IllnessMyopathy, congenital; differential diagnosis

NGS +

[Sanger]

Commonly, at least 7 forms of congenital myopathies are discerned, which differ in terms of symptoms, complications, treatment options and outlook.

Nemaline myopathy (NM) is the most common congenital myopathy. Infants usually have problems with breathing and feeding. Later, they may develop skeletal problems, such as scoliosis. Muscle weakness usually does not increase throughout life. NM itself is divided into 6 subtypes: severe congenital, Amish, moderate congenital, typical congenital, childhood-onset NM and adult-onset form. Most cases of NM with a known genetic cause are due to mutations in the NEB (50%) or ACTA1 (15-25%) genes. Mutations in other genes account for only a small percentage of cases in each case.

Myotubular myopathy (MTM) is rare. Weakness and floppiness are so severe that the mother may notice restricted movements of the baby during pregnancy. Significant breathing and swallowing difficulties usually occur; many children do not survive infancy. Osteopenia is also associated with MTM. Mutations in the MTM1 gene cause X-linked inherited MTM; autosomal dominant MTM is heralded by mutations in the BIN1 or DNM2 genes.

Centronuclear myopathy (CNM) is characterized by myopathy and atrophy of the skeletal muscles. The severity of CNM varies among affected individuals, even among members of the same family. CNM can begin at any time between birth and early adulthood. Some patients experience mild to severe breathing problems, ptosis and weakness of other facial muscles, a high palate and scoliosis. CNM is most commonly caused by mutations in the DNM2, BIN1 or TTN genes. Mutations in other genes are found in a small percentage of cases.

Central Core Disease (CCD) varies in severity and degree of deterioration over time in children. Typically, mild floppiness, delayed milestone achievement and moderate limb weakness occur in infancy and do not worsen significantly over time. However, children with CCD may have life-threatening reactions to general anesthesia. Mutations in the RYR1 gene cause CCD.

Multi-minicore disease (MMD) has several distinct subtypes, the classic form (75% of cases), the progressive form (10%), the prenatal form with arthrogryposis (10%) and the ophthalmoplegic form (5-10%). Common to most patients is severe weakness of the limbs and scoliosis. Respiratory problems are also not uncommon. The eye movements are weakened in some children. Mutations in the SELENON and RYR1 genes cause about half of all MMD cases.

Congenital fiber-type disproportion myopathy (CFDM) is rare and begins with floppiness, limb and facial weakness and breathing problems. CFDM patients generally have a long face, high palate and crowded teeth. CFDM may be caused by mutations in the genes TPM3, RYR1 and ACTA1 (35-50% of cases) or rarely in known (e.g., COL6A1-3, SELENON, TTN) and some unidentified genes.

In hyaline body myopathy (HBM), also known as myosin storage myopathy, the muscular symptoms are highly variable. Mutations in the MYH7 gene cause dominant and recessive HBM.

Cap myopathy (CM) primarily involves skeletal muscles throughout the body with myopathy and hypotonia, the face, neck and limbs are most severely affected. Weakness begins at birth or in infancy and may continue to worsen over time. CM sufferers may have problems with feeding and swallowing in infancy; motor skill development is delayed. In some cases, life-threatening respiratory problems may occur. CM patients may also have a high-arched palate, ptosis and a long face. Some affected individuals develop lordosis or scoliosis. Mutations in the ACTA1, TPM2 or TPM3 genes can cause CM.

In summary, all classic inheritance patterns occur in congenital myopathies. The symptomatology is largely overlapping in all forms of congenital myopathies, a comprehensive gene panel must be used to cover the extreme degree of genetic heterogeneity. Nevertheless, the diagnostic yield using molecular genetics often does not exceed 20-25%, very rarely 50-60%. Therefore, a negative DNA test result does not exclude clinical diagnosis.

References: https://doi.org/10.1016/j.nmd.2013.11.003

https://www.ncbi.nlm.nih.gov/books/NBK1432/

https://www.ncbi.nlm.nih.gov/books/NBK1146/

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

https://www.ncbi.nlm.nih.gov/books/NBK1433/

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

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

Congenital myopathies share some features, yet severity is highly variable. Affected individuals usually present early on with hypotonia, weakness, reduced tendon reflexes, delayed motor milestones, but normal intelligence. Weakness is usually generalized or more prominent in proximal and limb-girdle muscles rarely predominantly in distal, axial and respiratory muscles. Weakness is stable or slowly progressive over time. Specific congenital myopathies are characterized by histology features. In metabolic myopathies deficient muscle energy production results from defects in lipid and/or mitochondrial metabolism, glycogen storage or other metabolic pathways. All Mendelian inheritance patterns are observed. The DNA-diagnostic yield depends on the quality of the clinical work up and rarely exceeds 60% of cases. Thus exclusion of mutations does not exclude the clinical diagnosis.

