MedGen

X-linked myotubular myopathy (X-MTM), also known as myotubular myopathy (MTM), is characterized by muscle weakness that ranges from severe to mild. Approximately 80% of affected males present with severe (classic) X-MTM characterized by polyhydramnios, decreased fetal movement, and neonatal weakness, hypotonia, and respiratory failure. Motor milestones are significantly delayed and most individuals fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most individuals requiring 24-hour ventilatory assistance. It is estimated that at least 25% of boys with severe X-MTM die in the first year of life, and those who survive rarely live into adulthood. Males with mild or moderate X-MTM (~20%) achieve motor milestones more quickly than males with the severe form; many ambulate independently, and may live into adulthood. Most require gastrostomy tubes and/or ventilator support. In all subtypes of X-MTM, the muscle disease is not obviously progressive. Female carriers of X-MTM are generally asymptomatic, although manifesting heterozygotes are increasingly being identified. In affected females, symptoms range from severe, generalized weakness presenting in childhood, with infantile onset similar to affected male patients, to mild (often asymmetric) weakness manifesting in adulthood. Affected adult females may experience progressive respiratory decline and ultimately require ventilatory support. [from GeneReviews]

Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present. [from GeneReviews]

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections. [from GeneReviews]

CLPB (caseinolytic peptidase B) deficiency is characterized by neurologic involvement and neutropenia, which can range from severe to mild. In severe CLPB deficiency, death usually occurs at a few months of age due to significant neonatal neurologic involvement (hyperekplexia or absence of voluntary movements, hypotonia or hypertonia, swallowing problems, respiratory insufficiency, and epilepsy) and severe neutropenia associated with life-threatening infections. Individuals with moderate CLPB deficiency present with neurologic abnormalities in infancy including hypotonia and feeding problems, and develop spasticity, a progressive movement disorder (ataxia, dystonia, and/or dyskinesia), epilepsy, and intellectual disability. Neutropenia is variable, but not life threatening. In those with mild CLPB deficiency there is no neurologic involvement, intellect is normal, neutropenia is mild and intermittent, and life expectancy is normal. [from GeneReviews]

Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Treatment with cholinesterase inhibitors or amifampridine may be helpful (summary by Engel et al., 2015). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). [from OMIM]

Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss (summary by Zenker et al., 2004). Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5; 614199). [from OMIM]

Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015). [from OMIM]

ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies. [from GeneReviews]

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2) is an autosomal recessive multisystemic disorder characterized by cholestatic hepatitis, poor feeding associated with poor overall growth, and hypoglycemia apparent from infancy. Most, but not all, patients have variable global developmental delay. Additional common features include sensorineural deafness, retinal abnormalities with visual defects, and hypotonia. Some patients have endocrine abnormalities, including hyperinsulinemic hypoglycemia, pancreatic dysfunction, hypothyroidism, and primary amenorrhea. Additional features may include hypertriglyceridemia, anemia, proteinuria, increased lactate, and recurrent infections. Brain imaging often shows dysmyelination, thin corpus callosum, cerebral atrophy, and white matter abnormalities. Although the clinical manifestations and severity of the disorder are highly variable, death in early childhood may occur (summary by Williams et al., 2019 and Zeiad et al., 2021). For a discussion of genetic heterogeneity of IMNEPD, see IMNEPD1 (616263). [from OMIM]

Congenital myopathy-2C (CMYP2C) is an autosomal dominant disorder of the skeletal muscle characterized by severe congenital weakness usually resulting in death from respiratory failure in the first year or so of life. Patients present at birth with hypotonia, lack of antigravity movements, poor head control, and difficulties feeding or breathing, often requiring tube-feeding and mechanical ventilation. Decreased fetal movements may be observed in some cases. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype. Some patients with heterozygous mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation (CMYP2A; 161800). The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]

Hypomyelinating leukodystrophy-15 is an autosomal recessive neurodegenerative disorder characterized by onset of motor and cognitive impairment in the first or second decade of life. Features include dystonia, ataxia, spasticity, and dysphagia. Most patients develop severe optic atrophy, and some have hearing loss. Brain imaging shows hypomyelinating leukodystrophy with thin corpus callosum. The severity of the disorder is variable (summary by Mendes et al., 2018) For a discussion of genetic heterogeneity of HLD, see 312080. [from OMIM]

Short-rib thoracic dysplasia-21 (SRTD21) is characterized by rhizomelic limb shortening with bowing of long bones and metaphyseal abnormalities, narrow chest with short broad ribs, and trident pelvis. Other features include hypotonia and global developmental delay, with corpus callosum hypoplasia and cerebellar vermis abnormalities on brain imaging, which may show the 'molar tooth' sign (Hammarsjo et al., 2017). For a general phenotypic description and discussion of genetic heterogeneity of SRTD, see SRTD1 (208500). Mutation in the KIAA0753 gene also causes orofaciodigital syndrome (OFD15; 617127) and Joubert syndrome (JBTS28; 619476), phenotypes with features overlapping those of SRTD21. [from OMIM]

Developmental and epileptic encephalopathy-31B (DEE31B) is an autosomal recessive neurologic disorder with early-onset epilepsy, generalized muscular hypotonia, visual impairment, and severe neurodevelopmental delay (Yigit et al., 2022). [from OMIM]

Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (Chilton et al., 2020). [from OMIM]

Childhood-onset neurodegeneration with progressive microcephaly (CONPM) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from infancy. The phenotype is highly variable: the most severely affected individuals have severe and progressive microcephaly, early-onset seizures, lack of visual tracking, and almost no developmental milestones, resulting in early death. Less severely affected individuals have a small head circumference and severely impaired intellectual development with poor speech and motor delay. Additional features may include poor overall growth, axial hypotonia, limb hypertonia with spasticity, undescended testes, and cerebral atrophy with neuronal loss (Lam et al., 2019 and Vanoevelen et al., 2022). [from OMIM]

Childhood-onset remitting leukodystrophy (CORLK) is a very rare autosomal dominant disorder characterized in some patients by onset of a metabolic crisis at the end of the first year of life that leads to widespread demyelination and leukodystrophy on brain imaging and a dramatic loss of developmental abilities. Affected children recover over the following several months, regaining normal development accompanied by remyelination. Not all patients have documented acute episodes of metabolic demyelination in infancy, but individuals with the FBP2 mutation show persistent white matter abnormalities on brain imaging that resemble the abnormalities observed in infants with the acute crisis. Other neurologic disturbances that may or may not be related to the FBP2 mutation have been observed, including psychiatric manifestations, seizures, and mild learning difficulties (Gizak et al., 2021). [from OMIM]

Immunodeficiency-85 and autoimmunity (IMD85) is an autosomal dominant immunologic disorder characterized by onset of atopic eczema and recurrent respiratory infections in the first decade of life. Affected individuals also develop autoimmune enteropathy with vomiting, diarrhea, and poor overall growth. More variable features may include autoimmune oligoarthritis, interstitial pneumonitis, and EBV viremia. Laboratory studies show hypogammaglobulinemia and abnormal T-cell function, consistent with a combined immunodeficiency (Keskitalo et al., 2019). [from OMIM]

Severe fetal congenital myopathy-22B (CMYP22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]

Birk-Aharoni syndrome (BKAH) is a severe neurodevelopmental disorder characterized developmental delay, impaired intellectual development, absent speech, spastic tetraplegia with central hypotonia, chorea, inability to walk, hearing loss, micropenis, undescended testes, and mildly elevated liver enzymes (Aharoni et al., 2022). [from OMIM]