Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by distal joint laxity and a combination of distal and proximal joint contractures. The age at onset is highly variable, ranging from infancy to adulthood. Disease progression is slow and ambulation is usually retained into adulthood (summary by Butterfield et al., 2013). Genetic Heterogeneity of Bethlem Myopathy See Bethlem myopathy-1B (BTHLM1B; 620725), caused by mutation in the COL6A2 gene (120240) on chromosome 21q22; Bethlem myopathy-1C (620726), caused by mutation the COL6A3 gene (120250) on chromosome 2q37; and Bethlem myopathy-2 (BTHLM2; 616471), caused by mutation in the COL12A1 gene (120320) on chromosome 6q13-q14.

A form of limb-girdle muscular dystrophy that usually has a childhood onset (but can range from the first to third decade of life) of severe progressive proximal weakness, eventually involving the distal muscles. Some patients may remain ambulatory but most are wheelchair dependant 20 years after onset. Caused by homozygous mutation in the titin gene (TTN).

Nemaline myopathy-2 (NEM2) is an autosomal recessive skeletal muscle disorder with a wide range of severity. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. Muscle biopsy shows accumulation of Z-disc and thin filament proteins into aggregates named 'nemaline bodies' or 'nemaline rods,' usually accompanied by disorganization of the muscle Z discs. The clinical and histologic spectrum of entities caused by variants in the NEB gene is a continuum, ranging in severity. The distribution of weakness can vary from generalized muscle weakness, more pronounced in proximal limb muscles, to distal-only involvement, although neck flexor weakness appears to be rather consistent. Histologic patterns range from a severe usually nondystrophic disturbance of the myofibrillar pattern to an almost normal pattern, with or without nemaline bodies, sometimes combined with cores (summary by Lehtokari et al., 2014). Genetic Heterogeneity of Nemaline Myopathy See also NEM1 (255310), caused by mutation in the tropomyosin-3 gene (TPM3; 191030) on chromosome 1q22; NEM3 (161800), caused by mutation in the alpha-actin-1 gene (ACTA1; 102610) on chromosome 1q42; NEM4 (609285), caused by mutation in the beta-tropomyosin gene (TPM2; 190990) on chromosome 9p13; NEM5A (605355), also known as Amish nemaline myopathy, NEM5B (620386), and NEM5C (620389), all caused by mutation in the troponin T1 gene (TNNT1; 191041) on chromosome 19q13; NEM6 (609273), caused by mutation in the KBTBD13 gene (613727) on chromosome 15q22; NEM7 (610687), caused by mutation in the cofilin-2 gene (CFL2; 601443) on chromosome 14q13; NEM8 (615348), caused by mutation in the KLHL40 gene (615340), on chromosome 3p22; NEM9 (615731), caused by mutation in the KLHL41 gene (607701) on chromosome 2q31; NEM10 (616165), caused by mutation in the LMOD3 gene (616112) on chromosome 3p14; and NEM11 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. Several of the genes encode components of skeletal muscle sarcomeric thin filaments (Sanoudou and Beggs, 2001). Mutations in the NEB gene are the most common cause of nemaline myopathy (Lehtokari et al., 2006).

STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.

Nemaline myopathy-7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (summary by Ockeloen et al., 2012). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.

A rare genetic congenital muscular dystrophy due to extracellular matrix protein anomaly. The disease has characteristics of early motor development delay and muscle weakness with mild elevation of serum creatine kinase that may be followed by progressive disease course with predominantly proximal muscle weakness and atrophy, motor development regress, scoliosis and respiratory insufficiency. There is evidence this disease is caused by compound heterozygous mutation in the ITGA7 gene on chromosome 12q13.

