Download Garza Saúl, Mayén Dora, Ramírez Eva, Sosa David. Hospital

M YO PAT I C F E AT U R E S A N D AT Y P I C A L H Y S TO PAT H O L O G I C A L C H A N G E S I N A PAT I E N T W I T H
C . 1 1 8 9 9 _ 1 1 9 0 7 + 5 D E L I N T H E E X O M E 8 6 P L U S 5 N U C L E OT I D E S I N T H E A D J A C E N T I N T R O N I N C L U D I N G T H E
D O N O R S I T E O F S P L I C I N G I N RY R 1 G E N E
Garza Saúl, Mayén Dora, Ramírez Eva, Sosa David. Hospital Ángeles Lomas. [email protected]
INTRODUCTION
Centronuclear myopathies (CNM) are congenital muscle
diseases characterized by fibers with prominent
centralized nuclei in muscle biopsies. The disease is
clinically heterogeneous, ranging from severe neonatal
hypotonic phenotypes to adult-onset mild muscle
weakness, with multiple modes of inheritance and various
genes involved, including MTM1, DNM2, BIN1 and RYR1
(Jungblut et al, 2014) Clinically, RYR1-related CNM is of
intermediate
severity
with
facial
weakness,
ophthalmoplegia, predominantly
proximal
muscle
involvement but less bulbar respiratory impairment
(Wilmshurst et al., 2010). Patients with RYR1-related
CNM show a marked tendency to improve overtime,
even following an initially severe presentation (Bohm et
al., 2012). The present is an atypical clinical case with a
non-characteristic hystophatological biopsy and a
probable new mutation.
c.6067C>T
(p.Leu2023Phe)
RYR1 gene
c.11899_11907+5d
el RYR1 gene
c.6067C>T
(p.Leu2023Phe) /
c.11899_11907+5d
el RYR1 gene
Figure 2. Results of NGS, the mutations was confirmed by Sanger
CASE REPORT
A 5 year-old boy born from healthy parents attended at the Genetics Clinic with
muscular weakness and motor impairment since six months of age. In the family
history, a maternal first-degree aunt with Down syndrome, a maternal seconddegree aunt with muscular dystrophy and a paternal first-degree uncle of 40
years old who recently developed muscular weakness. At the physical
examination showed prominent ears with retroauricular fissures, permanent
opened mouth, thorax assimetry and scoliosis.
Multiple studies were performed to discard Fragile X, spinal muscular atrophy
and Pompe disease, MLPA for syndromes associated with motor impairment, all
of them were normal as well as a karyotype and a microarray study. Muscular
enzymes, electromyography and nerve conduction velocity test were normal.
The first muscular biopsy showed a myopatic pattern and the second one
distrophyc changes.
Figure 1. At 18 months, he showed myophatic face,
bilateral palpebral ptosis and permanent opened mouth.
The neurologic examination suggested a myopaty pattern, so we decided to
perform next generation sequencing (NextGeneDx®) of ACTA1, MYH7, RYR1,
SEPN1 and TPM3 genes. No abnormalities were seen in all genes except RYR1.
The patient is heterozigous for c.6067C>T (p.Leu2013Phe) and also for a
deletion of c.11899_11907+5del, no yet described in the literature.
Figure 3. At 18 moths and 5 years, he showed thorax
assymetry and scoliosis.
DISCUSSION
The c.6067C>T is a variant of unknown significance
probably benign, meanwhile the c.11899_11907+5del is
probably patogenic, since it includes a deletion in the
exome 86 plus 5 nucleotides in the adjacent intron
including the donor site of splicing. We suggested to the
parents the analysis of both changes on them in order
to established if those are inherited or de novo and if
they are localized in the same or different alleles.