Fetal globoid cell leukodystrophy in one of twins

Summary Twins with high-risk globoid cell leukodystrophy (GLD) at the 6th gestational month were studied morphologically and enzymatically. One of them was affected and the other was probably the carrier of this disease. Central nervous system and other viscera developed normally for the gestational age in both fetuses.The lesions of GLD were found in the fetus with marked deficiency of galactocerebrosidase, but not in the probable carrier. The lesions were located only in the considerably myelinated areas viz., the brain stem and the spinal cord. Ultrastructurally, the globoid cells in the fetal GLD seemed to originate from glial cells, probably oligodendroglia.     

Globoid cell leukodystrophy: Specialized contact of globoid cell with astrocyte in the brain of twitcher mouse

Summary Subplasmalemmal linear densities (Yajima et al. 1977 a) were the membrane specializations observed in globoid cells in globoid cell leukodystrophy (GLD) and in the cells of the mononuclear phagocytic system (Kawanami et al. 1980). In the spinal cord of the twitcher mouse, an authentic murine model of GLD, somewhat similar membrane specializations were noted in astrocytes, and on some occasions, a spot desmosome-like cellular contact was observed between globoid cells, which were likely to be mesodermal in origin, and astrocytes, which are of ectodermal origin. Possible significance of such apparent cellular contact is discussed briefly.Supported in part by research grants NS-03356, NS-10803, and HD-01799 and a training grant for experimental neuropathology, NS-07098, from the National Institute of Health, USPHS, USA     

Characteristic inclusions in the kidney of canine globoid cell leukodystrophy

Summary The kidney of a 7-month-old male Cairn terrier with globoid cell leukodystrophy (GLD) was investigated with light and electron microscopes. A few tubular epithelial cells in the inner medulla as well as some exfoliated cells in the lumina revealed PAS-positive cytoplasm in which needle-like structures were to be seen on occasion. At the ultrastructural level, characteristic inclusions of GLD were found in these cells. This observation indicates that in addition to our previous report in the kidney of murine GLD (Takahashi et al. 1984), kidney in canine GLD also is a site of abnormal storage of galactosylceramide, although so far no morphological or biochemical evidence of galactosylceramide storage was demonstrated in human GLDSupported in part by research grants NS-03356, NS-10803, and HD-07098 from NINCDS, USPHS.     

A case of pigmentary type of orthochromatic leukodystrophy with early onset and globoid cells

Summary We report herein a sporadic case of the pigmentary type of orthochromatic leukodystrophy with early onset and very rapid clinical course. The patient's development was normal until 2 years old, when he experienced visual disturbance. Rapid deterioration resulted in death 1.5 years after the onset. Metachromatic leukodystrophy, globoid cell leukodystrophy and adrenoleukodystrophy were excluded by biochemical assays. Autopsy findings were compatible with the diagnosis of the pigmentary type of orthochromatic leukodystrophy. However, there were unique findings of severe neuronal loss and the collection of globoid-like cells in the interface of the gray matter and the white matter. Immunohistochemical staining of myelin basic protein, proteolipid protein and galactocerebroside demonstrated that these myelin constituents were equally preserved in the posterior column, while absent in the lateral and anterior columns of the spinal cord.     

Pathogenesis of leukodystrophy for Krabbe disease: Molecular mechanism and clinical treatment

We reported the basic concept of the pathology of leukodystrophy with emphasis on Krabbe disease. First, the normal process of myelination and the pathology of demyelination will be described, emphasizing the course inducing neuro-inflammation in its progression. After classifying metabolic leukodystrophy, the features of Krabbe disease (globoid-cell leukodystrophy) are explained as well as molecular cloning and mutation analysis of the galactocerebrosidase (GALC) gene. Finally, the experience of hematopoietic stem cell transplantation for patients with Krabbe disease is reported and the future possibility of therapy for the disease is summarized.     

The twitcher mouse: an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease)

The Twitcher is a new neurological mutant of mouse which shows clinical and histopathological features similar to those of human and canine globoid cell leukodystrophy (Krabbe disease). Brain and liver tissues of affected mice showed a profound deficiency of galactosylceramidase and lactosylceramidase I activities. A distinct group with intermediate enzyme activities could be identified among the phenotypically normal mice, consistent with their being heterozygotes. The Twitcher mouse is, therefore, not only a clinically and morphologically, but also an enzymatically, authentic model of human globoid cell leukodystrophy. This is the first enzymatically authentic murine model of human sphingolipidosis.     

