Leukodystrophy Research Articles

Electrophysiologic studies in patients with Leukodystrophy

How to Cite This Article: Nafissi SH. Electrophysiologic studies in patients with Leukodystrophy. Iran J Child Neurol Autumn 2014;8:4 (suppl.1):8. Pls see pdf.

Neurometabolic Registry Site in Iran (Leukodystrophies)

How to Cite This Article: Ahmadabadi F. Neurometabolic Registry Site in Iran (Leukodystrophies). Iran J Child Neurol. Autumn 2014;8;4(Suppl.1):22. pls see pdf.

Leukodystrophies with Intracranial Calcifications

How to Cite This Article: Mahvelati Shamsabadi F. Leukodystrophies with Intracranial Calcifications. Iran J Child Neurol. Autumn 2014;8;4(Suppl.1):16-17. Pls see pdf.

Ethical management in the constitution of a European database for leukodystrophies rare diseases

BackgroundThe EU LeukoTreat program aims to connect, enlarge and improve existing national databases for leukodystrophies (LDs) and other genetic diseases affecting the white matter of the brain. Ethical issues have been placed high on the agenda by pairing the participating LD expert research teams with experts in medical ethics and LD patient families and associations. The overarching goal is to apply core ethics principles to specific project needs and ensure patient rights and protection in research addressing the context of these rare diseases. AimThis paper looks at how ethical issues were identified and handled at project management level when setting up an ethics committee. MethodsThrough a work performed as a co-construction between health professionals, ethics experts, and patient representatives, we expose the major ethical issues identified. ResultsThe committee acts as the forum for tackling specific issues tied to data sharing and patient participation: the thin line between care and research, the need for a charter establishing the commitments binding health professionals and the information items to be delivered. Ongoing feedback on the database, including delivering global results in a broad-audience format, emerged as a key recommendation. Information should be available to all patients in the partner countries developing the database and should be scaled to different patient profiles. ConclusionThis work led to a number of recommendations for ensuring transparency and optimizing the partnership between scientists and patients.

Leukodystrophy: When Gallbladder Offers a Clue to Diagnosis

Leukodystrophy: When Gallbladder Offers a Clue to Diagnosis

Death rates in the U.S. due to Krabbe disease and related leukodystrophy and lysosomal storage diseases

Leukodystrophies (LD) and lysosomal storage disorders (LSD) have generated increased interest recently as targets for newborn screening programs. Accurate epidemiological benchmarks are needed in the U.S. Age-specific mortality rates were estimated for Krabbe disease (KD) and nine related disorders. U.S. mortality records with E75.2 cause of death code during 1999-2004 were collected from 11 open record states. All E75.2 deaths in the United States were distributed into specific disease type based on proportions observed in these states. Yearly population sizes were obtained from the CDC and averaged. Mortality rates (per million individuals per year) by age group for the specific diseases were (for <5 or ≥5 years): Pelizaeus-Merzbacher (0.037/0.033); sudanophilic leukodystrophy (SLD) (0.037/0.004); Canavan (0.037/0.011), Alexander (0.147/0.022); Krabbe (0.994/0.007); metachromatic leukodystrophy (0.331/0.135); Fabry (0.000/0.124); Gaucher (0.221/0.073); Niemann-Pick (NP) (0.442/0.088); multiple sulfatase (0.000/0.004). This is the first report of mortality rates for the LD/LSD diseases in the U.S. Approximated birth prevalence rate for the early infantile Krabbe phenotype (onset 0-6 months) was based on the <5 year old mortality rate of one early infantile case per 244,000 births, which matches the 1 in 250,000 observed in the NYS newborn screening program as of 2011. It should be noted however that the NYS calculation refers only to the early infantile phenotype and does not include the majority of babies identified in the program with low GALC and two mutations who have remained clinically normal. It is presumed that most, if not all, will develop later onset forms of the disease, but this is by no means certain.

