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We report the clinical details and the pathology of the heart at autopsy of three neuronal ceroid lipofuscinosis (NCL) patients. Two patients were diagnosed as classical juvenile NCL and one as a variant juvenile NCL (JNCL) with granular osmiophilic deposits (GRODs). Cardiac findings during life were retrospectively evaluated and included left ventricular hypertrophy with repolarization disturbances (ECG findings) in two patients with classical JNCL and severe bradycardia with periods of sinus arrest in one of them, severe supraventricular tachycardias during anaesthesia in the variant JNCL-patient. At autopsy myocardial and valvular storage of lipopigments, diagnostic for NCL, was observed histologically and confirmed ultrastructurally in all three cases. In two patients with JNCL the storage was associated with hypertrophy and dilation of both ventricles, degenerative myocardial changes, interstitial fibrosis and fatty replacement. Abundant accumulation and degeneration were seen in all components of the conduction system in three patients, which outreached at several places by far the storage of the adjacent myocardium. Our observations indicate a prominent involvement of the heart in NCL, with preference of storage for the conduction system of the heart.

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A deficiency of palmitoyl-protein thioesterase (PPT) was recently shown to be the primary defect in infantile neuronal ceroid lipofuscinosis (INCL). The available enzyme assays are complicated and impractical for diagnostic use. We have recently developed a new, fluorometric assay for PPT based on the sensitive fluorochrome 4-methylumbelliferone, requiring an overnight incubation to measure PPT. Now we have synthesized an analogue of this substrate which allows PPT determinations in 1 h. This improved PPT assay is simple, sensitive, and robust and will facilitate the definition of the full clinical spectrum associated with a deficiency of PPT. PPT activity was readily detectable in fibroblasts, leukocytes, amniotic fluid cells, chorionic villi, plasma, and cerebrospinal fluid from controls. PPT activity was profoundly deficient in these tissues and fluids from INCL patients. Similarly, a deficiency of PPT activity was demonstrated in patients with the variant juvenile NCL with GROD. These results show the feasibility of rapid pre- and postnatal diagnosis of INCL and its variants.

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A subtype of neuronal ceroid lipofuscinosis (NCL) is well recognized which has a clinical course consistent with juvenile NCL (JNCL) but the ultrastructural characteristics of infantile NCL (INCL): granular osmiophilic deposits (GROD). Evidence supporting linkage of this phenotype, designated vJNCL/GROD, to the INCL region of chromosome 1p32 was demonstrated (pairwise lod score with D1S211 , Z max = 2.63, straight theta = 0.00). The INCL gene, palmitoyl-protein thioesterase (PPT ; CLN1), was therefore screened for mutations in 11 vJNCL/GROD families. Five mutations in the PPT gene were identified: three missense mutations, Thr75Pro, Asp79Gly, Leu219Gln, and two nonsense mutations, Leu10STOP and Arg151STOP. The missense mutation Thr75Pro accounted for nine of the 22 disease chromosomes analysed and the nonsense mutation Arg151STOP for seven. Nine out of 11 patients were shown to combine a missense mutation on one disease chromosome with a nonsense mutation on the other. Mutations previously identified in INCL were not observed in vJNCL/GROD families. Thioesterase activity in peripheral blood lymphoblast cells was found to be markedly reduced in vJNCL/GROD patients compared with controls. These results demonstrate that this subtype of JNCL is allelic to INCL and further emphasize the correlation which exists between genetic basis and ultrastructural changes in the NCLs.

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The juvenile-onset subtype of the neuronal ceroid lipofuscinoses (JNCL) is well known [Hofman, ISBN90-71534-19-7 1990] and ultrastructurally characterized by fingerprints and/or curvilinear bodies in many cell types. Linkage studies indicated a most likely location for CLN3, the gene involved in JNCL, in the interval between loci D16S297 and D16S57, within close proximity of the loci D16S298 and D16S299 [Mitchison et al., Genomics 22:465-468, 1993]. We present two sibs with a late onset progressive disease of mental deterioration, progressive macular degeneration, motor disturbances, and epilepsy. Histological symptoms of neuronal ceroid lipofuscinosis and ultrastructural granular osmiophilic deposits (GROD) in lymphocytes and neurons are found. Individual haplotypes at polymorphic marker loci on chromosome 16 were constructed to determine whether JNCL with GROD is linked to the CLN3 locus.

