Genetic disorders with central nervous system white matter abnormalities: An update.

Several genetic disorders have variable degree of central nervous system white matter abnormalities. We retrieved and reviewed 422 genetic conditions with prominent and consistent involvement of white matter from the literature. We herein describe the current definitions, classification systems, clinical spectrum, neuroimaging findings, genomics, and molecular mechanisms of these conditions. Though diagnosis for most of these disorders relies mainly on genomic tests, specifically exome sequencing, we collate several clinical and neuroimaging findings still relevant in diagnosis of clinically recognizable disorders. We also review the current understanding of pathophysiology and therapeutics of these disorders.

Hypomyelinating leukodystrophies in adults: Clinical and genetic features.

BACKGROUND AND PURPOSE: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood. METHODS: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel. RESULTS: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination. CONCLUSIONS: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years.

INTRODUCTION AND OBJECTIVES: Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. MATERIALS AND METHODS: A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones. RESULTS: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. CONCLUSIONS: Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.

Leukodystrophies and genetic leukoencephalopathies in children.

Leukodystrophies and genetic leukoencephalopathies are a large group of genetic disorders affecting central nervous system white matter. They can begin at any age, however this study focuses on disorders beginning in childhood and adolescence. We discuss the recent definitions, classifications, and classic syndromes, as well as genetic progress in the field through the identification of new genes and several new genetic syndromes.

Reprint of "Hypomyelinating disorders: An MRI approach.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

Hypomyelinating disorders: An MRI approach.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments. Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

General approach to treatment of genetic leukoencephalopathies in children and adults.

Despite the enormous advancements seen in recent years, curative therapies for patients with genetic leukoencephalopathies are available for only a relatively small number of disorders. Therefore, symptomatic treatment and preventive management of the multiple clinical manifestations of patients with genetic leukoencephalopathies are critical in their care. The goals of the symptomatic treatment are to improve patients' quality of life, increase their survival, and reduce the impact on medical resources and related expenses. The coordinated work of a multidisciplinary team, including all specialists involved in the care of these patients, is the gold standard approach to manage and treat their complex and evolving clinical picture. Along with a multidisciplinary team, the relationship and close collaboration with the patient and their caregivers are essential. Their insight into the disease manifestations and management of the different issues should be integrated with the assessments of the multidisciplinary team to prevent clinical complications and preserve the quality of life of patients and their caregivers. Genetic leukoencephalopathies are very heterogeneous in terms of age of onset, clinical features, and disease course. However, many clinical features and problems are shared by most forms. Consequently, common therapeutic strategies apply to the majority of these diseases. This chapter presents the symptomatic approach for shared core clinical features presented by patients with genetic leukoencephalopathies divided by systems and, for each system, the specificities of some genetic leukoencephalopathies.

Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

Health-Related Quality of Life for Patients With Genetically Determined Leukoencephalopathy.

BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.