Clinical, biochemical, neuropathological and molecular findings of the first Polish case of adenylosuccinase deficiency.

Adenylosuccinase (ADSL) deficiency is an autosomal recessive disorder affecting mainly the nervous system. The disease causes psychomotor retardation, frequently with autistic features and epilepsy. ADSL deficiency may be diagnosed by detection of two abnormal metabolites in body fluids--succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr). It is assumed that the former metabolite is neurotoxic. We present clinical, biochemical and neuropathological findings of a child affected by a severe form of ADSL deficiency. She had progressive neurological symptoms that started immediately after birth and died at 2.5 months of age. Macroscopically the brain showed signs of moderate atrophy. Histological examination of all grey matter structures showed widespread damage of neurons accompanied by microspongiosis of neuropile. Cerebral white matter showed lack of myelination in the centrum semiovale and diffuse spongiosis of neuropile. Myelination appropriate for the age was visible in posterior limb of internal capsule, in striatum, thalamus and in brain stem structures but diffuse destruction of myelin sheets was seen with severe marked astroglial reaction with signs of destruction of the cells and their processes. Ultrastructural examination showed enormous destruction of all cellular elements, but astonishingly mitochondria were relatively spared. The neuropathological changes can be considered as the neurotoxic result of metabolic disturbances connected with adenylosuccinase deficiency.

Brain and cerebellar hemidysplasia in a case with ipsilateral body dysplasia and suspicion of CHILD syndrome.

CHILD syndrome is an acronym for Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects. This is an X-linked dominant disorder affecting females with early lethality in hemizygous males. The clinical features are congenital hemidysplasia with ichthyosiform erythroderma and ipsilateral hypoplasia of limbs and other parts of the skeleton as well as defects of the brain, heart, kidney and lung. CHILD syndrome is caused by mutations in the NSDHL (steroid dehydrogenase-like protein) gene at Xq28, which affects cholesterol biosynthesis. A female premature newborn with left side body hemidysplasia and ipsilateral defects of the skin, visceral organs and brain is reported. Analysis of child DNA isolated from skin fibroblasts showed missense mutation c.1046A>G;PpY349C in the NSDHL gene that could cause the phenotype.

Giant cell ependymoma of the spinal cord and fourth ventricle coexisting with syringomyelia.

This report presents a case of widespread intramedullary giant cell ependymoma arising from the central canal of the C4 segment of the spinal cord in a 28-year-old man admitted to hospital with tetraplegia and signs of increased intracranial pressure, eight months after surgical spinal cervical decompression without tetraplegia improvement. Magnetic resonance imaging and autopsy revealed a tumour extending from segment C3/C4 of the spinal cord to the lower half of the fourth ventricle with coexisting syringomyelia. This slow-growing ependymoma of low-grade malignancy exhibited unusual morphology as well as degenerative and ischaemic changes. All intramedullary and ventricular tumour segments featured coexistence of two forms of neoplastic cell, classic ependymomal and pleomorphic multinucleated giant cells. The morphological diagnostic criteria of unusual giant-cell variant of ependymoma and tumour-related syringomyelia in adults are discussed, based on the presented case and a review of the literature.

Leukoencephalopathy with vanishing white matter due to homozygous EIF2B2 gene mutation. First Polish cases.

Leukoencephalopathy with vanishing white matter (VWM), also called childhood ataxia with central nervous system hypomyelination (CACH), is an autosomal recessive disease caused by mutations in any of the five genes encoding subunits of the eukaryotic translation initiation factor eIF2B. Neuropathological findings comprise a severe, cavitating orthochromatic leukodystrophy with only small amounts of myelin breakdown products, and predominantly involving the cerebral hemispheric white matter. Within the white matter abnormal oligodendroglial cells are present with abundant "foamy" cytoplasm. In some regions oligodendroglial cells are increased in numbers. We present three sisters, 18, 11 and 8 years old, with the early to late childhood phenotype. The first signs of the disease were gait disturbances at 4, 2 and 6 years of age, respectively. Neurological examination showed mild tremor of hands and head, truncal ataxia, dysarthria, and hypotonia, after several years followed by spasticity. The course of the disease was slowly progressive. Intellectual abilities are relatively spared. The MRI showed diffusely abnormal white matter of the cerebral hemispheres. The FLAIR images revealed rarefaction of the affected white matter with some stripe-like structures, suggesting the presence of remaining tissue strands. The abnormalities were most pronounced with the middle sister, who had the earliest onset of the disease. A homozygous point mutation in the EIF2B2 gene was found, 638A>G. Both the parents were found to be carriers of this mutation. This is the first description of a Polish family with VWM.

