||Dystrophinopathies are a spectrum of conditions including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy (DCM); dystrophinopathies are caused by pathogenic variants in the DMD gene and inherited in an X-linked manner. These conditions primarily affect the skeletal and cardiac muscles. Presentation of the disease is dependent on the specific variant. DMD is the most severe form and primarily affects male children, with onset of delayed motor skills in early childhood. Most individuals are wheelchair-dependent by adolescence. Intellectual disability, learning disabilities, and elevated serum creatine kinase levels are common . Symptoms of BMD are typically milder than DMD, with a later age of onset and slower disease progression. Males with DMD or BMD are at risk for cardiomyopathy in adulthood. Most individuals affected by DMD pass away in early adulthood due to heart or respiratory failure, while those with BMD have a life expectancy into their forties or older. DMD-associated DCM can affect both males and carrier females and is characterized by dilated cardiomyopathy without skeletal muscle weakness or wasting. DMD/BMD occurs in about 1 in 3,500 to 6,000 newborn males worldwide. Treatment is based on symptoms and includes mobility aids and supportive therapies; gene therapy is possible for individuals with specific variants.
||20301298, 33602943, 35419381, 34883113
|Glycogen storage disease
||GAA, PYGM, GBE1, PFKM, AGL
||Glycogen storage disease (GSD) is a group of inherited conditions characterized by abnormalities in the synthesis, storage, or breakdown of glucose. Age of onset and severity of symptoms vary depending on the genetic etiology, but most individuals have a degree of muscle and liver disease, delayed growth, and low blood sugar. General treatment of GSD includes supportive therapies, management of blood sugar levels through medication and diet. GSD, type II – also known as Pompe disease – can be treated with enzyme replacement therapy to improve symptoms and prevent long-term damage. The overall prevalence of GSD is estimated to be as high as 1 in 25,000 births.
||37476587, 20301489, 32745073, 20301788, 23285490
|Congenital myasthenic syndrome
||CHRNE, RAPSN, DOK7, SCN4A, SLC18A3, SNAP25, SYT2, AGRN, ALG14, ALG2, CHAT, CHRNA1, CHRNB1, CHRND, CHRNG, COL13A1, COLQ, DPAGT1, GFPT1, MUSK, PREPL
||Congenital myasthenic syndrome (CMS) is a group of inherited disorders characterized by skeletal muscle weakness and fatigue, including facial muscles and muscles controlling swallowing and sucking. Pathogenic variants in the CHRNE gene are the most common cause of CMS cases. Onset and severity of the disorder are variable; generally, the earlier the symptoms appear, the more pronounced the disease is likely to be. Affected infants may be delayed in learning to crawl or walk and later on display difficulty running or climbing stairs. Individuals may have joint deformities and breathing problems. There is no cure for CMS; however, there are medications available for some types of CMS that help to improve muscle strength and endurance. Worldwide prevalence of CMS is unknown, although it is estimated to occur in 1 in 500,000 newborns in Europe.
|Emery-Dreifuss muscular dystrophy
||LMNA, EMD, FHL1, SYNE1, TMEM43
||Emery-Dreifuss muscular dystrophy is a group of diseases characterized by weakness in the skeletal and cardiac muscles. Joint deformities called contractures are one of the earliest symptoms of the disorder and often restrict the movement of the elbows, ankles, and neck. Muscle weakness and wasting often begin in the upper arms and lower legs, then progress to the shoulders and hips. Most affected individuals develop cardiac disease in adulthood, long after the onset of skeletal muscle disease; untreated arrhythmia can lead to fainting, heart failure, and sudden cardiac death. Rarely, cardiac abnormalities present in childhood. Treatment is symptomatic and medical surveillance can improve the overall condition of life. Worldwide, approximately 1 in 100,000 male newborns are affected with Emery-Dreifuss muscular dystrophy.
|Limb-girdle muscular dystrophy
||CAPN3, DYSF, FKRP, TCAP, TNPO3, TRAPPC11, TRIM32, TTN, ANO5, BVES, DPM3, FKTN, GMPPB, HNRNPDL, LAMA2, PLEC, POMGNT1, POMGNT2, POMT1, POMT2, SGCA, SGCB, SGCD, SGCG
||Limb-girdle muscular dystrophy (LGMD) includes a group of inherited disorders that cause muscle weakness and decreased amount of skeletal muscle involving the muscles around the hips and shoulders; this weakness causes unusual walking gait, difficulty running, and eventual loss of the ability to walk. Onset of the disorder, progression rate, and the physical distribution of weakness are variable among the different subtypes of this disorder. The brain is generally unaffected, although developmental delays and intellectual disability have been reported. Individuals with some LGMD subtypes are at risk of cardiomyopathy and abnormal cardiac rhythm. There is no cure for LGMD; however medical surveillance and care may help to improve some symptoms and overall condition of life. The occurrence of all forms of limb-girdle muscular dystrophy is estimated to be 1 in 14,500 to 1 in 123,000 newborns.
