Marinesco-Sjögren syndrome (MSS) is characterized by cerebellar ataxia with cerebellar atrophy, dysarthria, nystagmus, early-onset (not necessarily congenital) cataracts, myopathy, muscle weakness, and hypotonia. Additional features may include psychomotor delay, hypergonadotropic hypogonadism, short stature, and various skeletal abnormalities. Children with MSS usually present with muscular hypotonia in early infancy; distal and proximal muscular weakness is noticed during the first decade of life. Later, cerebellar findings of truncal ataxia, dysdiadochokinesia, nystagmus, and dysarthria become apparent. Motor function worsens progressively for some years, then stabilizes at an unpredictable age and degree of severity. Cataracts can develop rapidly and typically require lens extraction in the first decade of life. Although many adults have severe disabilities, life span in MSS appears to be near normal.

Welander distal myopathy (WDM) is an autosomal dominant disorder characterized by adult onset of distal muscle weakness predominantly affecting the distal long extensors of the hands, with slow progression to involve all small hand muscles and the lower legs. Skeletal muscle biopsy shows myopathic changes and prominent rimmed vacuoles. Rare homozygous patients showed earlier onset, faster progression, and proximal muscle involvement. This disorder is common in Sweden and Finland (summary by Hackman et al., 2013).

Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in the elderly that results in severe disability. Although traditionally considered an inflammatory myopathy, it is now considered to be more consistent with a myodegenerative disease (Sugarman et al., 2002; Askanas and Engel, 2006).

Autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3) is characterized by slowly progressive proximal muscle weakness affecting the upper and lower limbs. Onset is usually in adulthood, but can occur during the teenage years. Affected individuals may also develop cataracts before age 50 (summary by Vieira et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).

Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.

Udd distal myopathy – tibial muscular dystrophy (UDM-TMD) is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 30 years. Disease progression is slow and muscle weakness remains confined to the anterior compartment muscles for many years. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, UDM-TMD can remain unnoticed even in the elderly. EMG shows profound myopathic changes in the anterior tibial muscle, but preservation of the extensor brevis muscle. Muscle MRI shows selective fatty degeneration of the anterior tibial muscles and other anterior compartment muscles of the lower legs. Serum CK concentration may be normal or slightly elevated. Muscle biopsy shows progressive dystrophic changes in the tibialis anterior muscle with rimmed vacuoles at the early stages and replacement with adipose tissue at later stages of the disease.

Autosomal dominant limb-girdle muscular dystrophy-2 (LGMDD2) is a myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients. Affected individuals also have distal muscle weakness of the hands and lower leg muscles. There is variability in presentation and progression. Some patients present in early childhood with mildly delayed walking and difficulty running and jumping, whereas others present as adults with mainly pelvic-girdle weakness. Patients with early onset tend to have a more severe disorder, and may develop contractures, loss of independent ambulation, and respiratory insufficiency. Muscle biopsy shows dystrophic changes with abnormal nuclei, rimmed vacuoles, and filamentous inclusions (summary by Melia et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).

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).

GNE myopathy is a slowly progressive muscle disease that typically presents between age 20 and 40 years with bilateral foot drop caused by anterior tibialis weakness. Lower-extremity muscle involvement progresses from the anterior to the posterior compartment of the lower leg, followed by hamstrings, then hip girdle muscles, with relative sparing of the quadriceps. A wheelchair may be needed about ten to 20 years after the onset of manifestations. The upper extremities, which may be affected within five to ten years of disease onset, do not necessarily follow a distal-to-proximal progression. In advanced stages, neck and core muscles can become affected.

Hereditary myopathy with early respiratory failure (HMERF) is a slowly progressive myopathy that typically begins in the third to fifth decades of life. The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness. Weakness eventually generalizes and affects both proximal and distal muscles. Most affected individuals require walking aids within a few years of onset; some progress to wheelchair dependence and require nocturnal noninvasive ventilatory support about ten years after onset. The phenotype varies even among individuals within the same family: some remain ambulant until their 70s whereas others may require ventilator support in their 40s.

Distal myopathy-3 (MPD3) is an autosomal dominant skeletal muscle disorder characterized by adult onset of slowly progressive distal muscular weakness and atrophy affecting the upper and lower limbs, leading to difficulties using the hands and walking difficulties. Proximal muscle involvement may occur later in the disease, but patients typically remain ambulatory. Muscle biopsy shows myopathic changes with rimmed vacuoles (Hackman et al., 2021).

