Hereditary Leukodystrophy Research Articles

Features of multiple sclerosis in childhood in the Republic of Tatarstan

Multiple sclerosis (MS) in children and adolescents is a genuine concern of pediatric neurology that specialists in all countries are dealing with. To date, neither the causes of onset nor the individual components of the pathogenesis of the disease have been reliably clarified, and the modern, changing picture of the clinical manifestation of the disease sometimes complicates timely diagnosis even in adult patients. There are more such questions in pediatric MS.Objective: to study the prevalence and clinical features of MS in children in the Republic of Tatarstan.Material and methods. We conducted a survey and data analysis of 128 children and adolescents aged 0 to 18 years inclusive. The examination of patients included neurological examination according to the classical scheme, neuroimaging examination, neurophysiological examination and cerebrospinal fluid examination. The diagnosis was based on the current (as of the time of diagnosis) criteria of McDonald and the International Pediatrics MS Study Group criteria. The severity of the patients' clinical condition was assessed using the Expanded Disability Status Scale (EDSS).Results. MS was diagnosed in 99 cases (77.3%), clinically isolated syndrome – in 10 (7.8%), acute disseminated encephalomyelitis – in 5 (3.9%), bilateral optic neuritis – in two patients (1.6%), disseminated encephalomyelitis – in one case (0.8%); other central nervous system diseases were diagnosed in 11 (8.6%) patients. After a detailed examination, the group “other diseases of the central nervous system” included such conditions as cerebral angiopathy, neurofibromatosis, brain mass, structural focal epilepsy, sequelae of viral encephalitis, and hereditary leukodystrophy. Among the patients, girls aged 15–17 years predominated. Monofocal manifestations were more frequently observed at debut. Moreover, the absolute predominance of the remitting type of course was also noted.Conclusion. The data obtained suggest a predominance of the predominantly remitting course type of MS with a monofocal onset, which is consistent with data from other studies of MS in pediatric practice.

CLINICAL CASE OF LEUKODYSTROPHY WITH A PRIMARY LESION OF THE CEREBELLUM

In the article, the authors analyze the clinical case of patient O., aged 19, with hereditary leukodystrophy. The patient is affected to a greater extent by both hemispheres of the cerebellum, there is a aggravated family history.

Unrelated umbilical cord blood transplantation for children with hereditary leukodystrophy: A retrospective study.

ObjectiveTo analyze the efficiency of unrelated umbilical cord blood transplantation (UCBT) in the treatment of hereditary leukodystrophy following busulfan- and cyclophosphamide-based myeloablative chemotherapy.MethodsA retrospective study was performed in patients with hereditary leukodystrophy who underwent UCBT after myeloablative chemotherapy between April 2015 and March 2020.ResultsThe study cohort included 12 pediatric patients (ten males), nine with cerebral adrenoleukodystrophy (ALD) and three with juvenile globoid cell leukodystrophy (GLD). All received HLA-matched or partially mismatched unrelated UCBT. There were no cases of graft rejection. Median neutrophil engraftment time was 20 days [12–33 days] and median platelet engraftment time was 29 days [14–65 days]. Median follow-up was 36 months [1–86 months], and the overall survival rate for patients with cerebral ALD and juvenile GLD after UCBT was 77.8% (7/9) and 100% (3/3), respectively. In patients with ALD, although lipid profiles (serum very-long-chain fatty acid) were improved post-UCBT, six patients demonstrated worse neurologic function score and performance status post-UCBT, and six patients had higher Loes scores at last follow-up compared with baseline. In patients with juvenile GLD, all patients showed stable neurologic function score and performance status despite the Loes score of one patient increased slightly after transplantation.ConclusionIn patients with cerebral ALD, patients with no or mild neurological symptoms can benefit from UCBT, while UCBT cannot reverse advanced disease. In patients with juvenile GLD, UCBT is safe and contributes to stabilize neurological function.

Two Novel Intronic Mutations in the CSF1R Gene in Two Families With CSF1R-Microglial Encephalopathy

Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease. Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation. Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members. Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.

