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Neuronal ceroid lipofuscinosis 5(CLN5)

MedGen UID:
376792
Concept ID:
C1850442
Disease or Syndrome
Synonyms: CEROID LIPOFUSCINOSIS, NEURONAL, 5, VARIABLE AGE AT ONSET; CLN5; CLN5 Disease; CLN5-Related Neuronal Ceroid-Lipofuscinosis; Neuronal ceroid lipofuscinosis Finnish variant; NEURONAL CEROID LIPOFUSCINOSIS, LATE INFANTILE, FINNISH VARIANT
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): CLN5 (13q22.3)
 
Monarch Initiative: MONDO:0009745
OMIM®: 256731
Orphanet: ORPHA228360

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 lipopigment patterns observed most often in CLN5 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (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
CLN5 disease is an inherited disorder that primarily affects the nervous system. The signs and symptoms of this condition can begin anytime between childhood and early adulthood, but they typically appear around age 5. Children with CLN5 disease often have normal development until they experience the first signs of the condition, which are usually problems with movement that might seem like clumsiness, and a loss of previously acquired motor skills (developmental regression). Other features of the condition include recurrent seizures that involve uncontrollable muscle jerks (myoclonic epilepsy), difficulty coordinating movements (ataxia), vision loss, speech problems, and a decline in intellectual function. The life expectancy of people with CLN5 disease varies; affected individuals usually survive into adolescence or mid-adulthood.\n\nCLN5 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/cln5-disease

Clinical features

From HPO
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.
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.
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.
Clumsiness
MedGen UID:
66690
Concept ID:
C0233844
Sign or Symptom
Lack of physical coordination resulting in an abnormal tendency to drop items or bump into objects.
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.
Dysdiadochokinesis
MedGen UID:
115975
Concept ID:
C0234979
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to perform rapidly alternating movements, such as pronating and supinating his or her hand on the dorsum of the other hand as rapidly as possible.
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.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Motor deterioration
MedGen UID:
356495
Concept ID:
C1866284
Finding
Loss of previously present motor (i.e., movement) abilities.
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.
Abnormal nervous system electrophysiology
MedGen UID:
867410
Concept ID:
C4021781
Pathologic Function
An abnormality of the function of the electrical signals with which nerve cells communicate with each other or with muscles as measured by electrophysiological investigations.
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.
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.
Rectilinear intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
338055
Concept ID:
C1850447
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a straight or rectilinear pattern.
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.
Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
Degeneration of the retina.
Progressive visual loss
MedGen UID:
326867
Concept ID:
C1839364
Finding
A reduction of previously attained ability to see.
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.
Rectilinear intracellular accumulation of autofluorescent lipopigment storage material
MedGen UID:
338055
Concept ID:
C1850447
Finding
An intracellular accumulation of autofluorescent lipopigment storage material in a straight or rectilinear 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
Li W, Fan X, Zhang Y, Huang L, Jiang T, Qin Z, Su J, Luo J, Yi S, Zhang S, Shen Y
BMC Med Genet 2020 May 11;21(1):100. doi: 10.1186/s12881-020-01039-5. PMID: 32393339Free PMC Article
Appu AP, Bagh MB, Sadhukhan T, Mondal A, Casey S, Mukherjee AB
J Inherit Metab Dis 2019 Sep;42(5):944-954. Epub 2019 May 14 doi: 10.1002/jimd.12106. PMID: 31025705Free PMC Article
Hosseini Bereshneh A, Garshasbi M
J Med Case Rep 2018 Sep 25;12(1):281. doi: 10.1186/s13256-018-1788-7. PMID: 30249282Free PMC Article

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
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
Gardner E, Bailey M, Schulz A, Aristorena M, Miller N, Mole SE
Hum Mutat 2019 Nov;40(11):1924-1938. Epub 2019 Jul 26 doi: 10.1002/humu.23860. PMID: 31283065Free PMC Article
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

Therapy

Estublier B, Cano A, Hoebeke C, Pichard S, Scavarda D, Desguerre I, Auvin S, Chabrol B
Eur J Paediatr Neurol 2021 Jan;30:17-21. Epub 2020 Dec 8 doi: 10.1016/j.ejpn.2020.12.002. PMID: 33348105
Lewis G, Morrill AM, Conway-Allen SL, Kim B
J Child Neurol 2020 Apr;35(5):348-353. Epub 2019 Dec 29 doi: 10.1177/0883073819895694. PMID: 31884868
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
Bosch ME, Aldrich A, Fallet R, Odvody J, Burkovetskaya M, Schuberth K, Fitzgerald JA, Foust KD, Kielian T
J Neurosci 2016 Sep 14;36(37):9669-82. doi: 10.1523/JNEUROSCI.1635-16.2016. PMID: 27629717Free 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
Kozina AA, Okuneva EG, Baryshnikova NV, Kondakova OB, Nikolaeva EA, Fedoniuk ID, Mikhailova SV, Krasnenko AY, Stetsenko IF, Plotnikov NA, Klimchuk OI, Popov YV, Surkova EI, Shatalov PA, Rakitko AS, Ilinsky VV
Mol Genet Genomic Med 2020 Jul;8(7):e1228. Epub 2020 May 15 doi: 10.1002/mgg3.1228. PMID: 32412666Free PMC Article
Parviainen L, Dihanich S, Anderson GW, Wong AM, Brooks HR, Abeti R, Rezaie P, Lalli G, Pope S, Heales SJ, Mitchison HM, Williams BP, Cooper JD
Acta Neuropathol Commun 2017 Oct 17;5(1):74. doi: 10.1186/s40478-017-0476-y. PMID: 29041969Free 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
Kamate M, Prashanth GP, Hattiholi V
Neurol India 2012 May-Jun;60(3):316-20. doi: 10.4103/0028-3886.98524. PMID: 22824694

Clinical prediction guides

Estublier B, Cano A, Hoebeke C, Pichard S, Scavarda D, Desguerre I, Auvin S, Chabrol B
Eur J Paediatr Neurol 2021 Jan;30:17-21. Epub 2020 Dec 8 doi: 10.1016/j.ejpn.2020.12.002. PMID: 33348105
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
Hosseini Bereshneh A, Garshasbi M
J Med Case Rep 2018 Sep 25;12(1):281. doi: 10.1186/s13256-018-1788-7. PMID: 30249282Free PMC Article
Bosch ME, Aldrich A, Fallet R, Odvody J, Burkovetskaya M, Schuberth K, Fitzgerald JA, Foust KD, Kielian T
J Neurosci 2016 Sep 14;36(37):9669-82. doi: 10.1523/JNEUROSCI.1635-16.2016. PMID: 27629717Free 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

Recent systematic reviews

Mole SE, Schulz A, Badoe E, Berkovic SF, de Los Reyes EC, Dulz S, Gissen P, Guelbert N, Lourenco CM, Mason HL, Mink JW, Murphy N, Nickel M, Olaya JE, Scarpa M, Scheffer IE, Simonati A, Specchio N, Von Löbbecke I, Wang RY, Williams RE
Orphanet J Rare Dis 2021 Apr 21;16(1):185. doi: 10.1186/s13023-021-01813-5. PMID: 33882967Free 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
Ysselstein D, Shulman JM, Krainc D
Mov Disord 2019 May;34(5):614-624. Epub 2019 Feb 6 doi: 10.1002/mds.27631. PMID: 30726573Free PMC Article

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