Neuronal ceroid lipofuscinoses (NCL) represent a group of common progressive encephalopathies of children which have a global incidence of 1 in 12,500. These severe brain diseases are divided into three autosomal recessive subtypes, assigned to different chromosomal loci. The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy. The molecular pathogenesis underlying the selective loss of neurons of neocortical origin has remained unknown. Here we report the identification, by positional candidate methods, of defects in the palmitoyl-protein thioesterase gene in all 42 Finnish INCL patients and several non-Finnish patients. The most common mutation results in intracellular accumulation of the polypeptide and undetectable enzyme activity in the brain of patients.

The most common NPHS1 gene mutations, Fin-major and Fin-minor, both lead to an absence of nephrin and podocyte slit diaphragms, as well as a clinically severe form of NPHS1, the Finnish type of congenital nephrotic syndrome.

To evaluate the frequency, clinical features, and prognosis of patients with osteitis caused by bacille Calmette-Guérin (BCG) vaccination, medical records from Finnish children based on nationwide registration from 1960 to 1988 were retrospectively analyzed. During the study period, three different BCG vaccine preparations were used. In 222 children, diagnostic criteria of BCG osteitis were fulfilled. The age at onset of BCG osteitis varied from 0.25 to 5.7 years. The most common sites of osteitis were metaphyses of the long bones. The lower extremity (58%) was affected more often than the upper (14%). Osteitis was situated in the sternum in 36 patients (15%) and in the ribs in 27 (11%). The frequency of BCG osteitis, but not the clinical parameters, was closely associated with the vaccine preparation used. Only 6 children were left with some sequelae. With adequate treatment, the prognosis for children vaccinated with BCG is good.

SUMMARY One hundred and fourteen children with primary nephrotic syndrome were followed up prospectively for periods of between 5 and 14 years. Urine samples from 94 of them became proteinfree during the initial 8-week course of prednisone, and the outcome for these children was good: 74 of them have been free of symptoms for at least 3 years, 18 have had relapses during the last 3 years, and only one child still has proteinuria. All these children have normal renal function and blood pressure. One child died accidentally. Twenty children did not respond to the initial prednisone treatment. Thirteen of them had remissions later, of whom 2 have had relapses during the last 3 years. Seven were totally resistant to prednisone 4 of whom died in renal failure, the remaining 3 have persistent proteinuria with normal levels of creatinine; one has high blood pressure too. Remission during the initial treatment indicated a good prognosis, but two-thirds of the initial non-responders also fared well.

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Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8. Here, we have developed a novel mouse model for the human vLINCL (CLN5) by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5-/- mice showed loss of vision and accumulation of autofluorescent storage material in the central nervous system (CNS) and peripheral tissues without prominent brain atrophy. The ultrastructure of the storage material accurately replicated the abnormalities in human patients revealing mixture of lamellar profiles including fingerprint profiles as well as curvilinear and rectilinear bodies in electronmicroscopic analysis. Prominent loss of a subset of GABAergic interneurons in several brain areas was seen in the Cln5-/- mice. Transcript profiling of the brains of the Cln5-/- mice revealed altered expression in several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected and this agrees well with the hypomyelination seen in the human vLINCL patients. In general, the progressive pathology of the Cln5-/- brain mimics the symptoms of the corresponding neurodegenerative disorder in man. Since the Cln5-/- mice do not exhibit significant brain atrophy, these mice could serve as models for studies on molecular processes associated with advanced aging.

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