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Kugelberg-Welander disease(SMA3)

MedGen UID:
101816
Concept ID:
C0152109
Disease or Syndrome
Synonyms: Juvenile Spinal Muscular Atrophy; Kugelberg-Welander syndrome; Muscular atrophy, juvenile; SMA 3; SMA III; SMA3; Spinal muscular atrophy type 3; Spinal muscular atrophy, mild childhood and adolescent form; SPINAL MUSCULAR ATROPHY, TYPE III
SNOMED CT: Spinal muscular atrophy type III (54280009); Spinal muscular atrophy, type III (54280009); SMA3 (54280009); SMA type III (54280009); Kugelberg-Welander disease (54280009); Familial spinal muscular atrophy (54280009); Juvenile spinal muscular atrophy (54280009)
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).
 
Genes (locations): SMN1 (5q13.2); SMN2 (5q13.2)
 
Monarch Initiative: MONDO:0009672
OMIM®: 253400
Orphanet: ORPHA83419

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 greater than 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 the disease. [from GeneReviews]
Authors:
Thomas W Prior  |  Meganne E Leach  |  Erika L Finanger   view full author information

Additional descriptions

From OMIM
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; 253300), II (SMA2; 253550), III (SMA3), and IV (271150), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by Fraidakis et al., 2012).  http://www.omim.org/entry/253400
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 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.

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.  https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy

Clinical features

From HPO
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.
Pelvic girdle muscle weakness
MedGen UID:
96534
Concept ID:
C0427064
Finding
Weakness of the muscles of the pelvic girdle (also known as the hip girdle), that is, lack of strength of the muscles around the pelvis.
Absent patellar reflexes
MedGen UID:
643630
Concept ID:
C0558844
Finding
Absence of the knee jerk reflex, which can normally be elicited by tapping the patellar tendon with a reflex hammer just below the patella.
Absent Achilles reflex
MedGen UID:
108240
Concept ID:
C0558845
Finding
Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Shoulder girdle muscle atrophy
MedGen UID:
339837
Concept ID:
C1847766
Finding
Amyotrophy affecting the muscles of the shoulder girdle.
Limb fasciculations
MedGen UID:
381469
Concept ID:
C1854657
Finding
Fasciculations affecting the musculature of the arms and legs.
Pelvic girdle amyotrophy
MedGen UID:
867170
Concept ID:
C4021528
Disease or Syndrome
Atrophy of the muscles of the pelvic girdle (also known as hip girdle), i.e., the gluteal muscles, the lateral rotators, the adductors, the psoas major and the iliacus muscle.
Hand tremor
MedGen UID:
68689
Concept ID:
C0239842
Finding
An unintentional, oscillating to-and-fro muscle movement affecting the hand.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Degeneration of anterior horn cells
MedGen UID:
375215
Concept ID:
C1843505
Finding
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.
Muscle spasm
MedGen UID:
52431
Concept ID:
C0037763
Sign or Symptom
Sudden and involuntary contractions of one or more muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Proximal lower limb amyotrophy
MedGen UID:
373171
Concept ID:
C1836767
Finding
Muscular atrophy affecting proximally located muscles of the legs, i.e., of the thigh.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
EMG: chronic denervation signs
MedGen UID:
871143
Concept ID:
C4025614
Finding
Evidence of chronic denervation on electromyography.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.

Term Hierarchy

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

Professional guidelines

PubMed

Ribero VA, Daigl M, Martí Y, Gorni K, Evans R, Scott DA, Mahajan A, Abrams KR, Hawkins N
J Comp Eff Res 2022 Apr;11(5):347-370. Epub 2022 Jan 18 doi: 10.2217/cer-2021-0216. PMID: 35040693
Butterfield RJ
Semin Pediatr Neurol 2021 Jul;38:100899. Epub 2021 May 29 doi: 10.1016/j.spen.2021.100899. PMID: 34183144Free PMC Article
Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group
Neuromuscul Disord 2018 Feb;28(2):103-115. Epub 2017 Nov 23 doi: 10.1016/j.nmd.2017.11.005. PMID: 29290580

