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Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75–99%, and C) 50–74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs. • Newborn screening for metachromatic leukodystrophy aligns with established newborn screening criteria. • Prediction of symptom onset should be based on family history, genotype and blood ARSA enzyme activity. • Recommendations for pre-symptomatic treatment depend on the predicted MLD subtype. • Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoietic stem cell transplantation (allo-HSCT) has been the best treatment option, following strict selection criteria. The outcome however is variable and morbidity remains high. This paved the way to the development of new treatment options, some of them aiming to be curative. In the light of this changing therapeutic field, newborn screening is becoming a valuable option. This narrative review aims to describe the outcome of allo-HSCT in the different MLD disease forms, and, in addition, reviews new treatment options. Finally, the shift of the field towards newborn screening for MLD is discussed. • MLD is a neurodegenerative disease. • Allo-hematopoietic stem cell transplantation increases life span but morbidity remains high. • New therapeutic developments including gene therapy aim to be curative. • This shifts the field towards newborn screening. [ABSTRACT FROM AUTHOR]

Leukodystrophies are monogenic disorders primarily affecting the white matter. We aimed to evaluate the utility of genetic testing and time-to-diagnosis in a retrospective cohort of children with suspected leukodystrophy. Medical records of patients who attended the leukodystrophy clinic at the Dana-Dwek Children's Hospital between June 2019 and December 2021 were retrieved. Clinical, molecular, and neuroimaging data were reviewed, and the diagnostic yield was compared across genetic tests. Sixty-seven patients (Female/Male ratio 35/32) were included. Median age at symptom onset was 9 months (interquartile range (IQR) 3–18 months), and median length of follow-up was 4.75 years (IQR 3–8.5). Time from symptom onset to a confirmed genetic diagnosis was 15months (IQR 11–30). Pathogenic variants were identified in 60/67 (89.6%) patients; classic leukodystrophy (55/67, 82.1%), leukodystrophy mimics (5/67, 7.5%). Seven patients (10.4%) remained undiagnosed. Exome sequencing showed the highest diagnostic yield (34/41, 82.9%), followed by single-gene sequencing (13/24, 54%), targeted panels (3/9, 33.3%) and chromosomal microarray (2/25, 8%). Familial pathogenic variant testing confirmed the diagnosis in 7/7 patients. A comparison between patients who presented before (n = 31) and after (n = 21) next-generation sequencing (NGS) became clinically available in Israel revealed that the time-to-diagnosis was shorter in the latter group with a median of 12months (IQR 3.5–18.5) vs. a median of 19 months (IQR 13–51) (p = 0.005). NGS carries the highest diagnostic yield in children with suspected leukodystrophy. Access to advanced sequencing technologies accelerates speed to diagnosis, which is increasingly crucial as targeted treatments become available. • NGS carries the highest diagnostic yield in leukodystrophy (LD). • CMA has low diagnostic yield in LD. • Access to next generation sequencing shortens time to diagnosis in LD patients. • LD frequencies differ between different geographical areas. [ABSTRACT FROM AUTHOR]

PYCR2 gene variants are extremely rare condition which is associated with hypomyelinating leukodystrophy type 10 with microcephaly (HLD10). The aim of the present study is to report the clinical findings of patients having novel PYCR2 gene variant that manifest Hereditary Spastic Paraplegia (HSP) is the only symptom without hypomyelinating leukodystrophy. This is the first study that report the PYCR2 gene variants as a cause of HSP in late childhood. We believe it can contribute to expanding the spectrum of the phenotypes associated with PYCR2. It is a retrospective study. Of the patients with similar clinical features from two related families, "patient 1" was designated as the index case, and was analyzed using Whole Exome Squence analysis (WES). The detected variation was investigated in the index case's parents, relatives, and sibling with a similar phenotype. Clinical, brain magnetic resonance (MR) images and MR spectroscopic findings of the patients were reported. A novel homozygous missense (NM_013328: c.383T > C, p.V128A) variant in the PYCR2 gene is detected in 5 patient from 2 related families. All the patients were male, their ages ranges from 6 to 26 years (15.58 ± 8,33 yrs). Developmantal milestones were normal without dysmorphic features. 4 (%80) patients exhibit mild intention tremor started at the age of approximately 6 years of age. 4 (%80) patients had gait difficulty and progressive lower limb spasticity started at the age of 8–12 years. White matter myelination was normal in all patients. Glycine peakes were detected on the MR spectroscopy in all patients. Some variants of PYCR2 gene are responsible for causing clinical features of HSP without hypomyelinating leukodystrophy in the pediatric patients. • PYCR2 gene variants can cause Hereditary Spastic Paraplegia (SPG) in the late childhood period. • Normal Brain MRI can de seen in PYCR2 gene variants although they are associated with hypomyelinating leukodystrophy type 10. • MR spectroscopy findings are helpful for diagnosis. [ABSTRACT FROM AUTHOR]

