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Biomedical subjects

Luigi D Notarangelo

Publications and source records attributed to Luigi D Notarangelo.

46 records · Page 3Linked to original sources
PubMed2003

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome: time to review diagnostic criteria?

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal-recessive syndrome defined by two of the following conditions: chronic mucocutaneous candidiasis, hypoparathyroidism, or Addison's disease. Other autoimmune conditions may be associated, such as hypothyroidism, hypogonadism, insulin-dependent diabetes mellitus, chronic active hepatitis, pernicious anemia, vitiligo, alopecia, biliary cirrhosis, and ectodermal dysplasia. APECED is caused by mutations in the autoimmune regulator gene, mapping to 21q22.3. We report on three patients whose clinical and molecular features challenge the currently used diagnostic criteria for APECED. AR presented at 15 yr of age with a history of recurrent infections and mucocutaneous candidiasis. He is now 21 yr old, and no other signs or symptoms of APECED have appeared to date. DR presented at 7 yr of age with hypocalcemia and a prolonged Q-T interval on the electrocardiogram. He also had minor facial dysmorphisms and mild mental retardation. Serum calcium levels were low, PTH levels were undetectable, and hypoparathyroidism was therefore diagnosed. All other biochemical, immunological, and endocrinological tests were normal. DR is now 8 yr old with no other signs or symptoms of APECED. ST presented at 14 yr of age for alopecia aerata and pitted nail dystrophy and goiter. Thyroid function was normal in the presence of thyroid-specific antibodies. No other signs or symptoms of APECED have appeared to date. Genetic analysis revealed a typical mutation (R257X) on a single allele in both AP and DR; in ST, heterozygosity for a novel mutation (V484M) involving one of the zinc fingers of the plant homeodomain of the protein was found. The finding of a typical APECED mutation in two patients presenting with one isolated major clinical APECED feature and of a novel mutation in a patient presenting with atypical features of APECED onset suggests that the time might have come for updating the diagnostic criteria of this syndrome.

Adolescent↗
PubMed2003

Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis.

UNLABELLED: Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family. INTRODUCTION: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown. MATERIALS AND METHODS: In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters. RESULTS AND CONCLUSIONS: In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may be associated with CNS involvement and have a very poor prognosis, whereas heterozygous ClCN7 mutations cause a wide range of phenotypes even in the same family, ranging from early severe to nearly asymptomatic forms. These findings have prognostic implications, might complicate prenatal diagnosis of human osteopetroses, and could be relevant to the management of these patients.

Adolescent↗
PubMed2003

Primary immune deficiencies unravel the molecular basis of immune response.

Primary immune deficiencies (PID) represent inborn errors of immunity. Over the years, detailed analysis of the clinical and laboratory features associated with these unique and rare disorders have shed light on the complex array of signals and processes that govern development and activation of the immune system. While the first examples of PID pertained to severe defects in lymphoid development, more recently a variety of gene defects have been identified in humans that do not compromize the ability to generate lymphocytes, but rather result in profound immune dysregulation. In many cases, identification of the molecular and cellular bases of PID has preceeded development of animal models by gene targeting. Finally, since the very first cases reported in humans, PID have also represented a unique tool to investigate the efficacy of novel therapeutic approaches (from molecular therapy to hematopoietic stem cell transplantation to somatic cells gene therapy), that have been applied or may apply to a variety of more common human diseases.

Cytokines↗
PubMed2002

Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency.

UNLABELLED: Common variable immunodeficiency (CVID) and X-linked lymphoproliferative (XLP) disease are two immunodeficiencies that may share a similar immunological phenotype making differential diagnosis difficult. We report two patients initially diagnosed as affected with CVID who, using molecular analysis, have been subsequently found to be affected with XLP disease. Distinguishing between these two diseases is essential since they have different prognosis, treatment and genetic counselling. CONCLUSION: current techniques, such as genetic analysis of the SH2D1A gene and expression of signalling lymphocyte activation molecule-associated protein, allow a definite diagnosis of X-linked lymphoproliferative disease.

Adult↗
PubMed2002

Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia.

Mutations of the WASP gene have been previously shown to be responsible for classical Wiskott-Aldrich syndrome, isolated X-linked thrombocytopenia, and severe, congenital X-linked neutropenia. We report herewith 2 families in which affected males had a history of intermittent thrombocytopenia with consistently reduced platelet volume, in the absence of other major clinical features, and carried missense mutations of the WASP gene that allowed substantial protein expression. This observation broadens the spectrum of clinical phenotypes associated with WASP gene defects, and it indicates the need for molecular analysis in males with reduced platelet volume, regardless of the platelet number.

Adult↗
PubMed2002

Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment.

We have identified 14 patients with diverse primary immunodeficiencies who have developed progressive neurodegeneration of unknown etiology. All patients had received immunoglobulin replacement therapy for a mean duration of 6.5 years (range of 0.5-13.5 years) at the time of first neurological symptoms. Diagnostic tests of blood and cerebrospinal fluid analyses included chemistry, cultures, PCR for viral genomes, and cytology. In addition, neuroimaging and electrophysiologic studies were performed. Brain tissue histology (n = 5) revealed nonspecific encephalitis with microglial infiltration and neuronal loss. Twelve patients died 6 months to 15 years (median 4.3 years) after onset of neurologic findings. No evidence of any infectious disease that could have explained our patients' progressive encephalopathy was found either during their lifetimes or postmortem. These patients may have had an unusual manifestation of primary immunodeficiency diseases, an autoimmune reaction against neuronal tissue, a yet undefined infectious agent, or a complication of IVIG therapy. To help determine the etiology of this rare complication, an international surveillance system for primary immunodeficiency patients who develop progressive neurodegeneration of unknown cause is recommended.

Adolescent↗
PubMed2002

Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study.

A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was present in 24 patients, in 15 already at diagnosis and in 9 more by 2000. The cumulative risk to present at diagnosis with CLD increased from 0.17 to 0.40 and 0.78 when the diagnosis was made at the ages of 5, 10, and 15 years respectively. For the 9 patients who developed CLD during follow-up, the duration of follow-up, rather than age at diagnosis; previous administration of intramuscular immunoglobulin; and residual IgG levels had a significant effect on the development of CLD. Chronic sinusitis was present in 35 patients (48%), in 15 already at diagnosis and in 20 by 2000. Sistemic infections such as sepsis and meningitis/meningoencephalitis decreased over follow-up, probably due to optimal protection provided by high circulating IgG levels reached with IVIG.

Adolescent↗
PubMed2002

Defective migration of monocyte-derived dendritic cells in LAD-1 immunodeficiency.

beta2 Integrins (CD18) are required for leukocyte migration. In fact, the absence of CD18 results in type-1 leukocyte adhesion deficiency (LAD-1). We analyzed the distribution phenotype and function of dendritic cells (DCs) in three LAD-1 patients with homozygous mutations of CD18. Two of them did not express CD18 (Patients A and C), and the other subject (Patient B) displayed reduced expression of beta2 integrins because of a missense mutation. Analysis of DCs derived from Patients A and B showed an abnormal morphology and a severe impairment in transendothelial migration and chemotactic response to CCL19/macrophage inflammatory protein-3beta, suggesting that CD18 is required for migration of monocyte-derived DCs. Nevertheless, DCs displayed normal macropinocytosis and underwent normal maturation after addition of tumor necrosis factor alpha. Finally, immunohistochemical analysis of lymph nodes from subjects B and C revealed a significant reduction in the number of factor-XIIIa(+) interstitial DCs in the interfollicular area in both patients, suggesting that CD18 plays a role in the migration of these cells in vivo.

CD18 Antigens↗