Developmental Splicing Deregulation in Leukodystrophies Related to EIF2B Mutations

Leukodystrophies (LD) are rare inherited disorders that primarily affect the white matter (WM) of the central nervous system. The large heterogeneity of LD results from the diversity of the genetically determined defects that interfere with glial cells functions. Astrocytes have been identified as the primary target of LD with cystic myelin breakdown including those related to mutations in the ubiquitous translation initiation factor eIF2B. EIF2B is involved in global protein synthesis and its regulation under normal and stress conditions. Little is known about how eIF2B mutations have a major effect on WM. We performed a transcriptomic analysis using fibroblasts of 10 eIF2B-mutated patients with a severe phenotype and 10 age matched patients with other types of LD in comparison to control fibroblasts. ANOVA was used to identify genes that were statistically significantly differentially expressed at basal state and after ER-stress. The pattern of differentially expressed genes between basal state and ER-stress did not differ significantly among each of the three conditions. However, 70 genes were specifically differentially expressed in eIF2B-mutated fibroblasts whatever the stress conditions tested compared to controls, 96% being under-expressed. Most of these genes were involved in mRNA regulation and mitochondrial metabolism. The 13 most representative genes, including genes belonging to the Heterogeneous Nuclear Ribonucleoprotein (HNRNP) family, described as regulators of splicing events and stability of mRNA, were dysregulated during the development of eIF2B-mutated brains. HNRNPH1, F and C mRNA were over-expressed in foetus but under-expressed in children and adult brains. The abnormal regulation of HNRNP expression in the brain of eIF2B-mutated patients was concomitant with splicing dysregulation of the main genes involved in glial maturation such as PLP1 for oligodendrocytes and GFAP in astrocytes. These findings demonstrate a developmental deregulation of splicing events in glial cells that is related to abnormal production of HNRNP, in eIF2B-mutated brains.

Clinical Epidemiologic Characterization of Orthopaedic and Neurological Manifestations in Children With Leukodystrophies

Leukodystrophies (LKDs) are spectra of clinical conditions characterized primarily by brain white matter abnormalities. Although this condition was previously defined around inherited disorders of the white matter of the brain, current application includes acquired and sporadic conditions and some rare conditions that affect gray matter. Over the past 2 decades, information had become available on the clinical subtypes due to neurodiagnostic imaging and improvement in the genetic studies (cytogenetics and molecular genetics) of LKD. However, the epidemiologic profile of LKD remains largely unknown. We aimed in this study to characterize LKD by demographics, family history, orthopaedic and neurological manifestations, and clinical subtypes. Trained medical personnel reviewed medical records of the study population diagnosed with LKD from 1986 to 2008. Using a retrospective review design, we determined the prevalence of the different clinical subtypes of LKD, family history, orthopaedic and neurological manifestations, and the demographics in LKD. The frequency and percentage (proportion, standard error, and 95% confidence interval for proportion) and the χ statistic and Fisher exact test for comparison of clinical subtypes were the statistical techniques used in the data analysis. Forty-four children were diagnosed with LKD between 1986 and 2008, of whom 25.0% had metachromatic LKD and 20.5% had Pelizaeus-Merzbacher LKD, whereas 40.9% were unspecified LKD. LKDs were more common among boys (63.6%), Whites (77.3%), and more likely to be diagnosed at age <3 years. Scoliosis (70.4%), hamstring contractures (81.8%), acquired hip dysplasia (88.6%), and equinus foot deformity (75.0%) were the most common orthopaedic manifestations. Common neurological manifestations were seizures (45.4%) and spasticity (77.3%). There was a statistically significant difference in sex and family history, seizures, hip dislocation, and hip subluxation, with respect to the clinical subtype of LKD, P<0.05. This epidemiologic characterization of LKD validates basic and clinical data on the familial history of LKD and its higher prevalence among boys. The orthopaedic manifestations common in LKD are scoliosis, hamstring contractures, acquired hip dysplasia, and equinus foot deformity, whereas common neurological manifestations are seizures and spasticity. These data are indicative of the need for orthopaedic surgeons to take into consideration this clinical epidemiologic aspect of LKD in the evaluation, treatment planning, and clinical expectations for these patients.

Gene therapy for leukodystrophies

Leukodystrophies (LDs) refer to a group on inherited diseases in which molecular abnormalities of glial cells are responsible for exclusive or predominant defects in myelin formation and/or maintenance within the central and, sometimes, the peripheral nervous system. For three of them [X-linked adrenoleukodystrophy (X-ALD), metachromatic (MLD) and globoid cell LDs], a gene therapy strategy aiming at transferring the disease gene into autologous hematopoietic stem cells (HSCs) using lentiviral vectors has been developed and has already entered into the clinics for X-ALD and MLD. Long-term follow-up has shown that HSCs gene therapy can arrest the devastating progression of X-ALD. Brain gene therapy relying upon intracerebral injections of adeno-associated vectors is also envisaged for MLD. The development of new gene therapy viral vectors allowing targeting of the disease gene into oligodendrocytes or astrocytes should soon benefit other forms of LDs.

