Prenatal diagnosis of congenital myopathies and muscular dystrophies

Clin Genet 2016: 90: 199 210 Printed in Singapore. All rights reserved Review 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12801 Prenatal diagnosis of congenital myopathies and muscular dystrophies Massalska D., Zimowski J.G., Bijok J., Kucińska-Chahwan A., Łusakowska A., Jakiel G., Roszkowski T. Prenatal diagnosis of congenital myopathies and muscular dystrophies. Clin Genet 2016: 90: 199 210. John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2016 Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. To date, curative care is not available for these diseases, which may severely affect both life-span and quality of life. We discuss prenatal diagnosis and genetic counseling for families at risk, as well as diagnostic possibilities in sporadic cases. Conflictofinterest Nothing to declare. D. Massalska a,j.g.zimowski b, J. Bijok a, A. Kucińska-Chahwan a, A. Łusakowska c, G. Jakiel a and T. Roszkowski a a Department of Obstetrics and Gynecology, Centre of Postgraduate Medical Education, Warsaw, Poland, b Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland, and c Department of Neurology, Medical University of Warsaw, Poland Key words: Duchenne and Becker muscular dystrophy Emery Dreifuss muscular dystrophy facioscapulohumeral muscular dystrophy limb-girdle muscular dystrophy myotonic dystrophy myotubular myopathy nemaline myopathy Corresponding author: Diana Massalska, Department of Obstetrics and Gynecology, Centre of Postgraduate Medical Education. Tel.: +48 534942524; fax: +48 225841160; e-mail: diana_massalska@wp.pl Received 2 March 2016, revised and accepted for publication 8 May 2016 Congenital myopathies and muscular dystrophies constitute a heterogeneous group of rare muscle diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. These diseases often represent a significant burden for affected individuals, their families and the public health care system (1). Congenital myopathies are caused by various genetic defects affecting the contractile apparatus of muscles. Symptoms include generalized weakness and hypotonia of variable severity manifesting from early childhood. In the most severe cases, respiratory insufficiency, severe hypotonia, bulbar dysfunction, and orthopedic complications are present at birth, and the prognosis is poor. Mortality during the first year of life exceeds 10% (2, 3). Muscular dystrophies are caused by genetic abnormalities primarily affecting the sarcolemmal membrane or its supporting structures, thus leading to pathological degeneration and regeneration of skeletal muscles characterized by progressive loss of skeletal muscle structure and function. Life-threatening cardiac and respiratory muscle involvement may occur (1, 4) (Table 1). Major advances in the identification of the genetic background of myopathies and muscular dystrophies have been reported recently (Tables 2 and 3). However, the determination of specific causes in individuals is demanding due to genetic heterogeneity, as well as variable phenotypic expression, even in members of the same family (1, 5). Although some promising therapies have been assessed in clinical trials, treatments primarily involve symptomatic management, rehabilitation, and prevention of complications (1). Given that these diseases 199

Massalska et al. Table 1. Characteristics of congenital myopathies and muscular dystrophies Congenital myopathies Muscular dystrophies Occurrence in the general population 0.7 4.4 per 100,000 (78, 79) 3.8 26.8 per 100,000 (80) Pathology Defects affecting the contractile apparatus of the muscles Defects affecting the sarcolemmal membrane or its supporting structures Mode of inheritance Variable Variable Main features Muscle weakness and hypotonia Muscle weakness and atrophy Manifestation Prenatal/at birth/early childhood Variable Creatine kinase level Normal/mildly elevated Elevated Clinical course Static/slowly progressive Progressive Prognosis Correlates well with the time and Depends on the subtype severity of presentation Importance of prenatal diagnosis Mostly in early onset cases Mostly in severe, progressive cases Prenatal features Rare Rare reported only for congenital muscular dystrophies and myotonic dystrophy may severely affect patient quality of life and life-span and that no curative care is available to date, genetic counseling and prenatal diagnosis should be offered to