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Werdnig-Hoffmann disease(SMA1)

MedGen UID:
21913
Concept ID:
C0043116
Disease or Syndrome
Synonyms: HMN (Hereditary Motor Neuropathy) Proximal Type I; Muscular atrophy, infantile; Proximal spinal muscular atrophy, type 1; SMA I; SMA, infantile acute form; SMA1; Spinal muscular atrophy 1
SNOMED CT: Werdnig-Hoffmann disease (64383006); Infantile spinal muscular atrophy (64383006); Progressive muscular atrophy of infancy (64383006); Spinal muscular atrophy type I (64383006); WHD - Werdnig-Hoffmann disease (64383006); Spinal muscular atrophy, type I (64383006)
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): SMN1 (5q13.2)
 
Monarch Initiative: MONDO:0009669
OMIM®: 253300
Orphanet: ORPHA83330

Disease characteristics

Excerpted from the GeneReview: Spinal Muscular Atrophy
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. [from GeneReviews]
Authors:
Thomas W Prior  |  Meganne E Leach  |  Erika Finanger   view full author information

Additional descriptions

From OMIM
Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy (summary by Wirth, 2000). Four types of SMA are recognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: type I, severe infantile acute SMA, or Werdnig-Hoffman disease; type II (253550), or infantile chronic SMA; type III (253400), juvenile SMA, or Wohlfart-Kugelberg-Welander disease; and type IV (271150), or adult-onset SMA. All types are caused by recessive mutations in the SMN1 gene. Lunn and Wang (2008) provided a detailed review of clinical features, molecular pathogenesis, and therapeutic strategies for SMA.  http://www.omim.org/entry/253300
From MedlinePlus Genetics
Spinal muscular atrophy is a genetic disorder characterized by weakness and wasting (atrophy) in muscles used for movement (skeletal muscles). It is caused by a loss of specialized nerve cells, called motor neurons that control muscle movement. The weakness tends to be more severe in the muscles that are close to the center of the body (proximal) compared to muscles away from the body's center (distal). The muscle weakness usually worsens with age. There are many types of spinal muscular atrophy that are caused by changes in the same genes. The types differ in age of onset and severity of muscle weakness; however, there is overlap between the types. Other forms of spinal muscular atrophy and related motor neuron diseases, such as spinal muscular atrophy with progressive myoclonic epilepsy, spinal muscular atrophy with lower extremity predominance, X-linked infantile spinal muscular atrophy, and spinal muscular atrophy with respiratory distress type 1 are caused by mutations in other genes.

Spinal muscular atrophy type 0 is evident before birth and is the rarest and most severe form of the condition. Affected infants move less in the womb, and as a result they are often born with joint deformities (contractures). They have extremely weak muscle tone (hypotonia) at birth. Their respiratory muscles are very weak and they often do not survive past infancy due to respiratory failure. Some infants with spinal muscular atrophy type 0 also have heart defects that are present from birth (congenital).

Spinal muscular atrophy type I (also called Werdnig-Hoffmann disease) is the most common form of the condition. It is a severe form of the disorder with muscle weakness evident at birth or within the first few months of life. Most affected children cannot control their head movements or sit unassisted. Children with this type may have swallowing problems that can lead to difficulty feeding and poor growth. They can also have breathing problems due to weakness of respiratory muscles and an abnormally bell-shaped chest that prevents the lungs from fully expanding. Most children with spinal muscular atrophy type I do not survive past early childhood due to respiratory failure.

Spinal muscular atrophy type II (also called Dubowitz disease) is characterized by muscle weakness that develops in children between ages 6 and 12 months. Children with this type can sit without support, although they may need help getting to a seated position. However, as the muscle weakness worsens later in childhood, affected individuals may need support to sit. Individuals with spinal muscular atrophy type II cannot stand or walk unaided. They often have involuntary trembling (tremors) in their fingers, a spine that curves side-to-side (scoliosis), and respiratory muscle weakness that can be life-threatening. The life span of individuals with spinal muscular atrophy type II varies, but many people with this condition live into their twenties or thirties.

Spinal muscular atrophy type III (also called Kugelberg-Welander disease) typically causes muscle weakness after early childhood. Individuals with this condition can stand and walk unaided, but over time, walking and climbing stairs may become increasingly difficult. Many affected individuals require wheelchair assistance later in life. People with spinal muscular atrophy type III typically have a normal life expectancy.

