The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

D-Lactic acidosis is seen in patients with intestinal bypass or short bowels in whom colonic produced D-lactate accumulates. An intestinal bypassed patient with D-lactic acidosis had higher fecal D-lactate (122.4 mmol/liter) and L-lactate (90.1 mmol/liter) than described before in humans. D-Lactate fluctuated between 0.5 and 3.1 mmol/liter in plasma (normal < 0.1 mmol/liter) and between 1.1 and 52.8 mmol/liter in urine (normal < 0.7 mmol/liter) within a few hours, indicating that the human organism do metabolize and excrete D-lactate. The patient with D-lactic acidosis had a 10-fold increased DL-lactate production from glucose in fecal homogenates compared to 14 healthy controls and a patient with intestinal bypass, who did not have D-lactic acidosis. A 67% carbohydrate (starch)-enriched diet resulted in a minor elevation of fecal and plasma lactate, whereas 50 + 100 + 150 g of ingested lactose increased D-lactate in feces (84.0 mmol/liter) and plasma (2.3 mmol/liter) considerably in the patient with D-lactic acidosis. Intestinal prolongation (22 cm ileum) had a temporary effect on fecal and plasma D-lactate, but intestinal continuity was reestablished 26 months later because D-lactic acidosis recurred (plasma 8.6 mmol/liter, urine 101.3 mmol/liter). Large amounts of lactulose (160 g/day) to 12 normal individuals increased D-lactate to 13.6 +/- 3.5 mmol/liter in feces, but never increased D-lactate in plasma or urine. The in vitro fermentation of glucose in fecal homogenates increased DL-lactate, which disappeared after complete metabolization of the glucose. L-Lactate was converted to D-lactate and vice versa, and both were degraded to the short-chain fatty acids acetate, propionate, and butyrate. An infrequent, but elevated ability of the colonic flora to produce lactate may be a prerequisite for D-lactic acidosis to occur and may explain why the syndrome is so seldom seen even in patients with intestinal bypass or short bowels. The suggestion that D-lactate is not metabolized and hence accumulates is probably not valid.

Objective: This review summarises the effects of lactic acid bacteria on lactose malabsorption, bacterialaviral or antibiotic associated diarrhoea, and describes the impact of lactic acid bacteria on cancer and the fermentative products in the colon. Results: Eight studies (including 78 patients) demonstrated that lactase de®cient subjects absorbed lactose in yogurt better than lactose in milk, while two studies (25 patients) did not support this. Two studies (22 patients) showed that unfermented acidophilus milk was absorbed better than milk, while six studies (68 patients) found no signi®cant differences. Addition of lactose hydrolysing enzyme, lactase, to milk improved lactose malabsorption in seven studies (131 lactose malabsorbers), while one study (10 malabsorbers) demonstrated no improvement. Lactic acid bacteria alleviated travellers' diarrhoea in one study (94 individuals) while a study including 756 individuals was borderline statistically signi®cant. One study (50 individuals) did not ®nd an effect of lactic acid bacteria on travellers' diarrhoea. Six studies (404 infants) demonstrated a signi®cant effect of lactic acid bacteria on infant diarrhoea, while one study (40 infants) did not. Lactic acid bacteria moderated antibiotic associated diarrhoea in three studies (66 individuals), while two studies (117 individuals) were insigni®cant. Conclusions: Lactase de®cient subjects bene®t from a better lactose absorption after ingestion of yoghurt compared with milk and from milk added lactase, whereas ingestion of unfermented acidophilus milk does not seem to improve lactose absorption. The majority of studies support that lactic acid bacteria alleviate bacterialaviral induced diarrhoea, especially in infants, while the effect on antibiotic associated diarrhoea is less clear.Experimental studies indicate an effect of lactic bacteria on human cell cancer lines, but clinical evidence is lacking. A`stabilising' effect of lactic acid bacteria on the colonic¯ora has not been documented.

Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.