A mild form of limb-girdle muscular dystrophy with characteristics of muscle weakness in the four limbs, mild scapular winging, severe atrophy of the quadriceps and anterior tibialis muscles, calf hypertrophy and lack of respiratory and cardiac involvement.

Autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) is characterized by adult onset of slowly progressive skeletal muscle weakness variably affecting the distal or proximal lower limbs. Some patients may also have upper limb involvement or neck muscle weakness, but respiratory and bulbar involvement only rarely occurs. EMG studies show a myopathic process, and myotonia may also be observed. Skeletal muscle biopsy shows myopathic features, rimmed vacuoles, and abnormal subsarcolemmal protein aggregation with activation of the autophagy pathway (Ruggieri et al., 2020).

A rare genetic neuromuscular disease with characteristics of adult-onset muscle weakness and atrophy in a scapuloperoneal distribution, mild involvement of the facial muscles, dysphagia, and gynaecomastia. Elevated serum CK levels and mixed myopathic and neurogenic abnormalities are associated clinical findings. Caused by heterozygous mutation in the DES gene on chromosome 2q35.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals.

Limb-girdle muscular dystrophy-dystroglycanopathy type C15 (MDDGC15) is an autosomal recessive disorder characterized by progressive proximal muscle weakness, manifest initially as unsteady gait, but later including more distal muscles, and dilated cardiomyopathy. The age at onset varies widely from the first decade to adulthood; those with earlier onset may have delayed motor development. Laboratory studies show increased serum creatine kinase and muscle biopsy shows dystrophic features with decreased alpha-dystroglycan (DAG1; 128239). Biochemical studies often show evidence of abnormal N-glycosylation of serum proteins, consistent with a congenital disorder of glycosylation (CDG) (summary by Svahn et al., 2019). For a discussion of genetic heterogeneity of muscular dystrophy- dystroglycanopathy type C, see MDDGC1 (609308). For a discussion of the classification of CDGs, see CDG1A (212065).

Congenital myopathy-10B (CMYP10B) 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 (CMYP10B) 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 (CMYP10A) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the HNRNPA1 gene.

Amyotrophic lateral sclerosis-21 (ALS21) is an autosomal dominant neurodegenerative disorder affecting upper and lower motor neurons, resulting in muscle weakness and respiratory failure. Some patients may develop myopathic features or dementia (summary by Johnson et al., 2014). For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD.

Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD.

Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death (RBMX1A; 300717), and a less severe form has onset in late childhood or adulthood (RBMX1B) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).

Axonal Charcot-Marie-Tooth disease type 2CC is an autosomal dominant peripheral neuropathy that predominantly affects the lower limbs, resulting in muscle weakness and atrophy and gait impairment. Other features include distal sensory impairment and less severe involvement of the upper limbs. The age at onset and severity are variable (summary by Rebelo et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Centronuclear myopathy-6 with fiber-type disproportion (CNM6) is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy (summary by Vasli et al., 2017). For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).

Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD.

Laing distal myopathy is characterized by early-onset weakness (usually before age 5 years) that initially involves the dorsiflexors of the ankles and great toes and then the finger extensors, especially those of the third and fourth fingers. Weakness of the neck flexors is seen in most affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness may be observed. Life expectancy is normal.

Autosomal dominant limb-girdle muscular dystrophy is characterized by proximal and/or distal muscle weakness and atrophy. The age at onset is variable and can range from the first to the sixth decade, although later onset is less common. Most patients present with proximal muscle weakness that progresses to distal involvement, but some can present with distal impairment. The severity is variable: patients with a more severe phenotype can lose ambulation after several decades and have facial weakness with bulbar and respiratory involvement. Muscle biopsy shows dystrophic changes with protein aggregates, myofibrillar degeneration, and rimmed vacuoles (summary by Ruggieri et al., 2015). Genetic Heterogeneity of Autosomal Dominant Limb-Girdle Muscular Dystrophy Other forms of autosomal dominant LGMD include LGMDD2 (608423), previously LGMD1F, caused by mutation in the TNPO3 gene (610032) on chromosome 7q32; LGMDD3 (609115), previously LGMD1G, caused by mutation in the HNRNPDL gene (607137) on chromosome 4q21; and LGMDD4 (618129), previously LGMD1I, caused by mutation in the CAPN3 gene (114240) on chromosome 15q15. For a discussion of autosomal recessive LGMD, see 253600.