The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable presentation with later onset and mainly lower limb spasticity. In view of emerging treatment options and in order to grade severity and progression, we developed a PMD myelination score. Myelination was scored in 15 anatomic sites (items) on conventional T2-and T1w images in controls (n = 328) and 28 PMD patients (53 MRI; n = 5 connatal, n = 3 transitional, n = 10 classic, n = 3 intermediate, n = 2 PLP0, n = 3 SPG2, n = 2 female). Items included in the score were selected based on interrater variability, practicability of scoring and importance of scoring items for discrimination between patients and controls and between patient subgroups. Bicaudate ratio, maximal sagittal pons diameter, and visual assessment of midsagittal corpus callosum were separately recorded. The resulting myelination score consisting of 8 T2-and 5 T1-items differentiates patients and controls as well as patient subgroups at first MRI. There was very little myelin and early loss in severely affected connatal and transitional patients, more, though still severely deficient myelin in classic PMD, ongoing myelination during childhood in classic and intermediate PMD. Atrophy, present in 50% of patients, increased with age at imaging. The proposed myelination score allows stratification of PMD patients and standardized assessment of follow-up. Loss of myelin in severely affected and PLP0 patients and progressing myelination in classic and intermediate PMD must be considered when evaluating treatment efficacy. • Routine MR images, used retrospectively, allowed to differentiate PMD subtypes and document changes in myelination. • Classic and intermediate PMD show ongoing myelination during childhood. • Severely affected patients show very little myelin and early loss of myelin signal. • Atrophy was present in 50% of patients and increased with age at imaging. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease characterized by progressive demyelination within the central and peripheral nervous system. Rapid diagnosis is crucial in view of evolving therapeutic options. Strabismus has anecdotally been described as a feature in children with MLD. Our first aim was to examine the prevalence of strabismus as an early or even presenting sign of MLD in two nationwide cohorts. Second, we aimed to investigate the temporal relation between the onset of strabismus and gross motor deterioration, other early onset eye movement disorders and brain white matter abnormalities. Clinical records of 204 MLD patients at the University Children's Hospital Tubingen and Amsterdam University Medical Center were reviewed on the presence of strabismus and other eye movement disorders. Gross motor deterioration and white matter abnormalities on brain MRI were evaluated by using the Gross Motor Function Classification in MLD and MLD LOES score, respectively. We identified strabismus as an early sign in MLD patients with the late-infantile form, with a prevalence of 27% (N = 17). The onset of strabismus preceded gross motor symptoms and brain white matter abnormalities in 71% and 46% respectively of the cases. Important characteristics were an acute-onset paralytic esotropia, partly accompanied by other eye movement abnormalities, and gadolinium enhancement of the cranial nerves. Acute-onset paralytic strabismus in toddlers should be considered a potential early sign of late-infantile MLD and might result from early cranial nerve involvement. Brain MRI with gadolinium contrast may facilitate early diagnosis. • Acute-onset paralytic strabismus can be a potential early clinical sign of MLD. • The prevalence of strabismus as an early sign in late-infantile MLD patients is 27%. • Strabismus preceded gross motor symptoms in 71% of the identified cases. • Strabismus preceded white matter abnormalities on brain MRI in 46% of the cases. • Strabismus in late-infantile MLD might result from early cranial nerve involvement. [ABSTRACT FROM AUTHOR]

CNTNAP1 encodes CASPR1, involved in the paranodal junction. Thirty-three patients, with CNTNAP1 biallelic mutations have been described previously. Most of them had a very severe neurological impairment and passed away in the first months of life. We identified four patients, from two unrelated families, who survived over the neonatal period. Exome sequencing showed compound heterozygous or homozygous variants. Severe hypotonia was a constant feature. When compared to previous reports, the most important clinical differences observed in our patients were the absence of antenatal problems and, in two of them, the lack of respiratory distress. Less commonly reported characteristics such as epileptic seizures, dystonia, and impaired communication skills were also observed. MRIs revealed hypomyelination or abnormal white matter signal, cerebral or cerebellar atrophy. The present observations support a wider than initially reported clinical spectrum, including survival after the neonatal period and additional neurological features. They contribute to better delineate the phenotype–genotype correlations for CNTNAP1. In addition, we report one more family with two sibs who carry a missense variant of uncertain significance which we propose could be associated with a milder phenotype. • CNTNAP1 mutations appear as a novel aetiology for severe hypotonia in newborns and infants. • This study confirms that survival after infancy can occur in patients with CNTNAP1 pathogenic variants. • Clinical spectrum is extended with new cases of dystonia, better motor and communication skills than previously described. • Three novel missense variants are described. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder manifesting as gradual or progressive loss of neurological functions. Most patients present with relapsing-remitting disease courses. Extensive research over recent decades has expounded our insights into the presentations and diagnostic features of MS. Groups of genetic diseases, CADASIL and leukodystrophies, for example, have been frequently misdiagnosed with MS due to some overlapping clinical and radiological features. The delayed identification of these diseases in late adulthood can lead to severe neurological complications. Herein we discuss genetic diseases that have the potential to mimic multiple sclerosis, with highlights on clinical identification and practicing pearls that may aid physicians in recognizing MS-mimics with genetic background in clinical settings. [ABSTRACT FROM AUTHOR]

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies. • MOGAD include a diverse range of demyelinating and encephalitis-like phenotypes. • ADEM in younger and ON and/or TM in older children comprise >90% of presentations. • All children with demyelination/encephalitis and abnormal MRI need MOG-ab testing. • We recommend an antibody-directed classification: MOG-ab-associated disorders. • Followed by addition of the disease course and clinical phenotype. [ABSTRACT FROM AUTHOR]

Hypomyelinating Leukodystrophies (HLDs) are a genetically heterogeneous, clinically overlapping group of disorders with the unifying MR imaging appearance of myelin deficit in the brain. In fact, it is the MRI phenotype that typically raises the diagnostic suspicion in this single largest group of undiagnosed leukodystrophies and guides gene testing for confirmation. This article reviews the neurobiology of myelination, focussing on the complex interplay of molecular genetic pathways and presents a practical clinico-radiological diagnostic algorithm based on the neuroimaging patterns of the common hypomyelinating disorders. The authors also address the current controversies about the definition and use of the term 'hypomyelination'. • Hypomyelination is a commonly encountered MR imaging phenotype in Paediatric Neurology practice. • Many clinically and genetically diverse group of disorders share the hypomyelination phenotype on imaging. It is imperative to differentiate primary delayed myelination and demyelination from this entity. • Clinical clues, pattern recognition and recognition of other associated imaging findings can help narrow these differential diagnoses and guide the diagnostic process. • Our understanding of normal myelination and disorders affecting it is still evolving. This leads to semantic confusions and diagnostic conundrums around hypomyelinating disorders. Accurate description of imaging features and reverse phenotyping after genetic diagnosis are possible practical solutions. [ABSTRACT FROM AUTHOR]

Objective: To examine disparities in the diagnosis of leukodystrophies including geographic factors and access to specialty centers.Study Design: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Abstract Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by the deficiency of the enzyme arylsulfatase A which is responsible for the desulfation of cerebroside sulfate, a myelin glycolipid. Accumulation of these sulfatides in the macrophages of various tissues causes a wide spectrum of presentations including central and peripheral nervous system dysfunction and gallbladder abnormalities. We report a case of a 6-year old girl with infantile Metachromatic Leukodystrophy who was found to have elevated liver enzymes, biliary markers and total and direct bilirubin during work-up for unexplained high-grade fever. Imaging showed dilated intra and extra hepatic biliary tree, markedly expanded CBD by dense content and multiple variable sized filling defects with narrowing in between. The dense content was confirmed to be mucosal papillomatosis with hyperplastic epithelium. To the authors' knowledge, obstructive extra-hepatic biliary tree polypoid masses and cystic dilation with metachromatic leukodystrophy have not previously been reported. [ABSTRACT FROM AUTHOR]