families at risk as a form of secondary prevention. As the clinical course of myopathies tends to be static or slowly progressive, the issue of prenatal diagnosis is important, especially in severe, early onset cases. In contrast, in progressive muscular dystrophies, prenatal diagnosis plays a crucial role also in cases with later onset. The aim of this article was to present the heterogeneity of the clinical features of congenital myopathies and muscular dystrophies and to discuss possible diagnostic approaches, especially in the prenatal period, based on a literature review and our experiences. Prenatal diagnosis for families at risk Prenatal diagnosis for families at risk is recommended in disease carriers and non-carrier parents of an affected child due to potential germ line mosaicism [Duchene/Becker muscular dystrophy (D/BMD) was detected in 2 out of 19 fetuses (10.5%) tested in our Genetics Department between 1992 and 2012 due to a risk of germ line mosaicism in a mother unpublished data] (6 9). Despite its availability, prenatal testing of families at risk for late-onset diseases resulting in relatively mild physical limitations is generally not reasonable. In familial X-linked diseases, molecular diagnosis includes sex identification and molecular testing in male fetuses, given that these diseases rarely produce symptoms in women, e.g. Turner s syndrome, monoparental disomy (the occurrence of two abnormal X chromosomes inherited from the carrier mother), translocation between X chromosome and an autosome with a break point affecting the pathogenic gene (10 12). Women are typically asymptomatic; therefore, prenatal testing for carrier status is controversial (13, 14). However, given the low percentage of at risk women assessed for carrier status before conception (only 41.4% of 169 women which underwent invasive prenatal testing for D/BMD in our Genetics Department between 1992 and 2012 unpublished data), carrier status testing in female fetuses should be offered (14). Targeted prenatal testing is possible only in cases with known familial mutations. When the mutation remains unknown, but the affected gene is identified, haplotyping enables the identification of disease-associated haplotype transmission to the fetus. The use of extragenic polymorphic markers may lead to a misdiagnosis due to recombination between the marker and the pathogenic gene, therefore, intragenic markers are preferred. Nevertheless, given the large size of the dystrophin gene and the high frequency of recombination (approximately 10%), the use of intragenic markers does not exclude the possibility of misdiagnosis and the use of several markers throughout the entire gene is recommended (15). The sampling methods for prenatal diagnosis include chorionic villus sampling performed after 11 gestational weeks, amniocentesis after 15 weeks or cordocentesis (16). Chorionic villus sampling is preferable as in case of potential pregnancy terminations, the earlier the procedure is performed, the lower the risk for the patient and the burden for the parents and medical staff (17) (Table 4). Invasive prenatal procedures are associated with an estimated 0.5 1% risk of pregnancy loss. In recent years, non-invasive testing of cell-free fetal DNA in maternal plasma has proven useful for sex identification (in X-linked diseases), as well as the identification of paternally inherited mutations or affected haplotypes, thus decreasing the number of invasive procedures (18 20). In familial cases with an unknown genetic background but specific histopathological changes in the muscles, fetal muscle biopsy may be useful (21). Moreover, in cases of complete merosinopathy, immunohistochemical assessment of the laminin α2 chain in trophoblasts was as reliable as targeted genetic testing (22). In Ullrich congenital muscular dystrophy (CMD), which is related to an unidentified mutation in the COL6A3 gene, haplotype analysis with collagen VI immunolabeling can be successfully performed on chorionic villi (23). Moreover, in myotonic dystrophy type 1 (DM1) the detection 200

