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Spinal muscular atrophy, distal, autosomal recessive, 1(DSMA1)

MedGen UID:
388083
Concept ID:
C1858517
Disease or Syndrome
Synonyms: DSMA1; HMN VI; Neuronopathy, distal hereditary motor, type VI; Neuronopathy, severe infantile axonal, with respiratory failure; Severe infantile axonal neuropathy with respiratory failure; Spinal muscular atrophy with respiratory distress 1; SPINAL MUSCULAR ATROPHY, DIAPHRAGMATIC
SNOMED CT: Distal spinal muscular atrophy type 1 (711483003); Distal hereditary motor neuronopathy type VI (711483003); Severe infantile axonal neuropathy with respiratory failure (711483003); Spinal muscular atrophy with respiratory distress type 1 (711483003); Spinal muscular atrophy with respiratory distress (711483003); Autosomal recessive distal spinal muscular atrophy 1 (711483003); Diaphragmatic spinal muscular atrophy (711483003)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM
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): IGHMBP2 (11q13.3)
 
Monarch Initiative: MONDO:0011436
OMIM®: 604320
Orphanet: ORPHA98920

Definition

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited condition that causes muscle weakness and respiratory failure typically beginning in infancy. Early features of this condition are difficult and noisy breathing, especially when inhaling; a weak cry; problems feeding; and recurrent episodes of pneumonia. Typically between the ages of 6 weeks and 6 months, infants with this condition will experience a sudden inability to breathe due to paralysis of the muscle that separates the abdomen from the chest cavity (the diaphragm). Normally, the diaphragm contracts and moves downward during inhalation to allow the lungs to expand. With diaphragm paralysis, affected individuals require life-long support with a machine to help them breathe (mechanical ventilation). Rarely, children with SMARD1 develop signs or symptoms of the disorder later in childhood.\n\nSoon after respiratory failure occurs, individuals with SMARD1 develop muscle weakness in their distal muscles. These are the muscles farther from the center of the body, such as muscles in the hands and feet. The weakness soon spreads to all muscles; however, within 2 years, the muscle weakness typically stops getting worse. Some individuals may retain a low level of muscle function, while others lose all ability to move their muscles. Muscle weakness severely impairs motor development, such as sitting, standing, and walking. Some affected children develop an abnormal side-to-side and back-to-front curvature of the spine (scoliosis and kyphosis, often called kyphoscoliosis when they occur together). After approximately the first year of life, individuals with SMARD1 may lose their deep tendon reflexes, such as the reflex being tested when a doctor taps the knee with a hammer.\n\nOther features of SMARD1 can include reduced pain sensitivity, excessive sweating (hyperhidrosis), loss of bladder and bowel control, and an irregular heartbeat (arrhythmia). [from MedlinePlus Genetics]

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary passage of urine outside the body.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Involuntary passage of urine outside the body.
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Camptodactyly of finger
MedGen UID:
98041
Concept ID:
C0409348
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
Intrauterine growth retardation
MedGen UID:
473406
Concept ID:
C1386048
Pathologic Function
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Degeneration of anterior horn cells
MedGen UID:
375215
Concept ID:
C1843505
Finding
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Peripheral axonal degeneration
MedGen UID:
871339
Concept ID:
C4025830
Finding
Progressive deterioration of peripheral axons.
Diaphragmatic paralysis
MedGen UID:
1632032
Concept ID:
C4551685
Finding
The presence of a paralyzed diaphragm.
Diaphragmatic eventration
MedGen UID:
8359
Concept ID:
C0011981
Congenital Abnormality
A congenital or acquired abnormality characterized by elevation of the hemidiaphragm.
Spinal muscular atrophy
MedGen UID:
7755
Concept ID:
C0026847
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.
Camptodactyly of finger
MedGen UID:
98041
Concept ID:
C0409348
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Diaphragmatic weakness
MedGen UID:
101067
Concept ID:
C0521532
Finding
A decrease in the strength of the diaphragm.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Denervation of the diaphragm
MedGen UID:
346925
Concept ID:
C1858529
Finding
Interruption of the innervation of the diaphragm.
EMG: neuropathic changes
MedGen UID:
867363
Concept ID:
C4021727
Finding
The presence of characteristic findings of denervation on electromyography (fibrillations, positive sharp waves, and giant motor unit potentials).
Diaphragmatic paralysis
MedGen UID:
1632032
Concept ID:
C4551685
Finding
The presence of a paralyzed diaphragm.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Inspiratory stridor
MedGen UID:
146165
Concept ID:
C0677600
Sign or Symptom
Inspiratory stridor is a high pitched sound upon inspiration that is generally related to laryngeal abnormalities.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
The significant impairment of gas exchange within the lungs resulting in hypoxia, hypercarbia, or both, to the extent that organ tissue perfusion is severely compromised. Causes include chronic obstructive pulmonary disease, asthma, emphysema, acute respiratory distress syndrome, pneumonia, pulmonary edema, pneumothorax, and congestive heart failure. Treatment requires intubation and mechanical ventilation until the time the lungs recover sufficient function.
Ventilator dependence with inability to wean
MedGen UID:
870643
Concept ID:
C4025097
Finding
Weak cry
MedGen UID:
65892
Concept ID:
C0234860
Finding
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.
Premature birth
MedGen UID:
57721
Concept ID:
C0151526
Pathologic Function
Birth when a fetus is less than 37 weeks and 0 days gestational age.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.

