Congenital Lactase Deficiency Research Articles

Concomitant infections in children with allergic pathology in the Kaliningrad region

The aim of our work was to study the structure and prevalence of the infectious syndrome in children from Kaliningrad Region with moderate-to-severe allergic pathology, with a complex manifestations of allergic reactions, both on skin and on the mucous membranes of the digestive and respiratory tract.
 Ninety children from 0 to 18 years old with various symptoms of allergic pathology were examined and included in the study group using standard clinical, objective and laboratory criteria. The severity of clinical course was associated with the severe and long-lasting symptoms, as well as with frequent bacterial and bacterial-fungal complications, with impaired quality of life and night sleep. The children were consulted by the specialists in otorhinolaryngology, hematology, pulmonology, surgery, ophthalmology, infectology, endocrinology, cardiology. Diagnoses according to nosological forms were made in accordance with the current clinical recommendations of Russian Ministry of Health. Our article presents data on concomitant infectious diseases and their impact on general condition and severity of hypersensitive responses. The average age of allergic manifestations in the group of children was 3.12±2.72 years. The average duration of the disease in the observed group was 7.5±0.88 years. The number of boys in our group prevailed (n = 56) by 1.6 times. Complicated heredity factors were reported by 15% of the patients’ parents. However, with careful collection of medical history taking, upon dynamic observation, the aggravated heredity on the mother’s side was detected in 45.56% (n = 41), and on the father’s side, in 31.1% of cases (n = 28). In eight families, both parents suffered from allergic pathology, in siblings, 21.1% (n = 19) of the examined children had allergies. In the families, including grandparents, allergic pathology was reported in 56 cases (62.2%).
 Almost all patients had problems with nasal breathing, 77 (85.6%) children with adenoid hypertrophy had a habit of breathing through the mouth. Postnasal drip syndrome was found in 78 cases. Allergic rhinitis with adenoid hypertrophy is, generally, accompanied by postnasal leakage, which can provoke aspiration bronchitis and pneumonia, especially if pathogenic or opportunistic flora is transferred to the nasal cavity and/or to the pharynx.
 Conclusions: 1. Identification and rehabilitation of chronic foci of infection, bacterial, fungal, should be a necessary component of the personalized therapy of allergic pathology in children. 2. In cases of recurrent sowing or finding of pathogenic flora (iodophilic flora, fungi, coccal flora) in the coprogram, one should exclude not only transient lactase deficiency, but also congenital lactase deficiency, thus preventing development of enterocolitis in the future like as worsening of skin status and respiratory manifestations. 3. In case of severe respiratory viral infections in children during the period of adaptation for pre-school institutions, one should exclude sensitization to allergens of house dust mites and epidermal allergens of domestic animals. 4. A comprehensive and personalized approach to the diagnosis of allergic disorders and comorbid conditions enables us to create conditions for stable remission, making it possible to conduct allergen-specific immunotherapy, which may provide a disease-modifying effect upon the hyperreactive states in our patients.

Estimating the prevalence of congenital disaccharidase deficiencies using allele frequencies from gnomAD

Background: There are currently three known congenital disaccharidase deficiencies: congenital lactase deficiency (CLD), congenital sucrase-isomaltase deficiency (CSD), and congenital trehalase deficiency (CTD). No congenital deficiency has been described for maltase-glucoamylase (MGAM).Methods: A literature search was performed in PubMed for the pathogenic variants CLD, CSD, and CTD and the articles retrieved were analyzed to estimate the prevalence of congenital disaccharidase deficiencies.Results: Based on reported variants, the estimated prevalence was 1.3 per 106 births (95% CI: 1.1–1.7) for CLD, and 31.4 per 106 births (95% CI: 28.3–34.8) for CSD. Using data on previously reported variants and variants predicted to be loss-of-function in gnomAD, the overall estimated prevalence was 2.3 per 106 births (95% CI: 1.9–2.9) for CLD, 57.6 per 106 births (95% CI:52.5–63.2) for CSD, and 9.2 per 106 births (95% CI: 2.5–3.7) for CTD.Conclusion: The prevalence of CSD was found to be relatively high, while for other congenital disaccharidase deficiencies, the estimated prevalence was very low.