Abstract Leukoencephalopathy with brain calcifications and cysts (LCC) is a genetic white matter disorder, which involves the brain small blood vessels. In the absence of extra-neurological symptoms, LCC has a pathognomonic radiological phenotype. Recently, biallelic mutations in the SNORD118 gene, which is a non-protein coding gene, were discovered to cause LCC. We present here two siblings with developmental delay and a typical MRI pattern, who were diagnosed with LCC. The mutations in the SNORD118 gene were initially missed with whole exome sequencing (WES), but recognition of the MRI patterns of both children raised the suspicion of LCC and led to a genetically proven diagnosis after re-evaluation of the WES data. Highlights • In the absence of extra-neurological symptoms, LCC has a pathognomonic radiological phenotype. • LCC is caused by biallelic mutations in the SNORD118 gene. • LCC may be the first recognizable neurologic disorder that belongs to the group of ribosomopathies. [ABSTRACT FROM AUTHOR]

Abstract Peroxisomal biogenesis disorders (PBDs) are autosomal recessive diseases caused by mutations in one of the 14 PEX genes described in the scientific literature. All of these syndromes may be associated with different mutations in the PEX genes, the most frequent being PEX1 for patients with Zellweger syndrome (ZS). In this paper, we present the case of a patient with a peculiar clinical history: evisceration of the left eye (LE) at 4 years of age because of a benign ocular teratoid medulloepithelioma and a progressive loss of visual acuity (VA) in the right eye (RE) beginning at 9 years of age, leading to the diagnosis of ZS. In addition, the patient presented a mutation in the PEX14 gene that has not been previously described in the literature. This case broadens the spectrum of clinical expression in ZS patients because of not only the presence of a benign ocular teratoid medulloepithelioma at 4 years of age but also the late clinical expression of ZS (at 9 years of age). [ABSTRACT FROM AUTHOR]

Background X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with leukodystrophy, myeloneuropathy and adrenocortical insufficiency. We performed a retrospective cohort study to evaluate long-term outcome of patients with X-ALD. Method All patients with X-ALD diagnosed between 1989 and 2012 were included. Electronic patient charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, neuroimaging, long-term outcome and treatment. Results Forty-eight patients from 18 unrelated families were included (15 females; 33 males). Seventeen patients were symptomatic at the time of the biochemical diagnosis including 14 with neurocognitive dysfunction and 3 with Addison disease only. Thirty-one asymptomatic individuals were identified by positive family history of X-ALD. During follow-up, eight individuals developed childhood cerebral X-ALD (CCALD), one individual developed adrenomyeloneuropathy (AMN), six individuals developed Addison disease only, and five individuals remained asymptomatic. Direct sequencing of ABCD1 confirmed the genetic diagnosis in 29 individuals. Seven patients with CCALD underwent hematopoietic stem cell transplantation (HSCT). Nine patients lost the follow-up. There was no correlation between clinical severity score, Loes score and elevated degree of elevated very long chain fatty acid (VLCFA) levels in CCALD. Conclusion Our study reports forty-eight new patients with X-ALD and their long-term outcome. Only 35% of the patients presented with neurological features or Addison disease. The remaining individuals were identified due to positive family history. Close monitoring of asymptomatic males resulted in early HSCT to prevent progressive lethal neurodegenerative disease. Identification of patients with X-ALD is important to improve neurodevelopmental outcome of asymptomatic males. [ABSTRACT FROM AUTHOR]

• Primary Angiitis of the Central Nervous System may mimic a leukodystrophy. • Brain biopsy might be considered in case of diffuse leukoencephalopathies. • It is mandatory to get a definite diagnosis when a creeping PACNS is suspected. Primary Angiitis of the Central Nervous System (PACNS) is a rare form of idiopathic CNS vasculitis. Neuroimaging is often abnormal and characterized by multifocal brain lesions, but brain biopsy definitely confirms the diagnosis. We report the rare case of a 45-year-old female presenting with symptoms of intracranial hypertension and leukodystrophy-like neuroimaging findings. A comprehensive diagnostic work-up led to the unexpected diagnosis of a definite PACNS which was successfully treated by immunosuppressive treatment. Although rarely, PACNS can present as diffuse leukoencephalopathy on neuroimaging, and mimic even an inherited leukodystrophy. Therefore, in adults with leukodystrophy-like neuroimaging findings, careful examination of clinical and non-clinical features is mandatory to avoid missing the diagnosis of a treatable acquired disease. [ABSTRACT FROM AUTHOR]

Background We present an unusual neuroimaging finding in a young girl with genetically confirmed vanishing white matter disease and a possible response to immunotherapy. Methods and results 2.5 yr old girl, presented with acute onset unsteadiness and encephalopathy following a viral illness. MRI showed global symmetric white matter abnormality, with symmetric enhancement of cranial nerves (III and V) and of cervical and lumbar roots. She received immunotherapy for her encephalopathic illness with white matter changes. Follow up neuroimaging showed resolution of white matter edema and resolution of the change in the brainstem. Genetic testing confirmed a diagnosis of vanishing white matter disease (VWMD). Conclusion Craniospinal nerve enhancement and possible response to immunotherapy has not been described in vanishing white matter disease. [ABSTRACT FROM AUTHOR]

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Background Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. Patients and Methods We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. Results All patients were found to carry biallelic mutations of RNASET2 . Conclusions Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2 -related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation. [ABSTRACT FROM AUTHOR]

Background Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. Patients and methods The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. Results The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. Conclusions TUBB4A -mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l -dopa should be considered in all patients presenting extrapyramidal symptoms. [ABSTRACT FROM AUTHOR]

