Prenatal diagnosis of congenital myopathies and muscular dystrophies

Size: px
Start display at page:

Download "Prenatal diagnosis of congenital myopathies and muscular dystrophies"

Transcription

1 Clin Genet 2016: 90: Printed in Singapore. All rights reserved Review 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: /cge 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: 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.: ; fax: ; 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

2 Massalska et al. Table 1. Characteristics of congenital myopathies and muscular dystrophies Congenital myopathies Muscular dystrophies Occurrence in the general population per 100,000 (78, 79) 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

3 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

4 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) per 100,000 (80) and per 100,000, respectively (80) per 100,000 (80) per 100,000 (80) per 100,000 (80) 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

5 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 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

6 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, ) 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

7 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, ) 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

8 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 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

9 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: Romero NB, Monnier N, Viollet L et al. Dominant and recessive central core disease associated with RYR1 mutations and fetal akinesia. Brain 2003: 126: Colombo I, Scoto M, Manzur AY et al. Congenital myopathies. Natural history of a large pediatric cohort. Neurology 2015: 84: Verhaert D, Richards K, Rafael-Fortney JA, Raman SV. Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations. Circ Cardiovasc Imaging 2011: 4 (1): North KN, Wang CH, Clarke N et al. Approach to the diagnosis of congenital myopathies. Neuromuscul Disord 2014: 24 (2): Laporte J, BiancalanaV, Tanner SM et al. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat 2000: 15: Kang PB, Morrison L, Iannaccone ST et al. Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular and Electrodiagnostic Medicine. Neurology 2015: 84 (13): Grimm T, Kress W, Meng G, Muller CR. Risk assessment and genetic counseling in families with Duchenne muscular dystrophy. Acta Myol 2012: 31 (3): Galluzzi G, Deidda G, Cacurri S et al. Molecular analysis of 4q35 rearrangements in facioscapulohumeral muscular dystrophy (FSHD): application to family studiem for a correct genetic advice and a reliable prenatal diagnosis of the disease. Neuromuscul Disord 1999: 9 (3): Satre V, Monnier N, Devillard F, Amblard F, Lunardi J. Prenatal diagnosis of DMD in a female fetus affected by Turner syndrome. Prenat Diagn 2004: 24 (11): Quan F, Janas J, Toth Fejel S, Johnson DB, Wolford JK, Popovich BV. Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy. Am J Hum Genet 1997: 60: Trippe H, Wieczorek S, Kotting J, Kress W, Schara U. Xp21/A translocation: a rarely considered genetic cause for manifesting carriers of Duchenne muscular dystrophy. Neuropediatrics 2014: 45 (5): Abbs S, Tuffery Giraud S, Bakker E, Ferlini A, Sejersen T, Mueller CR. Best Practice Guidelines on molecular diagnostics in Duchenne/Becker muscular dystrophies. Neuromuscul Disord 2010: 20: Helderman van den Enden AT, Madan K, Breuning MH et al. An urgent need for a change in policy revealed by a study on prenatal testing for Duchenne muscular dystrophy. Eur J Hum Genet 2013: 21 (1): Kim UK, Chae JJ, Lee SH, Lee CC, Namkoong Y. Molecular diagnosis of Duchenne/Becker muscular dystrophy by polymerase chain reaction and microsatellite analysis. Mol Cells 2002: 13 (3): Royal College of Obstetricians and Gynaecologists. Amniocentesis and chorionic villus sampling. RCOG, Kent A. Second trimester termination of pregnancy. Rev Obstet Gynecol 2011: 4 (2): Miura K, Higashijima A, Shimada T et al. Clinical application of fetal sex determination using cell-free fetal DNA in pregnant carriers of X-linked genetic disorders. J Hum Genet 2011: 56 (4): van den Oever JM, Minderhout IJ, Harteveld CL et al. A novel targeted approach for noninvasive detection of paternally inherited mutations in maternal plasma. J Mol Diagn 2015: 17 (5): Zeevi DA, Altarescu G, Weinberg-Shukron A et al. Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutations. J Clin Invest 2015: 125 (10): Kasperski SB, Brennan AM, Corteville JE et al. Utility of fetal muscle biopsy for diagnosis of nemaline myopathy. Fetal Diagn Ther 2008: 24 (4): Vainzof M, Richard P, Herrmann R et al. Prenatal diagnosis in laminie α2 chain (merosin)-deficient congenital muscular dystrophy: a collective experience of five international centers. Neuromuscul Disord 2005: 15 (9 10): Brockington M, Brown SC, Lampe A et al. Prenatal diagnosis of Ullrich congenital muscular dystrophy using haplotype analysis and collagen VI immunocytochemistry. Prenat Diagn 2004: 24 (6): Bonifazi E, Gullotta F, Vallo L et al. Use of RNA fluorescence in situ hybridization in the prenatal molecular diagnosis of myotonic dystrophy type I. Clin Chem 2006: 2 (52): Donker M, Eijckelhof BH, Tan GM, de Vries JI. Serial postural and motor assessment of fetal akinesia deformation sequence (FADS). Early Hum Dev 2009: 85 (12): Karadeniz N, Zenciroglu A, Gurer YK, Senbil N, Karadeniz Y, Topalolu H. De novo translocation t(5;6)(q35;q21) in an infant with Walker-Warburg syndrome. Am J Med Genet 2002: 109 (1): Evila A, Arumilli M, Udd B, Hackman P. Targeted next-generation sequencing assay for detection of mutations in primary myopathies. Neuromuscul Disord 2016: 26: Piluso G, Dionisi M, Del Vecchio BF et al. Motor chip: a comparative genomic hybridization microarray for copy-number mutations in 245 neuromuscular disorders. Clin Chem 2011: 57 (11): Nguyen K, Putoux A, Busa T et al. Incidental findings on array comparative genomic hybridization: detection of carrier females of dystrophinopathy without any family history. Clin Genet 2015: 87: Todd EJ, Yau KS, Ong R et al. Next generation sequencing in a large kohort of patients presenting with neuromuscular disease before or at birth. Orphanet J Rare Dis 2015: 10: Hall JG. Arthrogryposis (multiple congenital contractures): diagnostic approach to etiology, classification, genetics, and general principles. Eur J Med Genet 2014: 57 (8): Zaki M, Boyd PA, Impey L, Roberts A, Chamberlain P. Congenital myotonic dystrophy: prenatal ultrasound findings and pregnancy outcome. Ultrasound Obstet Gynecol 2007: 29: Esplin MS, Hallam S, Farrington PF, Nelson L, Byrne J, Ward K. Myotonic dystrophy is a significant cause of idiopathic polyhydramnios. Am J Obstet Gynecol 1998: 179 (4): Mashiach R, Rimon E, Achiron R. Tent mouth as a presenting symptom of congenital myotonic dystrophy. Ultrasound Obstet Gynecol 2002: 20: Rudnik-Schoneborn S, Zerres K. Outcome in pregnancies complicated by myotonic dystrophy: a study of 31 patients and review of the literature. Eur J Obstet Gynecol Reprod Biol 2004: 114: Dufour P, Berard J, Vinatier D et al. Myotonic dystrophy and pregnancy. A report of two cases and review of the literature. Eur J Obstet Gynecol Reprod Biol 1997: 72 (2): Dohrn N, Le VQ, Petersen A et al. ECEL1 mutation causes fetal arthrogryposis multiplex congenita. Am J Med Genet A 2015: 167A (4): Blin G, Rabbe A, Ansquer Y, Meghdiche S, Floch-Tudal C, Mandelbrot L. First-trimester ultrasound diagnosis in a recurrent case of Walker-Warburg syndrome. Ultrasound Obstet Gynecol 2005: 26 (3): Mulder EJ, Nikkels PG, Visser GH. Fetal akinesia deformation sequence: behavioural development in a case of congenital myopathy. Ultrasound Obstet Gynecol 2001: 18 (3):

