non-Hispanic patients was 13.8 (95% CI, 10.6-17.9) per 100 000 patients, compared with 5.8 (95% CI, 3.8-8.9), 2.4 (95% CI, 1.1-5.2), and 7.4 (95% CI, 5.2-10.4) per 100 000 in black non-Hispanic, black Hispanic, and white Hispanic patients, respectively. This reduced rate of diagnosis was out of proportion to the frequency of the different races in the Pediatric Health Information System database. Similar or higher frequencies of missense or loss-of-function alleles were measured in populations of Latino and African descent for the pathogenic leukodystrophy gene alleles. For example, for ABCD1, allele frequencies in those of Latino or African descent were 2.1 × 10-5 and 2.2 × 10-5, as compared with 1.4 × 10-5 for those of European non-Finnish descent. Patients of racial/ethnic minorities, including those from black, black Hispanic, and white Hispanic backgrounds, were significantly less likely to be diagnosed with a leukodystrophy. Leukodystrophy disease-associated allele frequencies were the same or higher in populations of Latino or African descent, arguing against a genetic founder effect being responsible for the lower diagnosis rates. This underdiagnosis has implications for newborn screening programs and treatment access and may reflect a more widespread problem in pediatric neurological and orphan diseases.

Whole exome sequencing in patients with white matter abnormalities.

Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases. Ann Neurol 2016;79:1031-1037.

Proton MR Spectroscopy in leukodystrophies

ObjectiveTo analyze MR Spectroscopic findings and metabolite ratios in regions of abnormal signal in children with leukodystrophies. MethodsThis prospective study was carried out on twenty-six children (17 males and 9 females); median age, 36months±54 inter-quartile range. The imaging protocol included axial T1 and T2-weighted spin-echo and FLAIR images, and coronal and sagittal T2-weighted spin-echo images. 1H-MRSI was performed during the same session for all patients. Spectra were acquired from a volume of interest in the affected white matter and intravoxel (NAA/Cr, Cho/Cr, and Cho/NAA) ratios were calculated. ResultsSpectroscopic analysis revealed abnormal (NAA/Cr, Cho/Cr, and Cho/NAA) ratios. Some were highly characteristic and specific as markedly elevated NAA resonance peak in cases with Canavan’s disease and significantly elevated lactate resonance peak in Leigh disease and MELAS syndrome. In the majority of cases, elevated Cho/Cr, decreased NAA/Cr and elevated Cho/NAA ratios were the dominant finding. One-way analysis of variance for the spectroscopic metabolite ratios revealed statistical significance (p<0.0001). ConclusionProton MR Spectroscopy complementary to conventional MRI proved to be a valuable tool to establish the diagnosis of leukodystrophies.

A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies.

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.

Imaging of adult leukodystrophies.

Leukodystrophies are genetically determined white matter disorders. Even though leukodystrophies essentially affect children in early infancy and childhood, these disorders may affect adults. In adults, leukodystrophies may present a distinct clinical and imaging presentation other than those found in childhood. Clinical awareness of late-onset leukodystrophies should be increased as new therapies emerge. MRI is a useful tool to evaluate white matter disorders and some characteristics findings can help the diagnosis of leukodystrophies. This review article briefly describes the imaging characteristics of the most common adult leukodystrophies.

Leukodystrophy associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFAF1 gene

Mitochondrial energy metabolism disorder is one of the important reasons of leukodystrophy. Mutations of mitochondrial complex I genes have been implicated in more common neurological disorders such as Leigh syndrome. We describe a case of a child manifested as regression of mental and motor development, aggravated obviously after suffering infection. Physical and auxiliary examinations demonstrated that a series of changes including white matter lesions of magnetic resonance imaging, peripheral neuropathy with high muscle tension and hyperreflexia of limbs pointed to the diagnosis of leukodystrophy, with what can’t explain the high levels of lactate and creatine kinase. Spontaneously, genetic analysis covered known leukodystrophy and mitochondrial genes were adapted for this child and his parents. Results showed the child was compound heterozygous mutation (c.278A > G; c.247G > A) within exon 2 in the NDUFAF1 gene, his parents carried a heterozygous mutation each. The authors report a case of leukodystrophy associated with mitochondrial complex I deficiency due to a novel mutation in the NDUFAF1 gene. This is the first report that NDUFAF1 mutations cause leukodystrophy.

Diagnosis of mitochondrial neurogastrointestinal encephalopathy disease in gastrointestinal biopsies