Background Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by inflammation of white matter in the central nervous system. It has been indicated that this inflammation causes increased levels of proinflammatory cytokines. Therefore, we aimed to evaluate if there is a possible association between inflammatory markers and the Expanded Disability Status Scale (EDSS) score in patients with MS. Methods We reviewed the data of 127 patients (91 women and 36 men) who were retrospectively diagnosed as MS according to the revised Mc Donald's criteria who were seen at our facility between January 2007 and December 2012. Patients were divided into two groups according to EDSS score: Group 1, EDSS < 5; and Group 2, EDSS ≥ 5. The risk factors that were evaluated included age and sex of the patients, duration of MS, drugs, thyroid function tests, vitamin B12 levels, homocysteine levels, immunoglobulins (Ig) A, G, and M, rheumatoid factor, complement 3 and 4, antistreptolysin O, C reactive protein (CRP), white blood cell count, and neutrophile-lymphocyte ratio (NLR). Results There was a statistically significant difference between the groups in terms of age, duration of the disease, drug received, Ig M, free T3, serum homocysteine levels, CRP, and NLR ( p < 0.05). Pearson's correlation analysis showed a significant correlation between age, duration of MS, IgM, serum homocysteine levels, CRP, and NLR. According to the receiver operating characteristic curve analysis, IgM and NLR were discriminative factors in patients in Group 2. Conclusion According to this study, inflammation may have a role in the pathogenesis of MS and in patients with EDSS > 5. Additionally, NLR and CRP levels may be discriminative factors of adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy is an inherited lysosomal disorder caused by recessive mutations in ARSA encoding arylsulfatase A. Low activity of arylsulfatase A results in the accumulation of sulfatides in the central and peripheral nervous system leading to demyelination. The disease is classified in a late-infantile, juvenile and adult onset type based on the age of onset, all characterized by a variety of neurological symptoms, which eventually lead to death if untreated. There is no curative treatment for all types and stages. This review discusses diagnostic process and efficacy of current and possible future therapies such as hematopoietic stem cell transplantation, enzyme replacement therapy and gene therapy. A systematic evaluation regarding the efficacy of hematopoietic stem cell transplantation and a longer follow up period for gene therapy are needed to come to a general conclusion and improve treatment options for metachromatic leukodystrophy. [ABSTRACT FROM AUTHOR]

Background The 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. Aim This paper looks at how ethical issues were identified and handled at project management level when setting up an ethics committee. Methods Through a work performed as a co-construction between health professionals, ethics experts, and patient representatives, we expose the major ethical issues identified. Results The 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. Conclusion This work led to a number of recommendations for ensuring transparency and optimizing the partnership between scientists and patients. [ABSTRACT FROM AUTHOR]

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder affecting myelination of the central nervous system, and is caused by mutations of the proteolipid protein 1 (PLP1) gene. Clinical manifestations of PMD are variable and major features include progressive nystagmus, spasticity, tremor, ataxia, and psychomotor delay. We describe a classical PMD patient who had been misdiagnosed as cerebral palsy. He had nystagmus and psychomotor delay since infancy and tremor with ataxia developing gradually. Brain MRI revealed demyelination over white matter of the cerebral hemispheres and posterior limbs of the internal capsules. Positive family history led to subsequent mutation analysis, which identified a novel mutation (c.88G>C) in PLP1 in the proband, as well as his affected brother and maternal uncle, and asymptomatic maternal grandmother, mother and two sisters. Therefore, PMD should be considered in a cerebral palsy-like patient with or without positive family history. Mutation analysis is crucial for early diagnosis and further genetic counseling. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mutations in the TREX1 and NOTCH3 genes cause retinal vasculopathy with cerebral leukodystrophy (RVCL) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), respectively. Both are hereditary small vessel diseases of the brain (HSVDB). Methods: We performed mutational analyses of TREX1 in genomic DNA from 39 unrelated patients who were NOTCH3-negative in genetic testing, selected out of 72 unrelated consecutive patients with HSVDB. Results: Only one patient had a TREX1 sequence variation, a heterozygous TREX1 c.294dupA, putatively resulting in a truncated protein, p.C99MfsX3. The medical history of the patient's family was scrutinized, which revealed that heterozygous TREX1 p.C99MfsX3 was not segregating with the HSVDB. Re-examination of the NOTCH3 sequence data of the proband led to the identification of a homozygous NOTCH3 c.1630C>T (p.R544C) mutation, which segregated with the HSVDB in the family. The proband had a slightly more severe phenotype in comparison with her heterozygous p.R544C sister. Conclusion: TREX1 mutation is not a common cause of HSVDB. TREX1 p.C99MfsX3 is not a dominant mutation. Homozygosity of the NOTCH3 p.R544C has a modestly deleterious effect on the CADASIL phenotype. The NOTCH3 mutation may cause CADASIL through a gain-of-toxic function effect, which can be modified by other genetic or environmental factors and results in the phenotypic variation of CADASIL. [Copyright &y& Elsevier]

Abstract: Aicardi–Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi–Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi–Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease. [Copyright &y& Elsevier]

Abstract: Background: Perivascular spaces of the brain, also known as Virchow-Robin spaces (VRS), are of immunological and neuropathological relevance and can be observed in magnetic resonance images (MRI). Their histopathological significance in X-linked adrenoleukodystrophy (ALD) has been reported. Aim of this study was to elucidate the prognostic or diagnostic value of VRS on MRI of the brain in the evaluation of onset or severity of the clinical course in ALD. Methods: Clinical data and MRI from 35 patients with the cerebral form of X-ALD, 29 with the asymptomatic form (including those with adrenal insufficiency), and 36 control patients were studied retrospectively. Results: VRS could be visualised by MRI in 87% of patients with asymptomatic ALD, in 80% of control patients, and in 47% of patients with cerebral ALD. None of them were found to be dilated. The number of visible VRS correlated negatively with the degree of demyelination both in patients with the cerebral and the asymptomatic form. Furthermore, in the group of patients with cerebral ALD the number of visible VRS correlated positively with a milder course of the disease. Conclusion: VRS on MRI of patients with ALD seem to reflect the perivascular inflammatory component of this disease. It is possible to speculate that the appearance or a higher number of visible VRS in ALD is associated with an earlier stage of the disease, or even a more benign clinical course. [Copyright &y& Elsevier]

