Marco Seri

MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term “MHY9-related disease,” which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.

Mowat–Wilson syndrome: Facial phenotype changing with age: Study of 19 Italian patients and review of the literature

Mowat–Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate‐to‐severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. ( 1998 ); J Med Genet 35:617–623], ∼179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21–q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition.

Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations

Background and Objectives Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients. Design and Methods We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences. Results In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-α and interferon-γ was increased during pancytopenia as compared to controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course. Interpretation and Conclusions These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.

Genetic predisposition to familial neuroblastoma: Identification of two novel genomic regions at 2p and 12p

Objectives: The rarity of familial neuroblastoma (NB) has allowed only a few linkage studies, most of which did not show any evidence of linkage to regions involved in somatic alterations or to genes implicated in other neurocristopathies seldom associated with NB. We screened a highly informative family with recurrent NB by genome-wide linkage analysis aimed at identifying chromosomal regions for NB predisposing genes. Methods: A genome-wide screen was performed using 382 microsatellite markers. Multipoint model-based linkage analysis was carried out under a dominant mode of inheritance for the disease using the ‘affected only’ approach. Results: Our analysis identified two haplotypes co-segregating with the disease on chromosomes 2p and 12p, and yielded maximum lod-score values of 3.01 (p < 0.0001) for markers on both intervals. Conclusions: Evidence of linkage was reported at 16p in North American families, whereas our studies excluded this interval and indicated other loci for disease predisposition, thus confirming the remarkable genetic heterogeneity of NB. These results suggest an oligogenic inheritance in NB involving more loci in genetic determination of the disease.

MYO7A mutation screening in Usher syndrome type I patients from diverse origins

Usher syndrome (USH) (OMIM 276901) is an autosomal recessive disorder characterised by hearing impairment associated with retinitis pigmentosa and in some cases vestibular dysfunction. This disease accounts for approximately 50% of individuals with combined deafness and blindness in developed countries. The estimated prevalence of USH ranges from 3.8 to 6.2/100 000.1–3 Phenotypically, three clinical types of Usher syndrome have been defined according to the severity of hearing impairment, age of retinitis pigmentosa onset and the presence or absence of vestibular response. Usher syndrome type I (USH1) is the most serious type, characterised by severe to profound congenital sensorineural hearing loss, balance deficiency and prepubertal onset of retinitis pigmentosa leading to blindness. USH2 is characterised by moderate to severe hearing impairment, normal vestibular function and later onset of retinal degeneration than USH1. USH3 displays progressive hearing loss, retinitis pigmentosa and variable vestibular phenotype. Six loci for USH1 (USH1B–USH1G) have been mapped and, to date, five genes have been identified.4,5 The MYO7A gene was found to be responsible for USH1B6 and is the most common subtype of USH1, accounting for approximately 50% of cases.7–9 Defects in MYO7A also cause autosomal dominant non-syndromic sensorineural hearing impairment (DFNA11) (MIM 601317),10 autosomal recessive deafness (DFNB2) (MIM 600060)11,12 as well as atypical types of Usher syndrome which are clinically similar to USH3.13 The MYO7A gene has 49 exons, of which 48 are coding, and spans approximately 87 kb of genomic sequence on chromosome 11q13.5. The encoded protein is an unconventional myosin, the myosin VIIA,14 predicted to consist of 2215 amino acids and has a molecular mass of 254 kDa. This protein contains three typical domains: the N terminal head or motor; the neck or regulatory domain consisting of five IQ motifs; and the tail …

Localization of a Gene for Nonsyndromic Renal Hypodysplasia to Chromosome 1p32-33

Nonsyndromic defects in the urinary tract are the most common cause of end-stage renal failure in children and account for a significant proportion of adult nephropathy. The genetic basis of these disorders is not fully understood. We studied seven multiplex kindreds ascertained via an index case with a nonsyndromic solitary kidney or renal hypodysplasia. Systematic ultrasonographic screening revealed that many family members harbor malformations, such as solitary kidneys, hypodysplasia, or ureteric abnormalities (in a total of 29 affected individuals). A genomewide scan identified significant linkage to a 6.9-Mb segment on chromosome 1p32-33 under an autosomal dominant model with reduced penetrance (peak LOD score 3.5 at D1S2652 in the largest kindred). Altogether, three of the seven families showed positive LOD scores at this interval, demonstrating heterogeneity of the trait (peak HLOD 3.9, with 45% of families linked). The chromosome 1p32-33 interval contains 52 transcription units, and at least 23 of these are expressed at stage E12.5 in the murine ureteric bud and/or metanephric mesenchyme. These data show that autosomal dominant nonsyndromic renal hypodysplasia and associated urinary tract malformations are genetically heterogeneous and identify a locus for this common cause of human kidney failure.