A 14-year-old boy with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease had a lifelong history of failure to thrive and gastrointestinal symptoms including vomiting, pain, and diarrhea, leading to progressive cachexia. At the age of 9 years, after an extensive workup, the diagnosis of Crohn disease was strongly suspected, and he underwent colonoscopy with multiple biopsies. At 11 years of age, vision change and poor balance lead to a diagnosis of leukodystrophy by magnetic resonance imaging. Investigations for metachromatic leukodystrophy, adrenal leukodystrophy, and globoid cell leukodystrophy were all negative. A diagnosis of MNGIE disease was suspected when he continued deteriorating with gastrointestinal symptoms, multiple neurologic deficits, and encephalopathy. Markedly diminished thymidine phosphorylase activity and increased thymidine plasma levels confirmed the diagnosis of MNGIE. At autopsy, megamitochondria were observed by light microscopy in submucosal and myenteric ganglion cells and in smooth muscle cells of muscularis mucosae and muscularis propria, along the entire gastrointestinal tract from the esophagus to the rectum. Megamitochondria in ganglion cells were also observed in a retrospective review of the endoscopic intestinal biopsies taken at age 9 and 13 years and in the appendectomy specimen obtained 1 month before his demise. This study corroborates the presence of megamitochondria in gastrointestinal ganglion cells in MNGIE disease, better illustrates their detailed morphology, and describes for the first time similar structures in the cytoplasm of gastrointestinal smooth muscle cells. Pathologists should be able to recognize these structures by light microscopy and be aware of their association with primary mitochondriopathies.

Advances In the Diagnosis of Leukodystrophies

Leukodystrophies are a heterogeneous group of inherited disorders that preferentially affect the CNS white matter. They are classified as demyelinating (or classic) or hypomyelinating according to brain MRI characteristics. As these disorders often have a similar clinical presentation according to their age of onset, the initial diagnostic approach is often challenging. This review aims to help clinicians approach these disorders using information from the history (e.g., age of onset), the examination (e.g., presence of macrocrania) and MRI scans in order to reduce the number of possible diagnoses for a given patient and to hopefully lead to a precise (molecular) diagnosis.

Netzwerkprojekte für die Erforschung von Leukodystrophien, einer Gruppe seltener Erkrankungen der weißen Substanz des Nervensystems

Leukodystrophies are a group of rare, genetic diseases, which affect myelin, the major constituent of brain and spinal cord white matter. Patients suffer from numerous, progressive neurologic symptoms, which frequently cause death. The molecular defects causing leukodystrophies are heterogeneous. For some leukodystrophies the genetic cause is known, whereas for others the disease-causing gene has not yet been identified. Except for a few leukodystrophies, in which bone marrow transplantation is an option to prevent disease progression, curative therapy is not available. However, clinical trials involving gene therapy and enzyme replacement therapy have been initiated as a result of accomplishments in basic research. The development of magnetic resonance imaging and spectroscopy has improved the diagnosis of leukodystrophies. Nevertheless, due to the insidious and frequently non-characteristic onset of leukodystrophies and the fact that most primary physicians have never before encountered patients with these rare diseases, diagnosis is often delayed. In Germany, the Federal Ministry of Education and Research supports a network (LEUKONET), which aims to recruit most of the German leukodystrophy patients and, in addition, offers information for physicians, patients and relatives. All German clinical centers experienced in treating leukodystrophy patients participate in this network. The network also includes a number of basic researchers whose projects intend to elucidate the primary cause and pathogenesis of these disorders.

Diagnostic algorithm in leucodystrophies – How to catch the right diagnosis in a short time?

Progress in molecular genetics, biochemical techniques, and neuroimaging, particularly magnetic resonance imaging, have facilitate the diagnosis of a significant proportion of leukodystrophies. A specific diagnosis allows the physician to give prognostic information, monitor for known complications, and ultimately may allow disease specific therapeutics. The purpose of this talk is to offer a practical tool for the fast and efficient diagnosis of leukodystrophies and other white matter disorders that may present with white matter disease. Firstly, conditions will be presented that may mimic leukodystrophy and discussed how to exclude them. Key disorders and their clinical, biochemical, and neuroimaging features are presented. Secondly, the talk will focus on classically described leukodystrophies and their diagnosis. Finally, a practical diagnostic algorithm to help the clinicians in the diagnosis of the patient with leukodystrophy will be presented.

Magnetic resonance techniques in the assessment of myelin and myelination

Leukodystrophy is a common central nervous system manifestation of inborn errors of metabolism. Until magnetic resonance imaging (MRI) emerged as a clinical tool, the diagnosis of leukodystrophy was difficult and imprecise; MRI has allowed new understandings and classifications of leukodystrophies that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. However, optimal use of MRI in this setting requires a fundamental understanding of myelin structure, myelin development, and the changes seen on MRI with myelination and demyelination. The purpose of this review is to provide the reader with the necessary tools for the use of MRI to diagnose and follow patients with leukodystrophies.

Tools for diagnosis of leukodystrophies and other disorders presenting with white matter disease

Advances in biochemical techniques, molecular genetics, and neuroimaging, particularly magnetic resonance imaging, have made possible the diagnosis of a significant proportion of leukodystrophies. A specific diagnosis allows the physician to give prognostic information, monitor for known complications, and ultimately may allow disease specific therapeutics. The purpose of this review is to familiarize the reader with pertinent tools in the diagnosis of leukodystrophies and other white matter disorders that may present with white matter disease. The first section discusses conditions that may mimic leukodystrophy and how to exclude them. Although not meant to be an exhaustive summary, several key disorders and their clinical, biochemical, and neuroimaging features are presented. The second section focuses on classically described leukodystrophies and their diagnosis. Finally, a third section provides a diagnostic algorithm to help the clinician in the diagnosis of the patient with leukodystrophy.