Biomedical subjects
Publications and source records attributed to I Harting.
Neurologic disease in glutaryl-CoA dehydrogenase (GCDH) deficiency usually presents with acute encephalopathic crises before 2 years of age. The authors report two previously asymptomatic patients with macrocephaly presenting with progressive neurologic deterioration and a severe leukoencephalopathy during adolescence or adulthood.
The authors describe four unrelated girls with a distinctive neurologic disorder with early-onset progressive ataxia and hypodontia with a characteristic pattern of delayed dentition. Cerebral MRI shows hypomyelinated white matter and cerebellar atrophy; 1H-MRS of white matter reveals a marked elevation of myo-inositol.
Magnetic resonance spectroscopy facilitates non-invasive determination of metabolic changes in vivo. The main metabolites are the neuronal marker N-acetylaspartate (NAA), cholines reflecting membrane turnover, creatine, lactate, and mobile lipids. Primary brain tumours exhibit reduced NAA and increased choline resonances compared to normal brain, and these abnormalities increase with higher malignancy. Increasing choline resonances on follow-up studies correlate with tumour progression, whereas the reduction of initially increased choline resonances indicates a transition from viable tumour to necrotic tissue. Metastases as non-neuroectodermal tumours lack NAA, but demonstrate elevated choline, lactate and lipid resonances. Lymphomas are characterised by massively increased lipid resonances with markedly elevated choline. Prominent alanine resonances are often observed in meningioma. Cystic/necrotic lesions demonstrate elevated lactate regardless of their aetiology. The characteristic finding of prominent resonances from acetate, succinate, and alanine, of leucine, isoleucine and valine in untreated bacterial abscesses allows the differentiation of bacterial abscesses from cystic/necrotic brain tumours.
Low-grade (WHO level I) meningiomas are slow-growing, benign tumours typically presenting with unspecific symptoms (e.g. headache), seizures, cranial nerve compression and neuropsychological symptoms determined by location and size of the lesion. Haemorrhagic onset and sequelae are rare, and have been described infrequently. This is a case of a 50-year-old male presenting with signs of tentorial herniation secondary to hyperacute intratumoural haemorrhage (ITH) into a previously undiagnosed meningioma. Emergency surgical decompression and exstirpation of the lesion helped to achieve a favourable outcome. ITH has been described in all including benign intracranial neoplasms. Factors associated with a higher risk for haemorrhage in meningiomas are discussed. Though haemorrhages associated with meningiomas have been reported, ITH into low-grade meningiomas leading to herniation remains a rarity. Bearers of known lesions and their treating physicians who opt for conservative or delayed treatment should be aware of this remote complication.
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Alpha-mannosidosis is an inherited lysosomal storage disease. The authors report three siblings (ages 38 to 47 years) with the rare adult variant. All three had late-onset ataxia and retinal degeneration, adding to hearing loss, cognitive impairment, and dysotosis multiplex. One sibling also had psychosis. MRI revealed cerebellar atrophy and predominantly parieto-occipital white matter changes. MR spectroscopy showed no evidence for demyelination. It appears that the disabling course of adult alpha-mannosidosis is caused by lysosomal accumulation rather than demyelination.
BACKGROUND: Two unrelated girls had early onset of nystagmus and epilepsy, absent psychomotor development, and almost complete absence of myelin on cerebral MRI. The clinical features and MR images of both patients resembled the connatal form of Pelizaeus-Merzbacher disease (PMD), which is an X-linked recessive disorder caused by duplications or mutations of the proteolipid protein gene (PLP). OBJECTIVE: To define a unique neurometabolic disorder with failure of myelination. METHOD: S AND RESULTS: 1H-NMR of CSF in both girls was performed repeatedly, and both showed highly elevated concentrations of N-acetylaspartylglutamate (NAAG). The coding sequence of the gene coding for glutamate carboxypeptidase II, which converts NAAG to N-acetylaspartate (NAA) and glutamate, was entirely sequenced but revealed no mutations. Even though both patients are girls, the authors sequenced the PLP gene and found no abnormality. CONCLUSIONS: NAAG is an abundant peptide neurotransmitter whose exact role is unclear. NAAG is implicated in two cases of unresolved severe CNS disorder. Its elevated concentration in CSF may be the biochemical hallmark for a novel neurometabolic disorder. The cause of its accumulation is still unclear.
