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Neuronal ceroid lipofuscinosis 3(CLN3)

MedGen UID:
155549
Concept ID:
C0751383
Disease or Syndrome
Synonyms: CLN3; CLN3 Disease; CLN3-Related Neuronal Ceroid-Lipofuscinosis; Spielmeyer Sjogren disease
SNOMED CT: Juvenile neuronal ceroid lipofuscinosis (61663001); Batten-Mayou disease (61663001); Spielmeyer-Vogt disease (61663001); Amaurotic idiocy, juvenile type (61663001); Cerebral lipidosis, myoclonic variant (61663001); Batten-Spielmeyer-Vogt disease (61663001); Cerebral lipidosis myoclonic variant (61663001); Batten-Mayou syndrome (61663001); Amaurotic idiocy juvenile type (61663001); Spielmeyer-Vogt type neuronal ceroid lipofuscinosis (61663001)
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): CLN3 (16p12.1)
 
Monarch Initiative: MONDO:0008767
OMIM®: 204200
Orphanet: ORPHA228346

Definition

The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005). The hallmark of CLN3 is the ultrastructural pattern of lipopigment with a 'fingerprint' profile, which can have 3 different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with CLN3 (Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). [from OMIM]

Additional description

From MedlinePlus Genetics
CLN3 disease is an inherited disorder that primarily affects the nervous system. After 4 to 6 years of normal development, children with this condition develop vision impairment, intellectual disability, movement problems, speech difficulties, and seizures, which worsen over time.\n\nIn children with CLN3 disease, problems with vision often begin between the ages of 4 and 8 years. Vision impairment is caused by a breakdown of the light-sensitive tissue at the back of the eye (retinal degeneration), which worsens with age. People with CLN3 disease are often blind by late childhood or adolescence. Also around age 4 to 8, children with CLN3 disease start to fall behind in school. They have difficulty learning new information and lose previously acquired skills (developmental regression), usually beginning with loss of the ability to speak in complete sentences.\n\nSeizures and movement abnormalities often develop in adolescence in people with CLN3 disease. These abnormalities include muscle rigidity or stiffness, clumsiness, slow or diminished movements (hypokinesia), and a stooped posture. Over time, affected individuals lose the ability to walk or sit independently and require wheelchair assistance. Rarely, people with CLN3 disease develop a distorted view of reality (psychosis) or false perceptions (hallucinations). Some affected individuals have an abnormal heart rhythm (arrhythmia) later in life. Most people with CLN3 disease live into early adulthood.\n\nCLN3 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), which may also be collectively referred to as Batten disease. All these disorders affect the nervous system and typically cause worsening problems with vision, movement, and thinking ability. The different NCLs are distinguished by their genetic cause. Each disease type is given the designation "CLN," meaning ceroid lipofuscinosis, neuronal, and then a number to indicate its subtype.  https://medlineplus.gov/genetics/condition/cln3-disease

Clinical features

From HPO
Concentric hypertrophic cardiomyopathy
MedGen UID:
68651
Concept ID:
C0238044
Finding
Hypertrophic cardiomyopathy with an symmetrical and concentric pattern of hypertrophy.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tenseness, or panic, often in reaction to interpersonal stresses; worry about the negative effects of past unpleasant experiences and future negative possibilities; feeling fearful, apprehensive, or threatened by uncertainty; fears of falling apart or losing control.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A mental disorder characterized by personality change, impaired functioning, and loss of touch with reality.
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.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Parkinsonism
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Psychomotor deterioration
MedGen UID:
373191
Concept ID:
C1836842
Finding
Loss of previously present mental and motor abilities.
Progressive inability to walk
MedGen UID:
332305
Concept ID:
C1836843
Finding
Increased extraneuronal autofluorescent lipopigment
MedGen UID:
347957
Concept ID:
C1859828
Finding
Lipofuscin, a generic term applied to autofluorescent lipopigment, is a mixture of protein and lipid that accumulates in most aging cells, particularly those involved in high lipid turnover (e.g., the adrenal medulla) or phagocytosis of other cell types (e g., the retinal pigment epithelium or RPE; macrophage). This term pertains if there is an increase in the extraneuronal accumulation of lipofuscin (also known as autofluorescent lipoprotein) more than expected for the age of the patient.
Abnormality of the cerebellum
MedGen UID:
400925
Concept ID:
C1866129
Anatomical Abnormality
Any structural abnormality of the cerebellum.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
A broad category of disorders characterized by an impairment to the intelligence an individual possesses. These impairments can result from trauma, birth, or disease and are not restricted to any particular age group.
Increased neuronal autofluorescent lipopigment
MedGen UID:
892355
Concept ID:
C4025728
Finding
Lipofuscin, a generic term applied to autofluorescent lipopigment, is a mixture of protein and lipid that accumulates in most aging cells, particularly those involved in high lipid turnover (e.g., the adrenal medulla) or phagocytosis of other cell types (e g., the retinal pigment epithelium or RPE; macrophage). This term pertains if there is an increase in the neuronal accumulation of lipofuscin (also known as autofluorescent lipoprotein) more than expected for the age of the patient.
Vacuolated lymphocytes
MedGen UID:
332307
Concept ID:
C1836855
Finding
The presence of clear, sharply defined vacuoles in the lymphocyte cytoplasm.
Vacuolated lymphocytes
MedGen UID:
332307
Concept ID:
C1836855
Finding
The presence of clear, sharply defined vacuoles in the lymphocyte cytoplasm.
Fingerprint intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
324619
Concept ID:
C1836851
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a trabecular or fingerprint-like pattern.
Curvilinear intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
323011
Concept ID:
C1836852
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a curved pattern.
Glaucoma
MedGen UID:
42224
Concept ID:
C0017601
Disease or Syndrome
Glaucoma refers loss of retinal ganglion cells in a characteristic pattern of optic neuropathy usually associated with increased intraocular pressure.
Macular degeneration
MedGen UID:
7434
Concept ID:
C0024437
Disease or Syndrome
A nonspecific term denoting degeneration of the retinal pigment epithelium and/or retinal photoreceptor cells of the macula lutea.
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.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as visual perception below 3/60 and/or a visual field of no greater than 10 degrees in radius around central fixation.
Progressive visual loss
MedGen UID:
326867
Concept ID:
C1839364
Finding
A reduction of previously attained ability to see.
Undetectable electroretinogram
MedGen UID:
383742
Concept ID:
C1855685
Finding
Lack of any response to stimulation upon electroretinography.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
Fingerprint intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
324619
Concept ID:
C1836851
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a trabecular or fingerprint-like pattern.
Curvilinear intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
323011
Concept ID:
C1836852
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a curved pattern.