A de novo nonsense mutation of PAX6 gene in a patient with aniridia, ataxia, and mental retardation

Claudio Graziano, Angela V. D’Elia, Laura Mazzanti, Filomena Moscano, Simonetta Guidelli Guidi, Emanuela Scarano, Daniela Turchetti, Emilio Franzoni, Giovanni Romeo, Giuseppe Damante, and Marco Seri* U.O. di Genetica Medica, Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Università degli Studi di Bologna, Bologna, Italy Dipartimento di Scienze e Tecnologie Biomediche, Università degli Studi di Udine, Udine, Italy Clinica Pediatrica, Dipartimento di Pediatria, Università degli Studi di Bologna, Bologna, Italy U.O. di Neuropsichiatria Infantile, Dipartimento di Pediatria, Università degli Studi di Bologna, Bologna, Italy Ottica Fisiopatologica, Policlinico S. Orsola-Malpighi, Bologna, Italy

Genetics of human enteric neuropathies

Knowledge of molecular mechanisms that underlie development of the enteric nervous system has greatly expanded in recent decades. Enteric neuropathies related to aberrant genetic development are thus becoming increasingly recognized. There has been no recent review of these often highly morbid disorders. This review highlights advances in knowledge of the molecular pathogenesis of these disorders from a clinical perspective. It includes diseases characterized by an infantile aganglionic Hirschsprung phenotype and those in which structural abnormalities are less pronounced. The implications for diagnosis, screening and possible reparative approaches are presented.

Adult-onset Alexander disease : report on a family.

AbstractPathogenic, dominant, de novo missense mutations in the glial fibrillary acidic protein (GFAP) have been found in the three subtypes of infantile, juvenile and adult Alexander disease.Here we describe four members of an Italian family (32 to 66-yearsold, 2 women and 2 men) affected by adult Alexander disease, the least common and the most clinically variable form.Direct sequencing of all coding regions of the GFAP gene, neurological examination and brain MRI were performed.Two novel missense mutations were found involving two very close codons, c.[988C > G, 994G > A], leading to p.[Arg330Gly, Glu332Lys]. Clinically, two members exhibited pseudo-bulbar signs, gait ataxia and spasticity, one showed a severe cranial sensory symptomatology, and one subject was asymptomatic.Medulla and cervical cord atrophy was present in all of them on MRI.Although adult Alexander disease shows a wide clinical variability, a more frequent pattern can be identified characterized by bulbar or pseudo-bulbar signs, gait ataxia, and spasticity, and including on MRI medulla and cervical cord atrophy. Our findings also confirm that the clinical spectrum of adult Alexander disease includes cases without overt neurological involvement and with minimal brain MRI alterations.

A novel locus for syndromic chronic idiopathic intestinal pseudo-obstruction maps to chromosome 8q23–q24

Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare and severe clinical syndrome characterized by symptoms and signs of intestinal occlusion, in the absence of any mechanical obstruction of the gut lumen. In the attempt to identify the genetic basis of CIIP, we analyzed a Turkish pedigree with a high degree of consanguinity in which three siblings presented with a syndromic form of CIIP. All affected family members were characterized by recurrent, self-limiting subocclusive episodes, long-segment Barrett esophagus, and a variety of minor cardiac valve or septal defects. In some patients full-thickness intestinal biopsy samples were obtained and tissues were processed for immunohistochemistry using antibodies to different markers of the intestinal neuromuscular tract. Full-thickness biopsies of the gut wall showed abnormalities of both the neural and muscular components suggesting an underlying intestinal neuro-myopathy. Blood samples were collected for DNA extraction from each available family member and DNAs were genotyped using 382 microsatellites spanning the entire genome with the aim to take advantage of the homozygosity mapping approach. Linkage analysis identified a new syndromic locus on chromosome 8q23–q24 (multipoint LOD score=5.01). Our data strongly support the presence of a new genetic locus associated with CIIP, long-segment Barrett esophagus, and cardiac involvement on chromosome 8.