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ABSTRACT: Hereditary gelsolin amyloidosis is an autosomally dominantly inherited systemic disease, first described in 1969 by the Finnish ophthalmologist Jouko Meretoja. The estimated number of disease carriers in Finland is almost 1 000, and the disease has subsequently been found in many other countries as well. It's typical initial manifestation is lattice corneal dystrophy, detected at biomicroscopic examination of the eye by the age of 25 to 30 years, followed by slowly progressing cranial neuropathy with bilateral facial palsy, polyneuropathy and generalized cutis laxa. Meretoja's disease is caused by mutations of the gelsolin gene, leading to the production and aberrant processing of variant gelsolin and deposition of its fragments in various tissues in the form of amyloid fibrils.
Duodecim; lääketieteellinen aikakauskirja 01/2010; 126(10):1162-71.
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Matti Haltia
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ABSTRACT: The neuronal ceroid-lipofuscinoses (NCLs) are inherited lysosomal storage diseases and constitute the most common group of children's progressive encephalopathies. Most childhood forms of NCL are clinically characterized by progressive loss of vision as well as mental and motor deterioration, epileptic seizures, and premature death, while the rare adult forms are dominated by dementia. All forms of NCL share common pathomorphological features. Autofluorescent, periodic acid-Schiff- and Sudan black B-positive granules, resistant to lipid solvents, accumulate in the cytoplasm of most nerve cells, and there is progressive and remarkably selective neuronal degeneration and loss. For a long time, the NCLs were grouped under the heading of the "amaurotic family idiocies" and conceived as lipidoses. However, in the late 1980s and 1990s the NCL storage cytosomes were shown to consist largely of two hydrophobic proteins: either subunit c of mitochondrial ATP synthase or sphingolipid activator proteins A and D. Since 1995 numerous mutations in at least seven different genes have been shown to underlie the multiple human and animal forms of NCL. This review discusses the historical evolution of the NCL concept and the impact of the recent biochemical and molecular genetic findings on our views on the classification and pathogenesis of these devastating brain disorders.
Biochimica et Biophysica Acta 11/2006; 1762(10):850-6. · 4.66 Impact Factor
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ABSTRACT: Congenital neuronal ceroid-lipofuscinosis (NCL) is a devastating inherited neurodegenerative disorder of unknown metabolic basis. Eight patients with this rare disorder, all with similar clinical and neuropathological findings, have been reported, and here we describe two further patients. Previously, we showed that a mutation in the cathepsin D gene causes congenital NCL in sheep. On the basis of the neuropathological and ultrastructural similarities between the sheep and patients affected with congenital NCL, we screened the cathepsin D gene for mutations in a patient of Pakistani origin. We identified a nucleotide duplication, c.764dupA, in the cathepsin D gene in homozygous form in the patient, and in heterozygous form in his father. This duplication is likely to be disease-causing, as it creates a premature stop codon, predicting a truncation of the protein. When transiently expressed in cell cultures, the mutant protein was enzymatically inactive, but stable. In paraffin-embedded brain tissue samples of two affected siblings of the Pakistani patient, cathepsin D was absent, suggesting rapid degradation of the c.764dupA mutant cathepsin D at mRNA or protein level in vivo. Further, we were able to confirm lack of cathepsin D in the brain tissue of yet another, unrelated, patient of English origin with congenital NCL. On the basis of the present data, and the nearly identical clinical and/or pathological phenotype of the other reported cases of congenital NCL, it is reasonable to suggest that cathepsin D deficiency caused by mutations in the corresponding gene may underlie all cases of congenital NCL. The present observations also suggest that cathepsin D deficiency should be considered as a possible diagnosis in microcephalic neonates, who present with seizures at or before birth.
Brain 07/2006; 129(Pt 6):1438-45. · 9.46 Impact Factor
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Duodecim; lääketieteellinen aikakauskirja 02/2006; 122(23):2919-28.
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ABSTRACT: To evaluate the effect of medical record use on figures for the incidence of dementia and the effect of apolipoprotein E (APOE) polymorphism on this incidence and neuropathologically defined Alzheimer's disease (AD) in very elderly individuals.
