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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, DIAPHRAGMATIC
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
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)
 
Gene (location): IGHMBP2 (11q13.3)
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.Soon 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.Other features of SMARD1 can include reduced pain sensitivity, excessive sweating (hyperhidrosis), loss of bladder and bowel control, and an irregular heartbeat (arrhythmia).
[from GHR]

Clinical features

Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Urinary incontinence (UI) is loss of bladder control. Symptoms can range from mild leaking to uncontrollable wetting. It can happen to anyone, but it becomes more common with age. Women experience UI twice as often as men. Most bladder control problems happen when muscles are too weak or too active. If the muscles that keep your bladder closed are weak, you may have accidents when you sneeze, laugh or lift a heavy object. This is stress incontinence. If bladder muscles become too active, you may feel a strong urge to go to the bathroom when you have little urine in your bladder. This is urge incontinence or overactive bladder. There are other causes of incontinence, such as prostate problems and nerve damage. Treatment depends on the type of problem you have and what best fits your lifestyle. It may include simple exercises, medicines, special devices or procedures prescribed by your doctor, or surgery. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
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
Reduced strength and weakness of the muscles of the arms and legs.
Talipes equinovarus
MedGen UID:
504945
Concept ID:
CN001602
Finding
Talipes equinovarus (also called clubfoot) typically has four main components: inversion and adduction of the forefoot; inversion of the heel and hindfoot; equinus (limitation of extension) of the ankle and subtalar joint; and internal rotation of the leg.
Diaphragmatic eventration
MedGen UID:
8359
Concept ID:
C0011981
Congenital Abnormality
A congenital abnormality characterized by the elevation of the DIAPHRAGM dome. It is the result of a thinned diaphragmatic muscle and injured PHRENIC NERVE, allowing the intra-abdominal viscera to push the diaphragm upward against the LUNG.
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Inability to move the muscles of respiration.
Denervation of the diaphragm
MedGen UID:
346925
Concept ID:
C1858529
Finding
Interruption of the innervation of the diaphragm.
Constipation
MedGen UID:
368096
Concept ID:
C1963087
Finding
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Inability to move the muscles of respiration.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Sign or Symptom
Reduction of neurologic reflexes such as the knee-jerk reaction.
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.
Diaphragmatic eventration
MedGen UID:
8359
Concept ID:
C0011981
Congenital Abnormality
A congenital abnormality characterized by the elevation of the DIAPHRAGM dome. It is the result of a thinned diaphragmatic muscle and injured PHRENIC NERVE, allowing the intra-abdominal viscera to push the diaphragm upward against the LUNG.
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Inability to move the muscles of respiration.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Denervation of the diaphragm
MedGen UID:
346925
Concept ID:
C1858529
Finding
Interruption of the innervation of the diaphragm.
Ventilator dependence with inability to wean
MedGen UID:
870643
Concept ID:
C4025097
Finding
Inspiratory stridor
MedGen UID:
505799
Concept ID:
CN004748
Finding
Inspiratory stridor is a high pitched sound upon inspiration that is generally related to laryngeal abnormalities.
Diaphragmatic eventration
MedGen UID:
8359
Concept ID:
C0011981
Congenital Abnormality
A congenital abnormality characterized by the elevation of the DIAPHRAGM dome. It is the result of a thinned diaphragmatic muscle and injured PHRENIC NERVE, allowing the intra-abdominal viscera to push the diaphragm upward against the LUNG.
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Inability to move the muscles of respiration.
Denervation of the diaphragm
MedGen UID:
346925
Concept ID:
C1858529
Finding
Interruption of the innervation of the diaphragm.
Constipation
MedGen UID:
368096
Concept ID:
C1963087
Finding
Spinal muscular atrophy
MedGen UID:
7755
Concept ID:
C0026847
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of SMN1 spans a continuum without clear delineation of subtypes. Nonetheless, classification by age of onset and maximum function achieved is useful for prognosis and management; subtypes include: SMA 0 (proposed), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure; SMA I, with onset before age six months; SMA II, with onset between age six and 12 months; SMA III, with onset in childhood after age 12 months and ability to walk at least 25 meters achieved; and SMA IV, with adult onset.
Respiratory paralysis
MedGen UID:
19748
Concept ID:
C0035232
Finding
Inability to move the muscles of respiration.
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.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Finding
Muscular atrophy affecting muscles in the distal portions of the extremities.
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).
Weak cry
MedGen UID:
65892
Concept ID:
C0234860
Finding
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.
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.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating).
Premature birth
MedGen UID:
57721
Concept ID:
C0151526
Finding
The birth of a baby of less than 37 weeks of 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

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. [Epub ahead of print] PMID: 26298607

Diagnosis

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. [Epub ahead of print] PMID: 26298607
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. [Epub ahead of print] PMID: 25280635
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. [Epub ahead of print] PMID: 25248952
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. [Epub ahead of print] 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

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. [Epub ahead of print] PMID: 26095024Free PMC Article

Prognosis

Hamilton MJ, Longman C, O'Hara A, Kirkpatrick M, McWilliam R
Neuromuscul Disord 2015 Feb;25(2):169-71. Epub 2014 Oct 22 doi: 10.1016/j.nmd.2014.10.005. [Epub ahead of print] PMID: 25454169
Gitiaux C, Bergounioux J, Magen M, Quijano-Roy S, Blanc T, Bonnefont JP, Desguerre I
J Child Neurol 2013 Jun;28(6):787-90. Epub 2012 Jul 12 doi: 10.1177/0883073812450209. [Epub ahead of print] PMID: 22791546
Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, Van Maldergem L, Hübner C, Schuelke M, von Au K
Pediatrics 2012 Jan;129(1):e148-56. Epub 2011 Dec 12 doi: 10.1542/peds.2011-0544. [Epub ahead of print] PMID: 22157136
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. [Epub ahead of print] PMID: 21353777Free PMC Article

Clinical prediction guides

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. [Epub ahead of print] PMID: 25280635
Jędrzejowska M, Madej-Pilarczyk A, Fidziańska A, Mierzewska H, Pronicka E, Obersztyn E, Gos M, Pronicki M, Kmieć T, Migdał M, Mierzewska-Schmidt M, Walczak-Wojtkowska I, Konopka E, Hausmanowa-Petrusewicz I
Eur J Paediatr Neurol 2014 Mar;18(2):183-92. Epub 2013 Dec 15 doi: 10.1016/j.ejpn.2013.11.006. [Epub ahead of print] PMID: 24388491
Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, Van Maldergem L, Hübner C, Schuelke M, von Au K
Pediatrics 2012 Jan;129(1):e148-56. Epub 2011 Dec 12 doi: 10.1542/peds.2011-0544. [Epub ahead of print] PMID: 22157136

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. [Epub ahead of print] PMID: 25248952

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