Nonspecific White Matter Abnormalities Research Articles

White matter abnormalities in 15 subjects with SPG76.

Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP. We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies. We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time. SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder.

A recurrent homozygous missense DPM3 variant leads to muscle and brain disease.

Biallelic pathogenic variants in the genes encoding the dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle-eye-brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease-dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra-rare homozygous pathogenic missense DPM3 variant NM_018973.4:c.221A>G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the N-glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides DPM1 and DPM2, defects in DPM3 can also lead to a muscle and brain phenotype.

Targeting the Diagnosis in an Adolescent with Epilepsy and Intellectual Disability through Next-Generation Metabolic Screening.

A 16-year-old boy, born to consanguineous parents in Syria and living as a refugee in the Netherlands since the age of 14 years, was admitted to our tertiary pediatric intensive care unit with status epilepticus after discontinuation of valproic acid. He was treated with valproic acid since early infancy for seizures of unknown cause, but as he had been seizure-free for many years, discontinuation was attempted. Brain magnetic resonance imaging showed nonspecific white matter abnormalities and changes attributable to prolonged seizures or meningitis, such as brain fullness with mildly effaced ventricles and mild meningeal enhancement in the precentral gyri. Chromosomal microarray analysis showed a normal XY profile. Biochemical screening for inherited metabolic disorders (IMD) was performed through next-generation metabolic screening (NGMS) (1), an ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (Agilent 6545 QTOF) metabolomics approach, validated under ISO15189 accreditation as first-tier diagnostic screening for IMD in our laboratory. In short, a panel of known IMD-related metabolites is filtered from the untargeted metabolomics data for initial diagnostic interpretation. For each patient, significantly altered metabolites are identified, and a semiquantitative fold change compared to controls is evaluated. The NGMS IMD-metabolite panel is frequently updated to include novel diagnostic metabolites encountered in the untargeted metabolomics data in a research setting. For example, the metabolites 2S, 6S- and 2S; 6R-oxopropylpiperidine-2-carboxylic acid; 6-oxopiperidine-2-carboxylic acid; and 6-(carboxymethyl)piperidine-2-carboxylic acid were recently added to the panel as novel biomarkers for pyridoxine dependent epilepsy due to deficiency of α-aminoadipic semialdehyde dehydrogenase, encoded by ALDH7A1 (PDE-ALDH7A1) (2, 3). PDE-ALDH7A1 is a defect in lysine catabolism (Fig. 1), leading to secondary deficiency of pyridoxine (vitamin B6) through complexation with accumulating piperideine-6-carboxylic acid.

Re-analysis of whole-exome sequencing data reveals a novel splicing variant in the SLC2A1 in a patient with GLUT1 Deficiency Syndrome 1 accompanied by hemangioma: a case report

BackgroundGLUT1 Deficiency Syndrome 1 (GLUT1DS1) is a neurological disorder caused by either heterozygous or homozygous mutations in the Solute Carrier Family 2, Member 1 (SLC2A1) gene. SLC2A1 encodes Glucose transporter type 1 (GLUT1) protein, which is the primary glucose transporter at the blood–brain barrier. A ketogenic diet (KD) provides an alternative fuel for brain metabolism to treat impaired glucose transport. By reanalyzing exome data, we identified a de novo heterozygous SLC2A1 variant in a girl with epilepsy. After reversed phenotyping with neurometabolic tests, she was diagnosed with GLUT1DS1 and started on a KD. The patient's symptoms responded to the diet. Here, we report a patient with GLUT1DS1 with a novel SLC2A1 mutation. She also has a hemangioma which has not been reported in association with this syndrome before.Case presentationA 5-year 8-month girl with global developmental delay, spasticity, intellectual disability, dysarthric speech, abnormal eye movements, and hemangioma. The electroencephalography (EEG) result revealed that she had epilepsy. Magnetic resonance imaging (MRI) showed that non-specific white matter abnormalities. Whole Exome Sequencing (WES) was previously performed, but the case remained unsolved. The re-analysis of WES data revealed a heterozygous splicing variant in the SLC2A1 gene. Segregation analysis with parental DNA samples indicated that the variant occurred de novo. Lumbar puncture (LP) confirmed the diagnosis, and the patient started on a KD. Her seizures responded to the KD. She has been seizure-free since shortly after the initiation of the diet. She also had decreased involuntary movements, her speech became more understandable, and her vocabulary increased after the diet.ConclusionsWe identified a novel de novo variant in the SLC2A1 gene in a patient who previously had a negative WES result. The patient has been diagnosed with GLUT1DS1. The syndrome is a treatable condition, but the differential diagnosis is not an easy process due to showing a wide range of phenotypic spectrum and the overlapping symptoms with other neurological diseases. The diagnosis necessitates a genomic testing approach. Our findings also highlight the importance of re-analysis to undiagnosed cases after initial WES to reveal disease-causing variants.

