6-8 November 2019
This year’s annual meeting was attended by approximately 100 people and was held in Ferrara, Italy.
Catteruccia M, D’Amico A, Bertini E
We present the clinical case of a baby who presented at birth with severe hypotonia and generalized muscle wakness, dysphagia and progressive respiratory insufficiency requiring tracheostomy and mechanichal ventilation at the age of 4 months.
At the age of 7 months she developed subacute hydocephalus requiring shunt. EMG/ENG and muscle biopsy showed neurogenic features. Muscle MRI showed corpus callosum dysgenesis. Mucle MRI showed almost complete fatty substitution of limb girlde and lower legs muscles. CGH array and molecular analysis for SMA and SMARD were negative.
The baby died at the age of 2 years for sepsis. Whole exome sequencing (WES) analysis showed a compound heterozygosity for the mutations c.1535+1G>A and c.3007G>A in ADCY6 gene. Mutations in adenylate cyclase 6 gene (ADCY6) have been reported so far only in one family with non-syndromic arthrogryposis multiplex congenita and lack of myelin in the peripheral nervous system.
Our report expands the clinical spectrum associated with the gene.
Presented by Davide Ognibene
We will describe novel and promising tools for the identification of rare/atypical DMD variants escaping characterization through standard (MLPA and NGS) analyses.
We will present a complex rearrangement (deletion of DMD 5’UTR associated with a duplication on X chromosome), identified with a custom DMD gene CGH array, in a patient with clinical diagnosis of dystrophinopathy confirmed by IIC on muscle biopsy and with no pathogenic mutations detected by MLPA/full sequencing. In a second uncharacterized DMD patient, transcriptional studies on Urine-derived stem cells (USCs), allowed us to identify a deep intronic splice site mutation, which determines the creation of two alternative exons both leading to premature stop codons.
USCs represent an extremely valuable, non-invasive, easy and low expensive source of cell that allows to spare consuming the precious muscle biopsy tissue that can be therefore preserved for other studies, where muscle expression profile is necessary for the research purposes and clinical trials outcome measures.
Presented by Fernanda Fortunato
A 7 year’s old boy, first child of Gipsy first cousins, presented at neonatal period a severe hypotonia, laryngeal stridor and feeding difficulties. First psychomotor developmental milestones were delayed.
In childhood he suffered from easy fatigability, inability to run and difficulty in climbing steps, difficulty in chewing and swallowing. Bilateral ptosis, hyperlaxity and a marked scoliosis were also observed.
Neurological examination at 4 years revealed: axial hypotonia, absent deep tendon reflexes, Babinski absent, an impaired deambulation, possible only with support.
CK levels were always only slightly increased (212 U/l in the newborn period, 195 at 6 years of age (with n.v. <170). EMG, ENG and EEG (4y) were reported normal but their interpretation was difficult due to the lack of cooperation of the patient. Muscle biopsy has never been performed. MRI (4y) revealed only a slight delay of myelination. SPECT was normal. Large metabolic screening moreover resulted negative.
Considering the clinical picture of the patient, several genetic analysis (a-CGH, molecular analysis of SMN1 gene, molecular analysis of Prader- Willi syndrome) were performed and resulted negative. Furthermore, taking into account the Gypsy ethnic origin of the patient, the 1267delG mutation in CHRNE gene was ruled out. Additionally, Next Generation Sequencing panels of genes related to congenital myasthenic syndromes and neuromuscular disorders were performed but no pathogenic mutations were identified.
Guido Primiano1, Rosalba Carrozzo2, Enrico Bertini2, Serenella Servidei1
1 Fondazione Policlinico Universitario A. Gemelli IRCCS and 2 Bambino Gesù Children’s Hospital, IRRCS, Roma, Italy
The topoisomerase III alpha (Top3a), as part of the BTRR complex, has a key role in the dissolution of double-Holliday junctions arising during homologous recombination. In 2018, TOP3A gene changes have been identified in the autosomal recessive MGRISCE2 (Microcephaly, Growth Restriction, and Increased Sister Chromatid Exchange 2) syndrome and mitochondrial DNA (mtDNA) depletion, and in one patient with late-onset progressive external ophthalmoplegia (PEOB5) and cerebellar ataxia. We report a novel pathogenic variant in TOP3A gene associated with adult-onset mitochondrial myo-cardiomyopathy.