Abstract: Diffusion and magnetization transfer imaging was performed on 29 children with encephalopathy and 69 children in the normal control group. Neurofibromatosis lesions had significantly lower magnetization transfer ratios and lower apparent diffusion coefficients than normal. Apparent diffusion coefficients of leukodystrophy, hypoxic/ischemic encephalopathy, and post-infectious encephalopathy were significantly higher than normal. Two radiologists independently detected more lesions and scored higher lesion contrast on T2- and FLAIR-weighted images than diffusion and magnetization transfer imaging. In conclusion, apparent diffusion coefficient and magnetization transfer ratio determination is not more sensitive than T2- and FLAIR-weighted imaging in assessing children with encephalopathy. [Copyright &y& Elsevier]

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• We propose a semi-automatic method to detect regions of increased susceptibility within MS WM lesions on 1.5 T MRI data. • The method proved to be sensitive and specific in detecting regions of increased susceptibility within MS WM lesions. • The number of WM lesions with regions of increased susceptibility correlated with disease duration in MS. The identification of regions of increased susceptibility (RoIS) in multiple sclerosis (MS) white matter lesions (WML) is currently performed by the radiologist's visual inspection of magnetic resonance imaging (MRI) data acquired with high-field MRI scanners. The aims of this study were: 1) to define and validate a semi-automatic method for detecting RoIS in WML from quantitative susceptibility maps (QSM) and susceptibility-weighted imaging (SWI) acquired with a 1.5 T MRI scanner; 2) to assess the prevalence of WML with RoIS and the susceptibility in those areas; and 3) to test the association between RoIS in WML and clinical outcomes. Thirty-eight MS patients were scanned on a 1.5 T MRI scanner. T2-hyperintense WML were segmented and superimposed on SWI and QSM images. Two intensity thresholds were defined and consecutively applied for identifying RoIS within WML (thr hyper_QSM to identify QSM hyperintensity within WML and thr hypoSWI to identify SWI hypointensity within WML). The sensitivity and specificity were assessed on a subgroup of subjects. The numbers of WML with RoIS and RoIS volume were determined. Differences between phenotypes and correlations with clinical outcome were tested. The method showed good sensitivity (95.6%) and specificity (92.1%). On average, 44.7% of the WML showed RoIS, occupying 11.0% of the total lesion volume, with an average susceptibility of 39.4 ± 12.2 ppb. The number of WML with RoIS was negatively correlated with disease duration (r = −0.342, p = 0.035). The proposed semi-automatic method proved to be suitable for the detection of RoIS in WML at 1.5 T. This approach may be useful in longitudinal studies aiming to monitor susceptibility in WML. [ABSTRACT FROM AUTHOR]

• Cholecystectomy is the only effective treatment for gallbladder polyps. • Asymptomatic lesions smaller than 1 cm in size should be annually monitored by ultrasound. • Surgical resection should be reserved for asymptomatic polyps larger than 1 cm or symptomatic patients. • Ultrasound screening of the gallbladder is recommended in metachromatic leukodystrophy. [ABSTRACT FROM AUTHOR]

Alexander disease is a rare genetic disorder that predominantly affects infants and children and is associated with cerebral white matter disease. Intracytoplasmicastrocytic inclusions known as Rosenthal fibers are the hallmark of Alexander disease.Sporadic mutations in the GFAP gene are the cause of most cases of Alexander disease. Four subtypes of Alexander disease — neonatal, infantile, juvenile, and adult — are traditionally recognized but a revised classification of Alexander disease proposes two subtypes - types I and II - based upon statistical analyses: type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, sudden deterioration, and typical neuroimaging features Type II onset may occur across the lifespan, and is characterized by autonomic dysfunction, eye movement abnormalities, bulbar symptoms, and atypical neuroimaging features Typical MRI features of Alexander disease are:Extensive cerebral white matter changes with frontal predominance, Periventricular rim of high T1 signal and low T2 signal, Basal ganglia and thalamic abnormalities, Brainstem abnormalities, Contrast enhancement of selected gray and white matter structures Less common MRI features of Alexander disease include: Multifocal brainstem lesions resembling multiple tumors, Medullary and cervical spinal cord signal abnormalities or atrophy and Ventricular garlands The diagnosis of Alexander disease can be established based upon clinical and radiographic (MRI) features. The diagnosis is usually confirmed by demonstrating a GFAP gene mutation. Although genetic testing is not necessarily required for the diagnosis, genetic confirmation should always be attempted due to the heterogeneity of the disease and its presentation. The differential diagnosis of Alexander disease involves consideration of other disorders that present with macrocephaly and/or cerebral white matter changes. Treatment of Alexander disease remains supportive. Canavan disease or aspartoacylase deficiency is an autosomal recessive spongiform leukodystrophy that is prevalent in the Ashkenazi Jewish population. The disease typically begins in infancy and is marked by relentless progression. Aspartoacylase deficiency is caused by mutations in the ASPA gene that encodes the enzyme aspartoacylase. The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in brain and to oligodendrocyte dysfunction, spongiform changes, and absence of myelin. However, the precise mechanisms causing to spongiform degeneration are uncertain. Aspartoacylase deficiency typically presents at about age three months with lethargy and listlessness, weak cry and suck, poor head control, and hypotonia with a paucity of extremity movement. Macrocephaly becomes prominent by three to six months. Thereafter hypotonia progresses to spasticity and tonic extensor spasms. By age six months, neurologic abnormalities are invariant. Little subsequent development is noted. Blindness from optic atrophy occurs between 6 and 18 months. Seizures are noted in about 50 percent of patients. Pseudobulbar signs and decerebrate posturing dominate the end stage. The presence of variant forms of aspartoacylase deficiency is controversial. Brain imaging by CT and MRI reveals diffuse and symmetrical white matter involvement. The gross pathologic findings are dominated by spongy degeneration of deep cortex, subcortical white matter, and cerebellum. The spongiform changes reflect vacuolated astrocytes in deeper cortical layers and in adjacent subcortical white matter. In symptomatic infants with compatible clinical features (eg, hypotonia, poor head control, macrocephaly) and neuroimaging findings, the diagnosis of aspartoacylase deficiency is supported by elevated levels of urine N-acetylaspartic acid (NAA) and deficient aspartoacylase activity in cultured skin fibroblasts. Genetic testing may be obtained for purposes of genetic counseling. The differential diagnosis of aspartoacylase deficiency includes other progressive white matter diseases of infancy, particularly Krabbe disease, metachromatic leukodystrophy, early-onset adrenoleukodystrophy, Alexander disease, and demyelinating disorders. No effective treatment is available for aspartoacylase deficiency. Management is supportive and aimed at maintaining nutrition and hydration, protecting the airway, preventing seizures, minimizing contractures, and treating infections. [ABSTRACT FROM AUTHOR]