Brain magnetic resonance imaging findings in children with headache.

The aim was to describe the findings on magnetic resonance imaging (MRI) in children with headache. Retrospective review of the medical records of patients who were admitted to our pediatric outpatient neurology clinics with the complaint of headache between January 2013 and December 2014. A total of 478 patients (273 female, 205 male) were admitted with the complaint of headache. The types of headache were migraine in 218 (45.6%), tension-type in 159 (33.3%), secondary in 39 (8.2%) and unspecified headaches in 62 (13%) patients. Brain MRI was performed in 407 (85%) patients and revealed cerebral abnormalities in 128 (31.4%) patients; 5 patients had cerebral abnormalities relevant with headache, including tumors. Amongst the others 123 patients, the most common findings were 42 cases (10%) of nonspecific white matter abnormalities, 17 cases (4%) of enlarged perivascular spaces, 17 cases (4%) of arachnoid cyst, 16 cases (3.9%) of asymmetric ventricles, 12 cases (2.9%) with Chiari type I and cerebellar tonsillar ectopia. Also, 17 (4.1%) patients had extra-cerebral MRI abnormalities including sinusitis, mucosal thickening and retention cysts of sinuses. In this study, the contribution of brain MRI in the diagnosis and management of the children with headache was still low.

Assessing behavioral syndromes in patients with brain tumors using the frontal systems behavior scale (FrSBe).

Personality changes following brain tumors may be due to disruption of frontal-subcortical networks. The relation between personality changes and tumor parameters such as volumes of the surgical cavity, residual tumor, or nonspecific white matter abnormalities is unknown. In this study we examined the relation between these tumor parameters and abnormal behaviors typically associated with frontal lobe dysfunction. Thirty-one patients with intracranial tumors who completed the Frontal Systems Behavior Scale (FrSBe) during clinical neuropsychological assessment and had a solitary, well-delimited brain lesion on MRI within 3 months of that assessment were included. Tumor parameters were manually segmented using OsiriX. Nonparametric statistics were used to determine the relationship between tumor parameters and frontal behavioral dysfunction as measured by FrSBe scores. Patients reported significantly more behavior problems after tumor diagnosis. Tumor cavity volume was correlated with self-reported Executive Dysfunction (rho = 0.450, P = .047), and there was a trend in the relationship with self-reported Apathy (rho = 0.438, P = .053). Nonspecific white matter abnormality volume was also correlated with self-reported Apathy (rho = 0.810, P = .01). There were no correlations between FrSBe scores and residual tumor volume or summed volumes of tumor-related parameters. Our results suggest that tumor parameters have differential effects on behaviors associated with frontal-subcortical networks and corroborate the high frequency of behavioral dysfunction in brain tumor patients. Examination of these relationships in a prospective trial is warranted to establish incidence, prevalence, risk factors, and consequences of behavioral disturbances in brain tumor patients.

Mutations in RNF216 do not cause 4H syndrome

We comment on the recent publication by Ganos etal. [1] classifying a patient with non-specific white matter abnormalities, cerebellar atrophy, hypogonadotropic hypogonadism and absent lower median incisors as 4H syndrome. He had mutations in RNF216. Mutations in this gene cause Gordon-Holmes syndrome, distinct from 4H syndrome.

PP15.11 – 3031: Brain magnetic resonance imaging findings in children with recurrent headache

Objective To describe the frequency of abnormal findings detected on magnetic resonance imaging (MRI) in children with recurrent headache and to determine the prevalence and significance of nonspesific white matter lesions. Methods Children who were admitted to our pediatric outpatient neurology department with the complaint of recurrent headache between July 2013 and December 2014 were included in the study. We retrospectively reviewed the clinical and neuroimaging data of the patients. The types of headache were classified according to the criteria of International Headache Society. Results A total of 478 patients (273 female, 205 male) were included in the study. The types of headache were migraine in 218 (45.6%), tension-type in 159 (33.3%), secondary in 39 (8.2%) and unspecified headaches in 62 (13%) patients. MRI were performed in 407 (85%) patients and were abnormal in 145 (35%) patients. Eighteen patients had abnormal MRI findings related with headache, 13 of them had sinusitis, the other 5 (3%) had tumors. None of these 5 patients with tumor had abnormal neurologic symptoms or signs. Among the 127 patients, the most common findings were 42 cases of nonspecific white matter abnormalities, 17 cases of enlarged perivasculer spaces, 16 cases of asymmetric ventricles, 17 cases of arachnoid cyst, 12 cases with chiari type 1 and cerebellar tonsillar ectopia. The half of the patients with nonspecific white matter abnormalities had migrane, but no difference between the frequency of nonspecific white matter abnormalities in migraine and the other types of patients was found (p=0.55). Conclusion Due to the demands of the parents, the usage of neuroimaging studies in children with headache is increasing. Despite the increase in neuroimaging studies, the contribution of brain MRI in the diagnosis and the management of the children with recurrent headache is still low.