10 Massalska et al. 40. Wallgren-Pettersson C, Laing NG. Report of the 70th ENMC International Workshop: nemaline myopathy, June 1999, Naarden, The Netherlands. Neuromuscul Disord 2000: 10: Ilkovski B, Cooper ST, Nowak K et al. Nemaline myopathy caused by mutations in the muscle alpha-skeletal action gene. Am J Hum Genet 2001: 68 (6): Lehtokari VL, Kiiski K, Sandaradura SA et al. Mutation update: the spectra of nebulin variants and associated myopathies. Hum Mutat 2014: 35 (12): Yonath H, Reznik-Wolf H, Berkenstadt M et al. Carrier state for the nebulin exon 55 deletion and abnormal prenatal ultrasound findings as potential signs of nemaline myopathy. Prenat Diagn 2012: 32 (1): Agrawal PB, Strickland CD, Midgett C et al. Heterogeneity of nemaline myopathy cases with skeletal muscle α-actin gene mutations. Ann Neurol 2004: 56 (1): Ravenscroft G, Miyatake S, Lehtokari VL et al. Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. Am J Hum Genet 2013: 93 (1): Nowak KJ, Davis MR, Wallgren-Pettersson C, Lamont PJ, Laing NG. Clinical utility gene card for: nemaline myopathy update Eur J Hum Genet 2015: 23:e1 e Longo G, Russo S, Novelli G, Sangiuolo F, D Apice MR. Mutation spectrum of the MTM1 gene in XLMTM patients: 10 years of experience in prenatal and postnatal diagnosis. Clin Genet 2016: 89 (1): Hernandez-Lain A, Husson I, Monnier N et al. De novo RYR1 heterozygous mutation (14898 T) causing lethal core-rod myopathy in twins. Eur J Med Genet 2011: 54 (1): Hanisch F, Muller T, Dietz A et al. Phenotype variability and histopathological findings in centronuclear myopathy due to DNM2 mutations. J Neurol 2011: 258 (6): Romero NB. Centronuclear myopathies: a widening concept. Neuromuscul Disord 2010: 20 (4): Bonnemann CG, Wang CH, Quijano-Roy S et al. Diagnostic approach to the congenital muscular dystrophies. Neuromuscul Disord 2014: 24 (4): Bertini E, D Amico A, Gualandi F, Petrini S. Congenital muscular dystrophies: a brief review. Semin Pediatr Neurol 2011: 18 (4): Saito K. Prenatal diagnosis of Fukuyama congenital muscular dystrophy. Prenat Diagn 2006: 26 (5): Kato R, Kawamura J, Sugawara H, Niikawa N, Matsumoto N. A rapid diagnostic method for a retrotransposal insertional mutation into the FCMD gene in Japanese patients with Fukuyama congenital muscular dystrophy. Am J Med Genet 2004: 127A (1): Ferlini A, Neri M, Gualandi F. The medical genetics of dystrophinopathies: molecular genetic diagnosis and its impact on clinical practice. Neuromuscul Disord 2013: 23 (1): Tuffery-Giraud S, Beroud C, Leturcq F et al. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationalwide knowledgebase. Hum Mutat 2009: 30 (6): Haldane JBS. The rate of spontaneous mutation of a human gene. J Genet 1935: 31 (3): Lee T, Takeshima Y, Kusunoki N et al. Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients. J Hum Genet 2014: 59 (1): Heatwole C, Johnson N, Bode R et al. Patient-reported impact of symptoms in myotonic dystrophy type 2 (PRISM-2). Neurology 2015: 85 (24): Martorell L, Cobo AM, Baiget M, Naudo M, Poza JJ, Parra J. Prenatal diagnosis in myotonic dystrophy type 1. Thirteen years of experience: implications for reproductive counselling in DM1 families. Prenat Diagn 2007: 27 (1): Brook JD, McCurrach ME, Harley HG et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3 end of a transcript encoding a protein kinase family member. Cell 1992: 68 (4): Barcelo JM, Mahadevan MS, Tsilfidis C, MacKenzie AE, Korneluk RG. Intergenerational stability of the myotonic dystrophy protomutation. Hum Mol Genet 1993: 2 (6): Lunt PW, Harper PS. Genetic counseling in facioscapulohumeral muscular dystrophy. J Med Genet 1991: 28 (10): Lin F, Wang ZQ, Lin MT, Murong SX, Wang N. New insights into genotype-phenotype correlations in Chinese facioscapulohumeral muscular dystrophy: a retrospective analysis of 178 patients. Chin Med J (Engl) 2015: 128 (13): Sakellariou P, Kekou K, Fryssira H et al. Mutation spectrum and phenotypic manifestation in FSHD Greek patients. Neuromuscul Disord 2012: 22 (4): Tonini MM, Passos-Bueno MR, Cerqueira A, Matioli SR, Pavanello R, Zatz M. Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord 2004: 14 (1): Goto K, Nishino I, Hayashi YK. Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A. J Med Genet 2004: 41 (1): e van Deutekom JC, Wijmenga C, van Tienhoven EA et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 1993: 2 (12): Larsen M, Rost S, El Hajj N et al. Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. Eur J Hum Genet 2015: 23 (6): Tan D, Yang H, Yuan Y et al. Phenotype-genotype analysis of Chinese patients with early-onset LMNA-related muscular dystrophy. PLoS One 2015: 10 (6): e Sarkozy A, Windpassinger C, Hudson J et al. Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene. Eur J Hum Genet 2011: 19 (10): Brown CA, Scharner J, Felice K et al. Novel and recurrent EMD mutations in patients with Emery-Dreifuss muscular dystrophy, identify exon 2 as a mutation hot spot. J Hum Genet 2011: 56 (8): Nigro V, Savarese M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol 2014: 33 (1): Tremolizzo L, Galbussera A, Tagliabue E et al. An apparently sporadic case of oculopharyngeal muscular dystrophy: the first Italian report. Neurol Sci 2007: 28 (6): Nadaj-Pakleza A, Richard P, Lusakowska A et al. Oculopharyngeal muscular dystrophy: phenotypic and genetic characteristics of 9 Polish patients. Neurol Neurochir Pol 2009: 43 (2): Robinson DO, Hammans SR, Read SP, Sillibourne J. Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum Genet 2005: 116 (4): Garibaldi M, Pennisi EM, Bruttini M et al. Dropped-head in recessive oculopharyngeal muscular dystrophy. Neuromuscul Disord 2015: 25 (11): Darin N, Tulinius M. Neuromuscular disorders in childhood: a descriptive epidemiological study from western Sweden. Neuromuscul Disord 2000: 10 (1): Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain 2009: 132: Theadom A, Rodrigues M, Roxburgh R et al. Prevalence of muscular dystrophies: a systematic literature review. Neuroepidemiology 2014: 43 (3 4): Marttila M, Lehtokavi VL, Marston S et al. Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies. Hum Mutat 2014: 35 (7): Ryan MM, Schnell C, Strickland CD et al. Nemaline myopathy: a clinical study of 143 cases. Ann Neurol 2001: 50 (3): Johnston JJ, Kelley RI, Crawford TO et al. A novel nemaline myopathy in the Amish caused by a mutation troponin T1. Am J Hum Genet 2000: 67 (4): Gommans IM, Davis M, Saar K et al. A locus on chromosome 15q for a dominantly inherited nemaline myopathy with core-like lesions. Brain 2003: 126: Sambuughin N, Yau KS, Olive M et al. Dominant mutations in KBTBD13, a member of the BTB/Kelch family, cause nemaline myopathy with cores. Am J Hum Genet 2010: 87 (6): Gupta VA, Ravenscroft G, Shaheen R et al. Identification of KLHL41 mutations implicates BTB-Kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy. Am J Hum Genet 2013: 93:

