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Severe X-linked myotubular myopathy(CNMX)

MedGen UID:
98374
Concept ID:
C0410203
Congenital Abnormality
Synonyms: CNMX; MYOTUBULAR MYOPATHY 1; Myotubular myopathy, X-linked; X-linked centronuclear myopathy
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
X-linked recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: X-linked centronuclear myopathy (46804001); Severe x-linked myotubular myopathy (46804001)
 
Gene (location): MTM1 (Xq28)
OMIM®: 310400
Orphanet: ORPHA596

Definition

X-linked centronuclear myopathy (XLCNM) (also known as myotubular myopathy [MTM]) is characterized by muscle weakness that ranges from severe to mild. Severe (classic) XLCNM presents prenatally with polyhydramnios and decreased fetal movement and in newborns with weakness, hypotonia, and respiratory distress. Affected males have significantly delayed motor milestones and most fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most affected individuals requiring 24-hour ventilatory assistance. A minority of males with severe XLCNM die in infancy. Males with moderate XLCNM achieve motor milestones more quickly than males with the severe form; about 40% require no ventilator support or intermittent support. Males with mild XLCNM may require ventilatory support only in the newborn period; they have minimally delayed motor milestones, are able to walk, and may lack myopathic facies. The muscle disease of XLCNM is not obviously progressive. Female carriers of XLCNM are generally asymptomatic, although rare manifesting heterozygotes have been described. [from GTR]

Additional descriptions

From GeneReviews
X-linked centronuclear myopathy (XLCNM) (also known as myotubular myopathy [MTM]) is characterized by muscle weakness that ranges from severe to mild. Severe (classic) XLCNM presents prenatally with polyhydramnios and decreased fetal movement and in newborns with weakness, hypotonia, and respiratory distress. Affected males have significantly delayed motor milestones and most fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most affected individuals requiring 24-hour ventilatory assistance. A minority of males with severe XLCNM die in infancy. Males with moderate XLCNM achieve motor milestones more quickly than males with the severe form; about 40% require no ventilator support or intermittent support. Males with mild XLCNM may require ventilatory support only in the newborn period; they have minimally delayed motor milestones, are able to walk, and may lack myopathic facies. The muscle disease of XLCNM is not obviously progressive. Female carriers of XLCNM are generally asymptomatic, although rare manifesting heterozygotes have been described.  https://www.ncbi.nlm.nih.gov/books/NBK1432
From GHR
X-linked myotubular myopathy is a condition that primarily affects muscles used for movement (skeletal muscles) and occurs almost exclusively in males. People with this condition have muscle weakness (myopathy) and decreased muscle tone (hypotonia) that are usually evident at birth.The muscle problems in X-linked myotubular myopathy impair the development of motor skills such as sitting, standing, and walking. Affected infants may also have difficulties with feeding due to muscle weakness. Individuals with this condition often do not have the muscle strength to breathe on their own and must be supported with a machine to help them breathe (mechanical ventilation). Some affected individuals need breathing assistance only periodically, typically during sleep, while others require it continuously. People with X-linked myotubular myopathy may also have weakness in the muscles that control eye movement (ophthalmoplegia), weakness in other muscles of the face, and absent reflexes (areflexia).In X-linked myotubular myopathy, muscle weakness often disrupts normal bone development and can lead to fragile bones, an abnormal curvature of the spine (scoliosis), and joint deformities (contractures) of the hips and knees. People with X-linked myotubular myopathy may have a large head with a narrow and elongated face and a high, arched roof of the mouth (palate). They may also have liver disease, recurrent ear and respiratory infections, or seizures.Because of their severe breathing problems, individuals with X-linked myotubular myopathy usually survive only into early childhood; however, some people with this condition have lived into adulthood.X-linked myotubular myopathy is a member of a group of disorders called centronuclear myopathies. In centronuclear myopathies, the nucleus is found at the center of many rod-shaped muscle cells instead of at either end, where it is normally located.  https://ghr.nlm.nih.gov/condition/x-linked-myotubular-myopathy