Recent clinical studies

Etiology

Kose M, Kose E, Ünalp A, Yılmaz Ü, Edizer S, Tekin HG, Karaoğlu P, Özdemir TR, Er E, Onay H, Yildirim ES
Neurol Sci 2021 Mar;42(3):1103-1111. Epub 2021 Jan 23 doi: 10.1007/s10072-021-05067-8. PMID: 33486620
Biswas A, Krishnan P, Amirabadi A, Blaser S, Mercimek-Andrews S, Shroff M
AJNR Am J Neuroradiol 2020 Oct;41(10):1930-1936. Epub 2020 Aug 27 doi: 10.3174/ajnr.A6726. PMID: 32855186Free PMC Article
Azad B, Efthymiou S, Sultan T, Scala M, Alvi JR, Neuray C, Dominik N; SYNaPS Study Group., Gul A, Houlden H
J Neurol Sci 2020 Jul 15;414:116826. Epub 2020 Apr 7 doi: 10.1016/j.jns.2020.116826. PMID: 32302805Free PMC Article
Parvin S, Rezazadeh M, Hosseinzadeh H, Moradi M, Shiva S, Gharesouran J
Neuromolecular Med 2019 Jun;21(2):160-169. Epub 2019 Mar 27 doi: 10.1007/s12017-019-08529-7. PMID: 30919163
Lehwald LM, Pappa R, Steward S, de Los Reyes E
Pediatr Neurol 2016 Jun;59:30-5. Epub 2016 Mar 3 doi: 10.1016/j.pediatrneurol.2016.02.009. PMID: 27105763

Diagnosis

Kose M, Kose E, Ünalp A, Yılmaz Ü, Edizer S, Tekin HG, Karaoğlu P, Özdemir TR, Er E, Onay H, Yildirim ES
Neurol Sci 2021 Mar;42(3):1103-1111. Epub 2021 Jan 23 doi: 10.1007/s10072-021-05067-8. PMID: 33486620
Biswas A, Krishnan P, Amirabadi A, Blaser S, Mercimek-Andrews S, Shroff M
AJNR Am J Neuroradiol 2020 Oct;41(10):1930-1936. Epub 2020 Aug 27 doi: 10.3174/ajnr.A6726. PMID: 32855186Free PMC Article
Gavin M, Khatoon S, Marchi EJ, Mevs CA, Bolton DC, Velinov MT, Junaid MA
Clin Chim Acta 2020 Aug;507:62-68. Epub 2020 Apr 13 doi: 10.1016/j.cca.2020.04.010. PMID: 32298681
Ge L, Li HY, Hai Y, Min L, Xing L, Min J, Shu HX, Mei OY, Hua L
J Child Neurol 2018 Nov;33(13):837-850. Epub 2018 Sep 28 doi: 10.1177/0883073818789024. PMID: 30264640
Lehwald LM, Pappa R, Steward S, de Los Reyes E
Pediatr Neurol 2016 Jun;59:30-5. Epub 2016 Mar 3 doi: 10.1016/j.pediatrneurol.2016.02.009. PMID: 27105763

