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Ceroid lipofuscinosis, neuronal, 4 (Kufs type)(CLN4)

MedGen UID:
320287
Concept ID:
C1834207
Disease or Syndrome
Synonyms: Ceroid lipofuscinosis neuronal 4B autosomal dominant; Ceroid lipofuscinosis neuronal Parry type; CLN4; Dominant form of adult neuronal ceroid-lipofuscinosis; Kufs disease autosomal dominant; Neuronal ceroid lipofuscinosis 4B
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): DNAJC5 (20q13.33)
 
Monarch Initiative: MONDO:0008083
OMIM®: 162350
Orphanet: ORPHA228343

Definition

Neuronal ceroid lipofuscinosis-4 (CLN4) is an autosomal dominant neurodegenerative disorder characterized by onset of symptoms in adulthood. It belongs to a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Several different forms have been described according to age of onset (see, e.g., CLN3, 204200). Individuals with the adult form, sometimes referred to as Kufs disease, develop psychiatric manifestations, seizures, cerebellar ataxia, and cognitive decline. Retinal degeneration is usually not present (summary by Benitez et al., 2011 and Velinov et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). [from OMIM]

Additional description

From MedlinePlus Genetics
CLN4 disease is a condition that primarily affects the nervous system, causing problems with movement and intellectual function that worsen over time. The signs and symptoms of CLN4 disease typically appear around age 30, but they can develop anytime between adolescence and late adulthood.

People with CLN4 disease often develop seizures and uncontrollable muscle jerks (myoclonic epilepsy), a decline in intellectual function (dementia), problems with coordination and balance (ataxia), tremors or other involuntary movements (motor tics), and speech difficulties (dysarthria). The signs and symptoms of CLN4 disease worsen over time, and affected individuals usually survive about 15 years after the disorder begins.

CLN4 disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs), which may also be collectively referred to as Batten disease. (The adult forms of NCLs, which includes CLN4 disease, are sometimes known as Kufs disease.) All the NCLs 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/cln4-disease

Clinical features

From HPO
Vascular granular osmiophilic material deposition
MedGen UID:
348472
Concept ID:
C1859833
Finding
Accumulation of granular osmiophilic material in blood vessel walls. Osmiophilic material becomes black upon staining with osmium tetroxide. Deposition of granular osmiophilic material (GOM) is the vascular pathological hallmark of CADASIL, which is the most prevalent hereditary small vessel disease and is caused by missense mutations in the NOTCH3 gene. GOM have been shown to contain NOTCH3 ectodomain (NOTCH3ECD) and extracellular matrix proteins, and can be visualized ultrastructurally in the tunica media of small arteries and capillaries. These electron dense GOM deposits are located in the basement membrane of mural cells, i.e. vascular smooth muscle cells and pericytes. In both manifest and pre-manifest CADASIL patients, GOM deposits are present not only in brain vessels, but also in vessels of other organs, such as the skin.
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).
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Auditory hallucination
MedGen UID:
115932
Concept ID:
C0233762
Sign or Symptom
Perception of sounds without auditory stimulus.
Visual hallucination
MedGen UID:
66688
Concept ID:
C0233763
Sign or Symptom
Visual perception in the absence of a visual stimulus.
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).
Parkinsonian disorder
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.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Abnormal cerebellum morphology
MedGen UID:
400925
Concept ID:
C1866129
Anatomical Abnormality
Any structural abnormality of the cerebellum.
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.
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
A myoclonic seizure is a type of motor seizure characterized by 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.
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.

Term Hierarchy

Follow this link to review classifications for Ceroid lipofuscinosis, neuronal, 4 (Kufs type) in Orphanet.

Professional guidelines

PubMed

Rus CM, Weissensteiner T, Pereira C, Susnea I, Danquah BD, Morales Torres G, Rocha ME, Cozma C, Saravanakumar D, Mannepalli S, Kandaswamy KK, Di Bucchianico S, Zimmermann R, Rolfs A, Bauer P, Beetz C
Orphanet J Rare Dis 2022 May 3;17(1):179. doi: 10.1186/s13023-022-02288-8. PMID: 35505348Free PMC Article

Recent clinical studies

Etiology

Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, Bonuccelli A, Peroni D, Michelucci R, Striano P
Seizure 2019 Oct;71:247-257. Epub 2019 Aug 23 doi: 10.1016/j.seizure.2019.08.012. PMID: 31476531Free PMC Article
Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM
Nat Rev Neurol 2019 Mar;15(3):161-178. doi: 10.1038/s41582-019-0138-8. PMID: 30783219Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Bennett MJ, Rakheja D
Dev Disabil Res Rev 2013;17(3):254-9. doi: 10.1002/ddrr.1118. PMID: 23798013
Chabrol B, Caillaud C, Minassian B
Handb Clin Neurol 2013;113:1701-6. doi: 10.1016/B978-0-444-59565-2.00038-1. PMID: 23622391