Degeneration of microglial cells in frontal and temporal lobes of chronic schizophrenics.

Schizophrenia is a social disease that occurs in 0.5-1% of the population. It shows a high variability in both clinical picture and theory of its pathogenesis. Its clinical manifestations are accompanied by biochemical, immunological and structural changes. A pivotal role in the development of psychotic disorders is attributed to the impaired limbic system. The aim of this study was to find out whether, and if so, to what extent immunocompetent cells of the central nervous system (microglia) are involved in the process of degeneration occuring in these structures. The study was carried out on 12 brains of female chronic schizophrenics. Sections of frontal and temporal cortex were subjected to ultrastructural as well as histochemical and immunohistochemical examinations by light microscopy. In the structures under study, a large number of ramified microglial cells showing on their surface the expression of the major histocompatibility complex class II (MHC II) was observed. Most cells showed degenerative traits (cytoplasm shrinkage, thinning, shortening and fragmentation of their processes) up to apoptotic changes. Perivascular microglia displayed the lowest intensity of degenerative changes. Ultrastructurally, some damaged microglial cells contained phagosomes and/or degenerated mitochondria. Most abnormal microglia showed morphological signs of the former normal function of immunocompetent and phagocytosing cells. Degeneration of microgial cells, resulting most likely from the primary impairment of the neuron-glia communication that damages their immunocompetent function, may lead to the exacerbation of structural damage and psychotic symptoms. Treatment of chronic schizophrenics should involve the supply of agents to prevent degeneration of microglia and/or long-term immunotherapy.

Neurodegenerative disease in infants with multiple congenital malformations--report of two cases.

During embryogenesis, about 40% of genes are involved in the development of the central nervous system (CNS). The same genes support the integrity and function of brain cells in humans. Birth defects cause different changes in genetic material during embryogenesis. They may also be responsible for precocious death of cells in postnatal period. We studied cases of two infants with similar congenital defects (prenatal onset growth deficiency, coloboma of iris, epicanthal folds, low set ears, clinodactyly of Vth fingers). The infants died at age 9 and 10 months with signs and symptoms of progressive CNS degeneration. In one case, chromosomal aberration was detected (4pter). Neuropathologicaly, there were small for the age brains, atrophy of cerebral cortex, white matter and basal ganglia (mainly nucleus caudatus) with loss of neurones, spongiosis and hypertrophic astroglia reaction as well as atrophy of cerebellar cortex. Severe damage of white matter was seen. We suggest that such cases are natural models for investigations of the role of genes in embryogenesis and pathogenesis of neurodegenerative diseases.

Morphological analysis of active microglia--rod and ramified microglia in human brains affected by some neurological diseases (SSPE, Alzheimer's disease and Wilson's disease).

The activation of microglial cells in pathological conditions is manifested primarily by their proliferation, as well as by the occurrence of a new morphological form--rod microglia. In the present study immunohistochemical identification of rod microglial phenotype against ramified microglia was performed on segments of 17 brains derived from 7 cases of encephalitis of viral aetiology (including 5 SSPE cases), 6 cases of Wilson's disease and 4 cases of Alzheimer's disease. Segments from frontal, temporal and occipital lobes, cerebellum and brainstem were subjected to histological, histochemical and immunohistochemical reactions. The presence of activated rod and ramified microglia was observed in sections derived from all structures of the brains under study. Both morphological forms of activated microglia reacted to antibodies: HLA II, CD68, HAM56 and lectin RCA-1. Expression of HLA II molecules was less intensive on the surface of microglial rod cells. A positive reaction to PCNA antibody was mainly observed in rod/elongated/cylinder-shaped nuclei, which is a characteristic feature of rod microglia. In the study material, the localisation of microglial processes seemed to depend rather on the structural topography of the cell in the brain than on the nuclear shape of the activated microglial cell. Our observations revealed a strong similarity between immunohistochemical phenotypes of both morphological forms of microglia with the indication that rod microglia is a first developmental form of activated microglia.