11 Prenatal diagnosis of myopathies and muscular dystrophies 87. Yuen M, Sandaradura SA, Dowling JJ et al. Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest 2014: 124 (11): Tajsharghi H, Thornell LE, Lindberg C, Lindvall B, Henriksson KG, Oldfors A. Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol 2003: 54 (4): Tajsharghi H, Oldfors A, Macleod DP, Swash M. Homozygous mutation in MYH7 in myosin storage myopathy and cardiomyopathy. Neurology 2007: 68 (12): Piteau SJ, Rossiter JP, Smith RG, MacKenzie JJ. Congenital myopathy with cap-like structures and nemaline rods: case report and literature review. Pediatr Neurol 2014: 51 (2): Hung RM, Yoon G, Hawkins CE, Halliday W, Biggar D, Vajsar J. Cap myopathy caused by a mutation of the skeletal alpha-actin gene ACTA1. Neuromuscul Disord 2010: 20 (4): Scacheri PC, Hoffman EP, Fratkin JD et al. A novel ryanodine receptor gene mutation causing both cores and rods in congenital myopathy. Neurology 2000: 55 (11): Monnier N, Romero NB, Lerale J et al. An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor. Hum Mol Genet 2000: 9 (18): Romero NB, Lehtokavi V, Quijano-Roy S et al. Core-rod myopathy caused by mutations in the nebulin gene. Neurology 2009: 73 (14): Jungbluth H, Muller CR, Halliger-Keller B et al. Autosomal recessive inheritance of RYR1 mutations in a congenital myopathy with cores. Neurology 2002: 59 (2): Ferreiro A, Quijano-Roy S, Pichereau C et al. Mutations of the selenoprotein N gene, which is implicated in rigid spine muscular dystrophy, cause the classical phenotype of multiminicore disease: reassessing the nosology of early-onset myopathies. Am J Hum Genet 2002: 71 (4): Carmignac V, Salih MA, Quijano-Roy S et al. C-terminal titin deletions cause a novel early-onset myopathy with fetal cardiomyopathy. Ann Neurol 2007: 61 (4): Jungbluth H, Wallgren-Pettersson C, Laporte J. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis 2008: 3: Bitoun M, Bevilacqua JA, Prudhon B et al. Dynamin 2 mutations cause a sporadic centronuclear myopathy with neonatal onset. Ann Neurol 2007: 62 (6): Nicot AS, Toussaint A, Tosch V et al. Mutations in amphiphysin 2(BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet 2007: 39 (9): Wilmshurst JM, Lillis S, Zhou H et al. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol 2010: 68 (5): Laing NG, Clarke NF, Dye D et al. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol 2004: 56 (5): Clarke NF, Waddell LB, Cooper ST et al. Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion. Hum Mutat 2010: 31 (7): E1544 E Clarke NF, Kidson W, Quijano-Roy S et al. SEPN1 associated with congenital fibre type disproportion and insulin resistance. Ann Neurol 2006: 59 (3): Butterfield RJ, Foley AR, Dastgir J et al. Position of glycine substitutions in the triple helix of COL6A1, COL6A2,andCOL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies. Hum Mutat 2013: 34 (11): Yis U, Uyanik G, Heck PB et al. Fukutin mutations in non-japanese patients with congenital muscular dystrophy: less severe mutations predominate in patients with a non-walker-warburg phenotype. Neuromuscul Disord 2011: 21 (1): MacLeod H, Pytel P, Wollmann R et al. A novel FKRP mutation in congenital muscular dystrophy disrupts the dystrophin glycoprotein complex. Neuromuscul Disord 2007: 17 (4): Saredi S, Ardissone A, Ruggieri A et al. Novel POMGnT1 point mutations and intragenic rearrangements associated with muscle-eye-brain disease. J Neurol Sci 2012: 318 (1 2): Balci B, Uyanik G, Dincer P et al. An autosomal recessive limb girdle muscular dystrophy (LGMD2) with mild mental retardation is allelic to Walker-Warburg syndrome (WWS) caused by a mutation in the POMT1 gene. Neuromuscul Disord 2005: 15 (4): van Reeuwijk J, Janssen M, van den Elzen C et al. POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet 2005: 42 (12): Meilleur KG, Zukosky K, Medne L et al. Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations. J Neuropathol Exp Neurol 2014: 73 (5): Moghadaszadeh B, Petit N, Jaillard C et al. Mutations in SEPN1 cause congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Nat Genet 2001: 29 (1): Vuillaumier-Barrot S, Bouchet-Seraphin C, Chelbi M et al. Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly. Am J Hum Genet 2012: 91 (6): Xiong H, Tan D, Wang S et al. Genotype/phenotype analysis in Chinese laminin-α2 deficient congenital muscular dystrophy patients. Clin Genet 2015: 87 (3): Stevens E, Carss KJ, Cirak S et al. Mutations in B3GALT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. Am J Hum Genet 2013: 92 (3): Carss KJ, Stevens E, Foley AR et al. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girgle muscular dystrophies associated with hypoglycosylation of α-dystroclycan. Am J Hum Genet 2013: 93 (1): Manzini MC, Tambunan DE, Hill RS et al. Exome sequencing and functional validation in zebrafish identify CTDC2 mutations as a cause of Walker-Warburg syndrome. Am J Hum Genet 2012: 91 (3): Jae LT, Raaben M, Riemersma M et al. Deciphering the glycosylome of dystroglycanopathies using haploid screens for lassa virus entry. Science 2013: 340 (6131): Buysse K, Riemersma M, Powell G et al. Missense mutations in β-1,3-n-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker-Warburg syndrome. Hum Mol Genet 2013: 22 (9): Hara Y, Balci-Hayta B, Yoshida-Moriguchi T et al. A dystroglycan mutation associated with limb-girgle muscular dystrophy. N Engl J Med 2011: 364 (10): Liang WC, Zhu W, Mitsuhashi S et al. Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype. Skelet Muscle 2015: 5: Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987: 51 (6): Raheem O, Olufemi S-E, Bachinski LL et al. Mutant (CCTG)n expansion causes abnormal expression of zinc finger 9 (ZNF9) in myotonic dystrophy type 2. Am J Pathol 2010: 177 (6): Hewitt JE, Lyle R, Clark LN et al. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet 1994: 3 (8): Reilich P, Krause S, Schramm N et al. A novel mutation in myotylin gene (MYOT) causes a severe form of limb girgle muscular dystrophy 1A (LGMD1A). J Neurol 2011: 258 (8): Muchir A, Bonne G, van der Kooi AJ et al. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girgle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000: 9 (9): Gazzerro E, Bonetto A, Minetti C. Caveolinopathies: translational implications of caveolin-3 in skeletal and cardiac muscle disorders. Handb Clin Neurol 2011: 101: Sarparanta J, Jonson PH, Golzio C et al. Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girgle muscular dystrophy. Nat Genet 2012: 44 (4): Cetin N, Balci-Hayta B, Gundesli H et al. A novel desmin mutation leading to autosomal recessive limb-girgle muscular dytrophy distinct histopathological outcomes compared with desminopathies. J Med Genet 2013: 50 (7): Torella A, Fanin M, Mutarelli M et al. Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. PLoS One 2013: 8 (5): e Vieira NM, Naslavsky MS, Licinio L et al. A defect in the RNA-processing protein HNRPDL causes limb-girgle muscular dystrophy 1G (LGMD1G). Hum Mol Genet 2014: 23 (15): Ramos E, Pardo S, Mas Rodriguez MF, Velez J. Limb-girgle muscular dystrophy type 2A resulting from c. C479G and c. G1818A mutations in the calpain-3 gene. J Clin Neuromuscul Dis 2015: 17 (2): Nguyen K, Bassez G, Krahn M et al. Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes. Arch Neurol 2007: 64 (8):

