Genetic Aspects of Myoclonus–Dystonia Syndrome (MDS)

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REVIEW

Genetic Aspects of Myoclonus – Dystonia Syndrome (MDS)

Laila Rachad¹_&Nadia El Kadmiri¹_&Ilham Slassi^1,2_&

Hicham El Otmani²&Sellama Nadifi¹

Received: 3 June 2015 / Accepted: 11 January 2016

#Springer Science+Business Media New York 2016

Abstract

Myoclonus–dystonia (M–D) is an autosomal- dominant movement disorder with onset in the first two decades of life. Mutations in the epsilon-sarcoglycan gene (SGCE, DYT11) on chromosome 7q21–q31 represent the major genetic cause of M

–

D in some populations. The syndrome was related with mutations in two other genes (DRD2 and DYT1). A second locus has been reported in one large M

–

D family (DYT15, 18p11), but no gene has been identified yet. In this review, we discuss genetic as- pects of myoclonus–dystonia.

Keywords

Myoclonus–dystonia . SGCE . DYT11 . DYT1 . DYT15

Introduction

Myoclonus

–

dystonia (M

–

D) is a rare movement disorder fea- tured by lightning-like myoclonic jerks and dystonic symp- toms [1]. It usually occurs in the first two decades of life [2].

The estimated prevalence of M

–

D in Europe is two out of 1, 000,000 [3,

4]. Myoclonus tends to be the predominant clin-

ical feature in the disease which characteristically involves the upper part of the body especially their proximal parts [2,

5].

Dystonia usually presents as cervical dystonia (also known as

torticollis) or writer’s cramp and occurs in more than 50 % of M

–

D patients [6]. Alcohol ingestion is reported to ameliorate the symptoms of the disease in most cases [7–12], and patients can show psychiatric abnormalities [13,

14]. To date, the path-

ophysiology of myoclonus

–

dystonia remains unclear [15].

Diagnostic Criteria

Mahloudji and Pikienly (1967) were the first to propose diag- nostic criteria for myoclonus

–

dystonia, which they called

“

he- reditary essential myoclonus” [16], and subsequently, these criteria have been updated [7,

10]. The following diagnostic

criteria have been slightly modified from Asmus and Gasser (2004):

Brief,

Blightning-like^

myoclonus as the primary feature, focal or segmental dystonia of subtle to marked severity may be also seen; rarely, dystonia is the only feature.

Autosomal-dominant inheritance with incomplete pene- trance and variable expressivity, but it may also occur in spo- radic patients.

Onset is usually in the first or second decade. Additional neurological features, such as cerebellar ataxia, spasticity, or dementia, are absent.

No structural abnormalities are found in cranial imaging;

there are no cortical events related to the muscle jerks and normal somatosensory evoked potentials.

Usually the condition follows a benign clinical course with no progression of symptoms and normal life expectancy [17].

DYT11 Locus and M–D

The DYT11 was the first M–D locus mapped on chromosome 7q21–q31 in a large family from North America [18] and confirmed in most families with M

–

D [19

–21]. The causative

* Nadia El Kadmiri elkadmiri1979@gmail.com

1 Laboratory of Medical Genetics and Molecular Pathology, Faculty of Medicine and Pharmacy Hassan II University of Casablanca, Casablanca, Morocco

2 Department of Neurology, IBN ROCHD Universitary Hospital, Casablanca, Morocco

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DOI 10.1007/s12035-016-9712-x

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gene within the DYT11 locus was determined and known as epsilon-sarcoglycan gene (SGCE) [22].

SGCE gene contains 13 exons resulting in three isoforms with 437, 451, and 462 amino acid long fragments depending on alternative splicing [23]. This gene encodes the epsilon- sarcoglycan protein. The sarcoglycans are transmembrane glycoproteins with six different isoforms

α,β,γ,δ,ε, andζ

[24]. In striated muscle, the heterotetrameric sarcoglycan com- plex, composed of

α-, β-, γ-, and δ-sarcoglycans, is an

important component of the dystrophin-associated glycopro- tein complex (DAGC). This complex mediates the structural stability of the plasma membrane and interactions between the extracellular matrix and the cytoskeleton [25]. Mutations in the genes encoding for this components (α-,

β-, γ-, and δ-sarcoglycans) are associated with limb–girdle muscular

dystrophy (LGMD), a heterogeneous group of inherited neu- romuscular disorders. The

ε-sarcoglycan has been identified

as a homologue to

α-sarcoglycan [24,25], and despite its

presence in skeletal muscle,

ε

-sarcoglycan is widely expressed in the body, such as in the brain, heart, and lung unlike to

α-sarcoglycan that is restricted to striated muscle.

