Bone marrow transplantation for feline mucopolysaccharidosis I.

Severe mucopolysaccharidosis type I (MPS I) is a fatal neuropathic lysosomal storage disorder with significant skeletal involvement. Treatment involves bone marrow transplantation (BMT), and although effective, is suboptimal, due to treatment sequelae and residual disease. Improved approaches will need to be tested in animal models and compared to BMT.

Niemann-Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2.

Niemann-Pick type C disease (NPC), a neurovisceral disorder characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system, is due to mutations on either the NPC1 or the NPC2 genes. We report the diagnosis of six unrelated patients with NPC2, all with homozygous mutations. We further attempted functional characterization of the p.

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS.

Gene therapy of the brain in the dog model of Hurler's syndrome.

Objective: A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno-associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme-deficient dogs.

Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal disease caused by a defect of the enzyme arylsulfatase A (ARSA) that disrupts the degradation of sulfatides (Sulf) in neurons and glial cells. Therapy for MLD requires active production of ARSA in the brain to prevent demyelination and neuronal damage, and efficient delivery of ARSA to act faster than disease progression, particularly in the rapidly progressive late infantile form. We used an adeno-associated virus serotype 5 (AAV5) vector to express the human ARSA gene in the brain of MLD mouse model.

[Fatal neonatal respiratory distress in Niemann-Pick C2 and prenatal diagnosis with mutations in gene HE1/NPC2].

Unlabelled: We report the fifth case of neonatal form of type C2 (NP-C2) Niemann-Pick disease with early and fatal respiratory distress. Eleven families presenting such cases are known to date in the world. Since December 2000, isolation of the underlying gene HE1/NPC2 and its mutations has allowed major advances in diagnosis.

Improved behavior and neuropathology in the mouse model of Sanfilippo type IIIB disease after adeno-associated virus-mediated gene transfer in the striatum.

Sanfilippo syndrome is a mucopolysaccharidosis (MPS) caused by a lysosomal enzyme defect interrupting the degradation pathway of heparan sulfates. Affected children develop hyperactivity, aggressiveness, delayed development, and severe neuropathology. We observed relevant behaviors in the mouse model of Sanfilippo syndrome type B (MPSIIIB), in which the gene coding for alpha-N-acetylglucosaminidase (NaGlu) is invalidated.

Prevention of neuropathology in the mouse model of Hurler syndrome.

A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts heparan and dermatan sulfate degradation and causes neuropathology in children with severe forms of mucopolysaccharidosis type I (MPSI, Hurler syndrome). Enzyme substitution therapy is beneficial but ineffective on the central nervous system. We could deliver the missing enzyme to virtually the entire brain of MPSI mice through a single injection of gene transfer vectors derived from adenoassociated virus serotype 2 (AAV2) or 5 (AAV5) coding for human IDUA.

Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone.

Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood neurodegenerative disease. The NP-C mouse recapitulates the cholesterol and sphingolipid storage, onset of neurological deficits, histopathological lesions, Purkinje cell loss and early death typical of the most severe form of human NP-C. Neurosteroids, steroids made in the brain, affect neuronal growth and differentiation, and modulate neurotransmitter receptors.

Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport.

Niemann-Pick C (NPC) disease is a fatal neurodegenerative disorder characterized by a lysosomal accumulation of cholesterol and other lipids within the cells of patients. Clinically identical forms of NPC disease are caused by defects in either of two different proteins: NPC1, a lysosomal-endosomal transmembrane protein and NPC2, a soluble lysosomal protein with cholesterol binding properties. Although it is clear that NPC1 and NPC2 are required for the egress of lipids from the lysosome, the precise roles of these proteins in this process is unknown.

Localization of a non-syndromic X-linked mental retardation gene (MRX80) to Xq22-q24.

Isolated mental retardation is clinically and genetically heterogenous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. We report here a linkage analysis in a large family including 15 members, 6 of whom presenting X-linked non-syndromic mental retardation (MRX). Two-point linkage analysis using 23 polymorphic markers covering the entire X chromosome demonstrated significant linkage between the causative gene and DXS8055 with a maximum LOD score of 2.