Prenatal diagnosis of myopathies and muscular dystrophies Table 2. Genetic background of congenital myopathies Congenital myopathy Occurrence Inheritance Gene(s) Nemaline myopathy (NM) 0.2 per 100,000 live births (40) AD, AR, sporadic α-tropomyosin SLOW (TPM3) (81) Nebulin (NEB) (42) α-actin (ACTA1) (82) Troponin T SLOW (TNNT1) (83) β-tropomyosin (TPM2) (82) Cofilin 2 (CFL2) (84) Kelch repeat and BTB domain-containing protein 13 (KBTBD13) (85) Kelch-like family member 40 (KLHL40) (45) Kelch-like family member 41 (KLHL41) (86) Leiomodin-3 (LMOD3) (87) Myosin storage myopathy (MSM) Rare a AD, AR, sporadic β-cardiac myosin heavy chain (MYH7) (88, 89) Cap disease Rare a AD, AR, sporadic β-tropomyosin (TPM2) (81) α-tropomyosin SLOW (TPM3) (81) Nebulin (NEB) (90) α-actin (ACTA1) (91) Central core disease (CCD) Rare a AD, AR, sporadic Ryanodine receptor (RYR1) (2) Core-rod myopathy Rare a AD, AR Ryanodine receptor (RYR1) (92, 93) β-tropomyosin (TPM2) (81) Nebulin (NEB) (94) Multiminicore disease (MmD) Rare a AR Ryanodine receptor (RYR1) (95) Selenoprotein N (SEPN1) (96) Titin (TTN) (97) Myotubular myopathy (MTM) 2 per 100,000 male X-L Myotubularin (MTM1) (47) births (98) Centronuclear myopathy (CNM) Rare a AD, AR, sporadic Dynamin 2 (DNM2) (99) Amphiphysin 2 (BIN1) (100) Ryanodine receptor (RYR1) (101) Endothelin converting enzyme-like 1 (ECEL1) (37) Congenital fiber-type disproportion (CFTD) Rare a AD, AR, X-L α-actin (ACTA1) (102) α-tropomyosin SLOW (TPM3) (81) β-tropomyosin (TPM2) (81) Ryanodine receptor (RYR1) (103) Selenoprotein N (SEPN1) (104) AD, autosomal dominant; AR, autosomal recessive; X-L, X-linked recessive. a Occurrence not reported. of characteristic ribonuclear foci in trophoblastic cells via RNA fluorescence in situ hybridization (RNA-FISH) may be helpful, especially in case of somatic mosaicism or when the CTG expansion size exceeds the PCR amplification range (24). Furthermore, when the causative mutation is unknown, but prenatal onset was reported earlier in the family, serial sonographic assessments may help to detect disease in a fetus at risk (25). Prenatal diagnosis in sporadic cases In sporadic cases, even if severe abnormalities are detected on ultrasound, detailed genetic testing is typically restricted to the postpartum period. However, in rare cases caused by chromosomal translocations, routine G-banding karyotyping may prove useful (26). Targeted diagnosis in the prenatal setting comprises next-generation sequencing assays or array comparative genomic hybridization (acgh) panels for the detection of copy-number variations in neuromuscular disorders (27, 28). Karyotyping by acgh, and whole-exome or whole-genome sequencing enables rapid identification of causative genetic defects in the majority of cases, but the high costs and limited availability of these techniques remain an obstacle (7, 29, 30). Fetal-onset phenotypes are recognized for certain subtypes of congenital myopathies and muscular dystrophies. However, sonographic features are heterogeneous and non-specific, and prenatal diagnosis is rare. Noteworthy, only severe early fetal immobilization leads to evident fetal akinesia deformation sequence (FADS; Pena-Shokeir phenotype), including arthrogryposis multiplex congenita, pulmonary hypoplasia, craniofacial anomalies, intrauterine growth restriction (IUGR) and polyhydramnios. Thus, in the majority of cases, no visible abnormalities are noted in the prenatal period (31, 32). Nevertheless, sonographically identifiable 201

Massalska et al. Table 3. Genetic background of muscular dystrophies Muscular Occurrence Inheritance Gene(s) Congenital muscular dystrophy (CMD) Duchenne and Becker muscular dystrophy (D/BMD) Myotonic dystrophy (DM1/DM2) Facioscapulohumeral muscular dystrophy (FSHD) Emery Dreifuss muscular dystrophy (EDMD) Limb-girdle muscular dystrophy (LGMD) 0.6 3.8 per 100,000 (80) 1.0 7.7 and 0.1 3.8 per 100,000, respectively (80) 0.5 18.1 per 100,000 (80) 0.8 4.6 per 100,000 (80) 0.1 1.9 per 100,000 (80) 0.8 5.7 per 100,000 (80) AD, AR, Collagen 6α1 (COL6A1) (105) sporadic Collagen 6α2 (COL6A2) (105) Collagen 6α3 (COL6A3) (105) Fukutin (FKTN) (106) Fukutin-related protein (FKRP) (107) Protein O-linked-mannose β-1,2-n-acetylglucosaminyltransferase 1 (POMGnT1) (108) Protein-O-mannosyltransferase 1 (POMT1) (109) Protein-O-mannosyltransferase 2 (POMT2) (110) Like-glycosyltransferase (LARGE) (111) Selenoprotein N (SEPN1) (112) Isoprenoid synthase domain containing (ISPD) (113) Lamin A/C (LMNA) (70) Merosin (LAMA2) (114) Beta-1,3-galactosyltranferase (B3GALNT2) (115) GDP-mannose pyrophosphorylase B (GMPPB) (116) N-acetylglucosaminyltransferase 2 (GTDC2) (117) Transmembrane protein 5 (TMEM5) (115) Protein kinase-like protein SgK196 (SGK196) (118) β-1,3-n-acetylglucosaminyltransferase 1(B3GNT1) (119) Dystroglycan 