Cognitive functions were examined in a cohort of 328 (92% of the very elderly people of a town participated in this study) nondemented Finnish elderly individuals 85 years of age or more in 1991. The examination was repeated in survivors in 1994, 1996, 1999 and 2001. Medical notes and social work records were evaluated. All these individuals were genotyped for APOE. Neuropathological analysis of AD-type pathology was performed on 159 of 303 subjects who died during the follow-up.
Age group, gender or APOE did not significantly affect the incidence of dementia, which was over 20% higher (85 vs. 69 per 1,000 person-years) if the cognitive status at death was ascertained by medical and social work records than without this evaluation. The APOE upsilon4 allele was highly significantly (p=0.002) and age almost significantly (p=0.06) associated with neuropathological AD in nondemented individuals.
Medical records should be analyzed in studies on the incidence of dementia in very elderly individuals. APOE polymorphism does not affect the incidence of dementia in this age group. However, clinical dementia diagnosis in very elderly individuals does not necessarily correlate well with the presence of neuropathological AD which, even in this age group, is significantly associated with the APOE upsilon4 allele.
Neuroepidemiology 02/2006; 26(2):76-82. · 2.31 Impact Factor
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Liisa Myllykangas,
Fabienne Wavrant-De Vrièze,
Tuomo Polvikoski,
Irma-Leena Notkola,
Raimo Sulkava,
Leena Niinistö,
Steven D Edland,
Sampath Arepalli,
Omanma Adighibe,
Danielle Compton,
John Hardy, Matti Haltia,
Pentti J Tienari
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ABSTRACT: Genetic linkage studies have provided evidence for a late-onset Alzheimer's disease (AD) susceptibility locus on chromosome 21q. We have tested, in a two-stage association study, whether allelic or haplotype variation of the beta-amyloid cleaving enzyme-2 (BACE2) locus on chromosome 21q affects the risk of late-onset AD. In stage-1, an unselected population-based sample of Finns aged 85 years or over (n=515) was analysed. Neuropathologic examination including beta-amyloid load quantification was possible in over 50% (n=264) of these subjects. AD patients (n=100) and controls (n=48) were defined by modified neuropathological NIA-RI criteria. Positive associations were taken as a hypothesis, and tested in stage-2 using 483 AD families from the USA. Four single nucleotide polymorphisms (SNPs) of BACE2 gene were tested in stage-1. A SNP close to exon-6 was associated with neuropathologically verified AD (p=0.02) and also with beta-amyloid load in non-selected autopsied subjects after conditioning with APOE genotype (p=0.001). In haplotype analysis a specific, relatively common haplotype (H5) was found to associate with AD (p=0.004) and a second haplotype (H7) showed a weaker association with protection against AD (p=0.04). In stage-2, the SNP association was not replicated, whereas the haplotype H5 association was replicated (p=0.004) and a trend to association was found with the putative protective haplotype H7 (two-sided p=0.08). BACE2 haplotype association with AD in two independent datasets provides further evidence for an AD susceptibility locus on chromosome 21q within or close to BACE2.
Journal of the Neurological Sciences 10/2005; 236(1-2):17-24. · 2.35 Impact Factor
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ABSTRACT: The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies.
Brain Pathology 11/2004; 14(4):349-57. · 3.99 Impact Factor
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ABSTRACT: The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies.
Brain Pathology 09/2004; 14(4):349 - 357. · 3.99 Impact Factor
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Journal of Child Neurology 07/2004; 19(6):465-70. · 1.75 Impact Factor
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ABSTRACT: Few data exist on the effects of specific Alzheimer's disease (AD)-related mutations on cognitive function. We present neuropsychological test results in eight members of a large kindred with variant Alzheimer's disease (VarAD) due to a deletion of the presenilin 1 (PS-1) gene, encompassing exon 9. The disease was neuropathologically characterized by the presence of large, unusual, "cotton wool" plaques (CWP). Four surviving patients were prospectively tested, and retrospective neuropsychological data were collected from additional four deceased patients. The neuropsychological evaluation was based on tests of verbal and visual memory, abstract thinking, and visuoconstructive and spatial functions. In addition, psychiatric symptoms were evaluated. In four patients, brain glucose metabolism was examined by positron emission tomography (PET). PET showed temporoparietal hypometabolism typical of AD. In addition, variable patterns of hypometabolism (hemispherical asymmetry and occipital accentuation) were related to individual deficits of cognitive performance. However, all these early-onset patients (age range 43-63 years) with a deletion mutation of PS-1 gene showed prominent memory impairment and deficits in visuoconstructive and intellectual functions.
