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Nemaline myopathy 9(NEM9)

MedGen UID:
816714
Concept ID:
C3810384
Disease or Syndrome
Synonym: NEM9
 
Gene (location): KLHL41 (2q31.1)
 
Monarch Initiative: MONDO:0014326
OMIM®: 615731

Definition

Nemaline myopathy-9 is an autosomal recessive muscle disorder characterized by onset of muscle weakness in early infancy. The phenotype is highly variable, ranging from death in infancy due to lack of antigravity movements, to slowly progressive distal muscle weakness with preserved ambulation later in childhood. Muscle biopsy shows typical rod-like structure in myofibers (summary by Gupta et al., 2013). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800. [from OMIM]

Additional description

From MedlinePlus Genetics
Nemaline myopathy is a disorder that primarily affects skeletal muscles, which are muscles that the body uses for movement. People with nemaline myopathy have muscle weakness (myopathy) throughout the body, but it is typically most severe in the muscles of the face; neck; trunk; and other muscles close to the center of the body (proximal muscles), such as those of the upper arms and legs. This weakness can worsen over time. Affected individuals may have feeding and swallowing difficulties, foot deformities, abnormal curvature of the spine (scoliosis), and joint deformities (contractures). Most people with nemaline myopathy are able to walk, although some affected children may begin walking later than usual. As the condition progresses, some people may require wheelchair assistance. In severe cases, the muscles used for breathing are affected and life-threatening breathing difficulties can occur.

Nemaline myopathy is divided into six types. In order of decreasing severity, the types are: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. The types are distinguished by the age when symptoms first appear and the severity of symptoms; however, there is overlap among the various types. The severe congenital type is the most life-threatening. Most individuals with this type do not survive past early childhood due to respiratory failure. The Amish type solely affects the Old Order Amish population of Pennsylvania and is typically fatal in early childhood. The most common type of nemaline myopathy is the typical congenital type, which is characterized by muscle weakness and feeding problems beginning in infancy. Most of these individuals do not have severe breathing problems and can walk unassisted. People with the childhood-onset type usually develop muscle weakness in adolescence. The adult-onset type is the mildest of all the various types. People with this type usually develop muscle weakness between ages 20 and 50.  https://medlineplus.gov/genetics/condition/nemaline-myopathy

Clinical features

From HPO
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Narrow chest
MedGen UID:
96528
Concept ID:
C0426790
Finding
Reduced width of the chest from side to side, associated with a reduced distance from the sternal notch to the tip of the shoulder.
Nemaline bodies
MedGen UID:
814369
Concept ID:
C3808039
Finding
Nemaline rods are abnormal bodies that can occur in skeletal muscle fibers. The rods can be observed on histological analysis of muscle biopsy tissue or upon electron microscopy, where they appear either as extensions of sarcomeric Z-lines, in random array without obvious attachment to Z-lines (often in areas devoid of sarcomeres) or in large clusters localized at the sarcolemma or intermyofibrillar spaces.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
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).
Cleft palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Breech presentation
MedGen UID:
654
Concept ID:
C0006157
Pathologic Function
A position of the fetus at delivery in which the fetus enters the birth canal with the buttocks or feet first.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Fetal akinesia deformation sequence 1
MedGen UID:
220903
Concept ID:
C1276035
Disease or Syndrome
Decreased fetal activity associated with multiple joint contractures, facial anomalies and pulmonary hypoplasia. Ultrasound examination may reveal polyhydramnios, ankylosis, scalp edema, and decreased chest movements (reflecting pulmonary hypoplasia).

Professional guidelines

PubMed

Scheibe F, Ostendorf L, Prüss H, Radbruch H, Aschman T, Hoffmann S, Blau IW, Meisel C, Alexander T, Meisel A
Eur J Neurol 2022 Jun;29(6):1847-1854. Epub 2022 Feb 10 doi: 10.1111/ene.15266. PMID: 35098616
Naddaf E, Milone M, Kansagra A, Buadi F, Kourelis T
Neurology 2019 Jul 16;93(3):e298-e305. Epub 2019 Jun 5 doi: 10.1212/WNL.0000000000007777. PMID: 31167932

Recent clinical studies

Etiology

Zhao B, Dai T, Zhao D, Ma X, Zhao C, Li L, Sun Y, Zhang Y, Yan Y, Lu JQ, Liu F, Yan C
Neurol Neuroimmunol Neuroinflamm 2022 Jul;9(4) Epub 2022 May 17 doi: 10.1212/NXI.0000000000001184. PMID: 35581006Free PMC Article
Scheibe F, Ostendorf L, Prüss H, Radbruch H, Aschman T, Hoffmann S, Blau IW, Meisel C, Alexander T, Meisel A
Eur J Neurol 2022 Jun;29(6):1847-1854. Epub 2022 Feb 10 doi: 10.1111/ene.15266. PMID: 35098616
Naddaf E, Milone M, Kansagra A, Buadi F, Kourelis T
Neurology 2019 Jul 16;93(3):e298-e305. Epub 2019 Jun 5 doi: 10.1212/WNL.0000000000007777. PMID: 31167932
Cassandrini D, Trovato R, Rubegni A, Lenzi S, Fiorillo C, Baldacci J, Minetti C, Astrea G, Bruno C, Santorelli FM; Italian Network on Congenital Myopathies
Ital J Pediatr 2017 Nov 15;43(1):101. doi: 10.1186/s13052-017-0419-z. PMID: 29141652Free PMC Article
Ilkovski B, Mokbel N, Lewis RA, Walker K, Nowak KJ, Domazetovska A, Laing NG, Fowler VM, North KN, Cooper ST
J Neuropathol Exp Neurol 2008 Sep;67(9):867-77. doi: 10.1097/NEN.0b013e318183a44f. PMID: 18716557Free PMC Article