A rare case of muscular dystrophy with POMT2 and FKRP gene mutation. Present by : Ghasem Khazaei Supervisor :Dr Mina Mohammadi Sarband

A rare case of muscular dystrophy with POMT2 and FKRP gene mutation. Present by : Ghasem Khazaei Supervisor :Dr Mina Mohammadi Sarband A rare case of muscular dystrophy with POMT2 and FKRP gene mutation Present by : Ghasem Khazaei Supervisor :Dr Mina Mohammadi Sarband Index : Congenital muscular dystrophy (CMD) Dystroglycanopathies Walker-Warburg

More information

MP Genetic Testing for Limb-Girdle Muscular Dystrophies

MP Genetic Testing for Limb-Girdle Muscular Dystrophies BCBSA Ref. Policy: 2.04.132 Last Review: 04/30/2018 Effective Date: 04/30/2018 Section: Medicine Related Policies 2.04.86 Genetic Testing for Duchenne and Becker Muscular Dystrophy 2.04.105 Genetic Testing

More information

Genetic Testing for Limb-Girdle Muscular Dystrophies

Genetic Testing for Limb-Girdle Muscular Dystrophies Applies to all products administered or underwritten by Blue Cross and Blue Shield of Louisiana and its subsidiary, HMO Louisiana, Inc.(collectively referred to as the Company ), unless otherwise provided

More information

Dysferlinopathies. LGMD2B, Miyoshi & Others. 2B Empowered Conference

Dysferlinopathies. LGMD2B, Miyoshi & Others. 2B Empowered Conference Dysferlinopathies LGMD2B, Miyoshi & Others 2B Empowered Conference Matthew P. Wicklund, MD, FAAN Professor of Neurology and Pediatrics Penn State Health May 24, 2015 Outline A. Empower you with knowledge

More information

Limb Girdle Muscular Dystrophy

Limb Girdle Muscular Dystrophy Limb Girdle Muscular Dystrophy Reza Shervin Badv MD, Pediatric Neurologist Children s Medical Center Pediatrics Center of Excellence Tehran University of Medical Sciences Limb-girdle muscular dystrophies(lgmd)

More information

Corporate Medical Policy

Corporate Medical Policy Corporate Medical Policy File Name: Origination: Last CAP Review: Next CAP Review: Last Review: mutation_testing_for_limb_girdle_muscular_dystrophies 01/01/2019 N/A 01/01/2020 01/01/2019 Description of

More information

Iowa Wellstone Center Muscle Tissue and Cell Culture Repository

Iowa Wellstone Center Muscle Tissue and Cell Culture Repository Iowa Wellstone Center Muscle Tissue and Cell Culture Repository Steven A. Moore, M.D., Ph.D. The University of Iowa Department of Pathology and Iowa Wellstone Muscular Dystrophy Cooperative Research Center

More information

Muscular Dystrophies. Pinki Munot Consultant Paediatric Neurologist Great Ormond Street Hospital Practical Neurology Study days April 2018

Muscular Dystrophies. Pinki Munot Consultant Paediatric Neurologist Great Ormond Street Hospital Practical Neurology Study days April 2018 Muscular Dystrophies Pinki Munot Consultant Paediatric Neurologist Great Ormond Street Hospital Practical Neurology Study days April 2018 Definition and classification Clinical guide to recognize muscular

More information

Genetic diagnosis of limb girdle muscular dystrophy type 2A, A Case Report

Genetic diagnosis of limb girdle muscular dystrophy type 2A, A Case Report Genetic diagnosis of limb girdle muscular dystrophy type 2A, A Case Report Roshanak Jazayeri, MD, PhD Assistant Professor of Medical Genetics Faculty of Medicine, Alborz University of Medical Sciences

More information

Genetic Testing for Muscular Dystrophies

Genetic Testing for Muscular Dystrophies MEDICAL POLICY 12.04.86 Genetic Testing for Muscular Dystrophies BCBSA Ref. Policies: 2.04.86*, 2.04.105*, 2.04.132* Effective Date: June 1, 2018 RELATED MEDICAL POLICIES: Last Revised: May 3, 2018 None

More information

Test Information Sheet

Test Information Sheet Neuromuscular Disorders (NMD) Panel Sequence Analysis and Exon-Level Deletion/Duplication* Testing of 80 Genes Panel Gene List: ACTA1, ANO5, ATP2A1, B3GALNT2, B3GNT1*, BAG3, BIN1, BICD2, CACNA1S, CAPN3,

More information

Next Generation Sequencing Panel for Congenital Myopathies

Next Generation Sequencing Panel for Congenital Myopathies Next Generation Sequencing Panel for Congenital Myopathies Congenital myopathies are typically characterized by the presence of specific structural and histochemical features on muscle biopsy and clinical

More information

Test Information Sheet

Test Information Sheet Prenatal Lissencephaly Panel Sequence Analysis and Exon-Level Deletion/Duplication Testing* of 24 Genes Panel Gene List: ACTB, ACTG1, X, ATP6V0A2, B3GALNT2*, B4GAT1*, DCX, FKRP*, FKTN, GMPPB*, ISPD, LAMB1,

More information

Corporate Medical Policy

Corporate Medical Policy Corporate Medical Policy Invasive Prenatal (Fetal) Diagnostic Testing File Name: Origination: Last CAP Review: Next CAP Review: Last Review: invasive_prenatal_(fetal)_diagnostic_testing 12/2014 3/2018

More information

Clinical and pathologic aspects of congenital myopathies

Clinical and pathologic aspects of congenital myopathies Neurol J Southeast Asia 2001; 6 : 99 106 88 Clinical and pathologic aspects of congenital myopathies Ikuya NONAKA MD National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Abstract The term

More information

Statutory Approvals Committee minutes

Statutory Approvals Committee minutes Statutory Approvals Committee minutes Centre 0102 (Guys Hospital) Pre-implantation Genetic Diagnosis (PGD) application for Muscular Dystrophy, Congenital, LMNA-related, (MDCL) OMIM #613205 Thursday, 25

More information

Limb-girdle Muscular Dystrophy with New Mutation in Sarcoglycan Beta Gene: A Case Report

Limb-girdle Muscular Dystrophy with New Mutation in Sarcoglycan Beta Gene: A Case Report Iran J Public Health, Vol. 47, No.12, Dec 2018, pp.1953-1957 Case Report Limb-girdle Muscular Dystrophy with New Mutation in Sarcoglycan Beta Gene: A Case Report Eskandar TAGHIZADEH 1,2, Hamed ABDOLKARIMI

More information

Next Generation Sequencing Panel for Neuromuscular Disorders

Next Generation Sequencing Panel for Neuromuscular Disorders Next Generation Sequencing Panel for Neuromuscular Disorders Clinical Features: Neuromuscular disorders (NMD) are a clinically and genetically diverse group of conditions affecting the peripheral nervous