Ophthalmoparesis Mimicking Myasthenia Gravis as Acute Manifestation of HashimotoÂ’s Encephalopathy

Hashimoto’s encephalopathy is a rare steroid-responsive disorder in which neuropsychological and neurological symptoms are associated with Hashimoto’s thyroiditis. Recently, it has gained attention in the differential diagnosis of encephalopathy of unknown origin, although its pathogenesis is poorly understood. The diagnosis of Hashimoto’s encephalopathy rests upon the association of autoimmune thyroiditis and neurological symptoms after excluding more common diseases, but is a serious challenge in atypical cases. We here present a patient with isolated ocular disorder as presenting and unic feature of Hashimoto’s encephalopathy that resolved with steroids therapy. Brain MRI showed non-specific white matter abnormalities; EEG and an extensive neurophysiological investigation were normal. The diagnosis in this euthyroid patient was supported by the presence of serum anti-thyroid antibodies and the identification in the CSF of anti-dimethylargininase-I and aldehyde reductase-I autoantibodies. The description of atypical cases of this rare but certainly underestimated condition is clinically important and adds relevant information for the clinical practice.

Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I

Limb-girdle muscular dystrophy 2I (LGMD2I) is a neuromuscular disorder with a heterogeneous phenotype. It is caused by mutations in the Fukutin Related Protein (FKRP) gene, which is ubiquitously expressed in human tissues. FKRP functions in CNS are largely unknown. To investigate possible cognitive impairment in LGMD2I and to describe brain MRI features. Ten LGMD2I patients (four males and six females, mean age 44 years, age range 19-69 years) were assessed with an extensive neuropsychological battery, psychopathological tests and neuromuscular specific quality-of-life questionnaire. Adults were compared with ten matched healthy controls. All patients underwent complete neurological examination, and nine underwent brain MRI scanning. Patients showed a fairly specific cognitive profile with mild impairment in executive functions and visuo-spatial planning without substantial impairment in global and logic IQ. MRI findings were heterogeneous: four patients showed non-specific white matter abnormalities; two patients showed moderate ventriculomegaly; three patients showed mild enlargement of subarachnoid spaces, without a specific pattern. Cerebellar atrophy was marked in one patient. Abnormal glycosylation of α-dystroglycan in LGMD2I may interfere with brain development and cognitive performances involving the frontal and posterior parietal regions, but does not result in specific brain MRI abnormalities.

Multiple Cranial Nerve Enhancement in Mitochondrial Neurogastrointestinal Encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare disease that often presents with nonspecific white matter abnormalities on magnetic resonance imaging. Ptosis and ophthalmoparesis are a part of its clinical features. We report multiple cranial nerve contrast enhancement on magnetic resonance imaging in a patient with MNGIE and postulate that demyelination may be the responsible substrate for this previously unreported finding. This finding may also explain the cranial neuropathies that patients with MNGIE have.

Comparing Noninvasive Dense Array and Intracranial Electroencephalography for Localization of Seizures

To compare the localization of the seizure onset zone estimated from ictal recordings with high spatial resolution, 256-channel scalp dense array electroencephalographic video long-term monitoring (LTM) with the aid of source analysis with that obtained from subsequent intracranial ictal recordings. Ten patients with medically refractory epilepsy, all surgical candidates, underwent intracranial LTM after standard noninvasive evaluation failed to provide adequate localizing information regarding ictal origins. Before invasive studies, all patients underwent dense array electroencephalographic LTM in which habitual clinical seizures were recorded for each patient. Source analysis was applied to ictal onsets. Intracranial electrode placement followed conventional guidelines, although the neurosurgeon was aware of the dense array electroencephalographic results. Patients ranged in age from 10 to 49 years (mean age, 24 y); 7 were male. Identified risk factors included closed head injury in 1 patient and childhood meningitis in another. No focal neurological signs were found in any patient. Magnetic resonance imaging findings were normal in 6 patients; 1 patient had cerebellar hypoplasia, 1 had right frontoparietal dysplasia, 1 had bilateral nonspecific white matter abnormalities, and 1 had bilateral cavernous angiomas. Ictal onsets, based on invasive recordings, were in the mesiotemporal lobe (3 patients), lateroparietal (2 patients), mesioparietal (1 patient), laterofrontal (1 patient), superolateral frontocentral (1 patient), frontopolar (1 patient), and posteroinferior temporo-occipital neocortex (1 patient). Dense array electroencephalography localized ictal onsets to the same region as intracranial monitoring in 8 of 10 cases; invasive studies disclosed an additional ictal focus in 2 of these patients. Surgical resections were based only on intracranial electroencephalographic findings. Dense array electroencephalography has the potential to assist in the noninvasive localization of epileptic seizures and to guide the placement of invasive electrodes for localizing seizure onset.