1 (DAG1) (120) Transport protein particie complex 11 (TRAPPC11) (121) X-L, sporadic Dystrophin (DMD) (122) AD Myotonin-protein kinase (DMPK) (61) Zinc finger 9 (ZNF9) (123) AD, sporadic Double homeobox 4 (DUX4) (124) Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) (69) AD, AR, X-L, Lamin A/C (LMNA) (70) sporadic Four-and-a-half LIM domain (FHL1) (71) Emerin (EMD) (72) AD, AR Myotilin (TTID) (125) Lamin A/C (LMNA) (126) Caveolin 3 (CAV3) (127) DnaJ/Hsp40 homologue, subfamily B (DNAJB6) (128) Desmin (DES) (129) Transportin 3 (TNPO3) (130) Heterogeneous nuclear ribonucleoprotein D-like protein (HNRPDL) (131) Calpain 3 (CPN3) (132) Dysferlin (DYSF) (133) γ-sarcoglycan (SGCG) (134) α-sarcoglycan (SGCA) (135) β-sarcoglycan (SGCB) (136) δ-sarcoglycan (SGCD) (137) Telethonin (TCAP) (138) Tripartite motif containing 32 (TRIM32) (139) Fukutin-related protein (FKRP) (140) Titin (TTN) (141) Protein-O-mannosyltransferase 1 (POMT1) (104) Anoctamin 5 (ANO5) (142) Fukutin (FKTN) (143) Protein-O-mannosyltransferase 2 (POMT2) (144) 202

Prenatal diagnosis of myopathies and muscular dystrophies Table 3. Continued Muscular Occurrence Inheritance Gene(s) Oculopharyngeal muscular dystrophy (OPMD) 0.1 per 100,000 (80) AD, AR, sporadic Protein-O-linked-mannose β-1,2-n-acetylglucosaminyltransferase 1 (POMGnT1) (145) Dystroglycan (DAG1) (120) Plectin (PLEC1) (146) Transport protein particle complex 11 (TRAPPC11) (147) GDP-mannose pyrophosphorylase B (GMPPB) (116) Isoprenoid synthase domain containing (ISPD) (148) Alpha-1,4-glucosidase (GAA) (149) Lim and senescent cell antigen-like domains 2 (LIMS2) (150) Poly(A) binding protein nuclear 1 (PABPN1) (76, 77) AD, autosomal dominant; AR, autosomal recessive; X-L, X-linked recessive. Table 4. Prenatal diagnostic methods for congenital myopathies and muscular dystrophies Sampling methods Gestational age Tested material Diagnostic possibilities Invasive prenatal diagnosis Non-invasive prenatal diagnosis Chorionic villus sampling (CVS) a 11 14 weeks Chorionic villi Mutation testing (in families with known causative mutation) Goldstandardin familial cases Haplotyping (in families with identified affected gene) Amniocentesis >15 weeks Amniocytes Cordocentesis Typically >20 weeks Fetal blood lymphocytes Gene panels for exome sequencing or array comparative genomic hybridization (acgh) Whole-exome or whole-genome sequencing, whole-genome acgh (in sporadic cases with severe prenatal presentation) Muscle biopsy Maternal blood collection Reported since second trimester Typically fetal gluteal muscles >8 weeks Cell-free fetal DNA (cff-dna) in maternal blood Histopathological examination (in families with identified histopathological changes in the muscles) Sex identification (in X-linked diseases) Identification of paternally inherited mutations Identification of affected haplotypes a For chorionic villi, immunohistochemical assessment of the laminin α2 chain may also be performed for complete merosinopathy; collagen VI immunolabeling, for Ullrich congenital muscular dystrophy; and RNA-FISH, for the detection of characteristic ribonuclear foci in myotonic dystrophy type I. features (polyhydramnios, reduced fetal movements, talipes or positional limb abnormalities, tent mouth, and borderline ventriculomegaly) in conjunction with maternal grip myotonia should arouse suspicion for myotonic dystrophy (DM), and genetic testing should be considered (33 36). Although first-trimester diagnoses of myopathies and muscular dystrophies have been reported (37, 38), sonographic abnormalities frequently develop in the third trimester of pregnancy (at approximately 28 gestational weeks) (25, 39). The occurrence of early prenatal sonographic abnormalities indicates a more severe course of disease and an extremely poor prognosis (32), thus making prenatal detection is especially important to offer parents adequate genetic counseling and informed choices regarding the subsequent course of the pregnancy. Prenatal sonographic features of congenital myopathies and muscular dystrophies are presented in Tables 5 and 6. Congenital myopathies Severe prenatal onset has been reported for myotubular myopathy (MTM), severe forms of nemaline 203