A syndrome of choreic movements in a young dog, caused by cerebral “leucodystrophy”

Summary A clinical and neurological investigation was performed on a 4 ½ month spaniel dog which was largely paralyzed and showed a syndrome of chorea. The animal showed constantly shaking movements of the head, the neck and the eyeballs from the age of two weeks. Clinical examination did not reveal any particular symptoms. The neurologic examination is described. Blood, urine and cerebrospinal fluid appeared normal. The histopathological examination revealed a symmetrical diffuse demyelination in the cerebrum and cerebellum. The use of the name “chorea” in dogs is briefly discussed. Zusammenfassung Ein Syndrom von chorea-artigen Bewegungen bei einem jungen Hund, hervorgerufen durch zerebrale “Leukodystrophie” An einem 4½ Monate alten Spaniel, der erhebliche Lahmungen und ein Chorea-Syndrom zeigte, wurden klinische und neurologische Untersuchungen ausgefuhrt. Das Tier litt seit seiner zweiten Lebenswoche standig an Schuttelbewegungen des Kopfes, des Halses und der Augapfel. Die klinische Untersuchung ergab keine besonderen Symptome. Blut, Urin und Zerebrospinalflussigkeit schienen normal. Die histopathologische Untersuchung ergab eine symmetrische, diffuse Entmyelinisierung in Gros- und Kleinhirn. Die Anwendung der Bezeichnung “Chorea” bei Hunden wird kurz diskutiert. Resume Un syndrome choreiforme chez un jeune chien, provoque par une “leucodystrophie” cerebrale Chez un Cocker de 4 mois et demi presentant des paralysies importantes et un syndrome choreiforme on effectua des etudes cliniques et neurologiques. Ce chien presentait depuis la deuxieme semaine de sa vie des mouvements convulsifs ininterrompus de la tete, du cou et du globe oculaire. L'examen clinique ne montra pas de symptomes particuliers. L'examen neurologique est rapporte. Le sang, l'urine et la liqueur cerebrospinale etaient normaux. L'analyse histopathologique montra une demyelinisation symetrique et diffuse dans le cerveau et le cervelet. L'emploi du terme “choree” chez le chien est discute brievement. Resumen Un sindrome de movimientos coreicos en un perro joven, provocado por una “leucodistrofia” cerebral En un spaniel de 4 meses y medio de edad, que presentaba considerables claudicaciones y un sindrome coreico, se realizaron estudios clinicos y neurologicos. El animal padecio desde su segunda semana de vida bajo constantes movimientos de agitacion de la cabeza, del cuello y de los bulbos oculares. La exploracion clinica no ofrecio ningun sintoma especial. Se describe el examen neurologico. La sangre, orina y liquido cefalorraquideo parecian normales. El estudio histopatologico evidencio una desmielinizacion simetrica difusa en cerebro y cerebelo. Se discute brevemente el concepto “corea” en perros.

A Novel Mutation of the Arylsulfatase A Gene in Late-Onset Metachromatic Leukodystrophy

A Novel Mutation of the Arylsulfatase A Gene in Late-Onset Metachromatic Leukodystrophy

Diagnostic value of muscle, sural nerve and skin biopsies in childhood neuromuscular disorders

