U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures(NEMMLAS)

MedGen UID:
1619876
Concept ID:
C4540192
Disease or Syndrome
Synonyms: NEMMLAS; NEURODEVELOPMENTAL DISORDER, MITOCHONDRIAL, WITH ABNORMAL MOVEMENTS AND LACTIC ACIDOSIS, WITH OR WITHOUT SEIZURES
SNOMED CT: WARS2-related combined oxidative phosphorylation defect (1260128008); Tryptophanyl tRNA synthetase 2, mitochondrial-related combined oxidative phosphorylation defect (1260128008); Mitochondrial tryptophanyl-tRNA synthetase deficiency (1260128008)
 
Gene (location): WARS2 (1p12)
 
Monarch Initiative: MONDO:0060578
OMIM®: 617710
Orphanet: ORPHA572798

Definition

NEMMLAS is an autosomal recessive multisystemic disorder characterized by delayed psychomotor development, intellectual disability, and abnormal motor function, including hypotonia, dystonia, ataxia, and spasticity. Patient tissues may show deficiencies in one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes, but this is not a constant finding (summary by Wortmann et al., 2017). [from OMIM]

Clinical features

From HPO
Limb hypertonia
MedGen UID:
333083
Concept ID:
C1838391
Finding
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Athetosis
MedGen UID:
2115
Concept ID:
C0004158
Disease or Syndrome
A slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Athetosis involves continuous smooth movements that appear random and are not composed of recognizable sub-movements or movement fragments. In contrast to chorea, in athetosis, the same regions of the body are repeatedly involved. Athetosis may worsen with attempts at movement of posture, but athetosis can also occur at rest.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Seizure
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.
Abnormality of speech or vocalization
MedGen UID:
11531
Concept ID:
C0037822
Disease or Syndrome
Abnormalities in the sound of a person's speech or vocalization are not necessarily associated with a known physical cause or due to stuttering or stammering.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
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.
Diffuse cerebral atrophy
MedGen UID:
108958
Concept ID:
C0598275
Finding
Diffuse unlocalised atrophy affecting the cerebrum.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
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).
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Severe temper tantrums
MedGen UID:
1370486
Concept ID:
C4476627
Mental or Behavioral Dysfunction
Temper tantrums, which occur with more severe symptomatology compared to a temper tantrum that occurs as a part of normal developmental process.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
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.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Amblyopia
MedGen UID:
8009
Concept ID:
C0002418
Disease or Syndrome
Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVNeurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures

Professional guidelines

PubMed

Zuberi SM, Wirrell E, Yozawitz E, Wilmshurst JM, Specchio N, Riney K, Pressler R, Auvin S, Samia P, Hirsch E, Galicchio S, Triki C, Snead OC, Wiebe S, Cross JH, Tinuper P, Scheffer IE, Perucca E, Moshé SL, Nabbout R
Epilepsia 2022 Jun;63(6):1349-1397. Epub 2022 May 3 doi: 10.1111/epi.17239. PMID: 35503712
Abboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, Christo PP, Dale RC, Fernandez-Fournier M, Flanagan EP, Gadoth A, George P, Grebenciucova E, Jammoul A, Lee ST, Li Y, Matiello M, Morse AM, Rae-Grant A, Rojas G, Rossman I, Schmitt S, Venkatesan A, Vernino S, Pittock SJ, Titulaer MJ; Autoimmune Encephalitis Alliance Clinicians Network
J Neurol Neurosurg Psychiatry 2021 Jul;92(7):757-768. Epub 2021 Mar 1 doi: 10.1136/jnnp-2020-325300. PMID: 33649022Free PMC Article
Ziobro J, Shellhaas RA
Semin Neurol 2020 Apr;40(2):246-256. Epub 2020 Mar 6 doi: 10.1055/s-0040-1702943. PMID: 32143234

Recent clinical studies

Etiology

Zelano J, Holtkamp M, Agarwal N, Lattanzi S, Trinka E, Brigo F
Epileptic Disord 2020 Jun 1;22(3):252-263. doi: 10.1684/epd.2020.1159. PMID: 32597766
Ziobro J, Shellhaas RA
Semin Neurol 2020 Apr;40(2):246-256. Epub 2020 Mar 6 doi: 10.1055/s-0040-1702943. PMID: 32143234
Shellhaas RA
Handb Clin Neurol 2019;162:347-361. doi: 10.1016/B978-0-444-64029-1.00017-5. PMID: 31324320
Gavvala JR, Schuele SU
JAMA 2016 Dec 27;316(24):2657-2668. doi: 10.1001/jama.2016.18625. PMID: 28027373
Patterson JL, Carapetian SA, Hageman JR, Kelley KR
Pediatr Ann 2013 Dec;42(12):249-54. doi: 10.3928/00904481-20131122-09. PMID: 24295158

Diagnosis

Ziobro J, Shellhaas RA
Semin Neurol 2020 Apr;40(2):246-256. Epub 2020 Mar 6 doi: 10.1055/s-0040-1702943. PMID: 32143234
Shellhaas RA
Handb Clin Neurol 2019;162:347-361. doi: 10.1016/B978-0-444-64029-1.00017-5. PMID: 31324320
Bank AM, Bazil CW
Semin Neurol 2019 Feb;39(1):73-81. Epub 2019 Feb 11 doi: 10.1055/s-0038-1677008. PMID: 30743294
Johnson EL
Med Clin North Am 2019 Mar;103(2):309-324. Epub 2018 Dec 3 doi: 10.1016/j.mcna.2018.10.002. PMID: 30704683
Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser WA
Epilepsia 2010 Apr;51(4):671-5. Epub 2009 Sep 3 doi: 10.1111/j.1528-1167.2009.02285.x. PMID: 19732133