Clinical features

Arachnodactyly
MedGen UID:
2047
Concept ID:
C0003706
Congenital Abnormality
A tall and slim body build with increased arm span to height ratio (>1.05) and a reduced upper-to-lower segment ratio (<0.85), i.e., unusually long arms and legs. The extremities as well as the hands and feet are unusually slim.
Flexion contracture
MedGen UID:
3227
Concept ID:
C0009917
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Cryptorchidism, unilateral or bilateral
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Diaphragmatic eventration
MedGen UID:
8359
Concept ID:
C0011981
Congenital Abnormality
A congenital abnormality characterized by the elevation of the DIAPHRAGM dome. It is the result of a thinned diaphragmatic muscle and injured PHRENIC NERVE, allowing the intra-abdominal viscera to push the diaphragm upward against the LUNG.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
A condition of abnormally high AMNIOTIC FLUID volume, such as greater than 2,000 ml in the LAST TRIMESTER and usually diagnosed by ultrasonographic criteria (AMNIOTIC FLUID INDEX). It is associated with maternal DIABETES MELLITUS; MULTIPLE PREGNANCY; CHROMOSOMAL DISORDERS; and congenital abnormalities.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Autosomal recessive nonsyndromic hydrocephalus is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. Affected individuals may have neurologic impairment (summary by Drielsma et al., 2012). Hydrocephalus can also be caused by Arnold-Chiari malformation, atresia of foramen of Magendie, stenosis of aqueduct of Sylvius (307000), toxoplasmosis, hydranencephaly, etc. Furthermore, it develops in infancy or childhood in achondroplasia (100800) and in Hurler disease (607014). Genetic Heterogeneity of Congenital Hydrocephalus See also autosomal recessive HYC2 (615219), caused by mutation in the MPDZ gene (603785) on chromosome 9p. An X-linked form (307000) is caused by mutation in the L1CAM gene on (308840) on chromosome Xq28.
Pyloric stenosis
MedGen UID:
18780
Concept ID:
C0034194
Pathologic Function
An abnormal narrowing of the pylorus.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Decreased liver function
MedGen UID:
39248
Concept ID:
C0086565
Pathologic Function
A finding that indicates abnormal liver function.
External ophthalmoplegia
MedGen UID:
57662
Concept ID:
C0162292
Disease or Syndrome
Paralysis of the external ocular muscles.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
A finding indicating the complete absence of neurological reflexes.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.
Neck muscle weakness
MedGen UID:
66808
Concept ID:
C0240479
Finding
Decreased strength of the neck musculature.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Facial paralysis
MedGen UID:
98103
Concept ID:
C0427055
Sign or Symptom
A reduction in the strength of the facial muscles.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
A reduction in the strength of muscles in multiple anatomic sites.
Neonatal respiratory distress
MedGen UID:
163106
Concept ID:
C0852283
Disease or Syndrome
Respiratory difficulty as newborn.
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Birth length greater than 97th percentile
MedGen UID:
326443
Concept ID:
C1839271
Finding
Severe muscular hypotonia
MedGen UID:
326544
Concept ID:
C1839630
Finding
A severe degree of muscular hypotonia characterized by markedly reduced muscle tone.
Narrow face
MedGen UID:
338616
Concept ID:
C1849121
Finding
Bizygomatic (upper face) and bigonial (lower face) width are both more than 2 standard deviations below the mean (objective); or, an apparent reduction in the width of the upper and lower face (subjective).
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Macrocephaly refers to an abnormally enlarged head inclusive of the scalp, cranial bones, and intracranial contents. Macrocephaly may be due to megalencephaly (true enlargement of the brain parenchyma), and the 2 terms are often used interchangeably in the genetic literature (reviews by Olney, 2007 and Williams et al., 2008). Autosomal recessive macrocephaly/megalencephaly syndrome is characterized by an enlarged cranium apparent at birth or in early childhood. Affected individuals have intellectual disability and may have dysmorphic facial features resulting from the macrocephaly (summary by Alfaiz et al., 2014).
Slender toe
MedGen UID:
866814
Concept ID:
C4021168
Finding
Digits are disproportionately narrow (reduced girth) for the hand/foot size or build of the individual.
Respiratory failure requiring assisted ventilation
MedGen UID:
870821
Concept ID:
C4025279
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Severe X-linked myotubular myopathy in Orphanet.

Professional guidelines

PubMed

Biancalana V, Beggs AH, Das S, Jungbluth H, Kress W, Nishino I, North K, Romero NB, Laporte J
Eur J Hum Genet 2012 Oct;20(10) Epub 2012 May 23 doi: 10.1038/ejhg.2012.91. PMID: 22617344Free PMC Article

Recent clinical studies

Prognosis

Tyson RW, Ringel SP, Manchester DK, Shikes RH, Goodman SI
Pediatr Pathol 1992 Jul-Aug;12(4):535-43. PMID: 1409152

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