The leukodystrophies are a heterogeneous group of diseases, which primarily affect white matter. An integrated description of the clinical, neuroimaging and pathophysiological features is crucial for categorizing these disorders. A group of leukoencephalopathies are associated with calcifications. In this article, we review these disorders briefly. Aicardi-Goutieres Syndrome: Aicardi-Goutieres syndrome (AGS) is a genetically heterogeneous autosomal recessive group of encephalopathies with 5 subtypes. Classic AGS is characterized by cerebral atrophy, white matter abnormalities, intracranial calcifications, chronic CSF lymphocytosis, and elevated CSF alphainterferon. Broadly speaking, 2 clinical presentations have been delineated: an early onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurologic function. Severe neurologic dysfunction becomes clinically apparent in infancy, and manifests as progressive microcephaly, spasticity, dystonic posturing, profound psychomotor retardation, and often death in early childhood. Outside the nervous system, thrombocytopenia, hepatosplenomegaly, and elevated hepatic transaminases along with intermittent fever may also erroneously suggest an infective process. It is important to exclude of pre-/perinatal infections, in particular the TORCH complex. Genetic screening for mutations in the four genes known to cause AGS allows definitive confirmation of the diagnosis in the majority (83%). Cockayne ‘s syndrome: Cockayne syndrome is an autosomal recessive disease due to a DNA repair defect. Patients show psychomotor developmental delay, dwarfism, progeroid appearance, microcephaly, deafness, pigmentary retinal degeneration, optic atrophy, and photosensitivity. Abnormal peripheral nerve conduction is due to a demyelinating polyneuropathy. Neuroimaging shows brain atrophy of variable degree, namely in brainstem and cerebellum; abnormally high signal intensity on T2-weighted images throughout the hemispherical white matter; late involvement of the subcortical fibers; abnormal hyperintensity on T1-weighted images in the basal ganglia corresponding to calcification. Cystic leukoencephalopathy without megalencephaly (RNASET 2-deficient cystic leukoencephalopathy): It is caused by homozygous or compound heterozygous mutation in the RNASET2 gene on chromosome 6q27. Neurologic deficits were noted within the first months of life, and included severe intellectual impairment, motor retardation, and spasticity. Brain MRI showed extensive cysts within the anterior temporal lobes, ventricular enlargement, and white matter disease. The signal intensities of the cysts were identical to those of cerebrospinal fluid. CT scans showed intracranial calcifications in some subjects. Cerebrotendinous xanthomatosis: Also called cerebral cholesterosis, is an autosomal recessive form of xanthomatosis. it is characterized by progressive cerebellar ataxia beginning after puberty and by juvenile cataracts, juvenile or infantile onset chronic diarrhea, childhood neurological deficit, and tendineous or tuberous xanthomas. The initial clinical manifestation may be neonatal cholestasis or chronic diarrhea from infancy. In 75% of cases, cataract is the first finding, often appearing in childhood. Pyramidal signs and/or cerebellar ataxia are present in the 20s or 30s. Patients may experience extrapyramidal manifestations (dystonia and atypical parkinsonism), and peripheral neuropathy. MRI shows bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter. Leukoencephalopathy with calcifications and cysts: Triad of leukoencephalopathy, cerebral calcifications and cysts (LCC) is a recently reported rare disease named ‘Labrune syndrome’. The clinical presentation is insidious and variable. Typically, initial symptoms are of raised intracranial pressure, later followed by focal neurologic deficits resulting in spasticity, dystonia, seizures, and cognitive decline. Cerebroretinal microangiopathy with calcifications and cysts, an autosomal recessive disorder caused by mutation in the CTC1 gene that shows phenotypic similarities to Labrune syndrome. CRMCC includes the neurologic findings of intracranial calcifications, leukodystrophy, and brain cysts, but also includes retinal vascular abnormalities and other systemic manifestations, such as osteopenia with poor bone healing, a high risk of gastrointestinal bleeding, hair, skin, and nail changes, and anemia and thrombocytopenia. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic. Naku-Hakola’s disease: Affected patients had onset in the third decade of pain and swelling following strain of the wrist or ankle; fractures occurred after minor accidents. Radiographs showed cystic rarefactions in the epiphyseal regions of bones. The cysts contained jellylike material and microscopically showed membranous and lamellar structures between fatty and collagenous connective tissue. In the fourth decade, patients developed neuropsychiatric symptoms, including memory impairment, euphoria, loss of social inhibitions, and impotency or frigidity. Neurologic examination showed exaggerated deep tendon reflexes, pathologic reflexes, and dysplasia. Patients usually die between ages 35 and 45, and the later features of the disorder resemble those of Alzheimer disease. Globoid Cell Leukodystrophy (Krabbe Disease): The manifestations of Krabbe disease are due to accumulation of galactocerebrosides and galactosylsphingosine, which in turn leads to loss of oligodendrocytes. Infantile Krabbe disease presents in the first 6 months of life as hyperirritability, increased muscular tone, fever, and developmental arrest. As the disease progresses, there is further cognitive decline, myoclonus, opisthotonus, nystagmus, and optic atrophy. Patients diagnosed in infancy rarely survive beyond 2 years. In an estimated 10% of cases, symptoms begin after the patient has begun to walk; these are considered “late-onset.” Central motor signs include spasticity, ataxia, and weakness. Of late-onset patients, 20% have abnormal peripheral nerve conduction studies with uniform slowing of conduction velocities. Demyelination of the deep WM, progressively involving the subcortical white matter. Calcifications within the thalami, basal ganglia, and corona radiata shown by CT scan. [ABSTRACT FROM AUTHOR]