(Basis diagnostic genes: ###; additional genes: ###)

Reference: https://www.nmd-journal.com/article/S0960-8966(13)00994-2/fulltext

• Allelic: Androgen insensitivity, partial, with/-out breast cancer (AR)
• Allelic: Cardiomyopathy, dilated, 1A (LMNA)
• Allelic: Cardiomyopathy, dilated, 1AA, with or without LVNC (ACTN2)
• Allelic: Cardiomyopathy, dilated, 1G (TTN)
• Allelic: Cardiomyopathy, dilated, 1KK (MYPN)
• Allelic: Cardiomyopathy, familial hypertrophic, 9 (TTN)
• Allelic: Cardiomyopathy, familial restrictive, 4 (MYPN)
• Allelic: Cardiomyopathy, hypertrophic, 1 (MYH7)
• Allelic: Cardiomyopathy, hypertrophic, 10 (MYL2)
• Allelic: Cardiomyopathy, hypertrophic, 22 (MYPN)
• Allelic: Cardiomyopathy, hypertrophic, 23, with or without LVNC (ACTN2)
• Allelic: Charcot-Marie-Tooth disease, AD intermediate B (DNM2)
• Allelic: Charcot-Marie-Tooth disease, axonal type 2M (DNM2)
• Allelic: Emery-Dreifuss muscular dystrophy 2, AD (LMNA)
• Allelic: Emery-Dreifuss muscular dystrophy 3, AR (LMNA)
• Allelic: Fetal akinesia deformation sequence 3 (DOK7)
• Allelic: Heart-hand syndrome, Slovenian type (LMNA)
• Allelic: Hutchinson-Gilford progeria (LMNA)
• Allelic: Hyperkalemic periodic paralysis, type 2 (SCN4A)
• Allelic: Hypokalemic periodic paralysis, type 2 (SCN4A)
• Allelic: Hypospadias 1, XL (AR)
• Allelic: Immunodeficiency 10 (STIM1)
• Allelic: Immunodeficiency 9 (ORAI1)
• Allelic: King-Denborough syndrome (RYR1)
• Allelic: Left ventricular noncompaction 5 (MYH7)
• Allelic: Lethal congenital contracture syndrome 4 (MYBPC1)
• Allelic: Lethal congenital contracture syndrome 5 (DNM2)
• Allelic: Lipodystrophy, familial partial, type 2 (LMNA)
• Allelic: Malignant hyperthermia susceptibility 1 (RYR1)
• Allelic: Malouf syndrome (LMNA)
• Allelic: Mandibuloacral dysplasia (LMNA)
• Allelic: Marden-Walker syndrome (PIEZO2)
• Allelic: Muscular dystrophy, limb-girdle, AR 10 (TTN)
• Allelic: Muscular dystrophy, rigid spine, 1 (SELENON)
• Allelic: Muscular dystrophy, rigid spine, 1 (SELENON)
• Allelic: Myopathy, distal, 6, adult onset (ACTN2)
• Allelic: Myopathy, scapulohumeroperoneal (ACTA1)
• Allelic: Myosclerosis, congenital (COL6A2)
• Allelic: Myotonia congenita, atypical, acetazolamide-responsive (SCN4A)
• Allelic: Restrictive dermopathy, lethal (LMNA)
• Allelic: Rhabdomyosarcoma 2, alveolar (PAX7)
• Allelic: Split-foot malformation with mesoaxial polydactyly (MAP3K20)
• Allelic: Thyrotoxic periodic paralysis, susceptibility to, 1 (CACNA1S)
• Allelic: Tibial muscular dystrophy, tardive (TTN)
• Allelic: Ullrich congenital muscular dystrophy 2 (COL12A1)
• Androgen insensitivity (AR)
• Arthrogryposis, distal, type 1A (TPM2)
• Arthrogryposis, distal, type 1B (MYBPC1)
• Arthrogryposis, distal, type 2A; Freeman-Sheldon (MYH3)
• Arthrogryposis, distal, type 2B1 (TNNI2)
• Arthrogryposis, distal, type 2B2 (TNNT3)
• Arthrogryposis, distal, type 2B3; Sheldon-Hall (MYH3)
• Arthrogryposis, distal, type 2B4 (TPM2)
• Arthrogryposis, distal, type 3 (PIEZO2)
• Arthrogryposis, distal, type 5 (PIEZO2)
• Arthrogryposis, distal, type 5D (ECEL1)
• Arthrogryposis, distal, with impaired proprioception + touch (PIEZO2)
• Bethlem myopathy 1 (COL6A1, COL6A2, COL6A3)
• Bethlem myopathy 2 (COL12A1)
• CAP myopathy 1 (TPM3)
• CAP myopathy 2 (TPM2)
• Carey-Fineman-Ziter syndrome (MYMK)
• Carney complex variant (MYH8)
• 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)
• Childhood-onset nemaline myopathy (RYR3)
• Congenital myopathy 11 (HACD1)
• Congenital myopathy 15 (TNNC2)
• Congenital myopathy 17 (MYOD1)