|Congenital disorders of glycosylation
||ALG2, DPAGT1, DPM1, DPM2
||Congenital disorders of glycosylation (CDG) are a group of inherited metabolic disorders caused by defects in glycosylation, the process of attaching sugars to proteins and lipids. There are over 100 CDG subtypes classified by genetic etiology and disease presentation; most subtypes are characterized by multi-organ disease including epilepsy, hypotonia, stroke-like episodes, and failure to thrive. Several CDG subtypes also present with congenital muscular dystrophy and muscle weakness. Generally, treatment involves dietary supplementation, antiepileptic drugs, and supportive therapies.
||ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1
||Nemaline myopathy is an inherited autosomal recessive muscle disorder that typically affects the muscles of the face, neck, and limbs. The common congenital form of nemaline myopathy is caused by biallelic pathogenic variants in the NEB gene and causes muscle weakness, feeding, and breathing problems in affected individuals. There are several types of nemaline myopathy classified based on the age of onset and symptoms in the affected individual. Individuals with severe nemaline myopathy typically do not survive past early childhood due to respiratory failure. The milder forms of the condition typically present with delayed motor skills such as crawling and walking, however, individuals can typically walk unassisted until later in adulthood. In most affected individuals with NEB-related nemaline myopathy, intellectual ability is not affected. There is no cure for nemaline myopathy; however medical surveillance and care may help to improve some symptoms and overall condition of life. NEB-related nemaline myopathy is found worldwide but is more common in the Ashkenazi Jewish population, where it affects 1 in 47,000 newborns.
|Congenital muscular dystrophy (incl. Walker-Warburg syndrome, muscle-eye-brain disease)
||B3GALNT2, B4GAT1, CHKB, CRPPA, DAG1, DPM3, FKRP, FKTN, GMPPB, LARGE1, POMGNT1, POMGNT2, POMT1, POMT2, RXYLT1
||Congenital muscular dystrophies, including Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama congenital muscular dystrophy, present at birth with muscle weakness. Depending on the genetic etiology, affected infants may also develop symptoms such as epilepsy, cardiomyopathy, respiratory insufficiency, and failure to thrive. Treatment is supportive and there is no cure for congenital muscular dystrophy.
||32644382, 20301385, 35338537
||BAG3, CRYAB, DES, FLNC, KY, LDB3, MYOT, PYROXD1, TTN
||Myofibrillar myopathy is an inherited disorder affecting primarily the skeletal muscles through degradation of the myofibrils, a part of the muscle. Pathogenic variants in several different genes such as DES or MYOT can result in a myofibrillar myopathy phenotype. Onset and severity of symptoms can vary from infancy to adulthood depending on the genetic etiology. Symptoms often begin with weakness in the extremities followed by the limbs and facial muscles. Affected individuals may be at risk for cardiac muscle involvement and cataracts. There is no cure for myofibrillar myopathy; however medical surveillance and care may help to improve some symptoms and overall condition of life. The prevalence of the disorder is unknown.
|Collagen VI-related dystrophies (Bethlem muscular dystrophy and Ullrich congenital muscular dystrophy)
||COL6A1, COL6A2, COL6A3
||Collagen VI-related dystrophies are a spectrum of conditions including the milder Bethlem muscular dystrophy and more severe Ullrich congenital muscular dystrophy (UCMD); collagen VI-related dystrophies are caused by pathogenic variants in COL6A1, COL6A2, or COL6A3. Bethlem muscular dystrophy is characterized by joint contractures, proximal muscle weakness, motor delays, and hypotonia in early childhood. Disease progression is relatively slow, and the majority of affected adults do not require mobility assistance. UCMD presents at birth or infancy with similar symptoms to Bethlem muscular dystrophy; some affected pregnancies exhibit decreased fetal movements. While some children learn to walk, almost all are unable to do so by their teenage years. Individuals with UCMD are at high risk for respiratory insufficiency. Treatment is supportive and includes mobility aids, physical therapy, and bilevel positive airway pressure (BiPAP). Collagen VI-related dystrophies are rare with unknown prevalence; however, the condition appears to be more common in northern England and Japan.
||ECEL1, MYH3, TNNI2, TNNT3, TPM2
||Distal arthrogryposis is characterized by joint contractures, particularly in the hands and feet. Distal arthrogryposis can occur alone or with additional neuromuscular symptoms such as muscle weakness, hypotonia, and neurological issues. The contractures are most often a result of decreased fetal movements and the subsequent formation of extra connective tissue in the joints; these contractures are therefore present at birth but do not progress over time. Even within families, the severity of the disease and number of joints involved can vary widely between individuals. Treatment includes physical therapy and medical management of other symptoms.
||MTM1, SPEG, BIN1, CCDC78, DNM2, TTN
||Centronuclear myopathy is an inherited disorder affecting the skeletal muscles through displacement of the nucleus in muscle cells; this abnormality results in muscle weakness and wasting. Pathogenic variants in genes such as DNM2 and BIN1 cause centronuclear myopathy. Age of onset of muscle weakness varies greatly between individuals and often progresses slowly. Some individuals also experience respiratory issues, weakness of the facial muscles, and cardiomyopathy. Centronuclear myopathy caused by the MTM1 gene, also known as X-linked myotubular myopathy (X-MTM), is a severe form of the condition and presents prenatally in male fetuses with polyhydramnios and decreased fetal movements; most infants require respiratory support. There is no cure for centronuclear myopathy, and treatment is based on management of symptoms.