Therapy

Marques ARA, Di Spiezio A, Thießen N, Schmidt L, Grötzinger J, Lüllmann-Rauch R, Damme M, Storck SE, Pietrzik CU, Fogh J, Bär J, Mikhaylova M, Glatzel M, Bassal M, Bartsch U, Saftig P
Autophagy 2020 May;16(5):811-825. Epub 2019 Jul 16 doi: 10.1080/15548627.2019.1637200. PMID: 31282275Free PMC Article
Wong LC, Hsu CJ, Lee WT
Brain Dev 2019 Oct;41(9):817-819. Epub 2019 May 21 doi: 10.1016/j.braindev.2019.05.001. PMID: 31122803
Lehwald LM, Pappa R, Steward S, de Los Reyes E
Pediatr Neurol 2016 Jun;59:30-5. Epub 2016 Mar 3 doi: 10.1016/j.pediatrneurol.2016.02.009. PMID: 27105763
Levin SW, Baker EH, Zein WM, Zhang Z, Quezado ZM, Miao N, Gropman A, Griffin KJ, Bianconi S, Chandra G, Khan OI, Caruso RC, Liu A, Mukherjee AB
Lancet Neurol 2014 Aug;13(8):777-87. Epub 2014 Jul 2 doi: 10.1016/S1474-4422(14)70142-5. PMID: 24997880Free PMC Article
Tokola AM, Salli EK, Åberg LE, Autti TH
Pediatr Neurol 2014 Feb;50(2):158-63. Epub 2013 Oct 30 doi: 10.1016/j.pediatrneurol.2013.10.013. PMID: 24411222

Prognosis

Ardicli D, Haliloglu G, Gocmen R, Gunbey C, Topcu M
Eur J Paediatr Neurol 2021 Jul;33:94-98. Epub 2021 Jun 4 doi: 10.1016/j.ejpn.2021.05.015. PMID: 34119739
Alkhars FZ, Bo Ali AY, Almohanna MA, Almajhad NA
Neurosciences (Riyadh) 2020 Jan;25(1):65-69. doi: 10.17712/nsj.2020.1.20190103. PMID: 31982899Free PMC Article
Chen FK, Zhang X, Eintracht J, Zhang D, Arunachalam S, Thompson JA, Chelva E, Mallon D, Chen SC, McLaren T, Lamey T, De Roach J, McLenachan S
Doc Ophthalmol 2019 Feb;138(1):55-70. Epub 2018 Nov 16 doi: 10.1007/s10633-018-9665-7. PMID: 30446867
Levin SW, Baker EH, Zein WM, Zhang Z, Quezado ZM, Miao N, Gropman A, Griffin KJ, Bianconi S, Chandra G, Khan OI, Caruso RC, Liu A, Mukherjee AB
Lancet Neurol 2014 Aug;13(8):777-87. Epub 2014 Jul 2 doi: 10.1016/S1474-4422(14)70142-5. PMID: 24997880Free PMC Article
Tokola AM, Salli EK, Åberg LE, Autti TH
Pediatr Neurol 2014 Feb;50(2):158-63. Epub 2013 Oct 30 doi: 10.1016/j.pediatrneurol.2013.10.013. PMID: 24411222

Clinical prediction guides

Seifert C, Storch S, Bähring R
J Biol Chem 2020 Aug 21;295(34):12099-12110. Epub 2020 Jul 7 doi: 10.1074/jbc.RA120.013828. PMID: 32641494Free PMC Article
Azad B, Efthymiou S, Sultan T, Scala M, Alvi JR, Neuray C, Dominik N; SYNaPS Study Group., Gul A, Houlden H
J Neurol Sci 2020 Jul 15;414:116826. Epub 2020 Apr 7 doi: 10.1016/j.jns.2020.116826. PMID: 32302805Free PMC Article
Gavin M, Khatoon S, Marchi EJ, Mevs CA, Bolton DC, Velinov MT, Junaid MA
Clin Chim Acta 2020 Aug;507:62-68. Epub 2020 Apr 13 doi: 10.1016/j.cca.2020.04.010. PMID: 32298681
Alkhars FZ, Bo Ali AY, Almohanna MA, Almajhad NA
Neurosciences (Riyadh) 2020 Jan;25(1):65-69. doi: 10.17712/nsj.2020.1.20190103. PMID: 31982899Free PMC Article
Lehwald LM, Pappa R, Steward S, de Los Reyes E
Pediatr Neurol 2016 Jun;59:30-5. Epub 2016 Mar 3 doi: 10.1016/j.pediatrneurol.2016.02.009. PMID: 27105763

Recent systematic reviews

Parvin S, Rezazadeh M, Hosseinzadeh H, Moradi M, Shiva S, Gharesouran J
Neuromolecular Med 2019 Jun;21(2):160-169. Epub 2019 Mar 27 doi: 10.1007/s12017-019-08529-7. PMID: 30919163

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