Journal of the Neurological Sciences 04/2004; 218(1-2):29-37. · 2.35 Impact Factor
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Matti Haltia
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ABSTRACT: The neuronal ceroid-lipofuscinoses (NCLs) collectively constitute the most common group of neurodegenerative diseases in childhood and usually show an autosomal recessive mode of inheritance. Despite varying ages of onset and clinical course characterized in most instances by progressive mental and motor deterioration, blindness, epileptic seizures, and premature death, all forms of NCL show unifying histopathological features. There is accumulation of autofluorescent, periodic acid-Schiff-, and Sudan black B-positive granules that are resistant to lipid solvents in the cytoplasm of most nerve cells and. to a lesser degree, of many other cell types. The storage process is associated with progressive and selective neuronal loss and gliosis with secondary white matter lesions. The ultrastructure of the storage deposits varies between different forms of NCL and, along with the age of onset, has provided the basis for the traditional classification of NCLs. Recent molecular genetic findings have established that defects in at least 7 different genes underlie the various forms of NCL. The purpose of this paper is to provide an overview of the NCLs, review recent molecular genetic and biochemical findings, and discuss their impact on our views on the classification and pathogenesis of these devastating brain disorders.
Journal of Neuropathology and Experimental Neurology 02/2003; 62(1):1-13. · 4.26 Impact Factor
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ABSTRACT: Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder reported worldwide in kindreds with a G654A or G654T gelsolin gene mutation. The clinically characteristic peripheral nerve involvement has been poorly characterized morphologically, and its pathogenesis remains unknown. We studied peripheral nerve and skeletal muscle biopsy or autopsy specimens of 35 patients with a G654A gelsolin gene mutation. Histological, immunohistochemical, and electron microscopic studies showed consistent deposition of gelsolin amyloid (AGel), particularly in the vascular walls and perineurial sheaths. Nerve roots were more severely affected than distal nerves. The amyloid deposits also displayed variable immunoreactivity for apolipoprotein E, amyloid P component, cystatin C, and alpha-smooth muscle actin. Sural nerve morphometry showed preferential age-related large myelinated nerve fiber loss and reduction of myelin sheath cross-sectional area. There was evidence of denervation atrophy and fiber type grouping in skeletal muscle. Our study shows that marked proximal nerve involvement with AGel angiopathy is an essential feature of AGel amyloidosis. The preferential large fiber loss, not generally seen in amyloid neuropathy, may be caused by ischemia due to AGel angiopathy. Deficient actin modulation by variant gelsolin in neurons and Schwann cells, however, may alter axonal transport and myelination and contribute to AGel polyneuropathy.
Journal of Neuropathology and Experimental Neurology 07/2002; 61(6):565-71. · 4.26 Impact Factor
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Matti Haltia
Duodecim; lääketieteellinen aikakauskirja 02/2002; 118(22):2279-88.
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Duodecim; lääketieteellinen aikakauskirja 02/2002; 118(15):1551-8.
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Matt Baker,
Daniel Graff-Radford,
Fabienne Wavrant DeVrièze,
Neill Graff-Radford,
Ronald C Petersen,
Emre Kokmen,
Brad Boeve,
Liisa Myllykangas,
Tuomo Polvikoski,
Raimo Sulkava,
Auli Verkoniemmi,
Pentti Tienari, Matti Haltia,
John Hardy,
Mike Hutton,
Jordi Perez-Tur
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ABSTRACT: We and others have previously identified two distinct haplotypes of the TAU gene in Caucasian populations. In this study, we have assessed whether these haplotypes show an association with Alzheimer's disease in a variety of populations. They do not. These data are consistent with the view that the involvement of TAU in Alzheimer's disease is a downstream event.
