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Rigidity and multifocal seizure syndrome, lethal neonatal(RMFSL)

MedGen UID:
482659
Concept ID:
C3281029
Disease or Syndrome
Synonym: RMFSL
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): BRAT1 (7p22.3)
 
Monarch Initiative: MONDO:0013784
OMIM®: 614498
Orphanet: ORPHA435845

Definition

Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by Saitsu et al., 2014). [from OMIM]

Clinical features

From HPO
Bradycardia
MedGen UID:
140901
Concept ID:
C0428977
Finding
A slower than normal heart rate (in adults, slower than 60 beats per minute).
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
The protrusion of a sac-like structure containing fibroadipose tissue through an abnormal opening in the inguinal region.
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
Abnormal autonomic nervous system physiology
MedGen UID:
8511
Concept ID:
C0013363
Disease or Syndrome
A functional abnormality of the autonomic nervous system.
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. It is a normal reflex up to the age of two. Its presence beyond that age indicates neurological damage.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Delayed myelination.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Neuronal loss in central nervous system
MedGen UID:
342515
Concept ID:
C1850496
Finding
Multifocal seizures
MedGen UID:
482664
Concept ID:
C3281034
Finding
Seizures that start from several different areas of the brain (i.e., with multiple ictal onset locations).
Myoclonic spasms
MedGen UID:
812772
Concept ID:
C3806442
Finding
Generalized myoclonic seizure
MedGen UID:
892704
Concept ID:
C4021759
Disease or Syndrome
A generalized myoclonic seizure is a type of generalized motor seizure characterised by bilateral, sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
The protrusion of a sac-like structure containing fibroadipose tissue through an abnormal opening in the inguinal region.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Muscular hypotonia of the trunk
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVRigidity and multifocal seizure syndrome, lethal neonatal

Recent clinical studies

Etiology

Van Ommeren RH, Gao AF, Blaser SI, Chitayat DA, Hazrati LN
J Neuropathol Exp Neurol 2018 Dec 1;77(12):1071-1078. doi: 10.1093/jnen/nly093. PMID: 30346566
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, Krivohlavek LA, Fellis J, Humphray S, Saffrey P, Kingsbury Z, Weir JC, Betley J, Grocock RJ, Margulies EH, Farrow EG, Artman M, Safina NP, Petrikin JE, Hall KP, Kingsmore SF
Sci Transl Med 2012 Oct 3;4(154):154ra135. doi: 10.1126/scitranslmed.3004041. PMID: 23035047Free PMC Article

Diagnosis

Smith NJ, Lipsett J, Dibbens LM, Heron SE
Am J Med Genet A 2016 Nov;170(11):3033-3038. Epub 2016 Aug 2 doi: 10.1002/ajmg.a.37853. PMID: 27480663
Srivastava S, Olson HE, Cohen JS, Gubbels CS, Lincoln S, Davis BT, Shahmirzadi L, Gupta S, Picker J, Yu TW, Miller DT, Soul JS, Poretti A, Naidu S
Am J Med Genet A 2016 Sep;170(9):2265-73. Epub 2016 Jun 9 doi: 10.1002/ajmg.a.37783. PMID: 27282546Free PMC Article
Fernández-Jaén A, Álvarez S, So EY, Ouchi T, Jiménez de la Peña M, Duat A, Fernández-Mayoralas DM, Fernández-Perrone AL, Albert J, Calleja-Pérez B
Eur J Paediatr Neurol 2016 May;20(3):421-5. Epub 2016 Feb 21 doi: 10.1016/j.ejpn.2016.02.009. PMID: 26947546Free PMC Article
Saitsu H, Yamashita S, Tanaka Y, Tsurusaki Y, Nakashima M, Miyake N, Matsumoto N
J Hum Genet 2014 Dec;59(12):687-90. Epub 2014 Oct 16 doi: 10.1038/jhg.2014.91. PMID: 25319849
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, Krivohlavek LA, Fellis J, Humphray S, Saffrey P, Kingsbury Z, Weir JC, Betley J, Grocock RJ, Margulies EH, Farrow EG, Artman M, Safina NP, Petrikin JE, Hall KP, Kingsmore SF
Sci Transl Med 2012 Oct 3;4(154):154ra135. doi: 10.1126/scitranslmed.3004041. PMID: 23035047Free PMC Article

Prognosis

Colak FK, Guleray N, Azapagasi E, Yazıcı MU, Aksoy E, Ceylan N
Acta Neurol Belg 2020 Dec;120(6):1425-1432. Epub 2020 Oct 10 doi: 10.1007/s13760-020-01513-0. PMID: 33040300Free PMC Article
Van Ommeren RH, Gao AF, Blaser SI, Chitayat DA, Hazrati LN
J Neuropathol Exp Neurol 2018 Dec 1;77(12):1071-1078. doi: 10.1093/jnen/nly093. PMID: 30346566
Hanes I, Kozenko M, Callen DJ
Pediatr Neurol 2015 Dec;53(6):535-40. Epub 2015 Sep 12 doi: 10.1016/j.pediatrneurol.2015.09.002. PMID: 26483087
Straussberg R, Ganelin-Cohen E, Goldberg-Stern H, Tzur S, Behar DM, Smirin-Yosef P, Salmon-Divon M, Basel-Vanagaite L
Eur J Paediatr Neurol 2015 Mar;19(2):240-2. Epub 2014 Nov 29 doi: 10.1016/j.ejpn.2014.11.004. PMID: 25500575
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, Krivohlavek LA, Fellis J, Humphray S, Saffrey P, Kingsbury Z, Weir JC, Betley J, Grocock RJ, Margulies EH, Farrow EG, Artman M, Safina NP, Petrikin JE, Hall KP, Kingsmore SF
Sci Transl Med 2012 Oct 3;4(154):154ra135. doi: 10.1126/scitranslmed.3004041. PMID: 23035047Free PMC Article

Clinical prediction guides

Van Ommeren RH, Gao AF, Blaser SI, Chitayat DA, Hazrati LN
J Neuropathol Exp Neurol 2018 Dec 1;77(12):1071-1078. doi: 10.1093/jnen/nly093. PMID: 30346566
Oatts JT, Duncan JL, Hoyt CS, Slavotinek AM, Moore AT
Ophthalmic Genet 2017 Dec;38(6):559-561. Epub 2017 Mar 2 doi: 10.1080/13816810.2017.1290118. PMID: 28635423
Fernández-Jaén A, Álvarez S, So EY, Ouchi T, Jiménez de la Peña M, Duat A, Fernández-Mayoralas DM, Fernández-Perrone AL, Albert J, Calleja-Pérez B
Eur J Paediatr Neurol 2016 May;20(3):421-5. Epub 2016 Feb 21 doi: 10.1016/j.ejpn.2016.02.009. PMID: 26947546Free PMC Article
Saitsu H, Yamashita S, Tanaka Y, Tsurusaki Y, Nakashima M, Miyake N, Matsumoto N
J Hum Genet 2014 Dec;59(12):687-90. Epub 2014 Oct 16 doi: 10.1038/jhg.2014.91. PMID: 25319849

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