Congenital myopathy-10B (CMYO10B) is an autosomal recessive skeletal muscle disorder characterized by infantile- or childhood-onset myopathy, areflexia, dysphagia, and respiratory distress that usually requires nocturnal ventilation. Other common features include facial and neck muscle weakness, feeding difficulties, contractures, scoliosis, high-arched palate, hyporeflexia, and difficulties walking. The disorder is slowly progressive and most patients follow a chronic course. Muscle biopsy shows variable findings, including type 1 fiber predominance, minicore lesions, and myofibrillar disorganization (Boyden et al., 2012; Harris et al., 2018). Patients with missense mutations affecting conserved cysteine residues in the EGF-like domain show the mild variant phenotype (CMYO10B) with later onset of respiratory failure and minicores on muscle biopsy, whereas patients with more damaging mutations, including nonsense or frameshift null mutations, show the severe variant phenotype (CMYO10A) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Nemaline myopathy-10 (NEM10) is an autosomal recessive severe congenital myopathy characterized by early-onset generalized muscle weakness and hypotonia with respiratory insufficiency and feeding difficulties. Many patients present antenatally with decreased fetal movements, and most die of respiratory failure in early infancy (summary by Yuen et al., 2014). Patients with a stable and much milder disease course have been described (Schatz et al., 2018). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800).

Autosomal recessive limb-girdle muscular dystrophy-21 (LGMDR21) is characterized by progressive limb-girdle weakness with age of onset ranging from congenital to adult. Muscle imaging shows a specific and selective pattern of fatty muscle degeneration (summary by Servian-Morilla et al., 2020). For a discussion of genetic heterogeneity of autosomal recessive LGMD, see LGMDR1 (253600).

Lipid storage myopathy due to FLAD1 deficiency is an autosomal recessive inborn error of metabolism that includes variable mitochondrial dysfunction. The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment (summary by Olsen et al., 2016).

Autosomal dominant limb-girdle muscular dystrophy-4 (LGMDD4) is characterized by onset of proximal muscle weakness in young adulthood. Affected individuals often have gait difficulties; some may have upper limb involvement. Other features include variably increased serum creatine kinase, myalgia, and back pain. The severity and expressivity of the disorder is highly variable, even within families (summary by Vissing et al., 2016). For a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see 603511.

Charcot-Marie-Tooth disease type 1G is an autosomal dominant progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade. Affected individuals have difficulty walking, distal sensory impairment with decreased or absent reflexes, and often have foot deformities. Median motor nerve conduction velocities (NCV) are decreased (less than 38 m/s) and sural nerve biopsy shows myelin defects and onion bulb formation (summary by Hong et al., 2016 and Motley et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Congenital myopathy-9B (CMYO9B) is an autosomal recessive early-onset skeletal muscle disorder mainly affecting proximal muscles. Affected individuals have neonatal hypotonia followed by mildly delayed walking in childhood. Muscle weakness is slowly progressive, resulting in positive Gowers sign and difficulty running or climbing, but most patients remain ambulatory. Some patients develop respiratory involvement requiring ventilatory support, whereas cardiac function is unaffected. Muscle biopsy shows type 1 fiber predominance with disorganized Z-lines and multiminicore myopathy (Estan et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Autosomal recessive limb-girdle muscular dystrophy-26 (LGMDR26) is a muscle disorder characterized by adult-onset weakness that primarily affects the proximal muscles of the lower limbs. The disorder is slowly progressive, with later involvement of the upper limbs and fatty replacement of muscle tissue apparent on MRI. Some patients may have calf hypertrophy. Serum creatine kinase is significantly elevated, and skeletal muscle biopsy shows typical dystrophic features with normal ultrastructural findings. There is no cardiac or respiratory involvement (summary by Vissing et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Oculopharyngodistal myopathy-2 (OPDM2) is an autosomal dominant muscle disorder characterized by onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. The disorder is slowly progressive, and patients develop facial weakness, bulbar weakness, and difficulty walking or climbing stairs. Some patients may have upper limb involvement and subclinical respiratory insufficiency. Laboratory studies show increased serum creatine kinase; skeletal muscle biopsy shows myopathic changes with abnormal cytoplasmic and intranuclear inclusions (summary by Deng et al., 2020). For a discussion of genetic heterogeneity of OPDM, see OPDM1 (164310).