Hereditary leukodystrophy with spheroids (HLDS) and Nasu-Hakola disease (NHD): Reports of seven Italian cases to highlight key diagnostic features

HLDS, an autosomal-dominant CSF1R-related leukoencephalopathy, and NHD, an autosomal-recessive TREM2- or TYROBP-related leukoencephalopathy, are ultra-rare adult-onset inherited microgliopathies. Based on their pathophysiology, hematopoietic stem cell transplantation (HSCT) might be a realistic therapy if performed at early stage. Aim of our work was to highlight diagnostic hints to promote prompt identification of affected subjects by reporting our experience.

New clinical characteristics and novel pathogenic variants of patients with hereditary leukodystrophies.

AimLeukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study.MethodsWhole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines.ResultsWe made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC.ConclusionOur results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.

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.

P2‐277: RAPID PROGRESSIVE DEMENTIA IN HDLS WITH A NOVEL CSF1R MUTATION

Hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia (HDLS) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. A 39-year old man gradually developed a decline in cognitive functions with spastic gait and parkinsonism. The patient was initially diagnosed with a progressive variant of young-onset dementia or parkinsonism. But gait disturbances and cognitive impairment became more severe, and then the differential diagnosis was made for other causes including genetic testing. Brain MRI showed fronto-temporal atrophy with hyperintense multiple small lesions in the deep cerebral white matter, and deep white matter diffusion abnormalities. The DNA analysis revealed a novel missense mutation c.2349C>A (p.Asn783Gln) of the CSF1R gene. We report a patient with rapid progression of cognitive and gait manifestations of HDLS and a novel CSF1R mutation. Hereditary diffuse leukoencephalopathy with axonal spheroids should be included in the differential diagnosis of young-onset progressive dementia and gait disturbance.

Recent advances in the genetics of frontotemporal dementia.

In this review we highlight recent advances in the human genetics of frontotemporal dementia (FTD). In addition to providing a broad survey of genes implicated in FTD in the last several years, we also discuss variation in genes implicated in both hereditary leukodystrophies and risk for FTD (e.g., TREM2, TMEM106B, CSF1R, AARS2, NOTCH3). Over the past five years, genetic variation in approximately 50 genes has been confirmed or suggested to cause or influence risk for FTD and FTD-spectrum disorders. We first give background and discuss recent findings related to C9ORF72, GRN and MAPT, the genes most commonly implicated in FTD. We then provide a broad overview of other FTD-associated genes and go on to discuss new findings in FTD genetics in East Asian populations, including pathogenic variation in CHCHD10, which may represent a frequent cause of disease in Chinese populations. Finally, we consider recent insights gleaned from genome-wide association and genetic pleiotropy studies. Recent genetic discoveries highlight cellular pathways involving autophagy, the endolysosomal system and neuroinflammation, and reveal an intriguing overlap between genes that confer risk for leukodystrophy and FTD.

Use of focused exome sequencing in adult-onset leukodystrophy to identify new genes and mutations

BackgroundThe leukodystrophies are a group of disorders that selectively involve degeneration of the white matter of the central nervous system. Recent discoveries in genetics have expanded our knowledge of hereditary leukodystrophies. We aimed to investigate the phenotypic spectrum of leukodystrophy genes without selection bias, thereby expanding the genotype–phenotype correlation. Methods18 patients with adult-onset, undiagnosed leukodystrophy were analysed with focused exome sequencing (SureSelect Focused Exome, Agilent Technologies, Santa Clara CA, USA). Suspected mutations were subsequently confirmed by Sanger sequencing. FindingsWe made a genetic diagnosis in six cases. Interestingly, in this adult-onset cohort, only one individual was found to have a mutation in an autosomal dominant gene (CSF1R) with the remainder with homozygous or compound heterozygous variants in the following autosomal recessive genes: POLR3A, EIF2B5, DARS2, MRPS22, and TREM2. No gene was responsible for more than one case, reflecting the extreme clinical and genetic heterogeneity of adult-onset leukodystrophy. These genes are responsible for mitochondrial health, RNA transcription, and microglial signalling. InterpretationFocused exome sequencing is a non-hypothesis driven approach allowing for association of clinical phenotype with otherwise unsuspecting molecular pathways. It is a cost-effective method that should be considered early in the diagnostic process, avoiding time and money spent on other more invasive investigations. This is of paramount importance for the patient in terms of early treatment and appropriate genetic counselling. FundingNational Institute for Health Research, Leonard Wolfson Experimental Neurology Centre.

