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Nemaline myopathy 5(NEM5A)

MedGen UID:
344273
Concept ID:
C1854380
Disease or Syndrome
Synonyms: NEM5A; Nemaline myopathy 5, Amish type; NEMALINE MYOPATHY 5A, AUTOSOMAL RECESSIVE, SEVERE INFANTILE; Nemaline Myopathy, Amish Type; Nemaline myopathy, caused by mutation in the troponin t1 gene
SNOMED CT: Amish nemaline myopathy (1197155007)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): TNNT1 (19q13.42)
 
Monarch Initiative: MONDO:0011539
OMIM®: 605355
Orphanet: ORPHA98902

Definition

Autosomal recessive severe infantile nemaline myopathy-5A (NEM5A) is a skeletal muscle disorder characterized by symptom onset soon after birth or in early infancy. Affected infants show axial hypotonia, stiffness, rigid spine with progressive kyphosis, pectus deformities, and contractures or limited movement of the large joints. Some patients show transient tremors. There is muscle atrophy and poor gross motor development. Respiratory insufficiency develops in the first years of life, often leading to death. Muscle biopsy shows nemaline rods (Johnston et al., 2000; Geraud et al., 2021). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030). [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
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Pectus carinatum
MedGen UID:
57643
Concept ID:
C0158731
Finding
A deformity of the chest caused by overgrowth of the ribs and characterized by protrusion of the sternum.
Progressive muscle weakness
MedGen UID:
68704
Concept ID:
C0240421
Finding
Shoulder flexion contracture
MedGen UID:
592333
Concept ID:
C0409336
Acquired Abnormality
Chronic reduction in active and passive mobility of the shoulder joint due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement.
Hip contracture
MedGen UID:
140815
Concept ID:
C0409354
Acquired Abnormality
Lack of full passive range of motion (restrictions in flexion, extension, or other movements) of the hip joint resulting from structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules and/or skin.
Decreased hip abduction
MedGen UID:
332244
Concept ID:
C1836589
Finding
Reduced ability to move the femur outward to the side.
Proximal amyotrophy
MedGen UID:
342591
Concept ID:
C1850794
Disease or Syndrome
Amyotrophy (muscular atrophy) affecting the proximal musculature.
Type 1 muscle fiber predominance
MedGen UID:
344274
Concept ID:
C1854387
Finding
An abnormal predominance of type I muscle fibers (in general, this feature can only be observed on muscle biopsy).
Z-band streaming
MedGen UID:
480908
Concept ID:
C3279278
Finding
Streaming or smearing of the Z band, which is then no longer confined to a narrow zone which bisects the I band. The Z disk may extend across the I band or the entire sarcomere in a zigzag manner. Focal thickening, smudging, and blurring of the Z band takes place concurrently. Myofibrillar disorganization is a frequent but not invariable accompanying change.
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.
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.

Professional guidelines

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

Uppin MS, Meena AK, Sundaram C
Neurol India 2013 May-Jun;61(3):254-9. doi: 10.4103/0028-3886.115064. PMID: 23860144
Thaha F, Gayathri N, Nalini A
Neurol India 2011 Nov-Dec;59(6):879-83. doi: 10.4103/0028-3886.91369. PMID: 22234203
Weiss K, Shapira Y, Glick B, Lerman-Sagie T, Shahar E, Goez H, Kutai M, Nevo Y
J Child Neurol 2007 Jun;22(6):732-6. doi: 10.1177/0883073807304193. PMID: 17641259

Diagnosis

D'Amico A, Fattori F, Fiorillo C, Paglietti MG, Testa MBC, Verardo M, Catteruccia M, Bruno C, Bertini E
Neuromuscul Disord 2019 Oct;29(10):766-770. Epub 2019 Sep 6 doi: 10.1016/j.nmd.2019.09.005. PMID: 31604653
Marra JD, Engelstad KE, Ankala A, Tanji K, Dastgir J, De Vivo DC, Coffee B, Chiriboga CA
Muscle Nerve 2015 May;51(5):767-72. Epub 2015 Feb 17 doi: 10.1002/mus.24528. PMID: 25430424
Uppin MS, Meena AK, Sundaram C
Neurol India 2013 May-Jun;61(3):254-9. doi: 10.4103/0028-3886.115064. PMID: 23860144
Weiss K, Shapira Y, Glick B, Lerman-Sagie T, Shahar E, Goez H, Kutai M, Nevo Y
J Child Neurol 2007 Jun;22(6):732-6. doi: 10.1177/0883073807304193. PMID: 17641259

Clinical prediction guides

Lee S, Eum J, Park S, Ki S, Hwang BJ, Kee Y, Chae JH
Neuromuscul Disord 2022 Feb;32(2):176-184. Epub 2021 Dec 16 doi: 10.1016/j.nmd.2021.12.003. PMID: 35165004
Streff H, Bi W, Colón AG, Adesina AM, Miyake CY, Lalani SR
Eur J Med Genet 2019 Nov;62(11):103567. Epub 2018 Nov 3 doi: 10.1016/j.ejmg.2018.11.001. PMID: 30395933Free PMC Article
Wei B, Lu Y, Jin JP
J Physiol 2014 Mar 15;592(6):1367-80. Epub 2014 Jan 20 doi: 10.1113/jphysiol.2013.268177. PMID: 24445317Free PMC Article

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