Demyelination in the spinal cord of murine globoid cell leukodystrophy (the twitcher mouse)

Summary Chronologic events of demyelination were investigated in the spinal cord of the twicher mouse, an authentic murine model of human globoid cell leukodystrophy (GLD) from 5 to 45 days postnatal. There was very little evidence of myelin degeneration before day 25 although clustered or scattered globoid cells were already noted in the dorsal columns and intramedullary portion of the ventral roots.Globoid cells contained typical cytoplasmic inclusions and in those which were found adjacent to degenerating myelin and naked axons, myelin debris were conspicuous in their cytoplasm.Vesiculation of myelin and a feature of globoid cells stripping myelin lamellae were noted in the area of demyelination. Myelin and oligodendroglial degeneration became pronounced throughout the spinal white matter after day 40 but globoid cells tended to be more concentrated in the dorsal columns.Our observations suggest that the emergence of globoid cells in GLD is in response to the changes in biochemical environment (i.e., excessive presence of galactosylceramide in the tissue?), and these cells appear to have a role as phagocytic cells in removing myelin lamellae.Supported in part by research grants NS-03356, NS-10803, and HD-01799 and a training grant for experimental neuropathology, NS-07098, from NINCDS     

Sub-plasmalemmal linear density: A common structure in globoid cells and mesenchymal cells

Summary Sub-plasmalemmal linear densities of variable length (0.11.0 ) were found to be a constant feature of globoid cells in human as well as in canine globoid cell leukodystrophy (GLD). Similar densities were also observed in experimental globoid cells and epithelioid cells in chronic granuloma but not in glial cells. The linear densities always appeared without any relation to basal laminae. These observations together with the other reports of similar structures in lymphoma, fibroma and sarcoidosis suggest that the sub-plasmalemmal density is a structure frequently observed in mesenchymal cells, and may be another supporting feature for possible mesenchymal origin of globoid cells.     

Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the "twitcher" mouse model of globoid cell leukodystrophy

The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.     

Late-onset globoid cell leukodystrophy

During the past 12 years, ten cases of globoidcell leukodystrophy (GLD) have been followed up: seven of these patients were affected by the late infantile form. The authors point out the clinical aspects and the course of these patients and stress the high frequency of this form of GLD in Sicily.     

Metachromatic leukodystrophy: On an atypical case

We describe an atypical case of juvenile metachromatic leukodystrophy. Motor conduction velocity was still within the normal range 3 years after clinical onset, in contrast to what is commonly found in this disease. Another unusual feature is the normal level of CSF protein. These data are discussed in the light of the sural nerve biopsy findings, which revealed only slight impairment.

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Sommario Gli autori descrivono un caso atipico di Leucodistrofia Metacromatica di tipo giovanile. A 3 anni di distanza dall'esordio clinico la VdC motoria è risultata ancora nella norma, in contrasto con quanto comunemente osservabile in tale patologia. Altro dato inusuale è la normalità del livello delle proteine nel CFS. Tali dati vengono discussi anche alla luce dei risultati della biopsia di nervo surale, che rivela solo modesta compromissione.

     

Biopsy diagnosis of a case of adult onset orthochromatic leukodystrophy. Clinical and brain biopsy findings

We report the intra vitam histopathological findings on the brain of a female patient presenting an adult form of orthochromatic leukodystrophy. At 38 years of age the patient began to show progressive dementia and a pseudobulbar syndrome. The pedigree revealed an autosomal dominant pattern of inheritance. The CT scan showed a wide hypodensity of the anterior white matter. Biochemical investigations showed only a slight elevation of serum VLCFA and no alteration of urinary enzymatic activities. Cortical and subcortical biopsy specimens from the rught frontal lobe showed: neuronal loss in the gray matter, accumulation of autofluorescent material within residual neurons and sudanophilic material within macrophages and astrocytes, sparing of axons. Electron microscopy showed lamination and fragmentation of the myelin and the presence of electrondense bodies and vesicular material into oligodendrocytes and astrocytes.We discuss the differential diagnosis of OLD forms with adult onset, namely between Löwenberg-Hill disease and the pure form of OLD with pigmented glial cells.

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Sommario Vengono riportate le caratteristiche istopatologiche cerebrali intra vitam di una paziente che presentava una forma ad inizio tardivo di leucodistrofia ortocromatica.All'età di 38 anni la paziente iniziò a manifestare un progressivo decadimento mentale ed una sindrome pseudobulbare. L'albero genealogico mostrava una ereditarietà a trasmissione autosomica dominante. Alle immagini Tc risultava un'ampia ipodensità della sostanza bianca anteriore. Le indagini biochimiche evidenziavano solo un modesto incremento dei VLCFA e nessuna alterazione delle attività enzimatiche urinarie. I campioni bioptici corticali e subcorticali prelevati dal lobo frontale mostravano una perdita neuronale nella sostanza grigia, accumulo di materiale autofluorescente dentro i neuroni residui e materiale sudanofilo all'interno dei macrofagi e degli astrociti, risparmio degli assoni. La microscopia eletronica rivelava slaminazione e frammentazione della mielina e la presenza di corpi elettrondensi e materiale vescicoloso all'interno di oligodendro ed astrociti. Viene discussa la diagnosi differenziale tra le forme di leucodistrofia ortocromatica ad esordio tardivo, quindi tra la malattia di Lowenber-Hill e la forma pura di leucodistrofia ortocromatica con accumulo di pigmento nelle cellule gliali.