Whether

ε

-sarcoglycan is associated with the other sarcoglycans in striated muscle is yet to be determined [26]

[27]. In the brain,

ε-sarcoglycan is found in the midbrain

monoaminergic neurons, in cerebellar Purkinje cells, and in other brain regions including the hippocampus and cortex [28], but the precise function of the SGCE protein in the brain has not been described yet [25]. In fact, mutations in

ε-sarcoglycan do not cause muscular dystrophy, but instead

are responsible for a hereditary form of myoclonus–dystonia, indicating its importance for brain function [29]. The patho- physiological relation of mutated

ε-sarcoglycan to the devel-

opment of the myoclonus–dystonia is not known [15].

Zimprich et al. [22] were the first to identify M

–

D-causing mutations in SGCE. However, mutations in SGCE gene are present in about 30–50 % of M–D cases [30]. More than 50 different mutations have been reported as causing myoclonus–

dystonia [4], and most of them lead to loss of function as a result of frameshift and protein truncation before the trans- membrane domain [4,

22,31]. Various mutations have been

described: nonsense, missense, deletions, and insertions [13].

The missense mutations produce proteins that are not traf- ficked to the plasma membrane but are retained intracellularly, ubiquitinated, and rapidly degraded by the proteasome [28].

In 2005, deletions of simple exons have been described in first two patients with M–D [32]. Exonic deletions are not readily detectable by conventional mutational screening (po- lymerase chain reaction and direct sequencing) which could explain at least part of the

Bmutation-negative^

cases [11].

Recently, exon deletions of the SGCE gene have been identi- fied in several M–D families as cause of myoclonus–dystonia.

The results of the study stress the importance of performing gene dosage analysis by multiple ligation-dependent probe

amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes [33].

Mutations in the SGCE gene are identified only in pa- tients with M–D; most are familial cases. The sporadic patients may have SGCE mutations; the absence of clinical history can be explained by the reduced penetrance of the gene [34]. This data suggests that sporadic cases should be screened for SGCE mutations when the phenotype is consistent with M–D. However, other studies suggest that

ε-sarcoglycan does

not play an important role in sporadic myoclonus–dystonia and supports genetic heterogeneity in familial cases [14,

35].

Myoclonus– dystonia is inherited in an autosomal- dominant manner with reduced penetrance due to the mecha- nism of maternal imprinting, i.e., most patients inherit the loss-of-function mutant allele from their father [36,

37].

In some reports, the syndrome was related to mutations in two other genes, dopamine D2 receptor (DRD2) (11q23) and DYT1 (9q34). However, in both cases, mutations were also found in the SGCE gene [14,

28,38,39].

Early-onset torsion dystonia is a severe form of hereditary, generalized dystonia, with most cases caused by 3-bp deletion in the DYT1 gene encoding torsinA (also known as TOR1A) with

∼30 % penetrance [40]. It was reported that there is an

association between both proteins, torsinA and SGCE, sug- gesting a role for torsinA in the recognition and processing of misfolded SGCE [13].

A recent study suggested that torsinA, which is encoded by the DYT1 gene binds

ε-sarcoglycan, promotes its degradation

and contributes to its quality control [40]; mice carrying mu- tations in both torsinA and SGCE have an earlier onset of the motor deficit compared with those that have just mutant SGCE or torsinA alone [40,

41].

However, the 3-bp deletion in the DYT1 gene is not in- volved in the pathogenesis of M–D [13].

In 2001, a 18-pb deletion in the DYT1 gene was found in a family with early-onset dystonia and myoclonic features [42].

In 2002, a missense mutation in the SGCE gene was identified in 2 sibs of this same family. The sibs had inherited the DYT1 deletion from their mother, who showed dystonic features, and the SGCE mutation from their father, who showed myoclonic features. The molecular mechanisms through which the de- tected mutations may contribute to myoclonus–dystonia re- main to be determined [39].

Grimes et al. [43] described a large Canadian family with

inherited myoclonus–dystonia, linkage analysis revealed a

novel locus on the chromosome 18p11. In this family, the

clinical features are totally in accordance with the M

–

D

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phenotype [43]. In 2004, two other families with M–D phe- notype were reported and showed possible linkage to this locus [14].

The locus was designated DYT15. The contribution of this locus to the genetic heterogeneity of M–D remains unclear since the gene has not been identified yet [44].

Conclusion

Myoclonus–dystonia is a genetically heterogeneous disorder.

Mutations in the SGCE represent the major genetic cause.

Many patients with DYT11 have been described in Caucasian population, only a few cases have been reported from other populations [43,

45,46], but the consequences of

the mutations on the

ε

-sarcoglycan protein have not been de- termined. More studies are needed to show how changes in SGCE protein function cause the M–D phenotype.

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