Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I.

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.

Non-neuronopathic lysosomal storage disorders: Disease spectrum and treatments.

Distinctive facial features, hepatosplenomegaly or cardiomyopathy with or without associated skeletal dysplasia are clinical manifestations that may be suggestive of an underlying lysosomal storage disorder (LSD), However, these features may not be evident in certain subtypes associated primarily with central nervous system involvement. Age at onset can be broad, ranging from infancy to adulthood. Diagnosis may be delayed, as manifestations may be slow to evolve (taking months to years), particularly in those with later (adult-)onset, and in isolated cases (i.e., those without a prior family history). Diagnosis of individual subtypes can be confirmed using a combination of biochemical and molecular assays. In a few LSDs, treatment with hematopoietic stem cell transplantation, enzyme replacement or substrate reduction therapy is available. Symptomatic and palliative measure may enhance quality of life for both treatable and currently untreatable cases. Genetic counseling is important, so patients and their families can be informed of reproductive risks, disease prognosis and therapeutic options. Investigations of underlying disease mechanisms are enhancing knowledge about rare diseases, but also other more common medical conditions, on account of potential convergent disease pathways.

The clinical spectrum and pathophysiology of skeletal complications in lysosomal storage disorders.

Lysosomal storage disorders affect multiple organs including the skeleton. Disorders with prominent skeletal symptoms are type 1 and 3 Gaucher disease, the mucopolysaccharidoses, the glycoproteinoses and pycnodysostosis. Clinical manifestations range from asymptomatic radiographical evidence of bone pathology to overt bone crises (Gaucher), short stature with typical imaging features known as dysostosis multiplex (MPS), with spine and joint deformities (mucopolysaccharidoses, mucolipidosis), or osteopetrosis with pathological fractures (pynodysostosis). The pathophysiology of skeletal disease is only partially understood and involves direct substrate storage, inflammation and other complex alterations of cartilage and bone metabolism. Current treatments are enzyme replacement therapy, substrate reduction therapy and hematopoietic stem cell transplantation. However, effects of these interventions on skeletal disease manifestations are less well established and outcomes are highly dependent on disease burden at treatment initiation. It is now clear that adjunctive treatments that target skeletal disease are needed and should be part of future research agenda.

Osteoimmunology in mucopolysaccharidoses type I, II, VI and VII. Immunological regulation of the osteoarticular system in the course of metabolic inflammation.

BACKGROUND: Mucopolysaccharidoses (MPSs) are rare genetic diseases caused by a deficient activity of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. These metabolic blocks lead to the accumulation of GAGs in various organs and tissues, resulting in a multisystemic clinical picture. The pathological GAG accumulation begins a cascade of interrelated responses: metabolic, inflammatory and immunological with systemic effects. Metabolic inflammation, secondary to GAG storage, is a significant cause of osteoarticular symptoms in MPS disorders. OBJECTIVE AND METHOD: The aim of this review is to present recent progress in the understanding of the role of inflammatory and immune processes in the pathophysiology of osteoarticular symptoms in MPS disorders and potential therapeutic interventions based on published reports in MPS patients and studies in animal models. RESULTS AND CONCLUSIONS: The immune and skeletal systems have a number of shared regulatory molecules and many relationships between bone disorders and aberrant immune responses in MPS can be explained by osteoimmunology. The treatment options currently available are not sufficiently effective in the prevention, inhibition and treatment of osteoarticular symptoms in MPS disease. A lot can be learnt from interactions between skeletal and immune systems in autoimmune diseases such as rheumatoid arthritis (RA) and similarities between RA and MPS point to the possibility of using the experience with RA in the treatment of MPS in the future. The use of different anti-inflammatory drugs requires further study, but it seems to be an important direction for new therapeutic options for MPS patients.

Acrodysostosis.

Acrodysostosis refers to a group of rare skeletal dysplasias that share in common characteristic clinical and radiological features including brachydactyly, facial dysostosis, and nasal hypoplasia. In the past, the term acrodysostosis has been used to describe patients with heterogeneous phenotypes, including, in some cases, patients that today would be given alternative diagnoses. The recent finding that mutations impairing the cAMP binding to PRKAR1A are associated with "typical" acrodysostosis and hormonal resistance initiates the era where this group of disorders can be categorized on a genetic basis. In this review, we will first discuss the clinical, radiologic, and metabolic features of acrodysostosis, emphasizing evidence that several forms of the disease are likely to exist. Second, we will describe recent results explaining the pathogenesis of acrodysostosis with hormonal resistance (ADOHR). Finally, we will discuss the similarities and differences observed comparing patients with ADOHR and other diseases resulting from defects in the PTHR1 signaling pathway, in particular, pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism.