Clinical phenotype, genetic and imaging features in vanishing white matter disease/cach

Introduction: VWM is an autosomal recessive hereditary leukodystrophy, linked to mutations in genes encoding the eukaryotic initiation factor 2B (eIF2B). Neurological features and clinical phenotypes are variable. The most common variant has a childhood onset and characteristic abnormalities on cranial MRI. Methods: Retrospective and prospective study: clinical, neuroimaging and genetic analysis. Patients were divided in groups according to age at onset: Group 1 (<2 years), group 2 (age 2-5) and group 3 (age >5), and according to disability scores (1=gait disturbance to 5=deceased). Results: 10 patients (7male/3female), 3 siblings. 9/10 had prior normal development. Average age at onset was 7 (1-13years), with gait disturbance (6/10), development regression (3/10) and tremor (1/10). History of cranial concussion (4/10) and febrile infection (1/10). Group distribution: 1 (n=2), 2 (n=1), 3 (n=7). Disability score distribution: 1 (n=6), 2 (n=1), 4 (n=2), 5 (n=1). Phenotypes: late childhood/early childhood onset (7/3). Symptoms: spasticity (7/10), cerebellar ataxia (7/10). Clinical monitoring: 3-12 years, rapidly progressive (n=6), progressive (n=2), fulminant (1) evolution. Brain MRI: diffuse, symmetrical abnormal white matter signal (10/10), most with cystic degeneration. Genetic study (9/10): IF2B5-R113H mutation (homozygous/heterozygous=2/6), IF2B4-R373C homozygous (1). Conclusion/Discussion: VWM is one of the most prevalent inherited childhood leucoencephalopathies, therefore it must be considered in the differential diagnosis. In this series the classical form was the most frequent, with characteristic white matter abnormalities in MRI, and the most with IF2B5- R113H mutation.

A new CSF1R mutation presenting with an extensive white matter lesion mimicking primary progressive multiple sclerosis

HDLS (Hereditary Diffuse Leukodystrophy with Spheroids) is a hereditary leukodystrophy whose main clinical manifestations include parkinsonism, spasticity, and ataxia. Genetic defects in the colony-stimulating factor 1 receptor (CSF1R) gene have been reported in many HDLS cases. The present report describes a new missense mutation Arg777Gln involving exon 18 of the CSF1R gene in a sporadic patient presenting with tumor-like lesions mimicking primary progressive multiple sclerosis. The patient was initially diagnosed with a progressive variant of multiple sclerosis and received inadequate treatments. Although most HDLS cases have a positive family history, this disease should also be suspected in sporadic patients showing unusual white matter lesions at MRI.

Brain Fludeoxyglucose F 18 Positron Emission Tomography Hypometabolism in Magnetic Resonance Imaging–Negative X-Linked Adrenoleukodystrophy

A38-YEAR-OLD MAN presented with progressive gait difficulties and urinary and erectile dysfunction of 10 years’ duration. Clinical examination showed right-sided predominant spastic paraparesis, bilateral Babinski signs, hyperreflexia, impaired vibration sensitivity in the distal legs, slight cerebellar dysfunction, and normal cognition. Brain (Figure) and spinal magnetic resonance imaging (MRI) findings were normal, as were copper and vitamins B12 and E levels and results of electromyography and a lumbar puncture. Differential diagnoses included primary lateral sclerosis (although the impaired vibration sensitivity and cerebellar dysfunction were atypical), familial spastic paraparesis, and hereditary leukodystrophy. Brain fludeoxyglucose F 18 positron emission tomography (FDG-PET) showed bilateral hypometabolism (confirmed by z scores between �3 and �4 SDs) in the paramedian frontal, anterior parietal, temporal polar, and cerebellar lobes, making primary lateral sclerosis unlikely. Predominant hypometabolism in the left lower limb motor cortex and both cerebellar lobes corresponded well with the right-sided predominance of the spastic paraparesis and the bilateral cerebellar dysfunction in our pa

Human demyelinating disease and the polyomavirus JCV

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies -which have a genetic basis; multiple sclerosis (MS) -where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML) -where the etiology is well-established as being viral. The human neurotropic polyomavirus -JC virus (JCV) -is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.