To elicit the usefulness of muscle, sural nerve and skin biopsies in neuromuscular disease, including its diagnostic value and indications for biopsy. The authors retrospectively evaluated the clinical data of every patient who underwent muscle, sural nerve and/or skin biopsy in the department between January 1999 and December 2004. One hundred and two patients with the suspected neuromuscular diseases were included. Muscle disease or hereditary metabolic/degenerative diseases with muscular injury were suspected in 82 patients, specific or typical histological findings confirmed diagnosis in 33 of these patients. The diagnosis included muscular dystrophies in 13 patients; inflammatory myopathies in 4 patients; congenital centronuclear myopathies in 2 patients; vacuole myopathy in 1 patient; mitochondrial myopathies in 8 patients; lipid storage myopathy in 1 patient; glycogenosis in 1 patient; spinal muscular atrophy in 3 patients. Nonspecific changes were seen in 25 patients, and in 24 patients nothing abnormal was revealed. Neuropathy or hereditary metabolic/degenerative diseases with peripheral nerve injury were suspected in 23 patients, specific or typical histological findings confirmed diagnosis in 10 of these patients, including hereditary motor and sensory neuropathy in 9 patients and metachromatic leukodystrophy with peripheral nerve abnormality in 1 patient. Nonspecific changes were seen in 11 patients and 2 patients had normal sural nerve. Skin biopsies were performed in 8 patients, specific or typical histological findings confirmed diagnosis in 4 of these patients. The diagnosis included neuronal ceroid lipofuscinosis in 2 patients, infantile axonal dystrophy in 1 patient, vacuole lysosomal disease in 1 patient, and 4 patients had normal skin biopsy. Muscle, sural nerve and skin biopsies play an important role in diagnosis of childhood neuromuscular disease, and should be done only in carefully selected cases after thorough clinical work-up. Muscle biopsy is essential for diagnosis of congenital and metabolic myopathies. Typical pathologic alterations of sural nerve have diagnostic value for hereditary neuropathies. Skin biopsy should be performed to verify neuronal ceroid lipofuscinosis.

The spectrum of neurodegeneration in children.

To find out the spectrum of diagnosis, clinical presentation and role of neuroimaging in neurodegenerative disorders of childhood. Observational study. Department of Neurology, Children's Hospital, Lahore from June, 2004 to May, 2005. A total of 1273 patients were admitted in the Neurology Department in the said period. Out of them, 66 children fulfilled the inclusion criteria. History, clinical examination and relevant investigations were carried out and proformas were filled. Data was analyzed for descriptive statistics. In a total sample of 66, the male to female ratio was 1.4:1. Age range was one to twelve years. Metachromatic leukodystrophy was the predominant type seen in 14 (21%), followed by 11 cases of adrenoleukodystrophy (16%) and 8 patients with SSPE (12%). Six children (9.8%) had Wilson's disease. Five cases (7.5%) were diagnosed as Friedrich ataxia, 4 cases (4%) as lipidosis, 3 case as Gaucher's disease (4.5%), and two cases (3%) each as Alexander disease, and Hellervorden-spatz disease; and one case each as multiple sclerosis and ataxia telangiectasia. In 6 cases, final diagnosis could not be made. MRI and CT scan of brain were done in 71% and 41% patients only. Furdos copy (in 65%), CSF examination in 59% and EEG in 56% were main non-imaging investigations utilized for diagnosis. Degenerative brain diseases are not an uncommon entity in paediatric population. Commonest presentation is regression of milestones, though, it may be variable. Because of limited diagnostic modalities, brain imaging has significant value. Facilities for enzyme studies should also be available at tertiary care hospitals.

THERAPY OF LEUKODYSTROPHIES

THERAPY OF LEUKODYSTROPHIES

LEUKODYSTROPHIES

LEUKODYSTROPHIES

The Yin and Yang of cell cycle progression and differentiation in the oligodendroglial lineage

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white matter, contact the axon, and differentiate into myelin-forming oligodendrocytes. Multiple mechanisms underlie the eventual progressive deterioration that typifies the natural history of developmental demyelination in LD and PVL and of adult-onset demyelination in MS. Over the past few years, pathophysiological studies have mostly focused on seeking abnormalities that impede oligodendroglial maturation at the level of migration, myelination, and survival. In contrast, there has been a strikingly lower interest for early proliferative and differentiation events that are likely to be equally critical for white matter development and myelin repair. This review highlights the Yin and Yang principles of interactions between intrinsic factors that coordinately regulate progenitor cell division and the onset of differentiation, i.e. the initial steps of oligodendrocyte lineage progression that are obviously crucial in health and diseases.

Leukodystrophies Diagnosed by Molecular Genetic Studies

Megalencephalic leukodystrophy with cysts (MLC) is a disorder defined only recently, by Topcu and colleagues (Brain Dev 1998; 20:142), Ben-Zeev and

Leukodystrophy incidence in Germany

Leukodystrophy incidence in Germany

Studies on patients with an unclassified leukodystrophy

Studies on patients with an unclassified leukodystrophy

A second opinion network on undiagnosed leukodystrophies

A second opinion network on undiagnosed leukodystrophies