More information

CUGC for Nemaline myopathy Article pg Abstract pg. 14

CUGC for Nemaline myopathy Article pg Abstract pg. 14 CUGC for Nemaline myopathy Article pg. 2-14 Abstract pg. 14 Clinical utility gene card for: Nemaline myopathy Kristen J Nowak 1*, Mark R Davis 2*, Carina Wallgren-Pettersson 3, Phillipa J Lamont 2 and

More information

CURRENT GENETIC TESTING TOOLS IN NEONATAL MEDICINE. Dr. Bahar Naghavi

CURRENT GENETIC TESTING TOOLS IN NEONATAL MEDICINE. Dr. Bahar Naghavi 2 CURRENT GENETIC TESTING TOOLS IN NEONATAL MEDICINE Dr. Bahar Naghavi Assistant professor of Basic Science Department, Shahid Beheshti University of Medical Sciences, Tehran,Iran 3 Introduction Over 4000

More information

Clinical utility gene card for: Nemaline myopathy - update 2015

Clinical utility gene card for: Nemaline myopathy - update 2015 (2015) 23, doi:10.1038/ejhg.2015.12 & 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15 www.nature.com/ejhg CLINICAL UTILITY GENE CARD UPDATE Clinical utility gene card for: Nemaline myopathy

More information

CONTENT ANATOMIC LOCI OF NM DISEASE ASSOCIATED FEATURES FUNCTIONAL DIFFICULTIES. CLINICAL HISTORY IN NEUROMUSCULAR DISEASES Weakness 06/11/60

CONTENT ANATOMIC LOCI OF NM DISEASE ASSOCIATED FEATURES FUNCTIONAL DIFFICULTIES. CLINICAL HISTORY IN NEUROMUSCULAR DISEASES Weakness 06/11/60 CONTENT HOW TO APPROACH LIMB GIRDLE AND NON-LIMB GIRDLE WEAKNESS Kongkiat Kulkantrakorn, M.D. Professor Thammasat University Clinical approach in NM disease and phenotype Common and uncommon LGMDs Common

More information

Tel: , Fax: ,

Tel: , Fax: , 1 Nemaline Myopathy Type 2 (NEM2): Two Novel Mutations in the Nebulin (NEB) Gene Anna Gajda MD 1*, Emese Horváth MD 2*, Tibor Hortobágyi MD, PhD 3, Gyurgyinka Gergev MA 1,4, Hajnalka Szabó MD, PhD 1, Katalin

More information

Introduction. Overview

Introduction. Overview Congenital muscular dystrophies Emma Clement MD ( Dr. Clement of Great Ormond Street Children's Hospital has no relevant financial relationships to disclose. ) Heinz Jungbluth MD PhD ( Dr. Jungbluth of

More information

We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists. International authors and editors

We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists. International authors and editors We are IntechOpen, the world s leading publisher of Open Access books Built by scientists, for scientists 4,000 116,000 120M Open access books available International authors and editors Downloads Our

More information

Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients

Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients (2014) 59, 46 50 & 2014 The Japan Society of Human Genetics All rights reserved 1434-5161/14 www.nature.com/jhg OPEN ORIGINAL ARTICLE Differences in carrier frequency between mothers of Duchenne and Becker

More information

Neonatal Hypotonia Guideline Prepared by Dan Birnbaum MD August 27, 2012

Neonatal Hypotonia Guideline Prepared by Dan Birnbaum MD August 27, 2012 Neonatal Hypotonia Guideline Prepared by Dan Birnbaum MD August 27, 2012 Hypotonia: reduced tension or resistance to range of motion Localization can be central (brain), peripheral (spinal cord, nerve,

More information

Muscular Dystrophy. Biol 405 Molecular Medicine

Muscular Dystrophy. Biol 405 Molecular Medicine Muscular Dystrophy Biol 405 Molecular Medicine Duchenne muscular dystrophy Duchenne muscular dystrophy is a neuromuscular disease that occurs in ~ 1/3,500 male births. The disease causes developmental

More information

Immunohistochemical Study of Dystrophin Associated Glycoproteins in Limb-girdle Muscular Dystrophies

Immunohistochemical Study of Dystrophin Associated Glycoproteins in Limb-girdle Muscular Dystrophies Dystrophin Immunohistochemical Study of Dystrophin Associated Glycoproteins in Limb-girdle Muscular Dystrophies NSC 89-2314-B-002-111 88 8 1 89 7 31 ( Peroxidase -AntiPeroxidase Immnofluorescence) Abstract

More information

Seminar. Muscular dystrophies

Seminar. Muscular dystrophies Muscular dystrophies Eugenio Mercuri, Francesco Muntoni Muscular dystrophies are a heterogeneous group of inherited disorders that share similar clinical features and dystrophic changes on muscle biopsy.

More information

Nemaline (rod) myopathies

Nemaline (rod) myopathies Nemaline (rod) myopathies Nemaline, or rod, myopathies are a group of conditions which fall under the umbrella of congenital myopathies. They are characterised by rod-like structures in the muscle cells,

More information

The Floppy Baby. Clare Betteridge

The Floppy Baby. Clare Betteridge The Floppy Baby Clare Betteridge The floppy baby Identification Evaluation Investigation Diagnosis Examples What is a floppy baby? Elbows and knees loosely extended. Head control is usually poor or absent.

More information

READ ORPHA.NET WEBSITE ABOUT BETA-SARCOGLYOCANOPATHY LIMB-GIRDLE MUSCULAR DYSTROPHIES

READ ORPHA.NET WEBSITE ABOUT BETA-SARCOGLYOCANOPATHY LIMB-GIRDLE MUSCULAR DYSTROPHIES READ ORPHA.NET WEBSITE ABOUT BETA-SARCOGLYOCANOPATHY LIMB-GIRDLE MUSCULAR DYSTROPHIES (LGMD) Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined disorders with a

More information

Corporate Medical Policy

Corporate Medical Policy Corporate Medical Policy Genetic Testing for Duchenne and Becker Muscular Dystrophy File Name: Origination: Last CAP Review: Next CAP Review: Last Review: genetic_testing_for_duchenne_and_becker_muscular_dystrophy

More information

Neonatal Hypotonia. Encephalopathy acute No encephalopathy. Neurology Chapter of IAP

Neonatal Hypotonia. Encephalopathy acute No encephalopathy. Neurology Chapter of IAP The floppy infant assumes a frog legged position. On ventral suspension, the baby can not maintain limb posture against gravity and assumes the position of a rag doll. Encephalopathy acute No encephalopathy

More information

Single Gene (Monogenic) Disorders. Mendelian Inheritance: Definitions. Mendelian Inheritance: Definitions

Single Gene (Monogenic) Disorders. Mendelian Inheritance: Definitions. Mendelian Inheritance: Definitions Single Gene (Monogenic) Disorders Mendelian Inheritance: Definitions A genetic locus is a specific position or location on a chromosome. Frequently, locus is used to refer to a specific gene. Alleles are

More information

Congenital myopathies: clinical phenotypes and new diagnostic tools

Congenital myopathies: clinical phenotypes and new diagnostic tools Cassandrini et al. Italian Journal of Pediatrics (2017) 43:101 DOI 10.1186/s13052-017-0419-z REVIEW Congenital myopathies: clinical phenotypes and new diagnostic tools Open Access Denise Cassandrini 1,

More information

A novel POMT2 mutation causes mild congenital muscular dystrophy with normal brain MRI