Necrotic meningiomas are relatively rare, accounting for 1.3-3.9% of primary intracranial tumours and for 10-15% of meningiomas, but are of special clinical importance as they may resemble metastases or malignant gliomas. We report the magnetic resonance findings of diffusion-weighted imaging, perfusion-weighted imaging, and spectroscopy in a patient with a necrotic meningioma, in whom clinical symptoms and signs suggested a central nervous system infection.
This article summarizes the magnetic resonance imaging features of glutaric aciduria type I (GA I) based on the cases presented at the 3rd International Workshop on Glutaryl-CoA Dehydrogenase Deficiency together with a review of previously reported neuroimaging characteristics of GA I. Previous reports have focused on characteristic findings, such as basal ganglia injury and frontotemporal atrophy or hypoplasia, subdural effusions and white-matter disease. Most of these findings have been demonstrated in symptomatic children, i.e. after manifestation of acute encephalopathic crises. In contrast, prospective investigations in presymptomatically diagnosed children are rare. Since more recent investigations have highlighted CNS changes in patients without encephalopathic crises, systematic prospective investigations of neuroradiological findings in this disease are indispensable for a better understanding of this disease. Based on these findings a suggestion for a MRI protocol is presented, supporting a standardized evaluation of patients with GA I.
Statistically tumors are the most likely cause of space-occupying intracranial lesions. However, many non-neoplastic diseases also manifest as mass lesions and may be indistinguishable from tumors. The most common of these are inflammatory and dysplastic lesions, which intraaxially imitate mostly glioma, lymphoma, and metastases and extraaxially meningeoma and neurinoma. Aside from a willingness on the part of the diagnostic radiologist to question the most obvious diagnosis, on clinical history and findings are prerequisites for a sound radiological differential diagnosis. The aim of this article is to provide a practical overview of the differential diagnosis of intracranial mass lesions with emphasis on non-neoplastic abnormalities.
Multiple sclerosis (MS) is the most common demyelinating inflammatory disease of the central nervous system (CNS), presenting with multifocal, disseminated inflammatory lesions referred to as plaques. Magnetic resonance imaging (MRI) typically depicts multiple, round to oval, circumscript lesions predominantly involving periventricular and subcortical white matter, brainstem and cerebellum. More recent investigations have demonstrated that the macroscopically visible plaques only present the tip of the iceberg: Already early in its course, MS causes neuroaxonal damage and diffusely involves the entire brain parenchyma including normal appearing white matter. These changes are reflected by strongly T1w hypointense lesions and atrophy of early onset, by reduction of the neuronal Marker N-acetylaspartate (NAA) on spectroscopy, by a decrease of the magnetization transfer ratio (MTR), by an increased in diffusibility and decreased anisotropy on diffusion-weighted imaging (DWI). MRI imaging is an important tool in the diagnosis of MS by revealing the characteristic spatial and temporal dissemination of the cerebral and spinal manifestations of this disease. Diagnostic criteria increase the diagnostic specificity and allow better differentiation from other diseases with multifocal white matter abnormalities.
PURPOSE: To describe MRI findings of four types of focal cortical dysplasia (FCD) and compare them with diagnostic criteria reported in the literature. MATERIAL AND METHODS: This study includes eight patients with seizures in whom cranial MRI diagnosed an FCD, with histologic confirmation in two patients. RESULTS: In all patients, the dysplastic cortex was thickened. Its signal was hyperintense on T 2 -weighted and FLAIR images, but variable on T 1 -weighted images. Blurring of the corticomedullary junction was present in 5 patients. In one patient, MRI demonstrated vascular proliferation within the FCD. Type l or II FCD was diagnosed in six patients, and transmantle FCD and type IV FCD with capillary proliferation in one patient each. DISCUSSION: Thickening and hyperintensity of the cortex on T 2 -weighted and FLAIR images are more reliable signs of FCD than blurring of the gray matter-white matter junction and signal changes on T 1 -weighted images. Typical vascular proliferation may be detectable with MRI and suggests the diagnosis of FCD with glial proliferation. Edema, calcification, or pathologic contrast enhancement has not been observed in FCD to date.