Background Cockayne syndrome is a rare autosomal recessive disease, with heterogeneous presentation which involves many organ systems and is characterized by failure to thrive, microcephaly, pigmentary retinopathy, and photosensitivity. The face of the patients resembles the face of the birds. There are 3 subtypes of this disorder. Type I, or classic Cockayne syndrome, presents in childhood with characteristic facies and somatic features that occur late in the first decade of life. Type II, or severe congenital or neonatal form, presents at birth with accelerated facial and somatic features. Type III Cockayne syndrome has the mildest symptoms of the three types and appears later in childhood. Patients with Cockayne syndrome type I typically have progressive neurologic degeneration with death occurring by the second or third decade of life, while patients with type II of the disease mostly do not survive the first decade of life. Pathophysiology A DNA repair defect is a prominent feature of Cockayne syndrome. Cockayne syndrome, xeroderma pigmentosa, and trichothiodystrophy are three distinct syndromes with cellular sensitivity to ultraviolet (UV) irradiation. These syndromes arise from mutations of genes critical for nucleotide-excision repair and RNA transcription. At least 28 genes are involved in the nucleotide excision repair pathway. The pathway is involved in protection against UV-induced DNA damage. Cells with a defective DNA repair mechanism are sensitive to UV light. Decreased DNA and RNA synthesis, increased sister chromatid exchanges, and increased chromosomal breaks may occur. Despite the photosensitivity and DNA repair defect, and unlike xeroderma pigmentosa Cockayne syndrome is not associated with skin cancer. Epidemiology Cockayne syndrome is rare throughout the world. No racial predilection is reported. No sexual predilection is described and the male-to-female ratio is equal. History Patients with Cockayne syndrome usually appear normal at birth, but eventually, they present with a typical facial appearance of a narrow face and a beaked nose. Mental retardation, microcephaly, and growth failure become evident over time. Photosensitivity and progressive worsening neurologic signs and symptoms of ataxia and quick jerky movements are also noted. In type I the signs become gradually more pronounced during the first decade of life, but in CS-II, severe developmental delays are evident from early postnatal days, and the facies may become characteristic by 2 years of age. Physical Exam Microcephaly, a thin nose, and large ears give the patient a Mickey Mouse appearance. Patients may be cachectic. Photosensitive eruption with erythema and scale may be observed. Affected areas show hyperpigmentation, telangiectasia, and atrophy. Subcutaneous lipoatrophy results in sunken eyes and an aged progeric appearance. Microcephaly, short stature, long limbs with joint contractures, large hands and feet, kyphosis, and osteoporosis may be observed. Dental caries may be present. Salt and pepper retinal pigment, miotic pupils, cataracts, optic atrophy, corneal opacity, and nystagmus may be seen in ophthalmologic exam. Vision is preserved. Neurologic findings Intracranial calcifications and diffuse demyelination of the central nervous system and the peripheral nerves result in progressive neurologic deterioration, such as ataxia, tremors, and cog wheeling. Mental retardation may be noted. Progressive sensorineural deafness may occur. Diagnosis Diagnosis is based on detection of the specific TCR defect that can be identified using a radioactive assay in cultured fibroblasts that measures the recovery of RNA synthesis after UV irradiation. This DNA repair test is a decisive tool for the diagnosis of CS. Differential Diagnoses - Bloom Syndrome (Congenital Telangiectatic Erythema) - Hartnup Disease - UV-sensitive syndrome - Xeroderma Pigmentosum Laboratory Studies Laboratory studies are mainly useful to eliminate other disorders. For example, skeletal radiography, endocrinologic tests, and chromosomal breakage studies can help in excluding disorders included in the differential diagnosis. Amniotic fluid cell culturing can be used to demonstrate that fetal cells are deficient in RNA synthesis after UV irradiation. Imaging Studies Brain imaging reveals diffuse hypomyelination of the cerebral white matter, calcifications in the putamen, and vermian atrophy. Cortical atrophy is also a nonspecific finding. Patients with early-onset disease display more severe hypomyelination and prominent calcifications in the sulcal depth of the cerebral cortex, but atrophy is less severe in late-onset patients. On proton MR spectroscopy, lactate is detected and Cho and NAA values are decreased. Medical Care and Prognosis Medical care for Cockayne syndrome patients includes photoprotection with sunscreens and clothing.The prognosis for Cockayne syndrome is poor, with death occurring in the second or third decade of life. A genetic counselor should educate the parents of the Cockayne syndrome patient. [ABSTRACT FROM AUTHOR]

