Andrea Barp
When “Ulysses struggles to find his way home”: a genetic odyssey of a challenging case of congenital myopathy
Autori
- ANDREA BARP (CENTRO CLINICO NEMO TRENTO, OSPEDALE RIABILITATIVO VILLA ROSA, AZIENDA SANITARIA PER I SERVIZI SANITARI (APSS), PERGINE VALSUGANA (TRENTO) – NEUROLOGIA)
- ISABELLA MORONI (DIPARTIMENTO DI NEUROSCIENZE PEDIATRICHE, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, MILANO – NEUROLOGIA PEDIATRICA)
- MARCELLA NERI (UNITÀ DI GENETICA MEDICA, DIPARTIMENTO MATERNO INFANTILE, ARCISPEDALE SANT’ANNA, FERRARA – GENETICA MEDICA)
- FERNANDA FORTUNATO (UNITÀ DI GENETICA MEDICA, DIPARTIMENTO MATERNO INFANTILE, ARCISPEDALE SANT’ANNA, FERRARA – GENETICA MEDICA)
- ILARIA VIVALDI (UNITÀ DI GENETICA MEDICA, DIPARTIMENTO MATERNO INFANTILE, ARCISPEDALE SANT’ANNA, FERRARA – GENETICA MEDICA)
- RICCARDO ZUCCARINO (CENTRO CLINICO NEMO TRENTO, OSPEDALE RIABILITATIVO VILLA ROSA, AZIENDA SANITARIA PER I SERVIZI SANITARI (APSS), PERGINE VALSUGANA (TRENTO) – FISIATRIA)
- LORENZO MAGGI (SC NEUROLOGIA 4 – NEUROIMMUNOLOGIA E MALATTIE NEUROMUSCOLARI, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, MILANO – NEUROLOGIA)
- ELIANA IANNIBELLI (SC NEUROLOGIA 4 – NEUROIMMUNOLOGIA E MALATTIE NEUROMUSCOLARI, FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA, MILANO – NEUROLOGIA)
- MATTEO DE IORIO (TECNOMED SRL, CENTRI DIAGNOSTICI, VERONA – RADIOLOGIA)
- MARIA IASCONE (LABORATORIO DI GENETICA MEDICA, ASST PAPA GIOVANNI XXIII, BERGAMO – GENETICA MEDICA)
- SILVIA MAZZOLA (SERVIZIO DI GENETICA MEDICA, AZIENDA SANITARIA PER I SERVIZI SANITARI (APSS), TRENTO – GENETICA MEDICA)
- FRANCESCA GUALANDI (UNITÀ DI GENETICA MEDICA, DIPARTIMENTO MATERNO INFANTILE, ARCISPEDALE SANT’ANNA, FERRARA – GENETICA MEDICA)
Presentatore
ANDREA BARP (CENTRO CLINICO NEMO TRENTO, OSPEDALE RIABILITATIVO VILLA ROSA, AZIENDA SANITARIA PER I SERVIZI SANITARI (APSS), PERGINE VALSUGANA (TRENTO))
Modalità
Neuromuscular Club
Abstract
This is the case of a 22 years old female who was diagnosed at age of 4 years as affected by a “congenital myopathy”. Starting from the age of 2 years she exhibited muscle weakness with frequent falls, toe-walking, and difficulty climbing stairs. Current neurological examination shows waddling gait, marked and diffuse muscular atrophy, a symmetric decreased power (predominantly at proximal muscles), mild facial weakness, interphalangeal joint hyperlaxity and scoliosis. Muscle MRI revealed an involvement of quadriceps with sparing of rectus femoris, gracilis, adductors and semitendinosus.
Muscle biopsy (at age 4 years-old) revealed hypotrophy of type 1 fibers compared to type 2, suggesting a fiber-type disproportion.
She underwent two first genetic tests (karyotype and SMN1 analysis) that resulted negative.
Single gene testing for SEPN1, ACTA1, TPM2 and TPM3 did not revealed any variants.
An array-CGH was also performed, and it resulted normal.
Whole Exome Sequencing (WES) with analysis of 209 genes has been inconclusive: three heterozygous TTN variants of unknown significance (VUS – all inherited by the mother), a heterozygous COL6A2 VUS (inherited by the father), a heterozygous COL12A1 LB/VUS variant and a heterozygous MYBPC3 VUS (of unknown parental origin) have been identified.
A targeted analysis of the recurrent intronic COL6A2 pathogenic variants and MYH7 MLPA analysis were performed and all resulted normal.
The identification of the causative gene can prove to be an arduous journey, despite the in-depth molecular diagnostics and the manifest myopathic phenotype, requiring to explore the challenging field of the nonconding DNA (WGS, Whole Genome Sequencing).