Spinal muscular atrophy type IV is rare and often begins in early adulthood. Affected individuals usually experience mild to moderate muscle weakness, tremors, and mild breathing problems. People with spinal muscular atrophy type IV have a normal life expectancy.  https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy

Clinical features

From HPO
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
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.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Proximal amyotrophy
MedGen UID:
342591
Concept ID:
C1850794
Disease or Syndrome
Amyotrophy (muscular atrophy) affecting the proximal musculature.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Proximal muscle weakness in lower limbs
MedGen UID:
356423
Concept ID:
C1866010
Finding
A lack of strength of the proximal muscles of the legs.
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).
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.
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.
Recurrent respiratory infections
MedGen UID:
812812
Concept ID:
C3806482
Finding
An increased susceptibility to respiratory infections as manifested by a history of recurrent respiratory infections.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Werdnig-Hoffmann disease in Orphanet.

Professional guidelines

PubMed

Boemer F, Caberg JH, Dideberg V, Dardenne D, Bours V, Hiligsmann M, Dangouloff T, Servais L
Neuromuscul Disord 2019 May;29(5):343-349. Epub 2019 Feb 15 doi: 10.1016/j.nmd.2019.02.003. PMID: 31030938
Goodkey K, Aslesh T, Maruyama R, Yokota T
Methods Mol Biol 2018;1828:69-76. doi: 10.1007/978-1-4939-8651-4_4. PMID: 30171535
Migita M, Migita M, Uchikoba Y, Orimo H, Shimada T, Shimada T, Matsumoto T, Hayakawa J, Fujino O, Saitoh M, Fukunaga Y
J Nippon Med Sch 2003 Feb;70(1):45-8. doi: 10.1272/jnms.70.45. PMID: 12646976

Curated

Rudnik-Schöneborn S, Eggermann T, Kress W, Lemmink HH, Cobben JM, Zerres K
Eur J Hum Genet 2012 Jun;20(6) Epub 2012 Apr 18 doi: 10.1038/ejhg.2012.62. PMID: 22510849Free PMC Article

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Exon 7 Deletion (Pathogenic Variant) in Survival Motor Neuron Gene (SMN1), Spinal Muscular Atrophy (SMA), 2020

ACMG Carrier Screening ACT Sheet Spinal Muscular Atrophy (SMA)

Suggested Reading

PubMed

Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, Yamashita M, Rigo F, Hung G, Schneider E, Norris DA, Xia S, Bennett CF, Bishop KM
Lancet 2016 Dec 17;388(10063):3017-3026. Epub 2016 Dec 7 doi: 10.1016/S0140-6736(16)31408-8. PMID: 27939059

Recent clinical studies

Etiology

Audic F, Barnerias C
Arch Pediatr 2020 Dec;27(7S):7S15-7S17. doi: 10.1016/S0929-693X(20)30271-2. PMID: 33357591
Thirunavukkarasu B, Gupta K, Bansal A, Dhanasekaran N, Baranwal A
Neurol India 2020 Jul-Aug;68(4):882-885. doi: 10.4103/0028-3886.293477. PMID: 32859833
Bach JR
Am J Phys Med Rehabil 2007 May;86(5):349-55. doi: 10.1097/PHM.0b013e31804b1d66. PMID: 17449979
Salviati L, Sacconi S, Rasalan MM, Kronn DF, Braun A, Canoll P, Davidson M, Shanske S, Bonilla E, Hays AP, Schon EA, DiMauro S
Arch Neurol 2002 May;59(5):862-5. doi: 10.1001/archneur.59.5.862. PMID: 12020273
Barth PG
Brain Dev 1993 Nov-Dec;15(6):411-22. doi: 10.1016/0387-7604(93)90080-r. PMID: 8147499

Diagnosis

Audic F, Barnerias C
Arch Pediatr 2020 Dec;27(7S):7S15-7S17. doi: 10.1016/S0929-693X(20)30271-2. PMID: 33357591
Thirunavukkarasu B, Gupta K, Bansal A, Dhanasekaran N, Baranwal A
Neurol India 2020 Jul-Aug;68(4):882-885. doi: 10.4103/0028-3886.293477. PMID: 32859833
Boemer F, Caberg JH, Dideberg V, Dardenne D, Bours V, Hiligsmann M, Dangouloff T, Servais L
Neuromuscul Disord 2019 May;29(5):343-349. Epub 2019 Feb 15 doi: 10.1016/j.nmd.2019.02.003. PMID: 31030938
Salviati L, Sacconi S, Rasalan MM, Kronn DF, Braun A, Canoll P, Davidson M, Shanske S, Bonilla E, Hays AP, Schon EA, DiMauro S
Arch Neurol 2002 May;59(5):862-5. doi: 10.1001/archneur.59.5.862. PMID: 12020273
Simic G, Seso-Simic D, Lucassen PJ, Islam A, Krsnik Z, Cviko A, Jelasic D, Barisic N, Winblad B, Kostovic I, Kruslin B
J Neuropathol Exp Neurol 2000 May;59(5):398-407. doi: 10.1093/jnen/59.5.398. PMID: 10888370