Diagnosis

Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW
N Engl J Med 2019 Oct 24;381(17):1644-1652. Epub 2019 Oct 9 doi: 10.1056/NEJMoa1813279. PMID: 31597037Free PMC Article
Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM
Nat Rev Neurol 2019 Mar;15(3):161-178. doi: 10.1038/s41582-019-0138-8. PMID: 30783219Free PMC Article
Nita DA, Mole SE, Minassian BA
Epileptic Disord 2016 Sep 1;18(S2):73-88. doi: 10.1684/epd.2016.0844. PMID: 27629553
Bennett MJ, Rakheja D
Dev Disabil Res Rev 2013;17(3):254-9. doi: 10.1002/ddrr.1118. PMID: 23798013
Kousi M, Lehesjoki AE, Mole SE
Hum Mutat 2012 Jan;33(1):42-63. Epub 2011 Nov 16 doi: 10.1002/humu.21624. PMID: 21990111

Therapy

Naseri N, Sharma M, Velinov M
Clin Genet 2021 Jan;99(1):111-118. Epub 2020 Aug 26 doi: 10.1111/cge.13829. PMID: 32783189Free PMC Article
Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW
N Engl J Med 2019 Oct 24;381(17):1644-1652. Epub 2019 Oct 9 doi: 10.1056/NEJMoa1813279. PMID: 31597037Free PMC Article
Mirza M, Vainshtein A, DiRonza A, Chandrachud U, Haslett LJ, Palmieri M, Storch S, Groh J, Dobzinski N, Napolitano G, Schmidtke C, Kerkovich DM
Mol Genet Genomic Med 2019 Dec;7(12):e859. Epub 2019 Sep 30 doi: 10.1002/mgg3.859. PMID: 31568712Free PMC Article
Markham A
Drugs 2017 Jul;77(11):1247-1249. doi: 10.1007/s40265-017-0771-8. PMID: 28589525
Taupin P
Curr Opin Mol Ther 2006 Apr;8(2):156-63. PMID: 16610769

Prognosis

Singh RB, Gupta P, Kartik A, Farooqui N, Singhal S, Shergill S, Singh KP, Agarwal A
Semin Ophthalmol 2021 Oct 3;36(7):582-595. Epub 2021 Jun 9 doi: 10.1080/08820538.2021.1936571. PMID: 34106804
Orsini A, Valetto A, Bertini V, Esposito M, Carli N, Minassian BA, Bonuccelli A, Peroni D, Michelucci R, Striano P
Seizure 2019 Oct;71:247-257. Epub 2019 Aug 23 doi: 10.1016/j.seizure.2019.08.012. PMID: 31476531Free PMC Article
Kälviäinen R
Semin Neurol 2015 Jun;35(3):293-9. Epub 2015 Jun 10 doi: 10.1055/s-0035-1552620. PMID: 26060909
Kousi M, Lehesjoki AE, Mole SE
Hum Mutat 2012 Jan;33(1):42-63. Epub 2011 Nov 16 doi: 10.1002/humu.21624. PMID: 21990111
Haltia M
J Neuropathol Exp Neurol 2003 Jan;62(1):1-13. doi: 10.1093/jnen/62.1.1. PMID: 12528813

Clinical prediction guides

Saleh MM, Hamhom AM, Al-Otaibi A, AlGhamdi M, Housawi Y, Aljadhai YI, Alameer S, Almannai M, Jad LA, Alwadei AH, Tabassum S, Alsaman A, AlAsmari A, Al Mutairi F, Althiyab H, Bashiri FA, AlHumaidi S, Alfadhel M, Mink JW, AlHashim A, Faqeih EA; Saudi NCL Study Consortium
Pediatr Neurol 2024 Jun;155:149-155. Epub 2024 Mar 7 doi: 10.1016/j.pediatrneurol.2024.03.004. PMID: 38653183
Nyame K, Hims A, Aburous A, Laqtom NN, Dong W, Medoh UN, Heiby JC, Xiong J, Ori A, Abu-Remaileh M
Mol Cell 2024 Apr 4;84(7):1354-1364.e9. Epub 2024 Mar 5 doi: 10.1016/j.molcel.2024.02.006. PMID: 38447580Free PMC Article
Huber RJ
Dis Model Mech 2021 Dec 1;14(12) Epub 2021 Dec 6 doi: 10.1242/dmm.049152. PMID: 34870700Free PMC Article
Nelvagal HR, Lange J, Takahashi K, Tarczyluk-Wells MA, Cooper JD
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165570. Epub 2019 Oct 31 doi: 10.1016/j.bbadis.2019.165570. PMID: 31678162
Kousi M, Lehesjoki AE, Mole SE
Hum Mutat 2012 Jan;33(1):42-63. Epub 2011 Nov 16 doi: 10.1002/humu.21624. PMID: 21990111

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
Chen ZR, Liu DT, Meng H, Liu L, Bian WJ, Liu XR, Zhu WW, He Y, Wang J, Tang B, Su T, Yi YH
Seizure 2019 Jul;69:180-185. Epub 2018 Sep 2 doi: 10.1016/j.seizure.2018.08.027. PMID: 31059981
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
Kuper WFE, van Alfen C, Rigterink RH, Fuchs SA, van Genderen MM, van Hasselt PM
J Inherit Metab Dis 2018 Mar;41(2):257-261. Epub 2018 Feb 1 doi: 10.1007/s10545-018-0143-x. PMID: 29392585Free PMC Article

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