A novel POMT2 mutation causes mild congenital muscular dystrophy with normal brain MRI Brain & Development 31 (2009) 465 468 Case report A novel POMT2 mutation causes mild congenital muscular dystrophy with normal brain MRI Terumi Murakami a,b, Yukiko K. Hayashi a, *, Megumu Ogawa a, Satoru

More information

Familial DilatedCardiomyopathy Georgios K Efthimiadis, MD

Familial DilatedCardiomyopathy Georgios K Efthimiadis, MD Familial DilatedCardiomyopathy Georgios K Efthimiadis, MD Dilated Cardiomyopathy Dilated LV/RV, reduced EF, in the absence of CAD valvulopathy pericardial disease Prevalence:40/100.000 persons Natural

More information

Evaluation of the Hypotonic Infant and Child

Evaluation of the Hypotonic Infant and Child Evaluation of the Hypotonic Infant and Child Basil T. Darras, M.D. Neuromuscular Program Boston Children s Hospital Harvard Medical School Boston, MA, USA Classification and General Clinical Evaluation

More information

Cardiac Considerations and Care in Children with Neuromuscular Disorders

Cardiac Considerations and Care in Children with Neuromuscular Disorders Cardiac Considerations and Care in Children with Neuromuscular Disorders - importance of early and ongoing treatment, management and available able medications. Dr Bo Remenyi Department of Cardiology The

More information

Next-generation sequencing-based molecular diagnosis of neonatal hypotonia in Chinese

Next-generation sequencing-based molecular diagnosis of neonatal hypotonia in Chinese Title page Next-generation sequencing-based molecular diagnosis of neonatal hypotonia in Chinese Population Yan Wang 1, #,Wei peng 1,#, Hong-Yan Guo 3,4, Hui Li 3,4, Jie Tian 3,4, Yu-Jing Shi 3,4, Xiao

More information

Association of motor milestones and SMN2 copy and outcome in spinal muscular. atrophy types 0 4

Association of motor milestones and SMN2 copy and outcome in spinal muscular. atrophy types 0 4 jnnp-2016-314292 1 - SUPPLEMENTARY FILE - Methods and additional data on clinical characteristics and motor development Association of motor milestones and SMN2 copy and outcome in spinal muscular atrophy

More information

Enterprise Interest Nothing to declare

Enterprise Interest Nothing to declare Enterprise Interest Nothing to declare A rare cause of myopathy in adults Jorge Pinheiro MD, José Manuel Lopes MD, PhD Joint Slide Seminar Electron Microscopy and Trainees: Understanding diseases through

More information

Muscle Diseases: The Muscular Dystrophies

Muscle Diseases: The Muscular Dystrophies Annu. Rev. Pathol. Mech. Dis. 2007. 2:87 109 The Annual Review of Pathology: Mechanisms of Disease is online at pathmechdis.annualreviews.org This article s doi: 10.1146/annurev.pathol.2.010506.091936

More information

Publications List. 1. General factsheets. 2. Medical conditions factsheets

Publications List. 1. General factsheets. 2. Medical conditions factsheets Publications List We produce a wide range of publications, from factsheets about specific medical conditions to comprehensive guides on adapting your home. To order a free publication: Call the Information

More information

An Overview of Congenital Myopathies Jean K. Mah, MD, MSc, FRCPC; Jeffrey T. Joseph, MD, PhD

An Overview of Congenital Myopathies Jean K. Mah, MD, MSc, FRCPC; Jeffrey T. Joseph, MD, PhD Review Article Downloaded from https://journals.lww.com/continuum by maxwo3znzwrcfjddvmduzvysskax4mzb8eymgwvspgpjoz9l+mqfwgfuplwvy+jmyqlpqmifewtrhxj7jpeo+505hdqh14pdzv4lwky42mcrzqckilw0d1o4yvrwmuvvhuyo4rrbviuuwr5dqytbtk/icsrdbt0hfryk7+zagvaltkgnudxdohhaxffu/7kno26hifzu/+bcy16w7w1bdw==

More information

Myotubular (centronuclear) myopathy

Myotubular (centronuclear) myopathy Myotubular (centronuclear) myopathy Myotubular, or centronuclear, myopathy falls under the umbrella of congenital myopathies. It is characterised by a specific pattern in the muscle tissue when viewed

More information

Non-Mendelian inheritance

Non-Mendelian inheritance Non-Mendelian inheritance Focus on Human Disorders Peter K. Rogan, Ph.D. Laboratory of Human Molecular Genetics Children s Mercy Hospital Schools of Medicine & Computer Science and Engineering University

More information

Clinical Genetics in Cardiomyopathies

Clinical Genetics in Cardiomyopathies Clinical Genetics in Cardiomyopathies Γεώργιος Κ Ευθυμιάδης Αναπληρωτής Καθηγητής Καρδιολογίας ΑΠΘ No conflict of interest Genetic terms Proband: The first individual diagnosed in a family Mutation: A

More information

Spieraandoeningen genpanel v2 (148 genen)

Spieraandoeningen genpanel v2 (148 genen) Spieraandoeningen genpanel v2 (148 genen) Gene ACADVL 99,8 VLCAD deficiency, 201475 ACTA1 99,1 Nemaline myopathy 3, autosomal dominant or recessive, 161800 Myopathy, actin, congenital, with excess of thin

More information

Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I

Hutterite brothers both affected with two forms of limb girdle muscular dystrophy: LGMD2H and LGMD2I (2005) 13, 978 982 & 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00 ARTICLE www.nature.com/ejhg Hutterite brothers both with two forms of limb girdle muscular dystrophy: LGMD2H and

More information

FEP Medical Policy Manual

FEP Medical Policy Manual FEP Medical Policy Manual FEP 2.04.132 Genetic Testing for Limb-Girdle Muscular Dystrophies Effective Date: July 15, 2018 Related Policies: 2.04.86 Genetic Testing for Duchenne and Becker Muscular Dystrophy

More information

Clinical and genetic heterogeneity in nemaline myopathy a disease of skeletal muscle thin filaments

Clinical and genetic heterogeneity in nemaline myopathy a disease of skeletal muscle thin filaments 362 Review 58 Braun, C. et al. (1999) Expression of calpain I messenger RNA in human renal cell carcinoma: correlation with lymph node metastasis and histological type. Int. J. Cancer 84, 6 9 59 Shiba,

More information

Breathing problems: and how to get on top of them

Breathing problems: and how to get on top of them Breathing problems: and how to get on top of them ANITA K SIMONDS PROF OF RESPIRATORY & SLEEP MEDICINE, ROYAL BROMPTON HOSPITAL MYOTUBULAR FAMILY DAY JULY 12 2014 GET THE BREATHING BASICS RIGHT Identify

More information

What is New in Genetic Testing. Steven D. Shapiro MS, DMD, MD

What is New in Genetic Testing. Steven D. Shapiro MS, DMD, MD What is New in Genetic Testing Steven D. Shapiro MS, DMD, MD 18th Annual Primary Care Symposium Financial and Commercial Disclosure I have a no financial or commercial interest in my presentation. 2 Genetic

More information

SEX-LINKED INHERITANCE. Dr Rasime Kalkan

SEX-LINKED INHERITANCE. Dr Rasime Kalkan SEX-LINKED INHERITANCE Dr Rasime Kalkan Human Karyotype Picture of Human Chromosomes 22 Autosomes and 2 Sex Chromosomes Autosomal vs. Sex-Linked Traits can be either: Autosomal: traits (genes) are located

More information

Amsterdam, The Netherlands, June 24 27, Teaching Course 18. How to diagnose a muscle disorder - Level 1. Muscle imaging