Autosomal dominant adult-onset distal myopathy-6 (MPD6) is a muscle disorder characterized by slowly progressive distal muscle weakness, primarily affecting the lower limbs and resulting in gait difficulties. Some patients develop involvement of proximal and upper limb muscles (summary by Savarese et al., 2019)

Oculopharyngodistal myopathy-1 (OPDM1) is an autosomal dominant disorder characterized by adult-onset ptosis, external ophthalmoplegia, facial muscle weakness, distal limb muscle weakness and atrophy, and pharyngeal involvement, resulting in dysphagia and dysarthria. Skeletal muscle biopsy shows myopathic changes with rimmed vacuoles. There are variable manifestations of the disorder regarding muscle involvement and severity (summary by Ishiura et al., 2019). Genetic Heterogeneity of Oculopharyngodistal Myopathy See also OPDM2 (618940), caused by trinucleotide repeat expansion in the GIPC1 gene (605072) on chromosome 19p13; OPDM3 (619473), caused by trinucleotide repeat expansion in the NOTCH2NLC gene (618025) on chromosome 1q21; and OPDM4 (619790), caused by trinucleotide repeat expansion in the RILPL1 gene (614092) on chromosome 12q24. Oculopharyngeal muscular dystrophy (OPMD; 164300) is a similar disorder with overlapping features. It is caused by a similar heterozygous trinucleotide repeat expansion in the PABPN1 gene (602279) (summary by Durmus et al., 2011).

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).

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal dominant myopathic disorder characterized by adult onset of muscle weakness affecting the distal upper and lower limbs, which may result in walking difficulties, as well as proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles (summary by Bucelli et al., 2015).

Oculopharyngodistal myopathy-3 (OPDM3) is a neuromyodegenerative disease characterized by progressive muscle weakness with ocular, facial, pharyngeal, and distal limb involvement, resulting in dysarthria and gait difficulties. The onset of the disorder is usually in adulthood, although childhood onset has rarely been reported. Additional features include hyporeflexia, proximal muscle weakness, neck muscle weakness, dysarthria, dysphagia, and ptosis. Some patients may develop pigmentary retinopathy, peripheral neuropathy, or hearing loss. Cognition is usually not affected, but there may be deficits or psychiatric manifestations. Brain imaging tends to show a leukoencephalopathy, often with a characteristic linear signal along the corticomedullary junction on brain imaging. Skin and muscle biopsy show intranuclear inclusions and rimmed vacuoles. Many of the clinical features are reminiscent of NIID, suggesting that these disorders likely fall within a broad phenotypic spectrum of diseases with neuromyodegenerative features associated with abnormal repeat expansions in this gene (summary by Ogasawara et al., 2020 and Yu et al., 2021). For a discussion of genetic heterogeneity of OPDM, see OPDM1 (164310).

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (MDHLO) is an autosomal recessive systemic disorder characterized by progressive muscle weakness, sensorineural hearing loss, and endocrine abnormalities, mainly primary amenorrhea due to ovarian insufficiency. Features of the disorder appear soon after birth, although endocrine anomalies are not noted until puberty. The severity of the phenotype is variable: some patients may lose ambulation and have significant respiratory insufficiency, whereas others retain the ability to walk (Foley et al., 2020).

Distal myopathy-5 (MPD5) is an autosomal recessive, slowly progressive muscle disorder characterized by adolescent onset of distal muscle weakness and atrophy predominantly affecting the lower limbs. Other features include facial weakness and hyporeflexia. Patients remain ambulatory even after long disease duration (summary by Park et al., 2016).

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).

Amyotrophic lateral sclerosis-28 (ALS28) is an autosomal dominant neurodegenerative disorder characterized by adult onset of slowly progressive limb muscle weakness and atrophy resulting in gait difficulties, loss of ambulation, and distal upper limb weakness. Facial involvement is rare, but some patients may have respiratory insufficiency. EMG and muscle biopsy show active and chronic denervation. Patient-derived motor neurons show accumulation of TDP43 (605078) and toxic intranuclear RNA accumulation (Kume et al., 2023). For discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).