Cystic changes in the white matter can be caused by heterogeneous neurologic disorders. They are classified in two main categories: a) cystic finding in association with known classic leukodystrophy and b) white matter cystic abnormalities that are not seen in the background of a classic leukodystrophy. The main disorders in group (a) are including: Megalencephalic leukoencephalopathy with subcortical cyst(MLC) or vanderknaap disease, RNAase T2 deficiency, congenital CMV infection, cerebroretinal microangiopathy with calcificationand cysts (coat's plus syndrome or CRMCC) and less commonly Aicardi-Goutieres syndrome and Alexander's disease. Group (b) consists of various disorders. Autistic spectrum disorders, mucopolysaccharidosis, structural chromosomal abnormalities, migraine headache, mitochondrial leukoencephalopathy (complex I, complex II and complex IV deficiency) and COL4A1 associated disorder are main diseases that can be classified in this group. For some of these disorders, such asautistic spectrum disorders and mucopolysaccharidosisCystic changes are thought to be due to dilated Virchowrobin or perivascular spaces. It is not cleared that cystic findings of white matter in these disorders are functional effects or are specific for diagnosis. Megalencephalicleukoencephalopathy with subcortical cyst (MLC) or van der Knaap's disease is characterized by a mild course and macrocephaly that is a cardinal feature for diagnosis and differentiates MLC from RNAase T2 deficient leukoencephalopathy, AGS and CMV infection. In the initial stages of disease, Patients show mild motor and cognitive delay. Later in life spastic ataxia, epilepsy, dysarthric speech and cognitive deterioration are seen. Important brain MRI features are including: diffuse white matter signal abnormality with relative sparing of central structures and cystic changes in temporal or frontoparietal regions. Genetic study and searching for MLC1 gene mutation confirms the diagnosis of MLC. RNAase T2 deficient leukoencephalopathy that was described for the first time by henneke in 2009 is characterized by psychomotor delay, spasticity and epilepsy. Its radiologic findings in brain MRI resemble congenital CMV infection and MLC, but in contrast to MLC the patient has normo- or microcephaly in association with intracranial calcifications. In another hand there is no evidence of CMV infection. It must to be mentioned that human RNAase T2 is a catalytic enzyme with some new known function about tumor suppression. Its role in this type of leukoencephalopathy is still unclear. Cerebroretinal microangiopathy with calcification and cysts (CRMCC)or labrunedisease is an obliterativevasculopathy with unidentified genetic etiology that involves multiple organs mainly brain, eyes, liver, intestine and bones. Therefore progressive neurologic symptoms, bone fracture and osteopenia, bilateral retinal telangectasia and portal hypertension are main clinical symptoms in this disease, although not all organs are involved in each patient. Neuroimaging findings are a distinct pattern of calcification in white matter of brain and cerebellum, basal ganglia and thalamus with parenchymal cysts and leukoencephalopathy. Aicardi-Goutieres syndrome (AGS) is a calcifying leukoencephalopathy that can present in both neonatal period or in older infants. Symptoms in neonatal period resemble a TORCH-like disorder such as congenital CMV, but in older infants the disease is characterized by progressive microcephaly, dystonia, seizures and progressive cerebral atrophy and calcification. One of important diagnostic criteria in AGS is CSF findings of leukocytes, pterins and interferon-alpha. Naidu described in 2005 a specific type of cystic leukoencephalopathy as named progressive cavitatingleukoencephalopathy, but it seems there is no consensus on this term and many things can cause cavitating degeneration of white matter. For example in recent years it has been found that some mitochondrial diseases such as complex I deficiency can present with progressive cavitating leukoencephalopathy. Some infectious agents such as CMV, HIV, and papoavirus that cause progressive cystic leukoencephalopathyare mentioned as a group of etiologic factors in association with cystic changes in white matter in the literature. Therefore, as mentioned before this, cystic leukoencephalopathy can be caused by heterogeneous factors that may be heritable or acquired. [ABSTRACT FROM AUTHOR]

Leukodystrophy(LD) means deterioration of white matter of the brain function. This deterioration manifests itself by regression of previously acquired skills which in majority of cases leads to devastating neurological function. Leukodystrophy(LD) are genetic diseases causing degeneration of myelin sheaths in the CNS and occasionally associated with peripheral nerves involvement. In this types of neurologic diseases, basic defect is directly related to the synthesis of myelin membranes and its maintenance. Most of the time clinical manifestation of Leukodystrophy(LD) appear during childhood or adolescence and almost all the times leads to progressive course, untreatable and premature death. Early diagnosis helps supportive and experimental therapies, family counseling and family members screening to detect unaffected individuals who currently are nonsymptomatic. The few treatments which have been proposed are effective in the early stages.Making definite diagnosis of leukodystrophy(LD) requires good knowledge of clinical features and having neuroimaging data. Being aware of typical age of onset of different clinical types and brain MRI patterns of leukodystrophies(LD) are essentials tools to the correct diagnosis. Precise diagnosis may need specific laboratory tests and other investigations to make leukodystrophy (LD) and undoutable entity. Clinical Features Age of onset The main symptoms of LD are neurological which mostly appear in children who previously enjoyed a good health. Progressive deterioration of motor skills and mental symptom in a child every or an adolescent, should arouse a high index of suspicion towards a leukodystrophy(LD). Physical features Except some of the patients who are macrocephalic, others do not show any physical stigma. Few of them have dysmorphic features, skeletal anomalies and dental abnormalities. Neurologic Symptoms Neurologic Symptoms of LD. Consist of increasing motor signs and symptoms and change of cognition and language. MRI of the head, nerve conduction studies, Evoked potentials, evaluation of other organs function likes: eye, heart and G.I are those investigating tools which help clear cut diagnosis of LD. [ABSTRACT FROM AUTHOR]

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant hereditary cerebrovascular disease characterised by migraine attacks, recurrent subcortical transient ischemic attacks or strokes, cognitive decline, and dementia. It is caused by mutations in the Notch3 gene on chromosome 19p13.1, which is the only gene currently known to be closely associated with CADASIL. We describe a novel 100 base pair base fragment deletion mutation (ENST 00000263388, c.512-611del) in the Notch3 gene from a Chinese patient with CADASIL. The present patient has the characteristic clinical and family history for CADASIL, which suggests that C.512del611 may be a cause of CADASIL as well as most of the previously reported Notch3 mutations. [Copyright &y& Elsevier]

Abstract: Pseudobulbar affect (PBA) manifests in a variety of neurologic illnesses suggesting a heterogeneous pathophysiology with common underpinnings. We report successful treatment of PBA with a selective serotonin reuptake inhibitor (SSRI) in a 54-year-old woman following progressive multifocal leukoencephalopathy (PML). In light of recent focus on dextromethorphan/quinidine (DM/Q) for the treatment of PBA, the clinician is reminded of the effectiveness of SSRIs. [Copyright &y& Elsevier]

L-2-Hydroxyglutaric aciduria is a rare autosomal recessive inherited neurometabolic disorder.It is characterized by slow progressive neurological dysfunction with cerebellar ataxia, pyramidal and extrapyramidal signs, intellectual decline, and seizures. Herein, we report a case of a 7-year-old boy from Tehran whose symptoms and signs indicated leukoencephalopathy with macrocephaly and motor delay. [ABSTRACT FROM AUTHOR]

Electrophysiologic tests are one of the major investigations in patients suffering from any type of leukodystrophy. These studies are aimed to detect different abnormalities in central and peripheral nervous system. The most widely studied subtypes of leukodystrophy are Krabbe disease, Metachromatic Leukodystrophy, and Adrenoleukodystrophy. Overall, the abnormalities are usually more prominent and widespread in earlier onset cases and as the age of onset increases, the probability of finding abnormal tests in peripheral and central nervous system and the severity of findings decreases. In this presentation, I will discuss different electrophysiologic abnormalities reported in leukodystrophies, mainly focused on nerve conduction studies and evoked potential abnormalities, relevant clinical findings and their importance as a diagnostic tool. [ABSTRACT FROM AUTHOR]