Curated

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)

Recent clinical studies

Etiology

Moreira ES, Vainzof M, Marie SK, Sertié AL, Zatz M, Passos-Bueno MR
Am J Hum Genet 1997 Jul;61(1):151-9. doi: 10.1086/513889. PMID: 9245996Free PMC Article
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Nature 1990 Apr 19;344(6268):767-8. doi: 10.1038/344767a0. PMID: 1970420
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Singh N, Sachdev KK, Susheela AK
Arch Neurol 1980 May;37(5):297-9. doi: 10.1001/archneur.1980.00500540075011. PMID: 7387450
Pearn J
J Med Genet 1978 Dec;15(6):418-23. doi: 10.1136/jmg.15.6.418. PMID: 745213Free PMC Article

Diagnosis

Salort-Campana E, Quijano-Roy S
Arch Pediatr 2020 Dec;27(7S):7S23-7S28. doi: 10.1016/S0929-693X(20)30273-6. PMID: 33357593
Kuru S, Sakai M, Konagaya M, Yoshida M, Hashizume Y, Saito K
Neuropathology 2009 Feb;29(1):63-7. Epub 2008 Apr 11 doi: 10.1111/j.1440-1789.2008.00910.x. PMID: 18410269
Takahashi N, Shimada T, Ishibashi Y, Sugamori T, Hirano Y, Oyake N, Murakami Y
Am J Med Sci 2006 Dec;332(6):354-6. doi: 10.1097/00000441-200612000-00009. PMID: 17170627
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SMITH JB, PATEL A
Neurology 1965 May;15:469-73. doi: 10.1212/wnl.15.5.469. PMID: 14288637

Therapy

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
Yasuma F, Kuru S, Konagaya M
Intern Med 2004 Oct;43(10):951-4. doi: 10.2169/internalmedicine.43.951. PMID: 15575246
Thomson JA, Seymour JF, Wolf M
Leuk Lymphoma 2001 Jul;42(3):561-6. doi: 10.3109/10428190109064618. PMID: 11699426
Urbánek K, Chudácková J, Velísková J
Acta Univ Palacki Olomuc Fac Med 1990;126:147-50. PMID: 1965389

Prognosis

Kuru S, Sakai M, Konagaya M, Yoshida M, Hashizume Y, Saito K
Neuropathology 2009 Feb;29(1):63-7. Epub 2008 Apr 11 doi: 10.1111/j.1440-1789.2008.00910.x. PMID: 18410269
Thomson JA, Seymour JF, Wolf M
Leuk Lymphoma 2001 Jul;42(3):561-6. doi: 10.3109/10428190109064618. PMID: 11699426
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
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Clin Genet 1971;2(4):203-9. PMID: 5146579

Clinical prediction guides

Kuru S, Sakai M, Konagaya M, Yoshida M, Hashizume Y, Saito K
Neuropathology 2009 Feb;29(1):63-7. Epub 2008 Apr 11 doi: 10.1111/j.1440-1789.2008.00910.x. PMID: 18410269
Moreira ES, Vainzof M, Marie SK, Sertié AL, Zatz M, Passos-Bueno MR
Am J Hum Genet 1997 Jul;61(1):151-9. doi: 10.1086/513889. PMID: 9245996Free PMC Article
Burlet P, Bürglen L, Clermont O, Lefebvre S, Viollet L, Munnich A, Melki J
J Med Genet 1996 Apr;33(4):281-3. doi: 10.1136/jmg.33.4.281. PMID: 8730281Free PMC Article
Lin MY, Nonaka I
Brain Dev 1991 Sep;13(5):331-8. doi: 10.1016/s0387-7604(12)80128-8. PMID: 1723849
Pearn J
J Med Genet 1978 Dec;15(6):418-23. doi: 10.1136/jmg.15.6.418. PMID: 745213Free PMC Article

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)

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