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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, 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

Andi Abeshi, Alice Bruson, 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 Bietti crystalline dystrophy (BCD). The disease has autosomal recessive inheritance, a prevalence of 1 per 67 000, and is caused by mutations in the CYP4V2 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, Carla Marinelli, 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 enhanced S-cone syndrome (ESCS). The disease has autosomal recessive inheritance, a prevalence of less than one per million, and is caused by mutations in the NR2E3 gene. Clinical diagnosis is based on clinical findings, ophthalmological examination, electroretinography, color vision testing 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, 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

Sandro Michelini, Mrco Cardone, Paolo Maltese, Alice Bruson, Alessandro Fiorentino and Matteo Bertelli

Abstract

Primary lymphedema can be familial (in which more than one member of the same family has a lymphedema phenotype), syndromic (in which lymphedema is one symptom of a complex clinical syndrome) or sporadic (in which an isolated family member has lymphedema). All types of lymphedema are determined by genetic alteration of one or more genes. Not all the genes involved are known.

Open access

Andi Abeshi, Francesca Fanelli, 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 Bardet- Biedl syndrome (BBS). The disease has autosomal recessive inheritance, a prevalence varying from one in 13 500 to one in 160 000, and is caused by mutations in the ARL6, BBIP1, BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, BBS10, BBS12, CEP290, IFT172, IFT27, LZTFL1, MKKS, MKS1, NPHP1, SDCCAG8, TRIM32, TTC8 and WDPCP genes. The clinical diagnosis of BBS is based on four primary features or three primary features plus two secondary features. 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, 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 cone rod dystrophies (CORDs). CORDs are caused by variations in the ABCA4, ADAM9, AIPL1, C8orf37, CACNA1F, CACNA2D4, CDHR1, CNGA3, CRX, DRAM2, GUCA1A, GUCY2D, HRG4, KCNV2, PDE6C, PITPNM3, POC1B, PROM1, PRPH2, RAB28, RAX2, RIMS1, RPGRIP1, RPGR SEMA4A, TTLL5 genes, with an overall prevalence of 1 per 40 000. Most genes have autosomal recessive inheritance; the others have autosomal dominant or X-linked recessive transmission. Clinical diagnosis is based on clinical findings, color vision testing, 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, Vincenza Precone, Tommaso Beccari, Munis Dundar, Benedetto Falsini and Matteo Bertelli

Abstract

Inherited eye diseases are a group of conditions with genetic and phenotypic heterogeneity. Advances in ocular genetic research have provided insights into the genetic basis of many eye diseases. Genetic and technological progress is improving the management and care of patients with inherited eye diseases. Diagnostic laboratories continue to develop strategies with high specificity and sensitivity that reduce the costs and time required for genetic testing. The introduction of next generation sequencing technologies has significantly advanced the identification of new gene candidates and has expanded the scope of genetic testing. Gene therapy offers an important opportunity to target causative genetic mutations. There are clinical trials of treatments involving vector-based eye gene therapies, and a significant number of loci and genes now have a role in the diagnosis and treatment of human eye diseases. Applied genetic technology heralds the development of individualized treatments, ushering ophthalmology into the field of personalized medicine. Many therapeutic strategies have demonstrated efficacy in preclinical studies and have entered the clinical trial phase. In this paper we review the topic of genetic testing in inherited eye diseases. We provide some background information about genetic counseling and genetic testing in ophthalmology and discuss how genetic testing can be helpful to patients and families with inherited eye diseases.