Therapy

Boemer F, Caberg JH, Dideberg V, Dardenne D, Bours V, Hiligsmann M, Dangouloff T, Servais L
Neuromuscul Disord 2019 May;29(5):343-349. Epub 2019 Feb 15 doi: 10.1016/j.nmd.2019.02.003. PMID: 31030938
Touznik A, Maruyama R, Yokota T
Methods Mol Biol 2018;1828:439-454. doi: 10.1007/978-1-4939-8651-4_27. PMID: 30171558
Goodkey K, Aslesh T, Maruyama R, Yokota T
Methods Mol Biol 2018;1828:69-76. doi: 10.1007/978-1-4939-8651-4_4. PMID: 30171535
Son HW, Yokota T
Methods Mol Biol 2018;1828:57-68. doi: 10.1007/978-1-4939-8651-4_3. PMID: 30171534
Arnold ES, Fischbeck KH
Handb Clin Neurol 2018;148:591-601. doi: 10.1016/B978-0-444-64076-5.00038-7. PMID: 29478602

Prognosis

Audic F, Barnerias C
Arch Pediatr 2020 Dec;27(7S):7S15-7S17. doi: 10.1016/S0929-693X(20)30271-2. PMID: 33357591
Schmalbruch H, Haase G
Brain Pathol 2001 Apr;11(2):231-47. doi: 10.1111/j.1750-3639.2001.tb00395.x. PMID: 11303798Free PMC Article
Thieme A, Mitulla B, Schulze F, Spiegler AW
Hum Genet 1993 Apr;91(3):295-7. doi: 10.1007/BF00218278. PMID: 8478016
Melki J, Abdelhak S, Burlet P, Raclin V, Kaplan J, Spiegel R, Gilgenkrantz S, Philip N, Chauvet ML, Dumez Y
J Med Genet 1992 Mar;29(3):171-4. doi: 10.1136/jmg.29.3.171. PMID: 1348092Free PMC Article
Pearn JH, Wilson J
Arch Dis Child 1973 Jun;48(6):425-30. doi: 10.1136/adc.48.6.425. PMID: 4712772Free PMC Article

Clinical prediction guides

Rudnik-Schöneborn S, Sztriha L, Aithala GR, Houge G, Laegreid LM, Seeger J, Huppke M, Wirth B, Zerres K
Am J Med Genet A 2003 Feb 15;117A(1):10-7. doi: 10.1002/ajmg.a.10863. PMID: 12548734
Hayashi M, Arai N, Murakami T, Yoshio M, Oda M, Matsuyama H
Neurosci Lett 1998 Feb 27;243(1-3):117-20. doi: 10.1016/s0304-3940(98)00105-0. PMID: 9535127
Melki J, Abdelhak S, Burlet P, Raclin V, Kaplan J, Spiegel R, Gilgenkrantz S, Philip N, Chauvet ML, Dumez Y
J Med Genet 1992 Mar;29(3):171-4. doi: 10.1136/jmg.29.3.171. PMID: 1348092Free PMC Article
Shishikura K, Hara M, Sasaki Y, Misugi K
Acta Neuropathol 1983;60(1-2):99-106. doi: 10.1007/BF00685353. PMID: 6880628
Fidziańska A
Acta Neuropathol 1976 Apr 26;34(4):321-7. doi: 10.1007/BF00696561. PMID: 1274524

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2020
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Exon 7 Deletion (Pathogenic Variant) in Survival Motor Neuron Gene (SMN1), Spinal Muscular Atrophy (SMA), 2020
    • ACMG ACT, 2018
      ACMG Carrier Screening ACT Sheet Spinal Muscular Atrophy (SMA)
    • EuroGenetest, 2012
      Clinical utility gene card for: proximal spinal muscular atrophy.

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