Therapy

Rosenthal ES
Continuum (Minneap Minn) 2021 Oct 1;27(5):1321-1343. doi: 10.1212/CON.0000000000001012. PMID: 34618762
Ziobro JM, Eschbach K, Shellhaas RA
Neurotherapeutics 2021 Jul;18(3):1564-1581. Epub 2021 Aug 12 doi: 10.1007/s13311-021-01085-8. PMID: 34386906Free PMC Article
von Wrede R, Helmstaedter C, Surges R
Clin Drug Investig 2021 Mar;41(3):211-220. Epub 2021 Feb 9 doi: 10.1007/s40261-021-01003-y. PMID: 33559102Free PMC Article
Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, Feucht M, Krsek P, Nabbout R, Jansen AC, Wojdan K, Sijko K, Głowacka-Walas J, Borkowska J, Sadowski K, Domańska-Pakieła D, Moavero R, Hertzberg C, Hulshof H, Scholl T, Benova B, Aronica E, de Ridder J, Lagae L, Jóźwiak S; EPISTOP Investigators
Ann Neurol 2021 Feb;89(2):304-314. Epub 2020 Nov 27 doi: 10.1002/ana.25956. PMID: 33180985Free PMC Article
Foster E, Carney P, Liew D, Ademi Z, O'Brien T, Kwan P
J Neurol Neurosurg Psychiatry 2019 Sep;90(9):1039-1045. Epub 2019 Apr 4 doi: 10.1136/jnnp-2018-320215. PMID: 30948624

Prognosis

Menghi V, Bisulli F, Cardinale F, Vignatelli L, Zenesini C, Mai R, Proserpio P, Francione S, Sartori I, Tinuper P, Nobili L
Epilepsy Behav 2022 Apr;129:108629. Epub 2022 Mar 7 doi: 10.1016/j.yebeh.2022.108629. PMID: 35272206
Salanova V, Sperling MR, Gross RE, Irwin CP, Vollhaber JA, Giftakis JE, Fisher RS; SANTÉ Study Group
Epilepsia 2021 Jun;62(6):1306-1317. Epub 2021 Apr 8 doi: 10.1111/epi.16895. PMID: 33830503
Sartori S, Nosadini M, Tessarin G, Boniver C, Frigo AC, Toldo I, Bressan S, Da Dalt L
Dev Med Child Neurol 2019 Jan;61(1):82-90. Epub 2018 Sep 7 doi: 10.1111/dmcn.14015. PMID: 30191957
Tatum WO, Langston ME, Acton EK
Epileptic Disord 2016 Jun 1;18(2):148-54. doi: 10.1684/epd.2016.0823. PMID: 27238051
Patterson JL, Carapetian SA, Hageman JR, Kelley KR
Pediatr Ann 2013 Dec;42(12):249-54. doi: 10.3928/00904481-20131122-09. PMID: 24295158

Clinical prediction guides

Struck AF, Tabaeizadeh M, Schmitt SE, Ruiz AR, Swisher CB, Subramaniam T, Hernandez C, Kaleem S, Haider HA, Cissé AF, Dhakar MB, Hirsch LJ, Rosenthal ES, Zafar SF, Gaspard N, Westover MB
JAMA Neurol 2020 Apr 1;77(4):500-507. doi: 10.1001/jamaneurol.2019.4656. PMID: 31930362Free PMC Article
Meisel C, Loddenkemper T
Neuropharmacology 2020 Aug 1;172:107898. Epub 2019 Dec 5 doi: 10.1016/j.neuropharm.2019.107898. PMID: 31839204
Xu MY
Stroke Vasc Neurol 2019 Mar;4(1):48-56. Epub 2018 Dec 9 doi: 10.1136/svn-2018-000175. PMID: 31105979Free PMC Article
Acharya UR, Hagiwara Y, Adeli H
Epilepsy Behav 2018 Nov;88:251-261. Epub 2018 Oct 11 doi: 10.1016/j.yebeh.2018.09.030. PMID: 30317059
Carney PR, Myers S, Geyer JD
Epilepsy Behav 2011 Dec;22 Suppl 1(Suppl 1):S94-101. doi: 10.1016/j.yebeh.2011.09.001. PMID: 22078526Free PMC Article

Recent systematic reviews

Vetkas A, Fomenko A, Germann J, Sarica C, Iorio-Morin C, Samuel N, Yamamoto K, Milano V, Cheyuo C, Zemmar A, Elias G, Boutet A, Loh A, Santyr B, Gwun D, Tasserie J, Kalia SK, Lozano AM
Epilepsia 2022 Mar;63(3):513-524. Epub 2022 Jan 3 doi: 10.1111/epi.17157. PMID: 34981509
Sultana B, Panzini MA, Veilleux Carpentier A, Comtois J, Rioux B, Gore G, Bauer PR, Kwon CS, Jetté N, Josephson CB, Keezer MR
Neurology 2021 Apr 27;96(17):805-817. Epub 2021 Mar 15 doi: 10.1212/WNL.0000000000011839. PMID: 33722992
Jafarpour S, Hirsch LJ, Gaínza-Lein M, Kellinghaus C, Detyniecki K
Seizure 2019 May;68:9-15. Epub 2018 May 21 doi: 10.1016/j.seizure.2018.05.013. PMID: 29871784
Mewasingh LD
BMJ Clin Evid 2014 Jan 31;2014 PMID: 24484859Free PMC Article
Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser WA
Epilepsia 2010 Apr;51(4):671-5. Epub 2009 Sep 3 doi: 10.1111/j.1528-1167.2009.02285.x. PMID: 19732133

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.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...