The proband is a 55-year-old Italian woman who came to our observation at the age of 44 because of exercise intolerance associated with about 10-fold increase of serum CK levels. Her medical history comprises a premature menopause and a pacemaker implantation for a second-degree atrioventricular block. The patient was of short stature with narrow face and prominent nose due to a paucity of the facial subcutaneous fat. Echocardiography revealed a dilated cardiomyopathy. The muscle biopsy showed a mitochondrial myopathy associated with multiple mtDNA deletions. A Next generation sequencing-based diagnostic panel revealed a novel pathogenic homozygous variant in the TOP3A gene (c.247A>C; p.Thr83Pro).
Our findings expand the phenotypic spectrum of the newly-identified TOP3A-related disorders and suggest to include TOP3A analysis in patients with ascertained instability of muscle mtDNA.
Giulia Ricci1, Marco Savarese2, Rossella Tupler3, Vincenzo Nigro4 and Gabriele Siciliano1
1Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
2Department of Medical Genetics, Medicum, University of Helsinki, Finland
3Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
4Laboratory of Medical Genetics, Department of Precisin Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
We describe the case of a Caucasian female, 62 years old, firstly came to our attention at age of 55 years for diffuse myalgias, especially at scapular girdle level, and precocious fatigability in daily life activities. She reported a positive family history for sudden death (nephew). In anamnesis she was affected by Wolff Parkinson White syndrome. At the neurological examination a mild proximal weakness was observed (MRC 4/5). The blood CK was normal, but the EMG showed a myopathic pattern. However, the patient refused to perform muscle biopsy and MRI. Therefore, several genetic analyses were planned, including DNA test for FSHD and the patient resulted carrier of a D4Z4 4qA allele of 35 kb. Moreover, at NGS analysis some variants in TTN were also detected, including a nonsense mutation in A-band.
During 7 years follow up, the neurological picture has been substantially stable, but, more recently, she has developed an arrhythmogenic cardiomyopathy and, three months ago, she has been implanted with dual-chamber cardioverter defibrillator. Moreover, in these last months, her 45-years-old daughter firstly presented episodes of cardiac syncope and was subjected to the implantation of a loop-recorder. We will discuss the diagnostic issues of this case.
Molnar V, Balicza P, Molnar MJ
Institute of Genomic Medicine and Rare Disorders, Semmelweis University
We present a clinical case of a female patient with muscle dystrophy mimicking mucopolysaccharidosis. The female patient showed mild psychomotor delay. At age 1,5 year generalized febrile seizures presented. Later bilateral cataract, cholecystolithiasis and spine deformities developed during childhood. After age 20 years, slowly progressive proximal muscle weakness started.
At age 30 diabetes mellitus, secondary amenorrhea and osteoporosis was diagnosed. Besides these symptoms progressive, unusual pattern of fat tissue a hyperplasia (lipomatosis) was observed. From age 40 years hyperkinesias were detected in the limbs. Physical examination detected coarse facial appearance similar to MPS cases, with severe kyphoscoliosis. Severe muscle weakness was present predominantly in the proximal muscles of the limbs.
The family history was negative. CK was between 1000-2000 U/l, muscle biopsy unidentified substance accumulation intermyofibrillary. Electron microscopy detected accumulation of desmin like substance, but immunhistochemistry for desmin is negative. Lipid vacoules and mitochondrial paracristallin like inclusions, tubular aggregates. Brain MRI showed lacunar lesions. MPS were ruled out with genetic and enzyme studies. Whole exome sequencing detected a homozygous variant in the INPP5K gene, associating with MDCCAID. Our report draws attention on the similarities with MPS (coarse facial features, CNS involvement, accumulating substance in the tissues) and the usefulness of WES in the diagnostic of such peculiar neuromuscular cases.