A new familial adult-onset leukodystrophy manifesting as cerebellar ataxia and dementia

Background: Among hereditary leukodystrophies, a considerable number remain unclassified. Patient and results: We investigated the clinical course and histopathology of one patient in a family of adult-onset leukodystrophy with possible dominant inheritance. A 44-year-old man presented with cerebellar ataxia as the initial symptom, and later, dementia and hyperreflexia with ankle clonus developed. T 2-weighted brain MRI showed brain atrophy and diffuse high signal intensity of the cerebral white matter and the brain stem. The patient’s mother and older brother also had cerebellar ataxia and dementia, and his older brother had been diagnosed as having spinocerebellar degeneration. An older sister of our patient possibly had similar neurological symptoms of adult-onset. Our patient died of pneumonia 5 years after the onset of disease. The histopathological findings consisted mainly of patchily observed vacuolar changes in the cerebral and cerebellar white matter and the brain stem. The subcortical regions and the cortex were unaffected. It is suggested that the pathological changes began in the cerebellum, and later spread to the frontal lobe and the brain stem. In the occipital regions, the vacuolations were associated with accumulation of macrophages and astrocytosis, which implied that the vacuolations were of recent origin. Conclusions: The diagnosis in this patient is adult-onset leukodystrophy with possibly autosomal dominant inheritance. The clinicopathological features are different from those, of previously reported adult-onset leukodystrophies.

Genetic localization of an autosomal dominant leukodystrophy mimicking chronic progressive multiple sclerosis to chromosome 5q31.

The hereditary leukodystrophies represent a group of neurological disorders, in which complete or partial dysmyelination occurs in either the central nervous system (CNS) and/or the peripheral nervous system. Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive, neurological disorder characterized by symmetrical widespread myelin loss in the CNS, and the phenotype is similar to that of chronic progressive multiple sclerosis. We report clinical, neuroradiological and neuropathological data from the originally reported ADLD family. Furthermore, we have localized the gene that causes ADLD to a 4 cM region on chromosome 5q31. Linkage analysis of this family yielded a LOD score of 5.72 at theta = 0.0 with the microsatellite marker D5S804. Genetic localization will lead to cloning and characterization of the ADLD gene and may yield new insights into myelin biology and demyelinating diseases.

Clinical and Pathological Features of an Autosomal Dominant, Adult-Onset Leukodystrophy Simulating Chronic Progressive Multiple Sclerosis

To study the clinical and pathological features of a kindred with an adult-onset autosomal dominant leukodystrophy. Five symptomatic and nine asymptomatic at-risk members of the kindred. Subjects underwent detailed histories and general and neurologic examinations. Further evaluation included electroencephalography, evoked potentials, electromyography, autonomic testing, and analysis of serum, urine, and cerebrospinal fluid. One patient underwent sural nerve biopsy and analysis. Another, previously studied patient, underwent a limited autopsy. Cerebellar and pyramidal dysfunction began in the fourth and fifth decades of life; subtle autonomic symptoms were often present years earlier. Frontal lobe dysfunction and abnormalities of the central visual pathways were mild and of late onset. Sensorineural hearing loss was common. The peripheral nervous system was spared. Autopsy results of one patient revealed severe degeneration of the white matter at all levels of the neuraxis, but most prominent in the frontoparietal and cerebellar regions, with sparing of the subcortical U fibers. Histological and ultrastructural examinations failed to show evidence of a specific pathogenetic mechanism or etiology. This disorder seems to be a distinct type of hereditary leukodystrophy, but its exact nature remains unknown.

A kindred of hereditary adult-onset leukodystrophy with sparing of the optic radiations

We describe a family with hereditary adult-onset leukodystrophy with sparing of the optic radiations, shown clinically, neuroradiologically and electrophysiologically. All five affected members developed their leukodystrophy in their fourth decade and clinical features steadily progressed. The sparing of the optic radiations is not typical of other leukodystrophies. We suggest that this is a new clinical entity.