Hypomorphic variants of lactase-phlorizin hydrolase in congenital lactase deficiency are trafficking incompetent and functionally inactive.

Patients with the rare autosomal recessive disorder congenital lactase deficiency (CLD) present with severe, potentially life-threatening symptoms shortly after birth. Several variants have been characterized within the gene for lactase-phlorizin hydrolase (LCT) that are associated with CLD. Here, we analyze at the biochemical and cellular levels LCT mutants harboring the genetic variants p.Y1390*, p.E1612*, p.S1150Pfs*19, p.S1121L, p.R1587H, and p.S688P. Our data unequivocally demonstrate that these mutants are absolutely transport incompetent, some of which are readily degraded, and are enzymatically inactive. The current study contributes to and expands our understanding on the pathogenesis of CLD at the molecular level.

Diarrhea triggered by breastfeeding; a novel variant causing congenital lactase deficiency

Diarrhea triggered by breastfeeding; a novel variant causing congenital lactase deficiency

Human Health Effects of Lactose Consumption as a Food and Drug Ingredient.

Lactose is a reducing sugar consisting of galactose and glucose, linked by a β (1→4) glycosidic bond, considered as an antioxidant due to its α-hydroxycarbonyl group. Lactose is widely ingested through the milk and other unfermented dairy products and is considered to be one of the primary foods. On the other hand, lactose is also considered as one of the most widely used excipients for the development of pharmaceutical formulations. In this sense, lactose has been related to numerous drug-excipient or drug-food pharmacokinetic interactions. Intolerance, maldigestion and malabsorption of carbohydrates are common disorders in clinical practice, with lactose-intolerance being the most frequently diagnosed, afflicting 10% of the world's population. Four clinical subtypes of lactose intolerance may be distinguished, namely lactase deficiency in premature infants, congenital lactase deficiency, adult-type hypolactasia and secondary lactase intolerance. An overview of the main uses of lactose in human nutrition and in the pharmaceutical industry and the problems derived from this circumstance are described in this review.

Molecular and cellular analysis of intestinal lactase‐phlorizin hydrolase gene variants unravel a heterogeneous pathogenic pattern of congenital lactase deficiency

Congenital lactase deficiency (CLD) is a rare autosomal recessive genetic disorder, leading to a dysfunctional lactase‐phlorizin hydrolase (LPH). LPH is a ß‐galactosidase located in the intestinal brush border membrane and indispensable for lactose digestion. Impaired LPH‐function results in severe symptoms within a few days after birth with the onset of nursing. The symptoms include watery diarrhea and consequently dehydration, leading to potential life‐threatening disease of the newborn. Several mutations in the coding region of LPH have been characterized, occurring in homozygote or compound heterozygote patterns of inheritance. The basis of the genotype‐phenotype relationship in CLD on a molecular and cellular level has not been studied in details. Here we analyze the influence of the mutations p.S688P, p.E1612X, p.S1121L, that have been identified in patients from different ethnic groups, on the structure, trafficking and function of the LPH protein. For this purpose, LPH‐mutants were generated by site‐directed mutagenesis and transiently expressed in COS‐1 cells. Additionally we concluded studies regarding the interaction of these mutants with the wild‐type‐LPH protein. The results reveal phenotypic variations in the protein trafficking of the mutants between the ER and the Golgi. Additionally, the LPH‐mutant harboring the mutation p.S688P showed residual lactose digesting capacity. These variations implicate possible clinical correlation as for example different course and severity of disease. These data are relevant for the further understanding of CLD, potential impact for heterozygote mutation carriers and possible invention of treatment strategies, as for example protein stabilization through chaperones.Support or Funding InformationIntramural funds, University of Veterinary Medicine Hannover

Congenital Lactase Deficiency: Mutations, Functional and Biochemical Implications, and Future Perspectives.