• Congenital myopathy [MONDO:0019952] (ASCC3)
• Contractures, pterygia spondylocarpotarsal fusion syndrome 1A + 1B (MYH3)
• Ehlers-Danlos syndrome, kyphoscoliotic type, 2 (FKBP14)
• Fetal akinesia deformation sequence 2 (RAPSN)
• Glycogen storage disease II (GAA)
• Hypokalemic periodic paralysis, type 1 (CACNA1S)
• Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2
• Klippel-Feil syndrome 4, Ar, with myopathy + facial dysmorphism (MYO18B)
• Laing distal myopathy (MYH7)
• Malignant hyperthermia, susceptibility to, 5 (CACNA1S)
• Minicore myopathy with external ophthalmoplegia (RYR1)
• Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD (SLC25A4)
• Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR (SLC25A4)
• Mitochondrial complex IV deficiency, nuclear type 18 (COX6A2)
• Muscular dystrophy, congenital (LMNA)
• Muscular dystrophy, congenital, Davignon-Chauveau type (TRIP4)
• Muscular dystrophy, congenital, merosin deficient or partially deficient (LAMA2)
• Myasthenic syndrome, congenital, 10 (DOK7)
• Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency (RAPSN)
• Myasthenic syndrome, congenital, 16 (SCN4A)
• Myasthenic syndrome, congenital, 5 (COLQ)
• Myasthenic syndrome, congenital, 6, presynaptic (CHAT)
• Myopathy with extrapyramidal signs (MICU1)
• Myopathy, XL, with excessive autophagy (VMA21)
• Myopathy, actin, congenital, with cores (ACTA1)
• Myopathy, actin, congenital, with excess of thin myofilaments (ACTA1)
• Myopathy, areflexia, respiratory distress + dysphagia, early-onset, mild variant (MEGF10)
• Myopathy, areflexia, respiratory distress, and dysphagia, early-onset (MEGF14)
• Myopathy, congenital proximal, with minicore lesions (FXR1)
• Myopathy, congenital with structured cores + Z-line abnormalities (ACTN2)
• Myopathy, congenital, Baily-Bloch (STAC3)
• Myopathy, congenital, progressive, with scoliosis (PAX7)
• Myopathy, congenital, with fast-twitch (type II) fiber atrophy (MYL1)
• Myopathy, congenital, with fiber-type disproportion (SELENON)
• Myopathy, congenital, with fiber-type disproportion (SELENON)
• Myopathy, congenital, with fiber-type disproportion (TPM3)
• Myopathy, congenital, with fiber-type disproportion 1 (ACTA1)
• Myopathy, congenital, with respiratory insufficiency + bone fractures (FRX1)
• Myopathy, congenital, with tremor (MYBPC1)
• Myopathy, distal, 5 (ADSS1 syn. ADSSL1)
• Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy (MYL2)
• Myopathy, myofibrillar, 8 (PYROXD1)
• Myopathy, myofibrillar, 9, with early respiratory failure (TTN)
• Myopathy, myosin storage, AD (MYH7)
• Myopathy, myosin storage, AR (MYH7)
• Myopathy, tubular aggregate, 1 (STIM1)
• Myopathy, tubular aggregate, 2 (ORAI1)
• Myotonic dystrophy 1 (DMPK)
• Myotubular myopathy, XL (MTM1)
• Nemaline myopathy 1, AD/AR (TPM3)
• Nemaline myopathy 10 (LMOD3)
• Nemaline myopathy 11, AR (MYPN)
• 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)
• Nemaline myopathy 9 (KLHL41)
• Neuromuscular disease, congenital, with uniform type 1 fiber (RYR1)
• Paramyotonia congenita (SCN4A)
• Progressive ext. ophthalmoplegia with mitochondrial DNA deletions, AD 2 (SLC25A4)
• Proximal myopathy + ophthalmoplegia (MYH2)
• Salih myopathy (TTN)
• Scapuloperoneal syndrome, myopathic type (MYH7)
• Spinal + bulbar muscular atrophy of Kennedy (AR_CAG)
• Spinal muscular atrophy with congenital bone fractures 1 (TRIP4)
• Spinal muscular atrophy-1, -2, -3. -4 (SMN1)
• Stormorken syndrome (STIM1)
• Trismus-pseudocamptodactyly syndrome (MYH8)
• Vici syndrome (EPG5)