gastrins and Nervous-System-Diseases

Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage disorder caused by mutations in the MCOLN1 gene, which encodes the 65-kDa protein mucolipin-1. The most common clinical features of patients with MLIV include severe mental retardation, delayed motor milestones, ophthalmologic abnormalities, constitutive achlorhydria, and elevated plasma gastrin levels. Here, we describe the first murine model for MLIV, which accurately replicates the phenotype of patients with MLIV. The Mcoln1(-/-) mice present with numerous dense inclusion bodies in all cell types in brain and particularly in neurons, elevated plasma gastrin, vacuolization in parietal cells, and retinal degeneration. Neurobehavioral assessments, including analysis of gait and clasping, confirm the presence of a neurological defect. Gait deficits progress to complete hind-limb paralysis and death at age ~8 mo. The Mcoln1(-/-) mice are born in Mendelian ratios, and both male and female Mcoln1(-/-) mice are fertile and can breed to produce progeny. The creation of the first murine model for human MLIV provides an excellent system for elucidating disease pathogenesis. In addition, this model provides an invaluable resource for testing treatment strategies and potential therapies aimed at preventing or ameliorating the abnormal lysosomal storage in this devastating neurological disorder.

Topics: Animals; Body Weight; Disease Models, Animal; Eye Diseases; Gastric Mucosa; Gastrins; Gene Targeting; Hindlimb; Inclusion Bodies; Longevity; Mice; Mice, Knockout; Mucolipidoses; Nervous System Diseases; Paralysis; Pyramidal Cells; Retinal Degeneration; Stomach Diseases; Survival Analysis; Transient Receptor Potential Channels; TRPM Cation Channels

In a study of the pathogenesis and clinical features of megaloblastic anaemia in southern Africa, we evaluated 144 consecutive Zimbabwean patients with megaloblastic haemopoiesis. Vitamin B12 deficiency was diagnosed in 86.1% of patients and was usually due to pernicious anaemia; isolated folate deficiency accounted for only 5.5% of cases. Anaemia was present in 95.8% of patients; the haemoglobin (Hb) was < or = 6 g/dl in 63.9%. Neurological dysfunction was noted in 70.2% of vitamin B12-deficient patients and was most striking in those with Hb values > 6 g/dl. Serum levels of methylmalonic acid, homocysteine, or both, were increased in 98.5% of patients. Vitamin B12 deficiency is the primary cause of megaloblastic anaemia in Zimbabwe and, contrary to textbook statements, is often due to pernicious anaemia. Isolated folate deficiency is less common. As reported in industrialized countries 75 years ago, anaemia is almost always present and often severe. Neurological dysfunction due to vitamin B12 deficiency is most prominent in patients with mild to moderate anaemia.

Topics: Anemia, Megaloblastic; Anemia, Pernicious; Erythrocyte Indices; Female; Folic Acid; Folic Acid Deficiency; Gastrins; Hemoglobins; Homocysteine; Humans; Methylmalonic Acid; Nervous System Diseases; Neutrophils; Vitamin B 12 Deficiency; Zimbabwe