Congenital lactase deficiency (CLD) is a severe autosomal recessive genetic disorder that affects the functional capacity of the intestinal protein lactase-phlorizin hydrolase (LPH). This disorder is diagnosed already during the first few days of the newborn’s life due to the inability to digest lactose, the main carbohydrate in mammalian milk. The symptoms are similar to those in other carbohydrate malabsorption disorders, such as congenital sucrase-isomaltase deficiency, and include severe osmotic watery diarrhea. CLD is associated with mutations in the translated region of the LPH gene that elicit loss-of-function of LPH. The mutations occur in a homozygote or compound heterozygote pattern of inheritance and comprise missense mutations as well as mutations that lead to complete or partial truncations of crucial domains in LPH, such as those linked to the folding and transport-competence of LPH and to the catalytic domains. Nevertheless, the identification of the mutations in CLD is not paralleled by detailed genotype/protein phenotype analyses that would help unravel potential pathomechanisms underlying this severe disease. Here, we review the current knowledge of CLD mutations and discuss their potential impact on the structural and biosynthetic features of LPH. We also address the question of whether heterozygote carriers can be symptomatic for CLD and whether genetic testing is needed in view of the severity of the disease.

Lactose intolerance diarrhea in a Quarter-Horse Foal

Among diarrhea etiologies in horses, lactose intolerance is a less common or undiagnosed condition. Primary (congenital) lactase deficiency has never been diagnosed in foals, and lactose intolerance secondary to bowel injury has never been described in Brazil. Former bacterial or viral infections that cause severe lesions in the intestinal brush border, the area responsible to produce lactase, will be followed by diarrhea due to a lack of enzyme activity. The present report describes the case of secondary lactase deficiency in a 3-month-old foal with chronic watery diarrhea. The foal had been treated with several antibiotics and dewormed without clinical improvement. Complementary exams made were complete blood count (CBC), white blood cell (WBC) count, fibrinogen levels, serum biochemistry (serum proteins, renal and hepatic functions), blood gas analysis, parasite egg count, abdominal ultrasonography, rectal swab culture for three consecutive days and transtracheal wash. Therapeutic diagnosis was performed through administration of 8 mg/kg of lactase (PO), every 4 hours, and stool normalization was observed in about eight hours after starting treatment. Lactose intolerance is an important differential diagnosis of diarrhea in young foals.

Congenital lactase deficiency: Identification of a new mutation

Congenital lactase deficiency: Identification of a new mutation

Compound heterozygous mutations elicit congenital lactase deficiency in a Japanese infant

Congenital lactase deficiency (CLD) is a rare severe autosomal recessive disorder, with symptoms like watery diarrhea, meteorism and malnutrition, which start a few days after birth by the onset of nursing. The most common rationales identified for this disorder are missense mutations or premature stop codons in the coding region of the lactase‐phlorizin hydrolase (LPH) gene. Recently, two heterozygous mutations, c.4419C>G (p.Y1473X) in exon 10 and c.5387delA (p.D1796fs) in exon 16, have been identified within the coding region of LPH in a Japanese infant with CLD.Here, we investigate the influence of these mutations on the structure, biosynthesis and function of LPH. We show that both mutant proteins are mannose‐rich glycosylated proteins that are not capable of exiting the endoplasmic reticulum. These mutant proteins are misfolded and turnover studies show that they are ultimately degraded. The enzymatic activities of these mutant forms are not detectable, despite the presence of lactase and phlorizin active sites in the polypeptide backbone of LPH‐D1796fs and LPH‐Y1473X respectively. Interestingly, wild type LPH retains its complete enzymatic activity and intracellular transport competence in the presence of the pathogenic mutants suggesting that heterozygote carriers presumably do not show symptoms related to CLD.Our study strongly suggests that the onset of severe forms of CLD is elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance.

Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene.

BackgroundCongenital lactase deficiency (CLD) is a rare severe autosomal recessive disorder, with symptoms like watery diarrhea, meteorism and malnutrition, which start a few days after birth by the onset of nursing. The most common rationales identified for this disorder are missense mutations or premature stop codons in the coding region of the lactase-phlorizin hydrolase (LPH) gene. Recently, two heterozygous mutations, c.4419C > G (p.Y1473X) in exon 10 and c.5387delA (p.D1796fs) in exon 16, have been identified within the coding region of LPH in a Japanese infant with CLD.MethodsHere, we investigate the influence of these mutations on the structure, biosynthesis and function of LPH. Therefore the mutant genes were transiently expressed in COS-1 cells.ResultsWe show that both mutant proteins are mannose-rich glycosylated proteins that are not capable of exiting the endoplasmic reticulum. These mutant proteins are misfolded and turnover studies show that they are ultimately degraded. The enzymatic activities of these mutant forms are not detectable, despite the presence of lactase and phlorizin active sites in the polypeptide backbone of LPH-D1796fs and LPH-Y1473X respectively. Interestingly, wild type LPH retains its complete enzymatic activity and intracellular transport competence in the presence of the pathogenic mutants suggesting that heterozygote carriers presumably do not show symptoms related to CLD.ConclusionsOur study strongly suggests that the onset of severe forms of CLD is elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance.