X-linked adult-onset distal myopathy-7 (MPD7) is an X-linked recessive disorder that affects only males. It is characterized by onset of distal muscle weakness predominantly affecting the lower limbs between 20 and 60 years of age. The disorder is slowly progressive, with most affected individuals developing distal upper limb involvement and some developing proximal muscle involvement, although patients remain ambulatory. Muscle biopsy shows variable myopathic changes as well as sarcoplasmic inclusions that may represent abnormally aggregated proteins (summary by Johari et al., 2021).

Inclusion body myopathy and brain white matter abnormalities (IBMWMA) is an autosomal dominant adult-onset disorder characterized predominantly by proximal limb girdle muscle weakness affecting the lower and upper limbs and resulting in gait difficulties and scapular winging. Additional features may include dysarthria, dysphagia, low back pain, and hyporeflexia. EMG is consistent with a myopathic process, although neuropathic findings have also been shown. Muscle biopsy shows fiber type variation, internal nuclei, rimmed vacuoles, and cytoplasmic protein aggregates or inclusions. Serum creatine kinase is usually elevated. Cognitive impairment or frontotemporal dementia occurs in some patients. The disorder is slowly progressive; some patients become wheelchair-bound after many years. Rare patients with this mutation develop ALS; some have both myopathy and ALS. Brain imaging shows white matter abnormalities using diffusion tensor imaging. The disorder is classified as multisystem proteinopathy-6 (MSP6) due to the characteristic disease mechanism of protein misfolding and abnormal tissue deposition (summary by Leoni et al., 2021).

Oculopharyngodistal myopathy-4 (OPDM4) is an autosomal dominant neuromuscular disorder characterized by progressive ptosis, ophthalmoparesis, facial and masseter weakness, and muscle weakness of the distal limbs. Initial symptoms of the disorder, ptosis and limited eye movements, most commonly appear in the second or third decades. There is slow progression with development of dysarthria, dysphagia, and distal limb weakness and atrophy associated with absent deep tendon reflexes; sensation is normal. Serum creatine kinase is often increased, and skeletal muscle biopsy typically shows chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions (summary by Yu et al., 2022). For a discussion of genetic heterogeneity of OPDM, see OPDM1 (164310).

Congenital myopathy-15 (CMYO15) is a skeletal muscle disorder characterized by symptom onset soon after birth. Affected infants are hypotonic and have severe respiratory insufficiency and feeding problems, sometimes requiring mechanical ventilation or tube feeding. The disorder is unique in that there is gradual improvement of the severe muscle weakness with time, although forced vital capacity remains decreased. Additional features include facial weakness, scoliosis, joint contractures, and persistent ptosis or external ophthalmoplegia (van de Locht et al., 2021). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Congenital myopathy-18 (CMYO18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood. Most affected individuals show delayed motor development with generalized hypotonia and progressive axial and limb muscle weakness beginning soon after birth or in infancy. Additional features may include swallowing difficulties, external ophthalmoplegia, ptosis, high-arched palate, and respiratory insufficiency, which can lead to death in severe cases. Muscle biopsy shows variable morphologic abnormalities, including alveolar changes in the intermyofibrillar network, fiber size variability, focal disorganization, internal nuclei, and dilated sarcoplasmic reticulum and T-tubules. The disorder results from a defect in excitation-contraction coupling in skeletal muscle (Schartner et al., 2017; Ravenscroft et al., 2021; Mauri et al., 2021; Yis et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Immunodeficiency-115 with autoinflammation (IMD115) is an autosomal recessive disorder characterized by the onset of symptoms of immune dysregulation in early infancy. Affected individuals have immunodeficiency with recurrent bacterial, viral, and fungal infections, as well as autoinflammatory features, including arthritis and dermatitis. Some patients may have more systemic involvement, such as myopathy, gastrointestinal abnormalities, and anemia. Laboratory studies show variable B-cell and T-cell defects, sometimes with defective antibody responses and hypogammaglobulinemia (Boisson et al., 2015; Oda et al., 2019).