Massalska et al. Table 5. Prenatal sonographic features of congenital myopathies Polyhydramnios Fetal akinesia/ hypokinesia Contractures Fractures Fetal growth restriction Increased nuchal translucency Others Nemaline myopathy (NM) (+) (+) (+) (+) (+) (+) Fetal hydrops Talipes (3, 42, 43, 45, 151 154) Cap disease (+) (+) (+) No visible stomach (155) Central core disease (CCD) (+) (+) (+) (+) Lung hypoplasia Short femurs Facial dysmorphism Cleft palate Clinodactyly of the second and fifth finger Breech presentation (2, 156) Core-rod myopathy (+) (+) (+) (45) Myotubular myopathy (MM) (+) (+) Macrocephaly Hydrocephaly Macrosomia (157, 158) Centronuclear (+) (+) (+) (37) myopathy (CNM) Congenital fiber-type disproportion (CFTD) (+) (+) Clubfoot (159) myopathy (NM) and myopathies caused by mutations in dynamin 2 (DNM2), ryanodine receptor (RYR1) or endothelin-converting enzyme-like 1 (ECEL1) genes, including core-rod myopathy, central core and multi-minicore diseases, centronuclear myopathy and congenital fiber-type disproportion. The sonographic features are similar for all types of congenital myopathies (Table 5). The most frequent prenatal manifestations reported by Colombo et al. in a study of 125 patients included reduced fetal movements (reported in 37.6% cases, n = 47), polyhydramnios (23.2%; n = 29) and talipes (8.8%; n = 11) (3). Nemaline myopathy Due to significant phenotypic variability, NM is classified into six groups according to symptom severity, including hypotonia; facial, neck and proximal limb muscle weakness; variable respiratory insufficiency and feeding problems (40, 41). The genetic background of NM is heterogeneous, but the most common recessive form is caused by mutations in the nebulin gene (NEB), which is primarily responsible for typical forms of the disease (42). However, cases of severe prenatal onset have been reported (42, 43). The most frequent cause of the congenital lethal form of NM (up to 50%) is de novo dominant mutations in the ACTA1 gene (44). In contrast to the phenotypic variability caused by NEB or ACTA1 mutations, KLHL40 mutations are always associated with a poor prognosis (average age of death is 5 months), and prenatal presentations have been documented in greater than 80% of cases (45). Seven other genetic loci and additional cases of NM not linked to any of the known loci have been identified, with variable clinical presentations (46). Myotubular myopathy MTM is a recessive X-linked disorder caused by a mutation in the myotubularin gene (MTM1). MTM constitutes a form of centronuclear myopathy with a severe male phenotype characterized by generalized weakness, hypotonia, external ophthalmoplegia and respiratory insufficiency at birth. Patient life expectancy is approximately 4 5 months; however, approximately 40% of boys achieve childhood (47). Approximately 80% of MTM cases are passed on to male offspring by an asymptomatic carrier mother (6). Due to a poor genotype phenotype correlation, providing prognostic information and genetic counseling for families at risk is challenging (47). Severe congenital myopathies related to dynamin 2 (DNM2), ryanodine receptor (RYR1) and endothelin-converting enzyme-like 1 (ECEL1) mutations: Different mutations in dynamin 2 (DNM2) and ryanodine receptor (RYR1) genes may result in variable histological subtypes of myopathy, including core-rod myopathy, central core and multi-minicore diseases, centronuclear myopathy and congenital fiber-type disproportion (5). Significant phenotypic variability in these myopathies has been shown, including cases with severe prenatal onset (2, 48, 49). Autosomal dominant mutations in the DNM2 gene cause centronuclear myopathy characterized by variable 204

Prenatal diagnosis of myopathies and muscular dystrophies Table 6. Prenatal sonographic features of muscular dystrophies Structural eye defects Others Lissencephaly type II Cerebellar malformations Hydrocephalus/ ventriculomegaly Fetal akinesia/ hypokinesia Contractures Polyhydramnios Fukuyama CMD (+) (+) (+) Cerebral cortical dysplasia (53, 160) Congenital muscular dystrophy (CMD) (+) (+) (+) (+) (161, 162) Muscle eye brain disease (+) (+) (+) (+) Macrocephaly Occipital encephalocele Cleft lip (38, 163 168) Walker Warburg syndrome (+) (+) (+) (+) Tent mouth Hydrops fetalis Talipes Breech presentation (32 36, 169) Myotonic dystrophy type 1 (MD1) phenotypic expression (weakness, external ophthalmoplegia and ptosis) (50). The severe phenotype is the characteristic of autosomal recessive mutations in the RYR1 gene, which are associated with heterogeneous histological and clinical manifestations, including weakness, generalized hypotonia, congenital hip