X-linked myotubular myopathy

Medical condition

X-linked myotubular myopathy
Other names	XLMTM

This condition is inherited in an X-linked recessive manner.

X-linked myotubular myopathy (MTM) is a form of centronuclear myopathy (CNM) associated with mutations in the myotubularin 1 gene. It is found almost always in male infants. It is one of the severest congenital muscle diseases and is characterized by marked muscle weakness, hypotonia and feeding and breathing difficulties.^{[citation needed]}

Genetics

This condition is caused by mutations in the myotubularin (MTM1) gene which is located on the long arm of the X chromosome (Xq28). Thus, almost all cases of X-linked MTM occurs in males. Females can be "carriers" for an X-linked genetic abnormality, but usually they will not be clinically affected themselves. Two exceptions for a female with a X-linked recessive abnormality to have clinical symptoms: one is a manifesting carrier and the other is X-inactivation. A manifesting carrier usually has no noticeable problems at birth; symptoms show up later in life. In X-inactivation, the female (who would otherwise be a carrier, without any symptoms), actually presents with full-blown X-linked MTM. Thus, she congenitally presents (is born with) MTM.^[1]

Thus, although MTM1 mutations most commonly cause problems in boys, these mutations can also cause clinical myopathy in girls, for the reasons noted above. Girls with myopathy and a muscle biopsy showing a centronuclear pattern should be tested for MTM1 mutations.^[1]

Abbreviations XL-MTM, XLMTM or X-MTM are sometimes used to emphasize that the mutation occurs on the X chromosome.

Research

Astellas Gene Therapies (earlier called Audentes Therapeutics) is developing an experimental gene therapy to treat the condition. A clinical trial was halted in 2020 after two boys participating in the trial died of liver inflammation and sepsis.^[2]

References

^ ^a ^b Jungbluth H, Sewry C, Buj-Bello A, Kristiansen M, Ørstavik K, Kelsey A, Manzur A, Mercuri E, Wallgren-Pettersson C, Muntoni F (2003). "Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation". Neuromuscul Disord. 13 (1): 55–9. doi:10.1016/S0960-8966(02)00194-3. PMID 12467733. S2CID 11161762.
^ Anonymous (2020). "Two boys die in gene therapy trial". Science. 369 (6499): 13.

External links

GeneReview/NCBI/NIH/UW entry on X-Linked Myotubular Myopathy

Classification	D ICD-10: G71.2 OMIM: 310400 MeSH: C538647
External resources	Orphanet: 596

Diseases of muscle, neuromuscular junction, and neuromuscular disease

Neuromuscular-
junction disease

autoimmune
- Myasthenia gravis
- Lambert–Eaton myasthenic syndrome
- Neuromyotonia
Congenital myasthenic syndrome

Myopathy

Muscular dystrophy
(DAPC)

AD	Limb-girdle muscular dystrophy 1 Oculopharyngeal Facioscapulohumeral Myotonic Distal (most)
AR	Calpainopathy Limb-girdle muscular dystrophy 2 Congenital Fukuyama Ullrich Walker–Warburg
XR	dystrophin Becker's Duchenne Emery–Dreifuss

Other structural

collagen disease
- Bethlem myopathy
PTP disease
- X-linked MTM
adaptor protein disease
- BIN1-linked centronuclear myopathy
cytoskeleton disease
- Nemaline myopathy
- Zaspopathy

Channelopathy

(ion channel)

Myotonia	Myotonia congenita Thomsen disease Becker disease Neuromyotonia Isaacs syndrome Paramyotonia congenita
Periodic paralysis	Hypokalemic Thyrotoxic Hyperkalemic
Other	Central core disease

ATPase disorder

(ion pump)

Brody disease (ATP2A1)

Metabolic myopathy

Endocrinopathy

Hypothyroid myopathy
- Kocher–Debre–Semelaigne syndrome
- Hoffmann syndrome
Hyperthyroid myopathy
- Thyrotoxic myopathy
Hypoparathyroid myopathy
Hyperparathyroid myopathy
Hypercortisolism
- Corticosteroid myopathy
Testosterone deficiency myopathy

General

X-linked disorders

X-linked recessive
Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency
Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia
Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita
Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry disease Mucopolysaccharidosis: Hunter syndrome Purine–pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome
Nervous system	X-linked intellectual disability: Coffin–Lowry syndrome MASA syndrome Alpha-thalassemia mental retardation syndrome PHF8 Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2
Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy
Neuromuscular	Becker muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1
Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus
Bone/tooth	AMELX Amelogenesis imperfecta
No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant
X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Deficiencies of intracellular signaling peptides and proteins

GTP-binding protein regulators

GTPase-activating protein	Neurofibromatosis type I Watson syndrome Tuberous sclerosis
Guanine nucleotide exchange factor	Marinesco–Sjögren syndrome Aarskog–Scott syndrome Juvenile primary lateral sclerosis X-linked intellectual disability 1

G protein

Heterotrimeic	cAMP/GNAS1: Pseudopseudohypoparathyroidism Progressive osseous heteroplasia Pseudohypoparathyroidism Albright's hereditary osteodystrophy McCune–Albright syndrome CGL 2
Monomeric	RAS: HRAS Costello syndrome KRAS Noonan syndrome 3 KRAS Cardiofaciocutaneous syndrome RAB: RAB7 Charcot–Marie–Tooth disease RAB23 Carpenter syndrome RAB27 Griscelli syndrome type 2 RHO: RAC2 Neutrophil immunodeficiency syndrome ARF: SAR1B Chylomicron retention disease ARL13B Joubert syndrome 8 ARL6 Bardet–Biedl syndrome 3

MAP kinase

Cardiofaciocutaneous syndrome

Other kinase/phosphatase

Tyrosine kinase	BTK X-linked agammaglobulinemia ZAP70 ZAP70 deficiency
Serine/threonine kinase	RPS6KA3 Coffin-Lowry syndrome CHEK2 Li–Fraumeni syndrome 2 IKBKG Incontinentia pigmenti STK11 Peutz–Jeghers syndrome DMPK Myotonic dystrophy 1 ATR Seckel syndrome 1 GRK1 Oguchi disease 2 WNK4/WNK1 Pseudohypoaldosteronism 2
Tyrosine phosphatase	PTEN Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos disease Cowden syndrome Proteus-like syndrome MTM1 X-linked myotubular myopathy PTPN11 Noonan syndrome 1 LEOPARD syndrome Metachondromatosis