INTRODUCTION :
Myoclonus-dystonia (M-D) is a hyperkinetic movement disorder defined as
a syndrome of sustained involuntary muscle contractions (myoclonus)
frequently causing repetitive twisting movements or abnormal postures
(dystonia) (Fahn et al., 1998). The myoclonic jerks typical of M-D most
often affect the neck, trunk, and upper limbs with less common
involvement of the legs. Approximately 50%
of affected individuals
have additional focal or segmental dystonia, presenting as cervical
dystonia and/or writer’scramp (Raymond et al, 2003). M-D is compatible
with an active life of normal span. Psychiatric disorders have been
reported to be associate with M-D, Obsessive-Compulsive Disorder (OCD),
anxiety-related disorder, depression and alcohol dependence. Most
affected adults report a dramatic reduction in myoclonus in response to
alcohol ingestion. Symptom onset is usually during the two first
decades: earlier (<1 year) or later (up to 40 years) (Raymond
et al., 2008).
Myoclonus-dystonia is transmitted in
an autosomal
dominant manner, and may occur sporadically. A
proband with
M-D may have inherited the disorder from a parent (50% chance of
inheriting the pathogenic variant) or have it as the result of
a de
novo pathogenic
variant. The SGCE gene is imprinted, with
incomplete penetrance,
which is dependent on the parental origin, and occurs only when
mutations affect the paternal copy of this gene. Thus, almost all
children who inherit an SGCE pathogenic variant from their father
develop symptoms, however close to 95% of children who inherit
an SGCE pathogenic variant from their mother do not (Grabowski et
al.,2002; Müller et al, 2002; Raymond et al., 2008). There are several
other human genes that are imprinted, including genes located on
chromosome 7, and many of them are involved in human diseases. Usually,
the mechanism of imprinting is a methylation of cytosine residues at the
promoter region that inactivates the gene. This mechanism has been
confirmed for the SGCE gene by showing a differential pattern of
methylation of the parental allele in patients with M-D (Grabowski et
al., 2002). In some of these patients a loss of imprinting with
subsequent biallelic expression of the SGCE gene has been demonstrated
(Müller et al., 2002).
The primary M-D locus identification has been done in a large North
American family in 1999 and was mapped on chromosome 7q21.3 (Nygaard et
al., 1999) and confirmed in other families (Klein et al., 2000; Asmus et
al., 2001; Vidailhet et al., 2001). The SGCE gene consists of 13 exons
(exon 1–11, 11b, 12) and encodes for a 438-amino acid protein with a
single transmembrane domain. The SGCE is a member of a gene family that
also includes α, β, δ, ε, and ξ sarcoglycans that constitute an
essential structure of dystrophin-associated glycoprotein complex in
striated muscle.
Mutations in the ε-sarcoglycan gene (SGCE , DYT11 locus, MIM
604149) represent the major genetic cause, but not the only one, other
loci are associated with the disease like DYT15 locus on chromosome
18p11 and in a proportion of patients no genetic alteration is found
(Grimes et al., 2002). Various mutations (>100) in theSGCE gene have been found to cause M-D, including nonsense,
missense, deletions and insertions (Asmus et al., 2001). Most of these
mutations lead to an abnormally short, non functional ε-sarcoglycan
protein that is quickly broken down (Esapa et al., 2007; Misbahuddin et
al, 2007). Other mutations prevent the protein from reaching the cell
membrane where it is needed. This lack of functional protein seems to
affect the regions of the brain involved in coordinating and controlling
movements and leads to the involuntary movement’s characteristic of
myoclonus-dystonia. It is unclear why SGCE gene mutations seem to
affect only these areas of the brain (Raymond, 2012).
The epidemiology of M-D is not well established. However, it is known
that M-D affects most, if not all, racial groups including Africans,
Europeans, Chinese, Indians, and Brazilians (Borge et al, 2007, Chen et
al, 2008). In Morocco, few studies have been conducted to exploreSGCE gene mutations responsible of Myoclonus-dystonia (M-D) but a
two different heterozygous SGCE mutations (c.769A>C)
and c.391-3 T> C) have been reported in a study including
12 patients with a sporadic M-D (Rachad et al, 2019). Here, we report
the first observation of a familial form of myoclonic dystonia, the case
of a Moroccan 17-year-old girl suffering from myoclonic dystonia, using
a new approach for medical genetics counselling in National Reference
Laboratory (LNR) based on Whole Exome Sequencing (CentoXome Gold®)
diagnostic strategy. Molecular explorations in neurogenetics using WES
have a positif impact on the patient and his family’s medical care
management, socio-professional adaptation and genetic counselling and
helps to the comprehension of the pathogenicity of mutations.