Diagnosis

Wang Q, Hu Z, Chang X, Yu M, Xie Z, Lv H, Zhang W, Xiong H, Yuan Y, Wang Z
Clin Genet 2020 Jun;97(6):878-889. Epub 2020 Apr 6 doi: 10.1111/cge.13745. PMID: 32222963
Fox MD, Carson VJ, Feng HZ, Lawlor MW, Gray JT, Brigatti KW, Jin JP, Strauss KA
Hum Mol Genet 2018 Sep 15;27(18):3272-3282. doi: 10.1093/hmg/ddy233. PMID: 29931346Free PMC Article
Cassandrini D, Trovato R, Rubegni A, Lenzi S, Fiorillo C, Baldacci J, Minetti C, Astrea G, Bruno C, Santorelli FM; Italian Network on Congenital Myopathies
Ital J Pediatr 2017 Nov 15;43(1):101. doi: 10.1186/s13052-017-0419-z. PMID: 29141652Free PMC Article
Abdulhaq UN, Daana M, Dor T, Fellig Y, Eylon S, Schuelke M, Shaag A, Elpeleg O, Edvardson S
Muscle Nerve 2016 Apr;53(4):564-9. Epub 2015 Sep 3 doi: 10.1002/mus.24885. PMID: 26296490
Wallgren-Pettersson C
Semin Pediatr Neurol 2002 Jun;9(2):132-44. doi: 10.1053/spen.2002.33804. PMID: 12138997

Therapy

van Kleef ESB, Langer D, van Engelen BGM, Ottenheijm CAC, Voermans NC, Doorduin J
J Neuromuscul Dis 2023;10(5):825-834. doi: 10.3233/JND-221665. PMID: 37458044Free PMC Article
Zhao B, Dai T, Zhao D, Ma X, Zhao C, Li L, Sun Y, Zhang Y, Yan Y, Lu JQ, Liu F, Yan C
Neurol Neuroimmunol Neuroinflamm 2022 Jul;9(4) Epub 2022 May 17 doi: 10.1212/NXI.0000000000001184. PMID: 35581006Free PMC Article
Naddaf E, Milone M, Kansagra A, Buadi F, Kourelis T
Neurology 2019 Jul 16;93(3):e298-e305. Epub 2019 Jun 5 doi: 10.1212/WNL.0000000000007777. PMID: 31167932

Prognosis

Naddaf E, Milone M, Kansagra A, Buadi F, Kourelis T
Neurology 2019 Jul 16;93(3):e298-e305. Epub 2019 Jun 5 doi: 10.1212/WNL.0000000000007777. PMID: 31167932
Cassandrini D, Trovato R, Rubegni A, Lenzi S, Fiorillo C, Baldacci J, Minetti C, Astrea G, Bruno C, Santorelli FM; Italian Network on Congenital Myopathies
Ital J Pediatr 2017 Nov 15;43(1):101. doi: 10.1186/s13052-017-0419-z. PMID: 29141652Free PMC Article
Abdulhaq UN, Daana M, Dor T, Fellig Y, Eylon S, Schuelke M, Shaag A, Elpeleg O, Edvardson S
Muscle Nerve 2016 Apr;53(4):564-9. Epub 2015 Sep 3 doi: 10.1002/mus.24885. PMID: 26296490
Wallgren-Pettersson C
Semin Pediatr Neurol 2002 Jun;9(2):132-44. doi: 10.1053/spen.2002.33804. PMID: 12138997
North KN, Laing NG, Wallgren-Pettersson C
J Med Genet 1997 Sep;34(9):705-13. doi: 10.1136/jmg.34.9.705. PMID: 9321754Free PMC Article

Clinical prediction guides

Gurgel-Giannetti J, Souza LS, Yamamoto GL, Belisario M, Lazar M, Campos W, Pavanello RCM, Zatz M, Reed U, Zanoteli E, Oliveira AB, Lehtokari VL, Casella EB, Machado-Costa MC, Wallgren-Pettersson C, Laing NG, Nigro V, Vainzof M
Int J Mol Sci 2022 Oct 9;23(19) doi: 10.3390/ijms231911995. PMID: 36233295Free PMC Article
van Kleef ESB, van Doorn JLM, Gaytant MA, de Weerd W, Vosse BAH, Wallgren-Pettersson C, van Engelen BGM, Ottenheijm CAC, Voermans NC, Doorduin J
Neuromuscul Disord 2022 Aug;32(8):654-663. Epub 2022 Jun 22 doi: 10.1016/j.nmd.2022.06.009. PMID: 35803773
Scheibe F, Ostendorf L, Prüss H, Radbruch H, Aschman T, Hoffmann S, Blau IW, Meisel C, Alexander T, Meisel A
Eur J Neurol 2022 Jun;29(6):1847-1854. Epub 2022 Feb 10 doi: 10.1111/ene.15266. PMID: 35098616
Fox MD, Carson VJ, Feng HZ, Lawlor MW, Gray JT, Brigatti KW, Jin JP, Strauss KA
Hum Mol Genet 2018 Sep 15;27(18):3272-3282. doi: 10.1093/hmg/ddy233. PMID: 29931346Free PMC Article
Wallgren-Pettersson C, Pelin K, Hilpelä P, Donner K, Porfirio B, Graziano C, Swoboda KJ, Fardeau M, Urtizberea JA, Muntoni F, Sewry C, Dubowitz V, Iannaccone S, Minetti C, Pedemonte M, Seri M, Cusano R, Lammens M, Castagna-Sloane A, Beggs AH, Laing NG, de la Chapelle A
Neuromuscul Disord 1999 Dec;9(8):564-72. doi: 10.1016/s0960-8966(99)00061-9. PMID: 10619714

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