     

Isoelectric focusing of CSF proteins and the future evolution of multiple sclerosis: a clinical follow-up

Summary A clinical follow-up covering a period of 5–10 years after onset was performed in 150 patients with optic neuritis or other potential onset symptoms of MS. Thin-layer isoelectric focusing had been used for the initial CSF-protein analysis. No evidence for a more probable alternative diagnosis appeared in 147 patients while a non-MS diagnosis was established in 3 patients. Among these 147 subjects the planned follow-up was accomplished in 131 patients, but not in 16. An evolution into clinically definite MS occurred in 59 subjects, in whom oligoclonal CSF immunoglobulin was found in 92%. Further clinical activity without spatial dissemination—i.e. lesser degrees of diagnostic probability for MS—were found in 35 patients in whom oligoclonal CSF immunoglobulin components were detected in 86%. Among the 131 patients with a complete follow-up, 45 remained free from further clinical activity; oligoclonal CSF immunoglobulin components occurred in 40% of these patients. The frequency of further clinical activity with or without spatial dissemination was significantly higher in subjects exhibiting oligoclonal CSF immunoglobulin components than in those without such changes.The initial part of the investigation was performed at the Department of Neurology, Karolinska Hospital, Stockholm, Sweden     

Fetal Krabbe leukodystrophy

Summary Two new cases of Krabbe disease were diagnosed prenatally in a family with two previous affected children. The activity of galactosylceramide--galactosidase was virtually absent in cultured amniotic cells.The prenatal diagnosis was confirmed enzymatically in cultured fibroblasts, brain, and visceral organs.Light and electron microscopy studies in both fetuses, 20 and 23 weeks of gestational age respectively, revealed the presence of typical globoid cells in the white matter of the spinal cord. Specific inclusions were also found in the brain stem and in peripheral nerves of the second fetus.A comparison with other Krabbe disease fetuses described in the literature contributes to the consensus that abnormal morphological findings can be expected in particular in the most actively myelinating areas of the nervous system.Although most of the cells containing the specific melusions are probably non-glial in nature, some of them could represent myelination glia.This work was supported by the FGWO (grants nos. 3.0033.77 and 3.0012.77), by the FRSM (grant no. 3.4542.79), and by the Baron Charles Bracht Foundation     

Clinical and CSF cyto-proteic findings in 23 patients with CSF eosinophilia

Clinical diagnosis and cerebrospinal fluid (CSF) protein pattern were studied in 23 patients who had eosinophilic granulocytes in the CSF. Clinical data revealed that an inflammatory disorder of the central nervous system (CNS) was evident in 20 cases. A lymphoid reaction and elevated CSF total protein were found in most of the cases, but the most important finding was an increase of CSF gamma-globulin in 12 patients, of whom 10 had oligoclonal patterns. Our results may give support to a relationship between intrathecal eosinophilic reaction and inflammatory diseases of the CNS with subacute or chronic course accompanied by intrathecal synthesis of immunoglobulins.     

Late-onset globoid cell leukodystrophy: unusual ultrastructural pathology and subtotal beta-galactocerebrosidase deficiency

An 11-year-old girl was found to have severely reduced beta-galactocerebrosidase activity as evidence of late-onset globoid cell leukodystrophy, while her mother had almost normal enzyme activity in circulating white blood cells. Clinically, the patient showed a remitting course marked by seizures, ataxia, white-matter disease on computed tomographic scan, and reduced conduction velocities of peripheral nerves. Symptoms improved somewhat around the age of 10 years. Two sural nerve biopsies, performed 6 years apart, disclosed a demyelinating neuropathy. By electron microscopy, membrane-bound vacuolar lysosomes in Schwann cells of myelinated axons, unlike the typical needlelike inclusions seen in classic infantile globoid cell leukodystrophy, were present in both specimens. Thus, clinical, morphologic, and biochemical data in this patient--and her mother--emphasize, compared with past reports on late-onset globoid cell leukodystrophy, considerable variation in the nosologic spectrum of late-onset globoid cell leukodystrophy and conspicuous differences from classic infantile globoid cell leukodystrophy.     

