Gerarda Mastrogiorgio1,2, Marina Macchiaiolo3,4, Paola Sabrina Buonuomo3,4, Emanuele Bellacchio4, Matteo Bordi5, Davide Vecchio3,4, Kari Payne Brown6, Natalie Karen Watson6, Benedetta Contardi6, Francesco Cecconi5,7, Marco Tartaglia4, Andrea Bartuli3,4. 1. Rare Diseases and Medical Genetics Unit, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio, 4, 00165, Rome, Italy. gera.mastrogiorgio@gmail.com. 2. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. gera.mastrogiorgio@gmail.com. 3. Rare Diseases and Medical Genetics Unit, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio, 4, 00165, Rome, Italy. 4. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 5. Department of Biology, University of Rome Tor Vergata, Rome, Italy. 6. Parents of patients affected by Adenylosuccinate lyase deficiency, Patient's Association "Our Journey with ADSL deficiency", Rome, Italy. 7. Onco-Haematology and Cellular and Gene Therapy Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Abstract
BACKGROUND: Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype-phenotype correlations. RESULTS: Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense. CONCLUSIONS: The study adds more details on the spectrum of ADSLD patients' phenotypes and molecular data.
BACKGROUND: Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype-phenotype correlations. RESULTS: Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense. CONCLUSIONS: The study adds more details on the spectrum of ADSLD patients' phenotypes and molecular data.
Authors: Yaping Yang; Donna M Muzny; Fan Xia; Zhiyv Niu; Richard Person; Yan Ding; Patricia Ward; Alicia Braxton; Min Wang; Christian Buhay; Narayanan Veeraraghavan; Alicia Hawes; Theodore Chiang; Magalie Leduc; Joke Beuten; Jing Zhang; Weimin He; Jennifer Scull; Alecia Willis; Megan Landsverk; William J Craigen; Mir Reza Bekheirnia; Asbjorg Stray-Pedersen; Pengfei Liu; Shu Wen; Wendy Alcaraz; Hong Cui; Magdalena Walkiewicz; Jeffrey Reid; Matthew Bainbridge; Ankita Patel; Eric Boerwinkle; Arthur L Beaudet; James R Lupski; Sharon E Plon; Richard A Gibbs; Christine M Eng Journal: JAMA Date: 2014-11-12 Impact factor: 56.272
Authors: M Castro; C Pérez-Cerdá; B Merinero; M J García; J Bernar; A Gil Nagel; J Torres; M Bermúdez; P Garavito; S Marie; F Vincent; G Van den Berghe; M Ugarte Journal: Neuropediatrics Date: 2002-08 Impact factor: 1.947
Authors: Sue Richards; Nazneen Aziz; Sherri Bale; David Bick; Soma Das; Julie Gastier-Foster; Wayne W Grody; Madhuri Hegde; Elaine Lyon; Elaine Spector; Karl Voelkerding; Heidi L Rehm Journal: Genet Med Date: 2015-03-05 Impact factor: 8.822
Authors: Taraka R Donti; Gerarda Cappuccio; Leroy Hubert; Juanita Neira; Paldeep S Atwal; Marcus J Miller; Aaron L Cardon; V Reid Sutton; Brenda E Porter; Fiona M Baumer; Michael F Wangler; Qin Sun; Lisa T Emrick; Sarah H Elsea Journal: Mol Genet Metab Rep Date: 2016-07-27