Congenital malformations.

Congenital malformations are single or multiple defects of the morphogenesis of organs or body districts identifiable at birth or during the intrauterine life. Their global birth prevalence is about 2-3%. Both genetic and environmental factors, as well as their combination in a multifactorial contest, may induce congenital defects. Congenital malformations may be classified on the basis of clinical, etiologic as well as pathogenetic criteria. Relevant diagnostic and therapeutic tools have been progressively improving in the last decades, contributing to a better identification and a reduction of long-term morbidity and mortality of these patients. A correct identification of a congenital defect is the first step in order to offer a helpful genetic counseling to the parental couple. Because of their increasing life expectancy, congenital malformations represent today a major issue in the health services for the amount of resources they need for the requested multidisciplinary assistance.

Orthopaedic aspects of mucopolysaccharidoses.

Skeletal abnormalities are an early and prominent feature of most mucopolysaccharide (MPS) disorders, with the degree of skeletal involvement varying between and within MPS subtypes. Most patients exhibit a constellation of radiographic abnormalities known as dysostosis multiplex, consisting of abnormally shaped vertebrae and ribs, enlarged skull, spatulate ribs, hypoplastic epiphyses, thickened diaphyses and bullet-shaped metacarpals. Thoracolumbar kyphosis or the gibbus deformity is often a key diagnostic clue. Also common are hip dysplasia, genu valgum and, later in the course of the disease, spinal cord compression, which can be life-threatening. Short stature is ubiquitous. Treatment of skeletal manifestations usually involves surgical intervention. All patients with MPS should be considered at high risk for surgical intervention requiring anaesthesia because of airway and cardiac disease manifestations. Regular imaging of the cervical, thoracic and lumbar spine, the hips and the lower extremities is recommended for patients with MPS.

Musculoskeletal manifestations of mucopolysaccharidoses.

The mucopolysaccharidoses (MPSs) are a heterogeneous group of inherited metabolic disorders caused by enzyme deficiencies that lead to progressive lysosomal storage of glycosaminoglycans. Musculoskeletal manifestations are common across all forms of MPS and are often apparent early in the disease course. Diagnostic delays occur frequently in these patients, especially those with more attenuated forms of disease. Treatments for many types of MPS are now available; however, they are most effective if started early before the development of irreversible damage. Some manifestations such as stiffness and joint contractures may mimic other conditions such as inflammatory arthritis, which may cause further delays. Rheumatologists and other specialists should be aware of the musculoskeletal manifestations of MPS so that diagnostic delays can be avoided and appropriate management initiated.

Jeune's syndrome (asphyxiating thoracic dystrophy): congenital and acquired.

Familial asphyxiating thoracic dystrophy (ATD), also known as Jeune's syndrome, is a rare autosomal recessive disorder with variable severity and multiple musculo-skeletal manifestations. Respiratory distress may be severe, resulting in death during infancy. Surgical repair techniques have typically involved median sternotomy (with graft interposition), resulting in poor outcomes. Acquired ATD may rarely result from impairment of chest wall growth following "open" (Ravitch-type) repair of pectus excavatum or carinatum deformities. Symptomatic patients may have profound restriction of pulmonary function. Repair techniques typically involve re-do Ravitch-type procedures or median sternotomy with rib graft interposition. Mild to moderate improvements in pulmonary function tests have been documented.

Notch signaling in development and disease.

Notch receptors and ligands were first identified in flies and worms, where they were shown to regulate cell proliferation, cell differentiation, and, in particular, binary cell fate decisions in a variety of developmental contexts. The first mammalian Notch homolog was discovered to be a partner in a chromosomal translocation in a subset of human T-cell leukemias. Subsequent studies in mice and humans have shown that Notch signaling plays essential roles at multiple stages of hematopoiesis, and also regulates the development or homeostasis of cells in many tissues and organs. Thus, it is not surprising that mutations which disrupt Notch signaling cause a wide range of cancers and developmental disorders. Perhaps because it is so widely used, Notch signaling is subject to many unusual forms of regulation. In this review, we will first outline key aspects of Notch signaling and its regulation by endocytosis, glycosylation, and ubiquitination. We will then overview recent literature elucidating how Notch regulates cell-lineage decisions in a variety of developmental contexts. Finally, we will describe the roles of dysregulated Notch signaling in causing several types of cancer and other pathologies.

Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.

Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects. SD is characterized by multiple hemivertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Cases may be sporadic or familial, with both autosomal dominant and autosomal recessive modes of inheritance reported. Autosomal recessive SD maps to a 7.8-cM interval on chromosome 19q13.1-q13.3 that is homologous with a mouse region containing a gene encoding the Notch ligand delta-like 3 (Dll3). Dll3 is mutated in the X-ray-induced mouse mutant pudgy (pu), causing a variety of vertebrocostal defects similar to SD phenotypes. Here we have cloned and sequenced human DLL3 to evaluate it as a candidate gene for SD and identified mutations in three autosomal recessive SD families. Two of the mutations predict truncations within conserved extracellular domains. The third is a missense mutation in a highly conserved glycine residue of the fifth epidermal growth factor (EGF) repeat, which has revealed an important functional role for this domain. These represent the first mutations in a human Delta homologue, thus highlighting the critical role of the Notch signalling pathway and its components in patterning the mammalian axial

Carbohydrate-deficient glycoprotein syndrome type I: a new cause of dysostosis multiplex.

We report on a 1-year-old boy, with carbohydrate-deficient glycoprotein (CDG) syndrome type I due to phosphomannomutase deficiency. Radiologic examination of the skeleton revealed previously unreported bone abnormalities that could be included in a dysostosis multiplex: wide ribs, squared iliac wings, horizontal acetabular roofs, widening and modeling abnormalities of ischial and pubic bones, dorsolumbar kyphosis, and slight hook-like dysplasia of the first lumbar vertebrae. Wormian bones were also present. We suggest that these features may be due to hypoglycosylation of bone proteins and that CDG syndrome type I should be included in the differential diagnosis of dysostosis multiplex.

Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres.

Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over a period of 15 years. The donor was an HLA identical relative in 10 cases, an HLA non-identical relative in 16 cases, and an HLA identical unrelated volunteer donor in 12 cases. Ten patients received a second transplant. One patient received three transplants. Thirteen engrafted patients have survived five years or more. Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed. Careful selection of patients may be necessary to ensure optimum results.

Bony changes in common mucopolysaccharidoses.

To evaluate the radiological features of mucopolysaccharidoses (MPS), 15 cases were collected for review in this hospital, retrospectively (1985-1995). Eight cases of Hurler syndrome, two cases of Hunter syndrome, two cases of Sanfilippo syndrome and three cases of Morquio syndrome were classified. Varying severity of dysostosis multiplex is the general bony manifestation of MPS, but special appearance may occur in particular types. Hurler syndrome is the prototype of MPS. The main findings were as follows: "J" shaped sella turcica, paddle-like ribs, anterior inferior beaking (hook-like) of lower thoracic-upper lumbar hypoplastic vertebral bodies, flared iliac wings, constrictive iliac bodies, diaphyseal expansion of long bones, distal ulna and radius tilt toward each other, bullet-like proximal phalanges and central pointing of proximal metacarpals. Hunter and Sanfilippo syndromes had the appearance of moderate to mild dysostosis multiplex. Morquio syndrome had distinctive bony changes as vertebral plana and tongue-like protrusion in the anterior part of the lower thoracic-upper lumbar vertebral bodies, particularly short of the distal deformed ulna and poor ossification of the proximal lateral tibial epiphyses. Although clinical presentations and the hallmarks of bony changes helped possible classification of MPS, definite diagnosis depends on enzyme analysis.

Study of the bone pathology in early mucolipidosis II (I-cell disease).

Histological examination of the bones obtained on autopsy of a 5-month-old child with mucolipidosis II (I-cell disease) revealed inhibition of the growth plate calcification with defective vascular invasion and signs of hyperparathyroidism. These findings are the chondro-osseous basis of the early radiological ricket-like appearance of bones in the neonatal period or soon thereafter. Whether the early skeletal abnormalities of mucolipidosis II result from a primary enzymatic defect of cartilage and bone cells or from factors controlling bone metabolism deserves further study.

Acrofacial dysostosis with postaxial limb deficiency.

Here we report on an adult man with the postaxial acrofacial dysostosis syndrome, as delineated by Miller et al [1979]. In addition to facial changes strikingly similar to that of the Teacher-Collins syndrome and a cleft soft and hard palate, symmetrical postaxial limb deficiencies with absence of the fifth digital rays in both the upper and lower limbs were present.