IllnessMuscular dystrophy, congenital; expanded differential diagnosis

NGS +

Congenital muscular dystrophies (CMDs) are defined as early-onset muscle disorders in which the muscle biopsy is consistent with the presence of a dystrophic process without histologic evidence of other neuromuscular disease. Nevertheless, there is overlap between CMDs and congenital myopathies at the clinical, morphologic and genetic levels. Mutations in several CMD genes can cause congenital myopathies as well as CMD-like manifestations. Myopathies reflect a pathology in which there is no clear evidence of degeneration and regeneration in most cases. The clinical and genetic complexity of the disorders subsumed under CMD has led to different genetic and clinical classification schemes. The incidence and prevalence of CMD in different populations ranges from 7-25/100 000. In Japan, the most commonly diagnosed CMD subtype is Fukuyama CMD, whereas fukutin mutations are very rare in other populations. Some CMD forms are rare. The molecular diagnosis is important for genetic counseling, prognosis and anticipatory management of these heterogeneous disorders, which are currently grouped under CMD to distinguish, for example, spinal muscular atrophy, dysferlinopathy, collagen VI-related dystrophies, LAMA2 muscular dystrophy, Emery-Dreifuss muscular dystrophy, congenital Fukuyama muscular dystrophy and so on. In addition to 17 guideline-curated CMD genes, the most important differential diagnostic considerations in hypotonic and weak infants include congenital myopathies and congenital myasthenic syndromes. The different CMDs are inherited according to different monogenic patterns. The overall molecular genetic diagnostic yield is not exceeding 20% by a large margin, so that a negative DNA test result by no means excludes the clinical diagnosis.