Amsterdam, The Netherlands, June 24 27, Teaching Course 18. How to diagnose a muscle disorder - Level 1. Muscle imaging 3 rd Congress of the European Academy of Neurology Amsterdam, The Netherlands, June 24 27, 2017 Teaching Course 18 How to diagnose a muscle disorder - Level 1 Muscle imaging Volker Straub Newcastle upon

More information

III./10.4. Diagnosis. Introduction. A.) Laboratory tests. Laboratory tests, electrophysiology, muscle biopsy, genetic testing, imaging techniques

III./10.4. Diagnosis. Introduction. A.) Laboratory tests. Laboratory tests, electrophysiology, muscle biopsy, genetic testing, imaging techniques III./10.4. Diagnosis Laboratory tests, electrophysiology, muscle biopsy, genetic testing, imaging techniques After studying this chapter, you will become familiar with the most commonly used diagnostic

More information

Patient L.L. KRISTEN ARREDONDO, MD CHILD NEUROLOGY PGY5, UT SOUTHWESTERN

Patient L.L. KRISTEN ARREDONDO, MD CHILD NEUROLOGY PGY5, UT SOUTHWESTERN Patient L.L. KRISTEN ARREDONDO, MD CHILD NEUROLOGY PGY5, UT SOUTHWESTERN Birth History LL was born to a healthy first time mother with an uncomplicated pregnancy Delivered at 38 weeks via C-section due

More information

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture JCN Open Access pissn 1738-6586 / eissn 2005-5013 / J Clin Neurol 2017;13(4):405-410 / https://doi.org/10.3988/jcn.2017.13.4.405 ORIGINAL ARTICLE Early-Onset LMNA-Associated Muscular Dystrophy with Later

More information

Applications of Chromosomal Microarray Analysis (CMA) in pre- and postnatal Diagnostic: advantages, limitations and concerns

Applications of Chromosomal Microarray Analysis (CMA) in pre- and postnatal Diagnostic: advantages, limitations and concerns Applications of Chromosomal Microarray Analysis (CMA) in pre- and postnatal Diagnostic: advantages, limitations and concerns جواد کریمزاد حق PhD of Medical Genetics آزمايشگاه پاتوبيولوژي و ژنتيك پارسه

More information

Muscular Dystrophies in Adulthood Matthew P. Wicklund, MD, FAAN Professor of Neurology University of Colorado School of Medicine

Muscular Dystrophies in Adulthood Matthew P. Wicklund, MD, FAAN Professor of Neurology University of Colorado School of Medicine Disclosure Information Disclosure of Relevant Financial Relationships Muscular Dystrophies in Adulthood Matthew P. Wicklund, MD, FAAN Professor of Neurology University of Colorado School of Medicine I

More information

Improving detection and genetic counseling in carriers of spinal muscular atrophy

Improving detection and genetic counseling in carriers of spinal muscular atrophy Clin Genet 2014: 85: 470 475 Printed in Singapore. All rights reserved Short Report 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12222 Improving detection

More information

Systematizing in vivo modeling of pediatric disorders

Systematizing in vivo modeling of pediatric disorders Systematizing in vivo modeling of pediatric disorders Nicholas Katsanis, Ph.D. Duke University Medical Center Center for Human Disease Modeling Rescindo Therapeutics www.dukegenes.org Task Force for

More information

Disorders of Muscle. Disorders of Muscle. Muscle Groups Involved in Myopathy. Needle Examination of EMG. History. Muscle Biopsy

Disorders of Muscle. Disorders of Muscle. Muscle Groups Involved in Myopathy. Needle Examination of EMG. History. Muscle Biopsy Disorders of Muscle Disorders of Muscle Zakia Bell, M.D. Associate Professor of Neurology and Physical Medicine & Rehabilitation Virginia Commonwealth University Cardinal symptom of diseases of the muscle

More information

DMD Genetics: complicated, complex and critical to understand

DMD Genetics: complicated, complex and critical to understand DMD Genetics: complicated, complex and critical to understand Stanley Nelson, MD Professor of Human Genetics, Pathology and Laboratory Medicine, and Psychiatry Co Director, Center for Duchenne Muscular

More information

Emerging Treatment Strategies for FSHD

Emerging Treatment Strategies for FSHD Department of Pharmacology Emerging Treatment Strategies for FSHD Peter L. Jones, Ph.D. and Takako I. Jones, Ph.D. Co-Principal Investigators Department of Pharmacology Disclosures: Peter Jones and Takako

More information

DSS-1. No financial disclosures

DSS-1. No financial disclosures DSS-1 No financial disclosures Clinical History 9 year old boy with past medical history significant for cerebral palsy, in-turning right foot, left clubfoot that was surgically corrected at 3 years of

More information

The limb girdle muscular dystrophies (LGMDs)

The limb girdle muscular dystrophies (LGMDs) The limb gird muscular dystrophies (LGMDs) This factsheet is for all peop for whom a diagnosis of limb gird muscular dystrophy (LGMD) has been suggested. This is a complicated subject since there are many

More information

Advances in genetic diagnosis of neurological disorders

Advances in genetic diagnosis of neurological disorders Acta Neurol Scand 2014: 129 (Suppl. 198): 20 25 DOI: 10.1111/ane.12232 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA Review Article Advances in genetic diagnosis

More information

Glossary of terms used in the Neuromuscular Disorders Service

Glossary of terms used in the Neuromuscular Disorders Service Great Ormond Street Hospital for Children NHS Foundation Trust: Information for Families Glossary of terms used in the Neuromuscular Disorders Service This glossary has been put together to help you during

More information

18 (2), DOI: /bjmg

18 (2), DOI: /bjmg 18 (2), 2015 71-76 DOI: 10.1515/bjmg-2015-0088 CASE REPORT SARCOLEMMAL DEFICIENCY OF SARCOGLYCAN COMPLEX IN AN 18-MONTH-OLD TURKISH BOY WITH A LARGE DELETION IN THE BETA SARCOGLYCAN GENE Diniz G 1,*, Tekgul

More information

The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN

The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies Stanley Jones P. Iyadurai, MSc, PhD, MD; John T. Kissel, MD, FAAN Review Article Downloaded from https://journals.lww.com/continuum by maxwo3znzwrcfjddvmduzvysskax4mzb8eymgwvspgpjoz9l+mqfwgfuplwvy+jmyqlpqmifewtrhxj7jpeo+505hdqh14pdzv4lwky42mcrzqckilw0d1o4yvrwmuvvhuyo4rrbviuuwr5dqytbtk/icsrdbt0hfryk7+zagvaltkgnudxdohhaxffu/7kno26hifzu/+bcy16w7w1bdw==

More information

22q11.2 DELETION SYNDROME. Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona)

22q11.2 DELETION SYNDROME. Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona) 22q11.2 DELETION SYNDROME Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona) Genomic disorders GENOMICS DISORDERS refers to those diseases

More information

Prenatal Diagnosis: Are There Microarrays in Your Future?

Prenatal Diagnosis: Are There Microarrays in Your Future? Financial Disclosure UCSF Antepartum Intrapartum Management Course June 8 I have no financial relationship with any aspect of private industry Prenatal Diagnosis: Are There Microarrays in Your Future?