dysplasia, multiple contractures, ophthalmoplegia, ptosis and respiratory involvement. De novo dominant RYR1 mutations with severe, prenatal onset have also been reported (2, 48). Moreover, severe prenatal presentations may occur in centronuclear myopathy caused by recessive missense mutations in the endothelin-converting enzyme-like 1 gene (ECEL1) (37). Muscular dystrophies Severe prenatal onset has been reported in CMDs (including sonographically detectable ocular and central nervous system abnormalities in dystroglycanopathies) andindm(table6). Congenital muscular dystrophy CMDs are a group of rare dystrophies with the onset at birth or during infancy. Three main categories of CMDs are noted: collagenopathies (i.e. Ullrich CMD, Bethlem myopathy), merosinopathies and dystroglycanopathies (i.e. Fukuyama CMD, muscle eye brain disease, Walker Warburg syndrome) (7). The phenotypes are variable, but the cardinal clinical features include progressive skeletal muscle weakness and hypotonia. Due to central nervous system involvement, greater than 50% of patients have moderate to severe cognitive impairment. Collagenopathies are characterized by distal joint hyperlaxity and contractures. White matter abnormalities are the characteristic of merosinopathy. In dystroglycanopathy, muscle weakness is often associated with structural eye defects and cortical brain abnormalities, including lissencephaly type II, polymicrogyria, white matter lesions, midbrain and pontocerebellar hypoplasia, subcortical cerebellar cysts, hydrocephalus or occipital encephalocele (7, 51, 52). The genetic background of CMDs is very heterogeneous. The majority of CMDs are autosomal recessive, but autosomal dominant inheritance was also reported with possible direct inheritance, de novo mutations or germ line mosaicism. Despite the availability of genetic testing for all genes associated with CMD, the clinical detection rate ranges between 20% and 46%, which may indicate that not all causative genes are known (7). However, for some entities, the detection rate achieves 100%, especially in the endemic regions (e.g. for Fukuyama CMD in Japan) (53, 54). Duchenne and Becker muscular dystrophy D/BMDs are allelic recessive X-linked disorders caused by a broad range of mutations in the dystrophin gene (DMD), which lead to a progressive, relentless, symmetrical degeneration of the muscles (55). Males affected 205

Massalska et al. with DMD lose the ability to walk independently before the age of 13, and their life expectancy is approximately 25 years due to progressive respiratory and cardiac failure. The BMD phenotype is less severe and more variable, ranging from nearly asymptomatic cases to patients in whom immobilization occurs around the age of 16 (56). Theoretically 2 / 3 of the mutations in a dystrophin gene are familial inherited from a carrier mother (57). The carrier frequency depends on the form of the disease and is statistically more frequent in BMD than in DMD (89.5% vs 57.6%; p < 0.05). Regarding DMD, the carrier frequency also depends on the type of pathogenic mutation (58). Myotonic dystrophy Two types of DM with different genetic backgrounds have been reported: DM1 and DM2. Both conditions are autosomal dominant. The symptoms of DM2 are less prominent, and no cases with prenatal or childhood onset have been reported (1, 59). The clinical presentation of DM1 is highly variable. The most severe congenital form presents at birth as generalized muscle hypotonia leading to respiratory failure and feeding difficulties. In these cases, mortality reaches 50% in the neonatal period, and the survivors present delayed motor development and mental retardation. At an older age, patients develop myotonia, progressive muscle weakness, cataracts, endocrinopathies (hyperinsulinism, hypothyroidism, and testicular atrophy), gastrointestinal motility impairment and cardiac disorders (32 34, 60). DM1 is caused by the expansion of a trinucleotide (CTG) repeat sequence in the non-coding region of the myotonin-protein kinase gene (DMPK) on chromosome 19 (61). The normal number of repeats ranges between 4 and 37. Alleles with greater than 55 repeats are associated with the disease, and the number of repeats correlates positively with the severity of symptoms and negatively with the age of onset (62). Expansion frequently occurs during parent-to-child transmission, thus explaining anticipation (the more severe course of the disease