“Benign” Imaging Abnormalities in Children and Adolescents With Headache

To study the frequency of "benign" abnormalities on brain imaging in children with headache, compare it with the frequency of imaging findings that dictate a change in patient management, and determine the association of benign findings with headache. A database of 681 headache patients from the pediatric outpatient neurology department over 2 years was reviewed. Patients with benign imaging abnormalities were compared to those with nonbenign findings. Benign abnormalities were defined as those that did not result in a change in patient management. Using literature review, we discuss the benign findings and their possible association with headache. Two-hundred and forty-one patients (35.4%) had imaging at our facility. Two-hundred and eighteen had brain magnetic resonance imaging and 23 had brain computed tomography (CT) only. Twenty-two patients had CT of the sinuses in addition to brain imaging. Forty-six (19.1%) were found to have 50 benign abnormalities including 13 sinus disease, 11 Chiari I malformations, 7 nonspecific white matter abnormalities, 5 venous angiomas, 5 arachnoid cysts, 4 enlarged Virchow-Robin spaces, 2 pineal cysts, 1 mega cisterna magna, 1 fenestration of the proximal basilar artery, and 1 periventricular leukomalacia. Twenty-three patients (9.5%) had findings requiring a change in management. These included 5 sinus disease, 4 tumors, 4 old infarcts, 3 Chiari I, 2 moyamoya, 1 intracranial vascular stenosis, 1 internal jugular vein occlusion, 1 arteriovenous malformation, 1 demyelinating disease, and 1 intracerebral hemorrhage. When excluding sinusitis, which was evident clinically prior to imaging, 3 patients had absence of abnormal neurologic symptoms and signs and imaging findings that resulted in a change in management. Approximately 20% of pediatric headache patients with brain imaging have benign abnormalities that do not result in a change in headache management. Imaging findings that require a change in management are rare in patients with an absence of abnormal neurologic symptoms and signs, occurring in 1.2% of patients imaged in this study.

Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic myopathy.

To compare brain involvement in myotonic dystrophy (DM) with that of proximal myotonic myopathy (PROMM). PROMM is a multisystem disease with many features in common with DM. Twenty patients with DM (CTGF[500-700), 20 patients with PROMM, and 20 normal control subjects were studied. Neuropsychological testing was performed in 12 patients with PROMM and in 18 patients with DM; brain MRI was performed in 17 of 20 PROMM patients and 15 of 20 DM patients. Ten patients with PROMM and 11 patients with DM were subjected to H2(15)O PET. Two-thirds of the patients with PROMM and one-half of those with DM were impaired on visual-spatial recall, whereas one-third of the patients with PROMM and less than half of those with DM showed an impairment in visual-spatial construction. Brain MRI was normal, or showed only nonspecific white matter abnormalities in both PROMM and DM patients. PET studies in PROMM patients showed a bilateral decrease in regional cerebral blood flow (rCBF) of the orbitofrontal and medial frontal cortex, whereas DM patients had more widespread hypoperfusion that extended to the dorsolateral frontal cortex and subcortical regions. Impaired visual-spatial function may be present in proximal myotonic myopathy. This correlates best with a reduction in regional cerebral blood flow observed in H2(15)O PET brain scans rather than with specific structural abnormalities observed on brain MRI.

In vivo magnetic resonance spectroscopy in HIV and HIV-related brain diseases.

Central nervous system involvement is common in the later stages of HIV infection. The pathophysiology for the development of cognitive impairment in HIV infection is still unclear. Magnetic resonance imaging shows brain atrophy and non-specific white matter abnormalities in some of the patients with HIV dementia. In vivo magnetic resonance spectroscopy (MRS) provides a biochemical profile of the brain and shows promise for furthering the understanding of the pathophysiology associated with HIV-related dementia. Moreover, MRS is a practical and non-invasive method which can help to differentiate the focal lesions of the most frequent opportunistic infections in AIDS.