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Nemaline myopathy 8(NEM8)

MedGen UID:
815539
Concept ID:
C3809209
Disease or Syndrome
Synonyms: NEM8
 
Gene (location): KLHL40 (3p22.1)
OMIM®: 615348

Disease characteristics

Excerpted from the GeneReview: Nemaline Myopathy
Nemaline myopathy (referred to in this entry as NM) is characterized by weakness, hypotonia, and depressed or absent deep tendon reflexes. Muscle weakness is usually most severe in the face, the neck flexors, and the proximal limb muscles. The clinical classification defines six forms of NM, which are classified by onset and severity of motor and respiratory involvement: Severe congenital (neonatal) (16% of all individuals with NM). Amish NM. Intermediate congenital (20%). Typical congenital (46%). Childhood-onset (13%). Adult-onset (late-onset) (4%). Considerable overlap occurs among the forms. There are significant differences in survival between individuals classified as having severe, intermediate, and typical congenital NM. Severe neonatal respiratory disease and the presence of arthrogryposis multiplex congenita are associated with death in the first year of life. Independent ambulation before age 18 months is predictive of survival. Most children with typical congenital NM are eventually able to walk. [from GeneReviews]
Authors:
Kathryn N North  |  Monique M Ryan   view full author information

Additional descriptions

From OMIM
Nemaline myopathy-8 is a severe autosomal recessive muscle disorder characterized by fetal akinesia or hypokinesia, followed by contractures, fractures, respiratory failure, and swallowing difficulties apparent at birth. Most patients die in infancy. Skeletal muscle biopsy shows numerous small nemaline bodies, often with no normal myofibrils (summary by Ravenscroft et al., 2013). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800).  http://www.omim.org/entry/615348
From GHR
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://ghr.nlm.nih.gov/condition/nemaline-myopathy

Clinical features

Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
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.
Facial palsy
MedGen UID:
346972
Concept ID:
C1858719
Finding
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Flexion contracture
MedGen UID:
3227
Concept ID:
C0009917
Anatomical Abnormality
Permanent contraction of a muscle as a result of spasm or paralysis.
Facial palsy
MedGen UID:
346972
Concept ID:
C1858719
Finding
Myofibrillar myopathy
MedGen UID:
395532
Concept ID:
C2678065
Finding
Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles. Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%. A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps. Peripheral neuropathy is present in about 20% of affected individuals. Overt cardiomyopathy is present in 15%-30%.
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.
Flexion contracture
MedGen UID:
3227
Concept ID:
C0009917
Anatomical Abnormality
Permanent contraction of a muscle as a result of spasm or paralysis.
Abnormality of the thorax
MedGen UID:
867424
Concept ID:
C4021797
Anatomical Abnormality
Any abnormality of the thorax (the region of the body formed by the sternum, the thoracic vertebrae and the ribs).
Facial palsy
MedGen UID:
346972
Concept ID:
C1858719
Finding
Flexion contracture
MedGen UID:
3227
Concept ID:
C0009917
Anatomical Abnormality
Permanent contraction of a muscle as a result of spasm or paralysis.
Fetal akinesia sequence
MedGen UID:
462870
Concept ID:
C3151520
Finding

