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Open access

Vanna Micheli and Matteo Bertelli

Abstract

Lesch-Nyhan Disease (LND) is a rare X-linked genetic disease with hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, due to mutation in the encoding gene, located on the X-chromosome. LND patients exhibit hyperuricemia with stones due to unrecycled purine accumulation and increased synthesis, and a devastating neurological syndrome with dystonia and self-injurious behaviour, choreoathetosis and spasticity. In spite of biochemical and molecular research, the fine connection between the neurological syndrome and HGPRT deficiency is still unclear, though there is consensus regarding brain neurotransmitter dysfunction with few dopaminergic neuron terminals in the striatum. The rarity of the disease makes it difficult to obtain homogeneous population of patients to study. The aim of this paper is to contribute to the understanding of the connection between genotype and phenotype in a cohort of Italian patients, to propose a reliable method of identifying carrier women in affected families, and to provide evidence of a possible link between HGPRT deficiency and altered adenosinergic and serotonergic neurotransmission. Biochemical and mutation analysis is reported in 28 LNS Italian patients from 25 families, with virtually no HGPRT activity and typical LNS phenotype. Genetic analysis identified 24 HPRT mutations, nine of which had never previously been reported, and no mutation hotspots. Carrier females were identified by a new semiquantitative real-time PCR. Studies performed by real-time PCR on knockout mice demonstrated altered adenosinergic and serotonergic pathways, with greatly increased ADORA1A receptor expression, slightly decreased ADORA2A expression and unchanged ADORA2B expression. Increased HTRC2 expression with no significant difference in mRNA editing suggested serotonergic involvement. The different approaches used allowed us to study certain aspects of LND, focusing on mutation analysis in patients and carriers and on simultaneous analysis of biochemical and genetic features. Mouse models elucidated the possible involvement of adenosine and serotonine receptors in the neurotransmission aberration occurring in HGPRT deficiency.

Open access

Elena Manara, Andi Abeshi and Matteo Bertelli

Abstract

MAGI is concerned with research and diagnosis of rare genetic diseases. It has been operating since 2006 in Italy and abroad. Today it has three centers in Italy, including a medical genetics laboratory specialized in next generation sequencing in Bolzano, a medical genetics laboratory specialized in MLPA in Rovereto (Trento) and a genetic diseases information center at San Felice del Benaco (Brescia). MAGI has also invested outside Italy, setting up non-profit genetics laboratories in countries such as Albania, Russia and in the near future, Kazakhstan.

Open access

Andi Abeshi, Francesca Fanelli, Tommaso Beccari, Munis Dundar, Falsini Benedetto and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for gyrate atrophy of the choroid and retina (GACR). GACR is inherited in an autosomal recessive manner, and has a prevalence of 1/50000 in Finland. In the international literature there are approximately 200 biochemically confirmed cases. GACR is caused by mutations in the OAT gene. Clinical diagnosis involves ophthalmological examination, electrophysiological testing (electroretinography - ERG), coherence tomography and assay of ornithine levels in body fluids. The genetic test is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Andi Abeshi, Carla Marinelli, Tommaso Beccari, Munis Dundar, Lucia Ziccardi and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of the genetic test for Sorsby’s fundus dystrophy (SFD). SFD is caused by variations in the TIMP3 gene. Prevalence is, currently unknown. SFD has autosomal dominant inheritance. Clinical diagnosis is based on clinical findings, color vision testing, optical coherence tomography, ophthalmological examination and electroretinography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Andi Abeshi, Francesca Fanelli, Tommaso Beccari, Munis Dundar, Benedetto Falsini and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of the genetic test for central areolar choroidal dystrophy (CACD). CACD is mostly inherited in an autosomal dominant manner. Transmission is rarely autosomal recessive. Overall prevalence is currently 1-9 per 100 000. CACD is caused by mutations in the PRPH2 and GUCY2D genes. Clinical diagnosis is based on clinical findings, ophthalmological examination, fluorescein angiography, electroretinography (showing cone dystrophy) and stereo fundus photography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Yeltay Rakhmanov, Paolo Enrico Maltese, Stefano Paolacci, Francesca Fanelli, Tommaso Beccari, Munis Dundar and Matteo Bertelli

Abstract

Atrioventricular septal defect (AVSD) is a congenital heart defect characterized by a shared atrioventricular junction coexisting with deficient atrioventricular septation. The main morphological characteristic of AVSD is a common atrioventricular canal. The prevalence of AVSD is estimated at 0.31/1000 live births and is higher among subjects with PTPN11 mutations. ASD may have autosomal dominant or autosomal recessive inheritance. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Andi Abeshi, Alice Bruson, Tommaso Beccari, Munis Dundar, Fabiana D’Esposito and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for X-linked juvenile retinoschisis (XJR). The disease has X-linked inheritance, a prevalence that varies from one in 5000 to one in 25000 males, and is caused by mutations in the RS1 gene. Clinical diagnosis is based on clinical findings, ophthalmological examination, electroretinography and optical coherence tomography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Andi Abeshi, Alice Bruson, Tommaso Beccari, Munis Dundar, Leonardo Colombo and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Usher syndrome (USH). USH is mostly transmitted in an autosomal recessive manner and is caused by variations in the ADGRV1, CDH23, CIB2, CLRN1, HARS, MYO7A, PCDH15, PDZD7, USH1C, USH1G, USH2A, WHRN genes. Prevalence is estimated to be 1:30,000. Clinical diagnosis is based on audiogram, vestibular tests, visual acuity test, fundus examination, color test, optical coherence tomography and electroretinography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Andi Abeshi, Alessandra Zulian, Tommaso Beccari, Munis Dundar, Leonardo Colombo and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Senior- Loken syndrome (SLSN). SLSN is inherited in an autosomal recessive manner, has a prevalence of one in a million, and is caused by variations in CEP164, CEP290, INVS, IQCB1, NPHP1, NPHP3, NPHP4, SDCCAG8, TRAF3IP1 and WDR19 genes. Clinical diagnosis is based on kidney (urine analysis, abdominal ultrasound, kidney function) and eye assessment (visual acuity test, fundus examination, refraction defects, color testing and electroretinography). The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Open access

Andi Abeshi, Pamela Coppola, Tommaso Beccari, Munis Dundar, Leonardo Colombo and Matteo Bertelli

Abstract

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Mendelian myopia (MM), a large and heterogeneous group of inherited refraction disorders. Variations in the SLC39A5, SCO2 and COL2A1 genes have an autosomal dominant transmission, whereas those in the LRPAP1, P3H2, LRP2 and SLITRK6 genes have autosomal recessive transmission. The prevalence of MM is currently unknown. Clinical diagnosis is based on clinical findings, family history, ophthalmological examination and other tests depending on complications. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.