Treatment with short-chain fatty acids (SCFAs) seems promising in ulcerative colitis and changes in colonocyte oxidation of butyrate have been suggested to be of importance for the development of this disease. The influence of small and large bowel length after surgery on SCFAs is only partly known. SCFAs and lactate were measured in consecutive fecal samples from 300 patients with ulcerative colitis (103), Crohn's disease (127), and noninflammatory bowel disease (70); 205 had had surgery, 52 had short bowels (< 200 cm). Lactate (mainly the L-isomer) was elevated in ulcerative colitis patients with pancolitis (mean +/- SEM, 17 +/- 5 mmol/liter) and proctitis (12 +/- 3 mmol/liter) compared with quiescent ulcerative colitis (3 +/- 1 mmol/liter, P < 0.01), and correlated with the index of Truelove (R = 0.52, P < 0.0005). Lactate was also increased in Crohn's colitis (21 +/- 8 mmol/liter), but not in isolated ileitis (4 +/- 2 mmol/liter), compared with quiescent Crohn's disease (7 +/- 2 mmol/liter, P < 0.02), but did not correlate with the activity index (CDAI; R = 0.18, P = 0.12). In contrast to earlier reports, SCFAs (including butyrate) did not correlate with inflammatory activity or localization in either ulcerative colitis or Crohn's disease. The length of the small bowel had no influence on SCFAs and lactate in patients with either no colonic function (ileostomies), or with > 50% and < 50% preserved colorectal length, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between faecal DL-lactate and intestinal inflammation or malabsorption was evaluated in 100 nonselected inpatients at a referral center for gastrointestinal disorders. Twenty-one (21%) had DL-lactate concentrations (range, 8-95 mmol/l) above the 95% limit (6.1 mmol/l) in healthy individuals. Inflammatory bowel disease with active proctitis was associated with increased faecal DL-lactate in 11 of 15 patients (73%) (mean, 32 mmol/l; range, 8-95 mmol/l) and in the 1 patient with pouchitis (8 mmol/l), whereas only 1 of 8 patients (13%) with active inflammatory bowel disease without proctitis had L-lactate elevation (25 mmol/l). Among 26 patients with malabsorption and quiescent or noninflammatory bowel disease, 3 of 17 (18%) with preserved colonic function and 3 of 9 (33%) with jejunostomy had increased faecal lactate. Only 2 of 50 (4%) patients with neither active inflammatory bowel disease nor malabsorption had faecal DL-lactate elevation. In vitro bacterial fermentation of most dietary polysaccharides did not cause accumulation of lactate, corresponding to a lack of correlation between faecal carbohydrate excretion and lactate accumulation. An isolated increase in faecal L-lactate was observed in 6 of 13 patients with inflammatory bowel disease, whereas D-lactate was not increased without a simultaneous increase of the L-lactate isomer. In conclusion, the faecal lactate concentration was frequently increased in patients with inflammatory bowel disease and proctitis, occasionally increased in patients with severe malabsorption, and often normal in patients with quiescent inflammatory bowel disease or localized Crohn's ileitis.(ABSTRACT TRUNCATED AT 250 WORDS)

The characteristic fermentation pattern seen with specific saccharides in incubations with pure cultures of Lactobacillus acidophilus and Bifidobacterium bifidum disappeared when incubated in 16.7% fecal homogenate. The productions of lactate and short-chain fatty acids in mixed bacterial-fecal incubations were similar to productions in fecal homogenates without L acidophilus and B bifidum and were mainly associated with the specific mono-, di-, and polysaccharides added to the incubate. B bifidum was cultured from ileostomic contents in eight of nine ileostomists after oral administration (2.4 x 10(10) cells), but did not influence the concentrations and productions of DL-lactate and short-chain fatty acids in the ileostomic outputs and incubates. Large amounts of ingested lactic acid bacteria (4.2 x 10(10) cells) did not ameliorate lactose malabsorption measured by the breath-hydrogen test in 12 lactose malabsorbers. This study shows that ingested lactic acid bacteria are indeed present in the colon, but it does not support the theory that they change the pattern of colonic fermentation or the degree of intestinal lactose malabsorption.