Lactose intolerance.

Lactose is the main carbohydrate in infant feeding, but its impact decreases as the child gets older and consumes less milk and dairy products. Congenital lactose intolerance is a very rare condition. However, lactase activity may be low and need to mature during the first weeks of life in many infants. However, the evidence that unabsorbed lactose is causing infantile crying and colic is contradictory. Unabsorbed lactose has a bifidogenic effect and improves calcium absorption. Lactose malabsorption may occur secondary and thus temporally to other etiologies such as infectious gastroenteritis, cow's milk allergy and celiac disease. One the cause is treated, lactase activity will gradually return to normal. The vast majority of Asian children will develop late onset congenital lactase deficiency. However, this entity only exceptionally causes symptoms before the age of 4-5 years. Symptoms are abdominal cramps, flatulence and watery, acid stools, and decrease the quality of life but lactose intolerance is not associated with "true disease". The diagnosis is made on clinical grounds and confirmed with a lactose breath test, if needed. These patients need to have a lifetime long reduced lactose intake to improve their quality of life.

Congenital Sucrase‐Isomaltase Deficiency

Congenital Sucrase‐Isomaltase Deficiency

Chronic Diarrhea in Children

Chronic Diarrhea in Children

Two Novel Mutations in the Lactase Gene in a Japanese Infant with Congenital Lactase Deficiency

Intestinal lactase is required for the hydrolysis of lactose that is the most essential carbohydrate in milk and the primary diet source of newborn. Congenital lactase deficiency [CLD (MIM 223000)] is a severe gastrointestinal disorder and is characterized by watery diarrhea due to an extremely low or the lack of lactase activity in the intestinal wall from birth. CLD is a rare disease and occurs more frequently in Finland. Recent studies have shown that mutations in the coding region of the lactase (LCT) gene underlie CLD in patients from Finland and other European countries. Here, we report two novel mutations in the LCT gene in a Japanese female infant with clinical features consistent with those of CLD. She suffered from severe watery diarrhea from the age of 2 days on breast milk/lactose containing cow's milk formula. With the lactose-free hydrolyzed cow's milk formula, diarrhea was stopped, and she has now developed well on a lactose-free diet. She shows a lactose-intolerance pattern on the lactose challenge test. Sequence analysis revealed the two mutations in her LCT gene: c.4419C>G (p.Y1473X) in exon 10 transmitted from her mother and c.5387delA (p.D1796fs) in exon 16 transmitted from her father. Both mutations cause premature truncation of lactase polypeptide and are supposed to be responsible for CLD. To our knowledge, this is the first report on mutations in the LCT gene in Japan. We suggest that an increased awareness is required regarding CLD.

Structural Hierarchy of Regulatory Elements in the Folding and Transport of an Intestinal Multidomain Protein

Human intestinal lactase-phlorizin hydrolase, LPH, encompasses four homologous domains, which presumably have evolved from two subsequent duplications of one ancestral gene. The profragment, LPHalpha, comprises homologous domains I and II and functions as an intramolecular chaperone in the context of the brush-border LPHbeta region of LPH. Here, we analyze the inter-relationship between homologous domains III and IV of LPHbeta and their implication in the overall structure, function, and trafficking of LPH. In silico analyses revealed potential domain boundaries for these domains as a basis for loop-out mutagenesis and construction of deletion or individual domain forms of LPH. Removal of domain IV, which contains lactase, results in a diminished phlorizin hydrolase activity, lack of dimerization in the endoplasmic reticulum (ER), but accelerated transport kinetics from the ER to the Golgi apparatus. By contrast, deletion of domain III, which harbors phlorizin hydrolase, generates a malfolded protein that is blocked in the ER. Interestingly, homologous domain III is transport-competent per se and sorted to the apical membrane in polarized Madin-Darby canine kidney cells. Nevertheless, it neither dimerizes nor acquires complete phlorizin hydrolase activity. Our data present a hierarchical model of LPH in which the homologous domain III constitutes (i) a fully autonomous core domain within LPH and (ii) another intramolecular chaperone besides the profragment LPHalpha. Nevertheless, the regulation of the trafficking kinetics and activity of domain III and entire LPH including elevation of the enzymatic activities require the correct dimerization of LPH in the ER, an event that is accomplished by the non-autonomous domain IV.