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Experiences with the care for the 37 patients with the juvenile type of neuronal (generalised) ceroid lipofuscinoses in a centre for multihandicapped people are described. Besides abnormalities of the visual and the nervous system attention is given to the psychopathological and cardiovascular symptoms. Remarkable is the great intra- and interindividual diversity in the course of the disease.

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4-(N-Acetylglycyl)amino-4,6-dideoxy-D-glucose has been identified as a component of the Shigella dysenteriae type 7 O-specific polysaccharide, in addition to the previously reported 2-acetamido-2-deoxy-D-glucose and 2-acetamido-2-deoxy-D-galacturonic acid. On the basis of selective cleavage with anhydrous hydrogen fluoride and analysis by 1H- and 13C-n.m.r. spectroscopy and f.a.b.-mass spectrometry, it was concluded that the tetrasaccharide repeating-unit of the polysaccharide has the following structure: (structure; see text) where D-GalNAcAN is 2-acetamido-2-deoxy-D-galacturonamide and D-Qui4N is 4-amino-4,6-dideoxy-D-glucose.

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The specific polysaccharide was obtained from the lipopolysaccharide of Shigella newcastle by mild acid hydrolysis and further purified by permeation chromatography on Sephadex G-50. It was found to consist of L-rhamnose, 2-acetamido-2-deoxy-D-galactose, D-galacturonic acid residues and O-acetyl groups in the molar ratios of 2:1:1:1. On the basis of 1H and 13C nuclear magnetic resonance spectroscopy, methylation analysis, partial acid hydrolysis, Smith degradation, and chromium trioxide oxidation, the following structure can be assigned to the repeating oligosaccharide unit of the polysaccharide:-4)DGalA(beta 1-3)DGalNAc-(beta 1-2)LAc3Rha(alpha 1-2)LRha(alpha 1-, where GalA = galacturonic acid. GalNAc = N-acetylgalactosamine, Ac3Rha = 3-O-acetylrhamnose. The structural and immunochemical data presented prove that Sh. newcastle lipopolysaccharide belongs to a 'non-classical' type of somatic antigens with acidic O-specific polysaccharide chains.

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The O-specific polysaccharide obtained from Shigella dysenteriae type-2 lipopolysaccharide by mild acid hydrolysis consisted of N-acetylgalactosamine, N-acetylglucosamine, D-galactose, D-glucose, and O-acetyl group in the ratio of 2:1:1:1:1. A number of oligosaccharides were obtained by deamination of the N-deacetylated polysaccharide and by Smith degradation of the both native and O-deacetylated polysaccharides. The identification of oligosaccharides along with methylation analysis and chromic anhydride oxidation showed that the polysaccharide was built up of the repeating pentasaccharide units whose proposed structure is given below: (see article) Serological properties of Sh. dysenteriae O-specific polysaccharides are discussed.

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On mild acid hydrolysis of lipolysaccharide from Shigella dysenteriae type 3 the O-specific polysaccharide (hapten) was obtained which appeared to be acidic branched hexosaminoglycan. The repeating unit of this polysaccharide represents a pentasaccharide composed of two D-galactose residues, N-acetyl-D-galactosamine, D-glucose and unidentified acidic component. On the basis of methylation analysis, periodate oxidation, partial acid hydrolysis and chromic anhydride oxidation it is concluded that the structure of the chemical repeating unit of polysaccharide is (see article) where Glcp is glucopyranose, Galp is galactopyranose, Galf is galactofuranose, GalNAcp is 2-acetamido-2-deoxygalactopyranose and where the configuration of galactofuranoside glycosidic linkage and the structure of the acidic monosaccharide A are not known.

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