Recent clinical studies

Etiology

Monforte M, Primiano G, Silvestri G, Mirabella M, Luigetti M, Cuccagna C, Ricci E, Servidei S, Tasca G
J Neurol 2018 Mar;265(3):542-551. Epub 2018 Jan 22 doi: 10.1007/s00415-018-8741-y. PMID: 29356967
Piga D, Magri F, Ronchi D, Corti S, Cassandrini D, Mercuri E, Tasca G, Bertini E, Fattori F, Toscano A, Messina S, Moroni I, Mora M, Moggio M, Colombo I, Giugliano T, Pane M, Fiorillo C, D'Amico A, Bruno C, Nigro V, Bresolin N, Comi GP
J Mol Neurosci 2016 Jul;59(3):351-9. Epub 2016 Apr 22 doi: 10.1007/s12031-016-0739-2. PMID: 27105866
Voermans NC, Benveniste O, Minnema MC, Lokhorst H, Lammens M, Meersseman W, Delforge M, Kuntzer T, Novy J, Pabst T, Bouhour F, Romero N, Leblond V, Bergh Pv, Vekemans MC, van Engelen BG, Eymard B
Neurology 2014 Dec 2;83(23):2133-9. Epub 2014 Nov 5 doi: 10.1212/WNL.0000000000001047. PMID: 25378674
Chahin N, Selcen D, Engel AG
Neurology 2005 Oct 25;65(8):1158-64. Epub 2005 Sep 7 doi: 10.1212/01.wnl.0000180362.90078.dc. PMID: 16148261
Sanoudou D, Haslett JN, Kho AT, Guo S, Gazda HT, Greenberg SA, Lidov HG, Kohane IS, Kunkel LM, Beggs AH
Proc Natl Acad Sci U S A 2003 Apr 15;100(8):4666-71. Epub 2003 Apr 3 doi: 10.1073/pnas.0330960100. PMID: 12677001Free PMC Article

Diagnosis

Monforte M, Primiano G, Silvestri G, Mirabella M, Luigetti M, Cuccagna C, Ricci E, Servidei S, Tasca G
J Neurol 2018 Mar;265(3):542-551. Epub 2018 Jan 22 doi: 10.1007/s00415-018-8741-y. PMID: 29356967
Piga D, Magri F, Ronchi D, Corti S, Cassandrini D, Mercuri E, Tasca G, Bertini E, Fattori F, Toscano A, Messina S, Moroni I, Mora M, Moggio M, Colombo I, Giugliano T, Pane M, Fiorillo C, D'Amico A, Bruno C, Nigro V, Bresolin N, Comi GP
J Mol Neurosci 2016 Jul;59(3):351-9. Epub 2016 Apr 22 doi: 10.1007/s12031-016-0739-2. PMID: 27105866
Kapoor S, Singh A, Lehtokari VL, Wallgren-Pettersson C, Batra VV
Indian J Pediatr 2013 Aug;80(8):691-3. Epub 2012 Sep 2 doi: 10.1007/s12098-012-0867-9. PMID: 22941215
Lehtokari VL, Pelin K, Herczegfalvi A, Karcagi V, Pouget J, Franques J, Pellissier JF, Figarella-Branger D, von der Hagen M, Huebner A, Schoser B, Lochmüller H, Wallgren-Pettersson C
Neuromuscul Disord 2011 Aug;21(8):556-62. Epub 2011 Jul 2 doi: 10.1016/j.nmd.2011.05.012. PMID: 21724397
Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E, North K, Laing N, Bydder G, Pelin K, Wallgren-Pettersson C, Muntoni F
Neuromuscul Disord 2004 Dec;14(12):779-84. doi: 10.1016/j.nmd.2004.08.005. PMID: 15564032

Therapy

Monforte M, Primiano G, Silvestri G, Mirabella M, Luigetti M, Cuccagna C, Ricci E, Servidei S, Tasca G
J Neurol 2018 Mar;265(3):542-551. Epub 2018 Jan 22 doi: 10.1007/s00415-018-8741-y. PMID: 29356967
Silva AMS, Mendonça RH, Moreno CAM, Estephan EP, Helito PVP, Carvalho MS, Zanoteli E
Neuromuscul Disord 2017 Aug;27(8):756-759. Epub 2017 May 12 doi: 10.1016/j.nmd.2017.05.008. PMID: 28606402
Voermans NC, Benveniste O, Minnema MC, Lokhorst H, Lammens M, Meersseman W, Delforge M, Kuntzer T, Novy J, Pabst T, Bouhour F, Romero N, Leblond V, Bergh Pv, Vekemans MC, van Engelen BG, Eymard B
Neurology 2014 Dec 2;83(23):2133-9. Epub 2014 Nov 5 doi: 10.1212/WNL.0000000000001047. PMID: 25378674
Portlock CS, Boland P, Hays AP, Antonescu CR, Rosenblum MK
Hum Pathol 2003 Aug;34(8):816-8. PMID: 14506646
Richards AJ
J Rheumatol 1998 Aug;25(8):1642-3. PMID: 9712114