Selected references: https://www.ncbi.nlm.nih.gov/books/NBK1168/

https://www.ncbi.nlm.nih.gov/books/NBK1206/

https://www.ncbi.nlm.nih.gov/books/NBK1303/

https://www.ncbi.nlm.nih.gov/books/NBK1352/

https://www.ncbi.nlm.nih.gov/books/NBK1436/

https://www.ncbi.nlm.nih.gov/books/NBK1503/

https://www.ncbi.nlm.nih.gov/books/NBK97333/

• Alias: Congenital muscular dystrophy due to laminin alpha2 deficiency (LAMA2)
• Alias: Congenital muscular dystrophy type 1A (LAMA2)
• Alias: Laminin subunit alpha 2-related congenital muscular dystrophy (LAMA2)
• Alias: Merosin-negative congenital muscular dystrophy (LAMA2)
• Alias: Muskeldystrophie, kongenitale, Merosin-negativ (LAMA2)
• Alias: Muskeldystrophie, kongenitale, durch Laminin-alpha 2-Mangel (LAMA2)
• Alias: Santavuori congenital muscular dystrophy (POMGNT1)
• Alias: Walker-Warburg syndrome (POMT1)
• Allelic: Becker muscular dystrophy (DMD)
• Allelic: Cardiomyopathy, dilated, 1A (LMNA)
• Allelic: Cardiomyopathy, dilated, 1X (FKTN)
• Allelic: Cardiomyopathy, dilated, 3B (DMD)
• Allelic: Charcot-Marie-Tooth disease, axonal type 2M (DNM2)
• Allelic: Charcot-Marie-Tooth disease, dominant intermediate B (DNM2)
• Allelic: Charcot-Marie-Tooth disease, type 2B1 (LMNA)
• Allelic: Dystonia 27 (COL6A3)
• Allelic: Emery-Dreifuss muscular dystrophy 2, AD (LMNA)
• Allelic: Emery-Dreifuss muscular dystrophy 3, AR (LMNA)
• Allelic: Emery-Dreifuss muscular dystrophy 6, XL (FHL1)
• Allelic: Epidermolysis bullosa simplex 5A, Ogna type (PLEC)
• Allelic: Epidermolysis bullosa simplex 5C, with pyloric atresia (PLEC)
• Allelic: Epidermolysis bullosa simplex 5D, generalized intermediate, AR (PLEC)
• Allelic: Heart-hand syndrome, Slovenian type (LMNA)
• Allelic: Hutchinson-Gilford progeria (LMNA)
• Allelic: King-Denborough syndrome (RYR1)
• Allelic: Lipodystrophy, familial partial, type 2 (LMNA)
• Allelic: Malignant hyperthermia susceptibility 1 (RYR1)
• Allelic: Malouf syndrome (LMNA)
• Allelic: Mandibuloacral dysplasia (LMNA)
• Allelic: Minicore myopathy with external ophthalmoplegia (RYR1)
• Allelic: Muscular dystrophy, limb-girdle, AR 23 (LAMA2)
• Allelic: Muscular dystrophy, rigid spine, 1 (SELENON)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 1 (POMT1)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 14 (GMPPB)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 2 (POMT2)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 3 (POMGNT1)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 4 (FKTN)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 5 (FKRP)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 7 (CRPPA)
• Allelic: Muscular dystrophy-dystroglycanopathy [limb-girdle], type C, 9 (DAG1)
• Allelic: Myopathy, scapulohumeroperoneal (ACTA1)
• Allelic: Myosclerosis, congenital (COL6A2)
• Allelic: Reducing body myopathy, XL 1b, with late childhood or adult onset (FHL1)
• Allelic: Restrictive dermopathy, lethal (LMNA)
• Allelic: Retinitis pigmentosa 76 (POMGNT1)
• Allelic: Scapuloperoneal myopathy, XLD (FHL1)
• Allelic: Spinocerebellar ataxia, AR 8 (SYNE1)
• Allelic: Split-foot malformation with mesoaxial polydactyly (MAP3K20)
• Allelic:Emery-Dreifuss muscular dystrophy 4, AD (SYNE1)
• Arthrogryposis multiplex congenita 3, myogenic type (SYNE1)
• Arthrogryposis multiplex congenita 6 (NEB)
• Arthrogryposis, distal, type 1A + 2B4 (TPM2)
• Bethlem myopathy 1 (COL6A1, COL6A2, COL6A3)
• Bethlem myopathy 2 (COL12A1)
• CAP myopathy 1 (TPM3)
• CAP myopathy 2 (TPM2)
• Carey-Fineman-Ziter syndrome [cong. myopathy +Moebius- + Robin sequences] (MYMK)
• Central core disease (RYR1)
• Centronuclear myopathy 1 (DNM2)
• Centronuclear myopathy 2 (BIN1)
• Centronuclear myopathy 4 (CCDC78)
• Centronuclear myopathy 5 (SPEG)
• Centronuclear myopathy 6 with fiber-type disproportion (MAP3K20)
• Centronuclear myopathy, autosomal, modifier of (MTMR14)
• Congenital disorder of glycosylation, type Im (DOLK)
• Congenital disorder of glycosylation, type Iu (DPM2)
• Duchenne muscular dystrophy (DMD)
• Epidermolysis bullosa simplex 5B, with muscular dystrophy (PLEC)
• Fetal akinesia deformation sequence 2 (RAPSN)
• Fetal akinesia deformation sequence 3 (DOK7)
• Kollagen-VI-Muskeldystrophie (COL12A1)
• Lethal congenital contracture syndrome 5 (DNM2)
• Marinesco-Sjogren syndrome [cong. cataracts, myopathy, hypotonia, ID, hyperg. hypogonadism] (SIL1)
• Muscular dystrophy, congenital (LMNA)
• Muscular dystrophy, congenital, due to ITGA7 deficiency (ITGA7)
• Muscular dystrophy, congenital, megaconial type (CHKB)
• Muscular dystrophy, congenital, merosin deficient or partially deficient (LAMA2)
• Muscular dystrophy, congenital, with cataracts + intellectual disability (INPP5K)
• Muscular dystrophy, limb-girdle, AR 17 (PLEC)
• Muscular dystrophy, limb-girdle, AR 18 (TRAPPC11)
• Muscular dystrophy, rigid spine, 1 (SELENON)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies, type A, 10 (RXYLT1)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 11 (B3GALNT2)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 13 (B4GAT1)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 14 (GMPPB)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 4 (FKTN)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 7 (CRPPA)
• Muscular dystrophy-dystroglycanopathy [cong. with brain + eye anomalies], type A, 9 (DAG1)
• Muscular dystrophy-dystroglycanopathy [cong. with mental retard.], type B, 1 (POMT1)
• Muscular dystrophy-dystroglycanopathy [cong. with mental retard.], type B, 2 (POMT2)
• Muscular dystrophy-dystroglycanopathy [cong. with mental retard.], type B, 3 (POMGNT1)
• Muscular dystrophy-dystroglycanopathy [cong. with mental retard.], type B, 6 (LARGE1)
• Muscular dystrophy-dystroglycanopathy [cong. with mental retardation], type B, 14 (GMPPB)
• Muscular dystrophy-dystroglycanopathy [cong. with/-out mental retard.], type B, 5 (FKRP)
• Muscular dystrophy-dystroglycanopathy [cong. without mental retard.], type B, 4 (FKTN)
• Myasthenia, congenital, 12, with tubular aggregates (GFPT1)
• Myasthenic syndrome, congenital, 10 ((DOK7)
• Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency (RAPSN)
• Myasthenic syndrome, congenital, 4A, slow-channel (CHRNE)
• Myasthenic syndrome, congenital, 4B, fast-channel (CHRNE)
• Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency (CHRNE)
• Myasthenic syndrome, congenital, 5 (COLQ)
• Myasthenic syndrome, congenital, 6, presynaptic (CHAT)
• Myopathy with extrapyramidal signs (MICU1)
• Myopathy, XL, with postural muscle atrophy (FHL1)
• Myopathy, actin, congenital, with cores (ACTA1)
• Myopathy, actin, congenital, with excess of thin myofilaments (ACTA1)
• Myopathy, congenital, with fiber-type disproportion (SELENON)
• Myopathy, congenital, with fiber-type disproportion (TPM3)
• Myopathy, congenital, with fiber-type disproportion 1 (ACTA1)
• Myopathy, mitochondrial, + ataxia (MSTO1)
• Myotonic dystrophy 1 (DMPK_CTG)
• Myotubular myopathy, XL (MTM1)
• Nemaline myopathy 1, AD/AR (TPM3)
• Nemaline myopathy 10 (LMOD3)
• Nemaline myopathy 2, AR (NEB)
• Nemaline myopathy 3, AD/AR (ACTA1)
• Nemaline myopathy 4, AD (TPM2)
• Nemaline myopathy 5, Amish type (TNNT1)
• Nemaline myopathy 6, AD (KBTBD13)
• Nemaline myopathy 7, AR (CFL2)
• Nemaline myopathy 8, AR (KLHL40)
• Neuromuscular disease, congenital, with uniform type 1 fiber (RYR1)
• Reducing body myopathy, XL 1a, severe, infantile or early childhood onset (FHL1)
• Spinal muscular atrophy-1, -2, -3, -4 (SMN1)
• Ullrich congenital muscular dystrophy 1 (COL6A1, COL6A2, COL6A3)
• Ullrich congenital muscular dystrophy 2 (COL12A1)
• Uruguay faciocardiomusculoskeletal syndrome (FHL1)