MedGen

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias. [from GeneReviews]

Autosomal recessive distal hereditary motor neuronopathy-1 (HMNR1) is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, most infants with the severe form of the disease die before 2 years of age. Affected individuals present in infancy with inspiratory stridor, weak cry, recurrent bronchopneumonia, and swallowing difficulties. The disorder is caused by distal and progressive motor neuronopathy resulting in muscle weakness (summary by Perego et al., 2020). Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy See also HMNR2 (605726), caused by mutation in the SIGMAR1 gene (601978); HMNR3 (607088) (encompassing Harding HMN types III and IV), which maps to chromosome 11q13; HMNR4 (611067), caused by mutation in the PLEKHG5 gene (611101); HMNR5 (614881), caused by mutation in the DNAJB2 gene (604139); HMNR6 (620011), caused by mutation in the REEP1 gene (609139); HMNR7 (619216), caused by mutation in the VWA1 gene (611901); HMNR8 (618912), caused by mutation in the SORD gene (182500); HMNR9 (620402), caused by mutation in the COQ7 gene (601683); and HMRN10 (620542), caused by mutation in the VRK1 gene (602168). [from OMIM]

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. [from GeneReviews]

Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010). Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q. [from OMIM]

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias. [from GeneReviews]

Fazio-Londe disease is a progressive bulbar palsy with onset in childhood that presents with hypotonia and respiratory insufficiency (summary by Bosch et al., 2011). [from OMIM]

Congenital myopathy-10A (CMYP10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011). Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYP10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYP10B) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]

Autosomal recessive distal hereditary motor neuronopathy-3 (HMNR3), also known as distal spinal muscular atrophy (DSMA) and distal hereditary motor neuronopathy (dHMN or HMN), is characterized by distal muscle weakness and wasting without significant sensory involvement. For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320). Harding (1993) classified autosomal recessive distal hereditary motor neuronopathy as dHMN IV (HMN4) and dHMN III (HMN3). Both have juvenile onset and differ only by less severe involvement in HMN3. However, Viollet et al. (2004) reported an extended Lebanese kindred in which both HMN III and HMN IV occurred, suggesting that the same gene was involved in both phenotypes (see Irobi et al., 2006). [from OMIM]

A rare genetic neuromuscular disorder characterized by proximal and symmetrical muscle weakness (particularly of neck, sternomastoid, facial and diaphragm muscles), spinal rigidity, joint contractures (Achilles tendon, elbows, hands), generalized muscle hypertrophy and early respiratory failure (usually in the first decade of life). Patients typically present delayed motor milestones and grossly elevated serum creatine kinase levels, and with disease progression, forced expiratory abdominal squeeze and nocturnal hypoventilation. [from SNOMEDCT_US]

Congenital myopathy-21 with early respiratory failure (CMYP21) is an autosomal recessive muscle disorder associated with diaphragmatic weakness and spinal rigidity. The age at symptom onset is highly variable, ranging from infancy to adulthood; the severity of the respiratory impairment, which can lead to death in the most severe cases, is also variable. Additional features, including developmental delay and hypertrophic cardiomyopathy, have been observed in one patient each (Weihl et al., 2023; Al-Kasbi et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]

A decrease in the strength of the diaphragm. [from HPO]