10 research outputs found
4H Leukodystrophy: A Brain Magnetic Resonance Imaging Scoring System
4H (hypomyelination, hypodontia and hypogonadotropic hypogonadism) leukodystrophy (4H) is an autosomal recessive hypomyelinating white matter (WM) disorder with neurologic, dental, and endocrine abnormalities. The aim of this study was to develop and validate a magnetic resonance imaging (MRI) scoring system for 4H. A scoring system (0-54) was developed to quantify hypomyelination and atrophy of different brain regions. Pons diameter and bicaudate ratio were included as measures of cerebral and brainstem atrophy, and reference values were determined using controls. Five independent raters completed the scoring system in 40 brain MRI scans collected from 36 patients with genetically proven 4H. Interrater reliability (IRR) and correlations between MRI scores, age, gross motor function, gender, and mutated gene were assessed. IRR for total MRI severity was found to be excellent (intraclass correlation coefficient: 0.87; 95% confidence interval: 0.80-0.92) but varied between different items with some (e.g., myelination of the cerebellar WM) showing poor IRR. Atrophy increased with age in contrast to hypomyelination scores. MRI scores (global, hypomyelination, and atrophy scores) significantly correlated with clinical handicap (p < 0.01 for all three items) and differed between the different genotypes. Our 4H MRI scoring system reliably quantifies hypomyelination and atrophy in patients with 4H, and MRI scores reflect clinical disease severity
X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1
An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.Noriko Miyake, Nicole I. Wolf, Ferdy K. Cayami, Joanna Crawford, Annette Bley … Stephen J. Bent … et al
Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.
CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder
SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections
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152686.pdf (publisher's version ) (Closed access)We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-beta signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-beta signaling pathway exhibit arterial aneurysms and dissections as key features
Diffuse hypomyelination is not obligate for POLR3-related disorders.
OBJECTIVE: To report atypical MRI patterns associated with POLR3A and POLR3B mutations. METHODS: This was a multicenter retrospective study to collect neuroradiologic, clinical, and molecular data of patients with mutations in POLR3A and POLR3B without the classic MRI phenotype, i.e., diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum. RESULTS: Eight patients were identified: 6 carried mutations in POLR3A and 2 in POLR3B. We identified 2 novel MRI patterns: 4 participants presented a selective involvement of the corticospinal tracts, specifically at the level of the posterior limbs of the internal capsules; 4 patients presented moderate to severe cerebellar atrophy. Incomplete hypomyelination was observed in 5 participants. CONCLUSION: Diffuse hypomyelination is not an obligatory feature of POLR3-related disorders. Two distinct patterns, selective involvement of the corticospinal tracts and cerebellar atrophy, are added to the MRI presentation of POLR3-related disorders
Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder. © 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society