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Nemaline myopathy 7(NEM7)

MedGen UID:
343979
Concept ID:
C1853154
Disease or Syndrome
Synonyms: NEM7; Nemaline myopathy 7, autosomal recessive
 
Gene (location): CFL2 (14q13.1)
 
Monarch Initiative: MONDO:0012538
OMIM®: 610687

Definition

Nemaline myopathy-7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (summary by Ockeloen et al., 2012). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800. [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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.  https://medlineplus.gov/genetics/condition/nemaline-myopathy

Clinical features

From HPO
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Knee flexion contracture
MedGen UID:
98042
Concept ID:
C0409355
Finding
A type of knee joint contracture in which the knee is in a fixed bent (flexed) configuration such that it cannot be straightened actively or passively.
Shoulder girdle muscle weakness
MedGen UID:
96533
Concept ID:
C0427063
Finding
The shoulder, or pectoral, girdle is composed of the clavicles and the scapulae. Shoulder-girdle weakness refers to lack of strength of the muscles attaching to these bones, that is, lack of strength of the muscles around the shoulders.
Genu recurvatum
MedGen UID:
107486
Concept ID:
C0546964
Anatomical Abnormality
An abnormally increased extension of the knee joint, so that the knee can bend backwards.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Muscle fibrillation
MedGen UID:
65418
Concept ID:
C0231531
Finding
Fine, rapid twitching of individual muscle fibers with little or no movement of the muscle as a whole. If a motor neuron or its axon is destroyed, the muscle fibers it innervates undergo denervation atrophy. This leads to hypersensitivity of individual muscle fibers to acetyl choline so that they may contract spontaneously. Isolated activity of individual muscle fibers is generally so fine it cannot be seen through the intact skin, although it can be recorded as a short-duration spike in the EMG.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Delayed gross motor development
MedGen UID:
332508
Concept ID:
C1837658
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Neck muscle weakness
MedGen UID:
66808
Concept ID:
C0240479
Finding
Decreased strength of the neck musculature.
Weakness of facial musculature
MedGen UID:
98103
Concept ID:
C0427055
Disease or Syndrome
Reduced strength of one or more muscles innervated by the facial nerve (the seventh cranial nerve).
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Frequent falls
MedGen UID:
163408
Concept ID:
C0850703
Finding
Lumbar hyperlordosis
MedGen UID:
263149
Concept ID:
C1184923
Finding
An abnormal accentuation of the inward curvature of the spine in the lumbar region.
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.
Fatty replacement of skeletal muscle
MedGen UID:
866735
Concept ID:
C4021082
Finding
Muscle fibers degeneration resulting in fatty replacement of skeletal muscle fibers
Minicore myopathy
MedGen UID:
961596
Concept ID:
CN279271
Disease or Syndrome
Multiple small zones of sarcomeric disorganization and lack of oxidative activity (known as minicores) in muscle fibers.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
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).
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.

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
Dalakas MC, Smith SA
Neurology 2008 Aug 12;71(7):472-3. doi: 10.1212/01.wnl.0000324861.44410.be. PMID: 18695157

Curated

Nowak KJ, Davis MR, Wallgren-Pettersson C, Lamont PJ, Laing NG
Eur J Hum Genet 2012 Jun;20(6) Epub 2012 Apr 18 doi: 10.1038/ejhg.2012.70. PMID: 22510848Free PMC Article

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
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
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
Sanoudou D, Beggs AH
Trends Mol Med 2001 Aug;7(8):362-8. doi: 10.1016/s1471-4914(01)02089-5. PMID: 11516997

Diagnosis

Christophers B, Lopez MA, Gupta VA, Vogel H, Baylies M
J Child Neurol 2022 Jun;37(7):652-663. Epub 2022 Jun 7 doi: 10.1177/08830738221096316. PMID: 36960434Free 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
Yin X, Pu C, Wang Z, Li K, Wang H
Acta Neurol Belg 2022 Jun;122(3):631-639. Epub 2021 Mar 19 doi: 10.1007/s13760-020-01542-9. PMID: 33742414Free 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
Wallgren-Pettersson C, Sewry CA, Nowak KJ, Laing NG
Semin Pediatr Neurol 2011 Dec;18(4):230-8. doi: 10.1016/j.spen.2011.10.004. PMID: 22172418

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
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
van Diemen CC, Kerstjens-Frederikse WS, Bergman KA, de Koning TJ, Sikkema-Raddatz B, van der Velde JK, Abbott KM, Herkert JC, Löhner K, Rump P, Meems-Veldhuis MT, Neerincx PBT, Jongbloed JDH, van Ravenswaaij-Arts CM, Swertz MA, Sinke RJ, van Langen IM, Wijmenga C
Pediatrics 2017 Oct;140(4) doi: 10.1542/peds.2016-2854. PMID: 28939701

Prognosis

Tanboon J, Uruha A, Arahata Y, Dittmayer C, Schweizer L, Goebel HH, Nishino I, Stenzel W
Brain Pathol 2021 May;31(3):e12962. doi: 10.1111/bpa.12962. PMID: 34043258Free PMC Article
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
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
Sanoudou D, Beggs AH
Trends Mol Med 2001 Aug;7(8):362-8. doi: 10.1016/s1471-4914(01)02089-5. PMID: 11516997
Goebel HH, Warlo I
Neuromuscul Disord 1997 Jan;7(1):13-9. doi: 10.1016/s0960-8966(96)00404-x. PMID: 9132135

Clinical prediction guides

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
Tanboon J, Uruha A, Arahata Y, Dittmayer C, Schweizer L, Goebel HH, Nishino I, Stenzel W
Brain Pathol 2021 May;31(3):e12962. doi: 10.1111/bpa.12962. PMID: 34043258Free PMC Article
Saito Y, Nishikawa A, Iida A, Mori-Yoshimura M, Oya Y, Ishiyama A, Komaki H, Nakamura S, Fujikawa S, Kanda T, Yamadera M, Sakiyama H, Hayashi S, Nonaka I, Noguchi S, Nishino I
Neurology 2020 Sep 15;95(11):e1500-e1511. Epub 2020 Jul 9 doi: 10.1212/WNL.0000000000010237. PMID: 32646962
Lee JM, Lim JG, Shin JH, Park YE, Kim DS
J Neurol Sci 2017 Dec 15;383:61-68. Epub 2017 Oct 12 doi: 10.1016/j.jns.2017.10.020. PMID: 29246625

Recent systematic reviews

Christophers B, Lopez MA, Gupta VA, Vogel H, Baylies M
J Child Neurol 2022 Jun;37(7):652-663. Epub 2022 Jun 7 doi: 10.1177/08830738221096316. PMID: 36960434Free PMC Article

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