Autosomal dominant leukodystrophy with axonal spheroids and pigmented glia: clinical and neuropathological characteristics

We report two autopsy cases of siblings with adult-onset autosomal dominant leukodystrophy characterized by destruction of cerebral white matter, large numbers of axonal spheroids and pigmented glia in the fronto-temporal lobes. Both patients presented with motor and cognitive symptoms and aphasia, 2–3 years before death. At autopsy, the brain showed brown coloration and decreased volume of white matter in the frontal and temporal lobes as well as corpus callosum. Microscopically, marked loss of myelin and axons and abundant axonal spheroids without apparent neuronal loss were observed in the frontal and temporal lobes, which was consistent with hereditary diffuse leukodystrophy with spheroids (HDLS). In addition, glial cells, most consistent with macrophages and containing pigments that were stained by Sudan III and PAS, were found in the white matter lesions. The present cases showed overlapping features with HDLS and pigmentary type of orthochromatic leukodystrophy, suggesting that the pathomechanisms of these two diseases are closely related.     

Adult onset leukodystrophy with neuroaxonal spheroids and demyelinating plaque‐like lesions

Adult onset leukodystrophy with neuroaxonal spheroids is an uncommon cause of dementia. Both hereditary (autosomal dominant) and sporadic cases have been described. A 41‐year‐old African woman presented with inappropriate behavior and personality change consistent with frontal lobe dysfunction. MRI demonstrated diffuse frontoparietal white matter signal abnormality and volume loss, as well as focal enhancing white matter lesions, while CT scan showed white matter calcifications. She had been gradually deteriorating over the last 5 years, diagnosed as having progressive demyelinating illness. She died of recurrent chest infections. There was no familial history. The brain showed prominent symmetrical white matter changes with greyish discolorization mainly affecting the frontal and parietal lobes, with less involvement of the temporal lobe and only mildly affecting the occipital white matter. Histology revealed deep white matter atrophy with many neuroaxonal spheroids labelled by neurofilament and β‐amyloid precursor protein. In addition, scattered inactive demyelinating plaque‐like lesions were found in the periventricular areas, brainstem and the cervical spinal cord. This case had typical features of an adult onset leukodystrophy with neuroaxonal spheroids. However, we also demonstrated demyelinating plaque‐like lesions, which has not been previously described. The possibility of a demyelinating origin contributing to the changes may be considered in the pathogenesis of this condition.     

Ultrasound imaging for diagnosis and follow‐up of persistent median artery thrombosis

Introduction: Adult‐onset Krabbe disease is clinically rare and usually affects the pyramidal tracts in the central nervous system. Patients develop a spastic gait, and peripheral neuropathy sometimes occurs simultaneously. Methods: A 55‐year‐old woman with consanguineous parents developed slowly progressive, asymmetric muscle weakness and atrophy in her forearms, while her ability to walk remained unaffected without pyramidal tract signs after onset at age 51 years. Results: Nerve conduction studies demonstrated an asymmetric demyelinating‐type peripheral neuropathy, and sural nerve biopsy documented reduced myelinated nerve fiber density with uniformly thin myelin sheaths, suggesting hypomyelination. Brain MRI demonstrated minor white‐matter injury along the optic radiations, which was associated with asymptomatic, mild, prolonged latency on visual evoked potentials. Laboratory analysis documented low enzyme activity of galactocerebrosidase (GALC) and a known mutation of the GALC gene. Conclusion: Isolated peripheral neuropathy occurs very rarely in adult‐onset Krabbe disease. Muscle Nerve 54 : 152–157, 2016     

Diffuse neuroaxonal leukodystrophy with spheroids of adult onset: MRI and pathological studies

A case of sudanophilic leukoencephalopathy of adult onset was reported. A 42-year-old Japanese woman showed progressive dementia, gait disturbance, apraxia of the left hand, left hemiparesis, and urinary and fecal incontinence. Magnetic resonance imaging (T2-weighted scans and proton images) revealed a symmetrical widespread increase in the signal intensity of cerebral white matter, more prominent in the frontal lobes. Blood levels of very long chain fatty acids and arylsulfatase A were within normal limits. A needle biopsy specimen from the frontal lobe revealed severe demyelination with sudanophilic granules and neurofilament protein-immunoreactive neuroaxonal spheroids in the white matter. The patient's mother was known to have similar symptoms and died at the age of 45, indicating an autosomal dominant inheritance. Because of the dominant inheritance, the psychiatric and neurological symptoms, and the characteristic neuroaxonal spheroids, the case was tentatively diagnosed as ‘hereditary diffuse leukoencephalopathy with spheroids’, a condition that has not been previously reported in Japan.