Haemangioblastoma of the posterior cranial fossa: clinico-neuropathological study.

Haemangioblastoma (HBs) may occur sporadically in the central nervous system, or in association with von Hippel-Lindau (VHL) disease. Haemangioblastoma of the central nervous system is often seen in the posterior cranial fossa. VHL is an autosomaly dominant disorder. In sporadic HBs tumours, VHL alleles are reported to be inactive in up to 50% of tumours. Five patients with tumours of the posterior cranial fossa were examined by scyntygrapghy, computed tomography or magnetic resonance imaging (MRI). Metastases were initially diagnosed by neuroimaging examinations in two patients, and HBs in the remaining cases. In four patients, tumours were removed neurosurgically. Two patients had evidence of VHL disease. All resected tumours and autopsy materials were studied histologically and immunohistologically. Most antibodies that were used showed positive immunoreactions with stromal, endothelial, and pericyte or macrophage cells in tumours diagnosed as haemangioblastoma. Preoperative diagnosis of haemangioblastoma is mostly precise with MRI or magnetic resonance angiograghy. The surgical treatment of HBs is only a part of the complex therapeutical process. Diagnosis based on the gene analysis can be very useful in early detection or protection against potential recurrence of this disease in patients and their families.

Ultrastructural evaluation of activated forms of microglia in human brain in selected neurological diseases (SSPE, Wilson's disease and Alzheimer's disease).

Activated forms of microglia were ultrastructurally evaluated in three neurological diseases of different aetiology (subacute sclerosing panencephalitis--SSPE, Wilson's disease and Alzheimer's disease). The occurrence of activated rod, ramified and amoeboid microglia was found in the investigated diseases. The widest ultrastructural variability of microglia was in SSPE, including the presence of mitotic chromosomes or centrioles in its cytoplasm, which indicates microglia proliferation. In the nuclei of activated microglia, some nuclear bodies with different structures were frequently seen, whereas lamellar structures (similar to developing Birbeck's bodies--pathognomonic to Langerhans-type dendritic cells) were observed in the cytoplasm. The activated forms of microglia with apoptotic features were found only in SSPE cases. Some apoptotic nuclei were filled with nucleocapsids of measles virus. In Alzheimer's disease, activated microglia was most frequently bound to senile plaques. Ramified microglia was in contact with amyloid fibrils, which penetrated its cytoplasm and reached the nuclear membrane and channels of rough endoplasmic reticulum, or was situated among dystrophic neurites. Rod microglia was found predominantly at the edge of senile plaques. In Wilson's disease, the ultrastructure of activated microglia showed mostly indirect forms between rod, ramified and amoeboid microglia. The microglia ultrastructure suggests that its morphological form may express functional involvement in the pathogenesis of a given disease entity.

Neuropathological and anatomopathological analyses of acardiac and "normal" siblings in an acardiac-twin pregnancy.

Acardiac twinning is a very rare complication of multiple pregnancy. The authors present the neuropathological and anatomopathological description of the twins of the multiple pregnancy complicated by the acardiac foetus and terminated at 26 weeks of gestation. An anatomopathological examination of the "normal" twin showed hyaline membrane syndrome, cardiomegaly and hepatomegaly. Neuropathologically, numerous hypoxic-ischaemic lesions, most likely associated with haemodynamic disorders during pregnancy as well as less pronounced perinatal changes were revealed. The acardiac foetus, classified as acardius acephalus, demonstrated the presence of some abdominal organs and a histologically well-developed spinal cord. In view of the neuropathological changes, monitoring "normal" twins for discreet pathological central nervous system signs, which may be similar in character to those described, may play a significant role.