More information

SALSA MLPA KIT P060-B2 SMA

SALSA MLPA KIT P060-B2 SMA SALSA MLPA KIT P6-B2 SMA Lot 111, 511: As compared to the previous version B1 (lot 11), the 88 and 96 nt DNA Denaturation control fragments have been replaced (QDX2). Please note that, in contrast to the

More information

Neuromuscular in the Pediatric Clinic: Recognition and Referral

Neuromuscular in the Pediatric Clinic: Recognition and Referral Neuromuscular in the Pediatric Clinic: Recognition and Referral Matthew Harmelink, MD Assistant Professor, Pediatric Neurology Medical College of Wisconsin Objectives: 1. Understand common presentations

More information

Congenital myopathies: diseases of the actin cytoskeleton

Congenital myopathies: diseases of the actin cytoskeleton Journal of Pathology Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/path.1648 Review Article Congenital myopathies: diseases of the actin cytoskeleton Emilie Clarkson,

More information

Corporate Medical Policy

Corporate Medical Policy Corporate Medical Policy File Name: Origination: Last CAP Review: Next CAP Review: Last Review: nusinersen_spinraza 03/2017 10/2018 10/2019 10/2018 Description of Procedure or Service Spinal muscular atrophy

More information

Basic Definitions. Dr. Mohammed Hussein Assi MBChB MSc DCH (UK) MRCPCH

Basic Definitions. Dr. Mohammed Hussein Assi MBChB MSc DCH (UK) MRCPCH Basic Definitions Chromosomes There are two types of chromosomes: autosomes (1-22) and sex chromosomes (X & Y). Humans are composed of two groups of cells: Gametes. Ova and sperm cells, which are haploid,

More information

Agro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17

Agro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17 Agro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17 INTRODUCTION - Our genes underlie every aspect of human health, both in function and

More information

SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY.

SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY. SAMPLE REPORT SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY. RESULTS SNP Array Copy Number Variations Result: GAIN,

More information

1/28/2019. OSF HealthCare INI Care Center Team. Neuromuscular Disease: Muscular Dystrophy. OSF HealthCare INI Care Center Team: Who are we?

1/28/2019. OSF HealthCare INI Care Center Team. Neuromuscular Disease: Muscular Dystrophy. OSF HealthCare INI Care Center Team: Who are we? Neuromuscular Disease: Muscular Dystrophy Muscular Dystrophy Association (MDA) and OSF HealthCare Illinois Neurological Institute (INI) Care Center Team The Neuromuscular clinic is a designated MDA Care

More information

SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY.

SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY. SAMPLE REPORT SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY. RESULTS SNP Array Copy Number Variations Result: LOSS,

More information

Benefits and pitfalls of new genetic tests

Benefits and pitfalls of new genetic tests Benefits and pitfalls of new genetic tests Amanda Krause Division of Human Genetics, NHLS and University of the Witwatersrand Definition of Genetic Testing the analysis of human DNA, RNA, chromosomes,

More information

Multiple Copy Number Variations in a Patient with Developmental Delay ASCLS- March 31, 2016

Multiple Copy Number Variations in a Patient with Developmental Delay ASCLS- March 31, 2016 Multiple Copy Number Variations in a Patient with Developmental Delay ASCLS- March 31, 2016 Marwan Tayeh, PhD, FACMG Director, MMGL Molecular Genetics Assistant Professor of Pediatrics Department of Pediatrics

More information

Genetics of Inclusion Body Myositis

Genetics of Inclusion Body Myositis Genetics of Inclusion Body Myositis Thomas Lloyd, MD, PhD Associate Professor of Neurology and Neuroscience Co-director, Johns Hopkins Myositis Center Sporadic IBM (IBM) Age at onset usually > 50 Prevalence

More information

FEP Medical Policy Manual

FEP Medical Policy Manual FEP Medical Policy Manual FEP 2.04.102 Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders Effective Date: April 15, 2017 Related Policies: 2.04.59 Genetic Testing for Developmental

More information

Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier

Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name Amyotrophic Lateral Sclerosis 10 (ALS10) and Amyotrophic Lateral Sclerosis 6 (ALS6)

More information

MRC-Holland MLPA. Description version 19;

MRC-Holland MLPA. Description version 19; SALSA MLPA probemix P6-B2 SMA Lot B2-712, B2-312, B2-111, B2-511: As compared to the previous version B1 (lot B1-11), the 88 and 96 nt DNA Denaturation control fragments have been replaced (QDX2). SPINAL

More information

Common Genetic syndromes. Dr. E.M. Honey Department Genetics Division Human Genetics University of Pretoria

Common Genetic syndromes. Dr. E.M. Honey Department Genetics Division Human Genetics University of Pretoria Common Genetic syndromes Dr. E.M. Honey Department Genetics Division Human Genetics University of Pretoria Definitions Deformation Malformation Disruption Dysplasia Syndrome Associations Complex Sequences

More information

Lecture 17: Human Genetics. I. Types of Genetic Disorders. A. Single gene disorders

Lecture 17: Human Genetics. I. Types of Genetic Disorders. A. Single gene disorders Lecture 17: Human Genetics I. Types of Genetic Disorders A. Single gene disorders B. Multifactorial traits 1. Mutant alleles at several loci acting in concert C. Chromosomal abnormalities 1. Physical changes

More information

Clinical Spectrum and Genetic Mechanism of GLUT1-DS. Yasushi ITO (Tokyo Women s Medical University, Japan)

Clinical Spectrum and Genetic Mechanism of GLUT1-DS. Yasushi ITO (Tokyo Women s Medical University, Japan) Clinical Spectrum and Genetic Mechanism of GLUT1-DS Yasushi ITO (Tokyo Women s Medical University, Japan) Glucose transporter type 1 (GLUT1) deficiency syndrome Mutation in the SLC2A1 / GLUT1 gene Deficiency

More information

Approach to Mental Retardation and Developmental Delay. SR Ghaffari MSc MD PhD

Approach to Mental Retardation and Developmental Delay. SR Ghaffari MSc MD PhD Approach to Mental Retardation and Developmental Delay SR Ghaffari MSc MD PhD Introduction Objectives Definition of MR and DD Classification Epidemiology (prevalence, recurrence risk, ) Etiology Importance

More information

CHROMOSOMAL MICROARRAY (CGH+SNP)

CHROMOSOMAL MICROARRAY (CGH+SNP) Chromosome imbalances are a significant cause of developmental delay, mental retardation, autism spectrum disorders, dysmorphic features and/or birth defects. The imbalance of genetic material may be due

More information

Cover Page. The handle holds various files of this Leiden University dissertation.

Cover Page. The handle   holds various files of this Leiden University dissertation. Cover Page The handle http://hdl.handle.net/1887/29354 holds various files of this Leiden University dissertation. Author: Straathof, Chiara Title: dystrophinopathies : heterogeneous clinical aspects of

More information

Corporate Medical Policy

Corporate Medical Policy Corporate Medical Policy File Name: Origination: Last CAP Review: Next CAP Review: Last Review: nusinersen_spinraza 03/2017 10/2017 10/2018 10/2017 Description of Procedure or Service Spinal muscular atrophy

More information

A Lawyer s Perspective on Genetic Screening Performed by Cryobanks

A Lawyer s Perspective on Genetic Screening Performed by Cryobanks A Lawyer s Perspective on Genetic Screening Performed by Cryobanks As a lawyer practicing in the area of sperm bank litigation, I have, unfortunately, represented too many couples that conceived a child

More information

Molecular Diagnostic Laboratory 18 Sequencing St, Gene Town, ZY Tel: Fax:

Molecular Diagnostic Laboratory 18 Sequencing St, Gene Town, ZY Tel: Fax: Molecular Diagnostic Laboratory 18 Sequencing St, Gene Town, ZY 01234 Tel: 555-920-3333 Fax: 555-920-3334 www.moldxlaboratory.com Patient Name: Jane Doe Specimen type: Blood, peripheral DOB: 04/05/1990

More information