We describe a boy presenting at the end of the first year of life with severely delayed motor development and only mild mental retardation. Neurological examination revealed axial hypotonia, mild ataxia and pyramidal signs. Elevated lactate and protein in cerebrospinal fluid were the most prominent laboratory abnormalities. Brain MRI showed severe supratentorial white matter changes. Cerebellar white matter appeared normal whereas the signal of the atrophic cerebellar cortex was markedly increased. In vivo 1H-magnetic resonance spectroscopy of the parietooccipital white matter region showed a distinct resonance of lactate. By means of biochemical analysis of respiratory chain enzymes in fibroblasts, the diagnosis of an isolated complex I deficiency could be established in our patient.
Diffusion magnetic resonance imaging (MRI) has become an important tool in the radiologic diagnosis of diseases of the brain as it measures molecular motion of water that characterizes the microstructure of tissues. Its most important clinical use to date is the early detection of cerebral ischemia by revealing the ischemic injury shortly after vessel occlusion and simultaneously providing therapy-relevant information on the tissue at risk. Furthermore, diffusion MRI is diagnostically promising in other diseases of the brain and is thus increasingly becoming part of routine clinical protocols in the diagnosis of tumors, inflammation, trauma, demyelination, dysmyelination and neurodegeneration. Although abnormalities of diffusion are generally not pathognomonic, diffusion MRI affords information about tissue changes for specific disorders that complements information obtained with standard MR techniques and frequently shows pathology earlier. In addition, diffusion MRI can be applied to plan, guide and follow-up biopsies or resective surgery. Particularly diffusion tensor imaging (DTI), which displays the orientation of white matter fibers, holds promise for improved surgical planning. Moreover, DTI can be used to detect changes in connectivity between functional brain areas. Therefore, DTI is highly relevant not only in advancing the knowledge of white matter diseases but also in stimulating research on normal brain development and brain aging.
Several recent studies have suggested that skeletal muscle bioenergetics are abnormal in patients with chronic obstructive pulmonary disease (COPD). This study investigates the activity of cytochrome oxidase (COX), the terminal enzyme in the mitochondrial electron transport chain, and the expression of two mitochondrial DNA genes related to COX (mRNA of subunit I of COX [COX-I] and the RNA component of the 12S ribosomal subunit [12S rRNA]), in quadriceps femoris muscle biopsies obtained from COPD patients with various degrees of arterial hypoxemia, and from healthy sedentary control subjects of similar age. The activity of COX was measured spectrophotometrically in fresh tissue at 37 degrees C with excess substrate. RNA transcripts were measured using reverse transcription and polymerase chain reaction. The measurements of mRNA COX-I and 12S rRNA were normalized to the mRNA of actin, which is a housekeeping gene not influenced by hypoxia. We found that, compared with control subjects, COPD patients with chronic respiratory failure (PaO2 < 60 mm Hg) showed increased COX activity (p < 0.05). Further, the activity of COX was inversely related to arterial PO2 value (Rho -0.59, p < 0.01). The COX-I mRNA content was not different between patients and control subjects but patients with chronic respiratory failure had higher levels of 12S rRNA (p < 0.05), which were again inversely related to PaO2 (Rho -0.49, p < 0.05). These results indicate that the activity of COX is increased in skeletal muscle of patients with COPD and chronic respiratory failure, and they suggest that this is likely regulated at the translational level by increasing the number of mitochondrial ribosomes.
A new protocol was established for the quantitative analysis of gene expression in small muscle biopsies. Reverse transcription-PCR was performed with a preparation of total nucleic acids (DNA+RNA), amplifying the sequences of interest (targets; mitochondrial transcripts: 12S rRNA, cytochrome-c-oxidase [COX I] mRNA) together with an endogenous, non-transcribed reference sequence (template: D-loop region of mtDNA). Synthesis of PCR products at consecutive cycles within the exponential phase was quantified by measuring incorporation of radioactivity. Product accumulation was determined by regression analysis of these data. Gene expression could then be quantified as a ratio of target transcripts to reference DNA. The results revealed a ratio of 12S rRNA:mtDNA and COX I mRNA:mtDNA of 14 and 2, respectively, or a ratio of 12 S rRNA:COX I mRNA of 7 in human left ventricle and are in good agreement with previously published values for rat liver and muscle. In addition to the investigation of mitochondrial gene expression in the steady state and during mitochondrial proliferation, this newly developed method will easily be applicable to expression analysis of any nuclear gene using an intron sequence as endogenous reference.