Prognosis

Monforte M, Primiano G, Silvestri G, Mirabella M, Luigetti M, Cuccagna C, Ricci E, Servidei S, Tasca G
J Neurol 2018 Mar;265(3):542-551. Epub 2018 Jan 22 doi: 10.1007/s00415-018-8741-y. PMID: 29356967
Amarasinghe C, Hossain MM, Jin JP
Biochemistry 2016 Aug 16;55(32):4560-7. Epub 2016 Aug 2 doi: 10.1021/acs.biochem.6b00577. PMID: 27429059
Voermans NC, Benveniste O, Minnema MC, Lokhorst H, Lammens M, Meersseman W, Delforge M, Kuntzer T, Novy J, Pabst T, Bouhour F, Romero N, Leblond V, Bergh Pv, Vekemans MC, van Engelen BG, Eymard B
Neurology 2014 Dec 2;83(23):2133-9. Epub 2014 Nov 5 doi: 10.1212/WNL.0000000000001047. PMID: 25378674
Kapoor S, Singh A, Lehtokari VL, Wallgren-Pettersson C, Batra VV
Indian J Pediatr 2013 Aug;80(8):691-3. Epub 2012 Sep 2 doi: 10.1007/s12098-012-0867-9. PMID: 22941215
Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E, North K, Laing N, Bydder G, Pelin K, Wallgren-Pettersson C, Muntoni F
Neuromuscul Disord 2004 Dec;14(12):779-84. doi: 10.1016/j.nmd.2004.08.005. PMID: 15564032

Clinical prediction guides

Amarasinghe C, Hossain MM, Jin JP
Biochemistry 2016 Aug 16;55(32):4560-7. Epub 2016 Aug 2 doi: 10.1021/acs.biochem.6b00577. PMID: 27429059
Piga D, Magri F, Ronchi D, Corti S, Cassandrini D, Mercuri E, Tasca G, Bertini E, Fattori F, Toscano A, Messina S, Moroni I, Mora M, Moggio M, Colombo I, Giugliano T, Pane M, Fiorillo C, D'Amico A, Bruno C, Nigro V, Bresolin N, Comi GP
J Mol Neurosci 2016 Jul;59(3):351-9. Epub 2016 Apr 22 doi: 10.1007/s12031-016-0739-2. PMID: 27105866
Garg A, O'Rourke J, Long C, Doering J, Ravenscroft G, Bezprozvannaya S, Nelson BR, Beetz N, Li L, Chen S, Laing NG, Grange RW, Bassel-Duby R, Olson EN
J Clin Invest 2014 Aug;124(8):3529-39. Epub 2014 Jun 24 doi: 10.1172/JCI74994. PMID: 24960163Free PMC Article
Gineste C, Duhamel G, Le Fur Y, Vilmen C, Cozzone PJ, Nowak KJ, Bendahan D, Gondin J
PLoS One 2013;8(8):e72294. Epub 2013 Aug 20 doi: 10.1371/journal.pone.0072294. PMID: 23977274Free PMC Article
Jungbluth H, Sewry CA, Counsell S, Allsop J, Chattopadhyay A, Mercuri E, North K, Laing N, Bydder G, Pelin K, Wallgren-Pettersson C, Muntoni F
Neuromuscul Disord 2004 Dec;14(12):779-84. doi: 10.1016/j.nmd.2004.08.005. PMID: 15564032

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