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Neuronal ceroid lipofuscinosis 9(CLN9)

MedGen UID:
332304
Concept ID:
C1836841
Disease or Syndrome
Synonym: CLN 9
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 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).
 
Monarch Initiative: MONDO:0012188
OMIM®: 609055
Orphanet: ORPHA228357

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). For a discussion of genetic heterogeneity of neuronal ceroid lipofuscinosis, see CLN1 (256730). [from OMIM]

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.
Mutism
MedGen UID:
6476
Concept ID:
C0026884
Disease or Syndrome
Inability to speak or communicate verbally past the age of typical language development.
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.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Scanning speech
MedGen UID:
116113
Concept ID:
C0240952
Mental or Behavioral Dysfunction
An abnormal pattern of speech in which the words are as if measured or scanned; there is a pause after every syllable, and the syllables themselves are pronounced slowly.
Psychomotor deterioration
MedGen UID:
373191
Concept ID:
C1836842
Finding
Loss of previously present mental and motor abilities.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
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.
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.
Vacuolated lymphocytes
MedGen UID:
332307
Concept ID:
C1836855
Finding
The presence of clear, sharply defined vacuoles in the lymphocyte cytoplasm.
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.
Decreased light- and dark-adapted electroretinogram amplitude
MedGen UID:
326793
Concept ID:
C1839025
Finding
Descreased amplitude of eletrical response upon electroretinography.
Progressive visual loss
MedGen UID:
326867
Concept ID:
C1839364
Finding
A reduction of previously attained ability to see.
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.
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.

Professional guidelines

PubMed

Leal-Pardinas F, Truty R, McKnight DA, Johnson B, Morales A, Bristow SL, Yar Pang T, Cohen-Pfeffer J, Izzo E, Sankar R, Koh S, Wirrell EC, Millichap JJ, Aradhya S
Epilepsia 2022 Jul;63(7):e68-e73. Epub 2022 May 10 doi: 10.1111/epi.17269. PMID: 35474188Free PMC Article
Sands MS
J Child Neurol 2013 Sep;28(9):1151-8. doi: 10.1177/0883073813495960. PMID: 24014510Free PMC Article
Zhong NA, Wisniewski KE, Ju W, Moroziewicz DN, Jurkiewicz A, McLendon L, Jenkins EC, Brown WT
Genet Test 2000;4(3):243-8. doi: 10.1089/10906570050501452. PMID: 11142754

Recent clinical studies

Etiology

Liu W, Kleine-Holthaus SM, Herranz-Martin S, Aristorena M, Mole SE, Smith AJ, Ali RR, Rahim AA
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165772. Epub 2020 Mar 24 doi: 10.1016/j.bbadis.2020.165772. PMID: 32220628
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
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
Minnis CJ, Thornton CD, FitzPatrick LM, McKay TR
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165559. Epub 2019 Oct 23 doi: 10.1016/j.bbadis.2019.165559. PMID: 31655107Free PMC Article
Kauss V, Dambrova M, Medina DL
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165553. Epub 2019 Sep 12 doi: 10.1016/j.bbadis.2019.165553. PMID: 31521819

Diagnosis

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
Badilla-Porras R, Echeverri-McCandless A, Weimer JM, Ulate-Campos A, Soto-Rodríguez A, Gutiérrez-Mata A, Hernández-Con L, Bogantes-Ledezma S, Balmaceda-Meza A, Brudvig J, Sanabria-Castro A
Orphanet J Rare Dis 2022 Jan 10;17(1):13. doi: 10.1186/s13023-021-02162-z. PMID: 35012600Free PMC Article
Thompson DA, Handley SE, Henderson RH, Marmoy OR, Gissen P
Eye (Lond) 2021 Sep;35(9):2438-2448. Epub 2021 Jul 16 doi: 10.1038/s41433-021-01594-y. PMID: 34272513Free PMC Article
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Iannaccone Farkašová S, Vasovčák P, Sopková D, Pisarčíková M, Švajdler M, Fröhlichová L, Mistríková L, Farkaš D
Cesk Patol 2019 Fall;55(3):176-181. PMID: 31726844