Professional guidelines

PubMed

Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A; Participants of the International Conference on SMA Standard of Care.
J Child Neurol 2007 Aug;22(8):1027-49. doi: 10.1177/0883073807305788. PMID: 17761659

Recent clinical studies

Etiology

Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C
Neuromuscul Disord 2019 Feb;29(2):114-126. Epub 2018 Oct 31 doi: 10.1016/j.nmd.2018.10.002. PMID: 30598237
Wagner JD, Huang L, Tetreault M, Majewski J, Boycott KM, Bulman DE; Care4Rare Canada Consortium., Dyment DA, McMillan HJ
Neuromuscul Disord 2015 Oct;25(10):794-9. Epub 2015 Aug 5 doi: 10.1016/j.nmd.2015.07.017. PMID: 26298607

Diagnosis

Kim YA, Jin HY, Kim YM
J Korean Med Sci 2019 Mar 11;34(9):e54. Epub 2019 Feb 7 doi: 10.3346/jkms.2019.34.e54. PMID: 30863264Free PMC Article
Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C
Neuromuscul Disord 2019 Feb;29(2):114-126. Epub 2018 Oct 31 doi: 10.1016/j.nmd.2018.10.002. PMID: 30598237
Wu S, Chen T, Li Y, Chen L, Xu Q, Xiao F, Bai Z
Eur J Med Genet 2018 Oct;61(10):602-606. Epub 2018 Apr 11 doi: 10.1016/j.ejmg.2018.04.001. PMID: 29653221
Pierson TM, Tart G, Adams D, Toro C, Golas G, Tifft C, Gahl W
Neuromuscul Disord 2011 May;21(5):353-5. Epub 2011 Feb 25 doi: 10.1016/j.nmd.2011.02.005. PMID: 21353777Free PMC Article
Basel-Vanagaite L, Taub E, Drasinover V, Magal N, Brudner A, Zlotogora J, Shohat M
Genet Test 2008 Mar;12(1):53-6. doi: 10.1089/gte.2007.0030. PMID: 18298318

Therapy

Shababi M, Feng Z, Villalon E, Sibigtroth CM, Osman EY, Miller MR, Williams-Simon PA, Lombardi A, Sass TH, Atkinson AK, Garcia ML, Ko CP, Lorson CL
Mol Ther 2016 May;24(5):855-66. Epub 2016 Feb 10 doi: 10.1038/mt.2016.33. PMID: 26860981Free PMC Article
Vanoli F, Rinchetti P, Porro F, Parente V, Corti S
J Cell Mol Med 2015 Sep;19(9):2058-66. Epub 2015 Jun 20 doi: 10.1111/jcmm.12606. PMID: 26095024Free PMC Article

Prognosis

Saladini M, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S
J Cell Mol Med 2020 Jan;24(2):1169-1178. Epub 2019 Dec 4 doi: 10.1111/jcmm.14874. PMID: 31802621Free PMC Article
Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C
Neuromuscul Disord 2019 Feb;29(2):114-126. Epub 2018 Oct 31 doi: 10.1016/j.nmd.2018.10.002. PMID: 30598237
Wright M, Manzur A, Bush A
Thorax 2018 Aug;73(8):788-790. Epub 2018 Jan 30 doi: 10.1136/thoraxjnl-2017-211058. PMID: 29382800
Nandhagopal R, Meftah D, Al-Kalbani S, Scott P
Eur J Neurol 2018 Feb;25(2):395-403. Epub 2017 Dec 12 doi: 10.1111/ene.13519. PMID: 29115704
Pierson TM, Tart G, Adams D, Toro C, Golas G, Tifft C, Gahl W
Neuromuscul Disord 2011 May;21(5):353-5. Epub 2011 Feb 25 doi: 10.1016/j.nmd.2011.02.005. PMID: 21353777Free PMC Article

Clinical prediction guides

Forotti G, Nizzardo M, Bucchia M, Ramirez A, Trombetta E, Gatti S, Bresolin N, Comi GP, Corti S
Exp Neurol 2019 Nov;321:113041. Epub 2019 Aug 21 doi: 10.1016/j.expneurol.2019.113041. PMID: 31445043
Viguier A, Lauwers-Cances V, Cintas P, Manel V, Peudenier S, Desguerre I, Quijano-Roy S, Vanhulle C, Fradin M, Isapof A, Jokic M, Mathieu-Dramard M, Dieterich K, Petit F, Magdelaine C, Giuliano F, Gras D, Haye D, Nizon M, Magen M, Bieth E, Cances C
Neuromuscul Disord 2019 Feb;29(2):114-126. Epub 2018 Oct 31 doi: 10.1016/j.nmd.2018.10.002. PMID: 30598237
Surrey V, Zöller C, Lork AA, Moradi M, Balk S, Dombert B, Saal-Bauernschubert L, Briese M, Appenzeller S, Fischer U, Jablonka S
Neuroscience 2018 Aug 21;386:24-40. Epub 2018 Jun 19 doi: 10.1016/j.neuroscience.2018.06.019. PMID: 29928949
Nandhagopal R, Meftah D, Al-Kalbani S, Scott P
Eur J Neurol 2018 Feb;25(2):395-403. Epub 2017 Dec 12 doi: 10.1111/ene.13519. PMID: 29115704
Han C, Mai J, Tian T, He Y, Liao J, Wen F, Yi X, Yang Y
Brain Dev 2015 May;37(5):542-5. Epub 2014 Oct 1 doi: 10.1016/j.braindev.2014.09.004. PMID: 25280635

Recent systematic reviews

Porro F, Rinchetti P, Magri F, Riboldi G, Nizzardo M, Simone C, Zanetta C, Faravelli I, Corti S
J Neurol Sci 2014 Nov 15;346(1-2):35-42. Epub 2014 Sep 16 doi: 10.1016/j.jns.2014.09.010. PMID: 25248952

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