in successive generations). Extreme amplification, which causes the congenital form of DM1, occurs almost exclusively by maternal inheritance and may be passed on even by an asymptomatic mother, in whom the diagnosis of the disease is established only after the birth of an affected child (32, 60). Facioscapulohumeral muscular dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is a familial autosomal dominant muscle disorder. Clinical symptoms include progressive and often asymmetrical muscle weakness of the facial, shoulder and upper arm muscles. Trunk, pelvic girdle and leg muscle involvement is also possible. De novo mutations are detected in approximately 10% of affected individuals (63). Clinical symptoms include progressive, asymmetrical muscle weakness affecting the facial and proximal lower limbs muscles, the shoulder muscles and the pelvic girdle muscles. Phenotypic presentation ranges from asymptomatic gene carriers to early wheelchair dependency with mental retardation and epilepsy (64). The reported prevalence of asymptomatic carriers ranges between 3% and 50% (65 67). In approximately 95% of cases, FSHD is caused by a contraction of the D4Z4 repeats on 4q35 (1 10 D4Z4 repeats in FSHD patients compared with 11 150 in normal individuals) (68). An inverted correlation between repeat numbers and age-corrected clinical severity scores is observed, with significantly increased repeat number variability in females, as well as possible atypical phenotypes (64). Moreover, SMCHD1 mutations cause FSHD2 and influence the severity of symptoms in FSHD1 (69). Given the difficulties in providing an accurate clinical prognosis, especially in asymptomatic gene carriers, genetic counseling is demanding. Prenatal diagnosis is justified when at least one severely affected individual is present in the family (9). Emery Dreifuss muscular dystrophy Emery Dreifuss muscular dystrophy (EDMD) is a progressive muscle disorder with a triad of characteristic symptoms, including early childhood joint contractures, progressive muscle weakness and cardiac involvement, which can result in sudden death. Remarkable inter- and intrafamilial variability of phenotypes has been noted, ranging from early, severe presentations in childhood to slow progressive onset in adulthood. However, most affected individuals develop symptoms in the second decade of life (70, 71). EDMD may be inherited in an X-linked (EMD and FHL1 mutations) or autosomal dominant or recessive manner (LMNA mutations). Most of the dominant LMNA mutations are de novo (70 72). Limb-girdle muscular dystrophy Limb-girdle muscular dystrophy (LGMD) is a highly heterogenous group of muscle disorders characterized by progressive weakness of the proximal limb muscles. Other muscles may also be affected, including the heart and respiratory muscles. The phenotypic spectrum is broad, ranging from minimal symptoms to severe, early onset weakness greatly affecting quality of life and life-span. There are several types of LGMD-exhibiting autosomal dominant (LGMD1) and autosomal recessive (LGMD2) modes of inheritance, as well as heterogenous genetic backgrounds. Thus, molecular testing and genetic counseling are highly demanding. However, remarkably, autosomal recessive cases generally exhibit earlier onset and more rapid progression (73). Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy (OPMD) is either an autosomal dominant or an autosomal recessive 206

Prenatal diagnosis of myopathies and muscular dystrophies late-onset neuromuscular disorder. De novo cases are rare (74). Symptoms, including progressive ptosis, dysphagia, and proximal muscle weakness, typically develop in the fifth or sixth decade of life (75). The disease is caused by abnormal expansion of the GCG or GCA trinucleotides (coding alanine) in the polyalanine-binding protein nuclear 1 gene (PABPN1) (76, 77). Prenatal diagnosis is generally not reasonable. Conclusions Congenital myopathies and muscular dystrophies are rare muscle diseases with great genetic and phenotypic variability. In familial cases, identification of genetic background is crucial for reliable counseling and prenatal diagnosis. Sporadic cases constitute always significant diagnostic challenges. References 1. Cardamone M, Darras BT, Ryan MM. Inherited myopathies and muscular dystrophies. Semin Neurol 2008: 28: 250 259. 2. Romero NB, Monnier N, Viollet L et al. 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