Impaired Trafficking and Subcellular Localization of a Mutant Lactase Associated With Congenital Lactase Deficiency

Congenital lactase deficiency (CLD) is a cause of disaccharide intolerance and malabsorption characterized by watery diarrhea in infants fed breast milk or lactose-containing formulas. The molecular basis of CLD is unknown. Mutations in the coding region of the brush border enzyme lactase phlorizin hydrolase (LPH) were found to cause CLD in a study of 19 Finnish families. We analyzed the effects of one of these mutations, G1363S, on LPH folding, trafficking, and function. We introduced a mutation into the LPH complementary DNA that resulted in the amino acid substitution G1363S. The mutant gene was transiently expressed in COS-1 cells, and the effects were assessed at the protein, structural, and subcellular levels. The mutant protein LPH-G1363S was misfolded and could not exit the endoplasmic reticulum. Interestingly, the mutation creates an additional N-glycosylation site that is characteristic of a temperature-sensitive protein. The intracellular transport and enzymatic activity, but not correct folding, of LPH-G1363S were partially restored by expression at 20 degrees C. However, a form of LPH that contains the mutations G1363S and N1361A, which eliminates the N-glycosylation site, did not restore the features of wild-type LPH. Thus, the additional glycosyl group is not required for the LPH-G1363S defects. This is the first characterization, at the molecular and subcellular levels, of a mutant form of LPH that is involved in the pathogenesis of CLD. Mutant LPH accumulates predominantly in the endoplasmic reticulum but can partially mature at a permissive temperature; these features are unique for a protein involved in a carbohydrate malabsorption defect implicating LPH.

Four novel mutations in the lactase gene (LCT) underlying congenital lactase deficiency (CLD)

BackgroundCongenital lactase deficiency (CLD) is a severe gastrointestinal disorder of newborns. The diagnosis is challenging and based on clinical symptoms and low lactase activity in intestinal biopsy specimens. The disease is enriched in Finland but is also present in other parts of the world. Mutations encoding the lactase (LCT) gene have recently been shown to underlie CLD. The purpose of this study was to identify new mutations underlying CLD in patients with different ethnic origins, and to increase awareness of this disease so that the patients could be sought out and treated correctly.MethodsDisaccharidase activities in intestinal biopsy specimens were assayed and the coding region of LCT was sequenced from five patients from Europe with clinical features compatible with CLD. In the analysis and prediction of mutations the following programs: ClustalW, Blosum62, PolyPhen, SIFT and Panther PSEC were used.ResultsFour novel mutations in the LCT gene were identified. A single nucleotide substitution leading to an amino acid change S688P in exon 7 and E1612X in exon 12 were present in a patient of Italian origin. Five base deletion V565fsX567 leading to a stop codon in exon 6 was found in one and a substitution R1587H in exon 12 from another Finnish patient. Both Finnish patients were heterozygous for the Finnish founder mutation Y1390X. The previously reported mutation G1363S was found in a homozygous state in two siblings of Turkish origin.ConclusionThis is the first report of CLD mutations in patients living outside Finland. It seems that disease is more common than previously thought. All mutations in the LCT gene lead to a similar phenotype despite the location and/or type of mutation.

Index of Suspicion

Index of Suspicion

Caution With Committee Recommendations for Soy Protein–Based Formulas

To the Editor. — In the May 2008 issue of Pediatrics , Drs Bhatia and Greer and the American Academy of Pediatrics Committee on Nutrition1 made some broad recommendations on the use of soy-based formula. They indicate that breastfeeding remains the “formula” of choice and smartly reinforce that there are only rare indications (galactosemia, congenital lactase deficiency, and vegetarian dieting) when a switch to soy is clearly preferred over cow milk–based formula. However, we …