[MELAS--mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome--two cases confirmed by biochemical and molecular investigations. Differential diagnosis of stroke causes]. / Zespól MELAS--mitochondrialna encefalomiopatia z kwasica mleczanowa i epizodami udaropodobnymi: przypadki potwierdzone biochemicznie i molekularnie oraz diagnostyka róznicowa przyczyn udarów.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is a maternally inherited multisystem disease caused by mutations of the mitochondrial DNA. The characteristic clinical features are: encephalopathy manifesting as dementia and seizures, stroke-like episodes at young age (usually < 40), lactic acidosis and myopathy with ragged-red fibres. Other frequent manifestations include: sensorineural deafness, diabetes, hypoparathyroidism, peripheral neuropathy and cardiomyopathy. We present two patients with MELAS who were diagnosed 4 and 9 years respectively following the onset of the disease despite the characteristic clinical pictures. The differential diagnostics of inborn and acquired disorders causing stroke is included. We regard that mitochondrial diseases are still insufficiently known and are frequently misdiagnosed. The knowledge is indispensable for establishing diagnosis and accurate genetic counselling. Although there is no specific therapy for mitochondrial diseases to date, coenzyme Q and various vitamins as well as moderate degree exercise might be recommended.

Capillary vessel wall in CADASIL angiopathy.

The study was aimed at investigating the morphology of capillaries in four skin and muscle biopsy specimens obtained from CADASIL patients. In all cases diagnosis confirmed at the ultrastructural level, and additionally in three cases, the genetic test revealed the Notch3 gene mutations. Using histological and immunohistochemical (IHC) markers for components of capillary vessel wall we showed the reduction and loss of pericytes and and fibrous vessel wall including the thickened basement membrane. The thorough ultrastructural study revealed the presence of widespread GOM deposits in capillary wall, but less numerous than in arterioles. They were located in the vicinity of pericytes and also in pericyte infolding like vascular smooth muscle cells (VSMC) in arterioles. Sometimes GOM deposits were observed near endothelial cells. The endothelial cells, damaged but not lost, were also observed while most of capillaries revealed only residual pericytes. The destruction and loss of pericytes in capillary wall, like those of VSMC in arteriole wall, was the main vascular pathology in our the examined cases consistent to that pericytes functionally correspondent to VSMC. The Notch3 receptor is expressed on VSMC and pericytes, the results of our study confirm that in capillaries devoid of VSMC, pericytes are the primary morphological target of the Notch3 gene mutation. It should be indicated that in diagnostic ultrastructural examinations of skin and/or skeletal muscle biopsies, not only arterioles but also capillaries, occurring in a larger amount, should be thoroughly analysed, because such an approach may facilitate the detection of GOM deposits - the pathognomonic feature of CADASIL.

Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI, clinical, biochemical and neuropathological findings of Polish patients.

Adenylosuccinate lyase (ADSL) deficiency is an autosomal recessive disorder caused by mutation in the ADSL gene. The disease was identified in 1984 by Jaeken and van der Berghe as the first inborn defect of purine biosynthesis. Affected children revealed encephalopathy with epilepsy and marked psychomotor retardation. A neurological examination showed hypotonia, followed sometimes after years by spasticity. The diagnosis is based on detection in the urine and CSF succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAr). We present brain MR examinations of seven patients with ADSL deficiency in the correlation with their clinical findings. In all cases lack of myelination or of delayed myelination of cerebral white matter was seen. Additionally cerebral and cerebellar atrophy was observed. Neuropathological findings revealed damage of all cellular elements of brain tissue and are cause of observed MR changes. Hypo/dysmyelination seemed to be secondary to damage of oligodendroglia and axons of damaged neuronal cells.

Malformations of the brain in two fetuses with a compound heterozygosity for two PAX6 mutations.

PPAX6 is an important transcription factor which plays an essential role in brain morphogenesis and eye development. It is related to migration of neuroblasts to the cerebral cortex and deep telencephalic nuclei, and the specification of cellular and regional identity. Disturbances of brain development in two sib fetuses whose parents were aniridic (both sporadic cases) are reported. Molecular analysis in both parents has shown different mutations in PAX6 gene and a compound heterozygosity for two PAX6 mutations in both fetuses. Neuropathologically both cases showed severe brain malformations with increased germinal proliferation, gross disturbances of migration and organization of the CNS.