Therapy

Schulz A, Specchio N, de Los Reyes E, Gissen P, Nickel M, Trivisano M, Aylward SC, Chakrapani A, Schwering C, Wibbeler E, Westermann LM, Ballon DJ, Dyke JP, Cherukuri A, Bondade S, Slasor P, Cohen Pfeffer J
Lancet Neurol 2024 Jan;23(1):60-70. doi: 10.1016/S1474-4422(23)00384-8. PMID: 38101904
Johnson TB, White KA, Brudvig JJ, Cain JT, Langin L, Pratt MA, Booth CD, Timm DJ, Davis SS, Meyerink B, Likhite S, Meyer K, Weimer JM
Mol Ther 2021 Jan 6;29(1):162-175. Epub 2020 Sep 24 doi: 10.1016/j.ymthe.2020.09.033. PMID: 33010819Free PMC Article
Kauss V, Dambrova M, Medina DL
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165553. Epub 2019 Sep 12 doi: 10.1016/j.bbadis.2019.165553. PMID: 31521819
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
Cain JT, Likhite S, White KA, Timm DJ, Davis SS, Johnson TB, Dennys-Rivers CN, Rinaldi F, Motti D, Corcoran S, Morales P, Pierson C, Hughes SM, Lee SY, Kaspar BK, Meyer K, Weimer JM
Mol Ther 2019 Oct 2;27(10):1836-1847. Epub 2019 Jul 10 doi: 10.1016/j.ymthe.2019.06.015. PMID: 31331814Free PMC Article

Prognosis

Cooper JD, Mole SE
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165681. Epub 2020 Jan 8 doi: 10.1016/j.bbadis.2020.165681. PMID: 31926264
Adams HR, Mink JW; University of Rochester Batten Center Study Group
J Child Neurol 2013 Sep;28(9):1128-36. doi: 10.1177/0883073813494813. PMID: 24014508Free PMC Article
Pérez-Poyato MS, Milà Recansens M, Ferrer Abizanda I, Montero Sánchez R, Rodríguez-Revenga L, Cusí Sánchez V, García González MM, Domingo Jiménez R, Camino León R, Velázquez Fragua R, Martínez-Bermejo A, Pineda Marfà M
J Inherit Metab Dis 2011 Oct;34(5):1083-93. Epub 2011 Apr 16 doi: 10.1007/s10545-011-9323-7. PMID: 21499717
Vashishta A, Ohri SS, Vetvicka V
Endocr Metab Immune Disord Drug Targets 2009 Dec;9(4):385-91. doi: 10.2174/187153009789839174. PMID: 19807669
Dyken PR
J Child Neurol 1989 Jul;4(3):165-74. doi: 10.1177/088307388900400302. PMID: 2671115

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
Badilla-Porras R, Echeverri-McCandless A, Weimer JM, Ulate-Campos A, Soto-Rodríguez A, Gutiérrez-Mata A, Hernández-Con L, Bogantes-Ledezma S, Balmaceda-Meza A, Brudvig J, Sanabria-Castro A
Orphanet J Rare Dis 2022 Jan 10;17(1):13. doi: 10.1186/s13023-021-02162-z. PMID: 35012600Free PMC Article
Klein M, Kaleem A, Oetjen S, Wünkhaus D, Binkle L, Schilling S, Gjorgjieva M, Scholz R, Gruber-Schoffnegger D, Storch S, Kins S, Drewes G, Hoffmeister-Ullerich S, Kuhl D, Hermey G
Autophagy 2022 Sep;18(9):2068-2085. Epub 2021 Dec 29 doi: 10.1080/15548627.2021.2016232. PMID: 34964690Free PMC Article
Cooper JD, Mole SE
Biochim Biophys Acta Mol Basis Dis 2020 Sep 1;1866(9):165681. Epub 2020 Jan 8 doi: 10.1016/j.bbadis.2020.165681. PMID: 31926264
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

Recent systematic reviews

Yoganathan S, Whitney R, Thomas M, Danda S, Chettali AM, Prasad AN, Farhan SMK, AlSowat D, Abukhaled M, Aldhalaan H, Gowda VK, Kinhal UV, Bylappa AY, Konanki R, Lingappa L, Parchuri BM, Appendino JP, Scantlebury MH, Cunningham J, Hadjinicolaou A, El Achkar CM, Kamate M, Menon RN, Jose M, Riordan G, Kannan L, Jain V, Manokaran RK, Chau V, Donner EJ, Costain G, Minassian BA, Jain P
Epilepsia 2024 Mar;65(3):709-724. Epub 2024 Jan 17 doi: 10.1111/epi.17880. PMID: 38231304
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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