Neuroscience Letters 06/2000; · 2.11 Impact Factor
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Richard Crook,
Auli Verkkoniemi,
Jordi Perez-Tur,
Nitin Mehta,
Matt Baker,
Henry Houlden,
Matt Farrer,
Mike Hutton,
Sarah Lincoln,
John Hardy,
Katrina Gwinn,
Mirja Somer,
Anders Paetau,
Hannu Kalimo,
Raija Ylikoski,
Minna P|[ouml]|yh|[ouml]|nen,
Steve Kucera, Matti Haltia
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ABSTRACT: We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for A but lacked a con-gophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (9) of the presenilin 1 (PSI) gene from the mRNA: unlike previous examples of the 9 variant, the deletion was not caused by a splice acceptor site mutation.
Nature Medicine. 03/1998; 4(4):452-455.
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ABSTRACT: Autopsy reports are presented of three cases of a rapidly progressive encephalopathy with clinical onset around one year of age, early amaurosis, and microcephaly. Convulsions were few or absent. The disorder led to an extraordinary degree of brain atrophy, due to total loss of neurons from the cerebral and cerebellar cortex, and an advanced degree of neuronal destruction in most subcortical centres. The giant cells of Betz and the primary motor and sensory neurons were notable exceptions. The surviving neurons, other neuroectodermal cells, and a number of extraneural cell types showed accumulation of autofluorescent sudanophilic granules, resistant to lipid solvents, in their cytoplasm. Ultrastructurally, these granules were of the residual body type, consisting of membrane-bound conglomerations of spherical globules 0.2–0.5 m in diameter, with a homogeneous, finely granular internal structure. These lesions were associated with a pronounced astrocytic and mesenchymal reaction with the presence of large numbers of phagocytic cells in the grey matter of the CNS and, to a lesser extent, in other tissues. In addition, there was almost total loss of myelin from the brain, apparently due to Wallerian degeneration.The characteristic clinical, histological and ultrastructural features differentiate this condition from other progressive encephalopathies of the age group in question, including the late infantile type of the Batten-Vogt syndrome. Recent ultrastructural and biochemical findings indicate that the disease of our patients is identical with the progressive encephalopathy with disturbed polyunsaturated fat metabolism described by Hagberget al. (1968).
Acta Neuropathologica 05/1973; 26(2):157-170. · 9.32 Impact Factor
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Guy Prihar,
Auli Verkkoniem,
Jordi Perez-Tur,
Richard Crook,
Sarah Lincoln,
Henry Houlden,
Mirja Somer,
Anders Paetau,
Hannu Kalimo, Andrew Grover,
Liisa Myllykangas,
Mike Hutton,
John Hardy, Matti Haltia
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ABSTRACT: Finland and the Finns have been the subject of numerous genetic and genealogical studies, owing to enrichment of certain rare hereditary disorders in the Finnish population. Two types of NCL have so-far been found almost exclusively in Finland: Finnish variant late infantile NCL, vLINCL (CLN5), and the Northern epilepsy syndrome or Progressive epilepsy with mental retardation, EPMR (CLN8). The first symptoms of Finnish vLINCL are concentration problems or motor clumsiness by 3 to 6 years of age, followed by mental retardation, visual failure, ataxia, myoclonus, and epilepsy. Northern epilepsy, the newest member of the NCL family with the most protracted course, is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are slight and late, while myoclonus has not been observed. Both the Finnish vLINCL and Northern epilepsy are pathologically characterized by intraneuronal cytoplasmic deposits of autofluorescent granules which are Luxol fast blue-, PAS-, and Sudan black B-positive in paraffin sections. In Northern epilepsy the intraneuronal storage process and neuronal destruction are generally of mild degree but highly selective and, in contrast to other forms of childhood onset NCL, the cerebellar cortex is relatively spared. By electron microscopy the storage bodies mainly contain rectilinear complex type and fingerprints profiles in Finnish vLINCL and structures resembling curvilinear profiles in Northern epilepsy. Mitochondrial ATP synthase subunit c is the main stored protein in both disorders. Both the CLN5 and CLN8 genes encode putative membrane proteins with yet unknown functions. Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8.
Advances in Genetics.
