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Ceroid lipofuscinosis, neuronal, 6B (Kufs type)(CLN6B)

MedGen UID:
1794137
Concept ID:
C5561927
Disease or Syndrome
Synonyms: Ceroid lipofuscinosis neuronal 4A autosomal recessive; Neuronal ceroid lipofuscinosis 4A
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).
 
Gene (location): CLN6 (15q23)
 
Monarch Initiative: MONDO:0008768
OMIM®: 204300
Orphanet: ORPHA228340

Definition

Neuronal ceroid lipofuscinosis-6B (CLN6B) is an autosomal recessive form of 'Kufs disease,' which refers in general to adult-onset neuronal ceroid lipofuscinosis without retinal involvement. CLN6B is a neurodegenerative disorder with a mean onset of symptoms at around age 28 years, although onset in the teens and later adulthood may also occur. Patients typically present with progressive myoclonus epilepsy, ataxia, loss of motor function, dysarthria, progressive dementia, and progressive cerebral and cerebellar atrophy on brain imaging. Ultrastructural examination typically shows fingerprint profiles and granular osmiophilic deposits in some tissues, including brain samples (summary by Arsov et al., 2011 and Berkovic et al., 2019). However, pathologic findings in peripheral tissues in adults is not as accurate for diagnosis as it is in children with the disease (Cherian et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). [from OMIM]

Additional description

From MedlinePlus Genetics
CLN6 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.

Some people with CLN6 disease do not show signs or symptoms of the condition until adulthood, typically after age 30. These individuals can have epilepsy, ataxia, dysarthria, and a progressive loss of intellectual function. CLN6 disease usually does not cause vision loss in affected adults. Adults with this condition do not often survive more than 10 years after diagnosis.

Most children with CLN6 disease initially experience the loss of previously acquired skills (developmental regression). Affected individuals can also develop recurrent seizures (epilepsy), difficulty coordinating movements (ataxia), muscle twitches (myoclonus), impaired speech (dysarthria), and vision loss. The movement problems worsen over time until affected children cannot walk, stand, or sit without assistance. Intellectual function also declines over time. Most children with CLN6 disease do not survive into adulthood.

CLN6 disease is an inherited disorder that primarily affects the nervous system. The signs and symptoms of this condition typically begin between early and late childhood, but sometimes they can appear in adulthood.  https://medlineplus.gov/genetics/condition/cln6-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.
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).
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
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.
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.
Focal-onset seizure
MedGen UID:
199670
Concept ID:
C0751495
Disease or Syndrome
A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.
Status epilepticus without prominent motor symptoms
MedGen UID:
199677
Concept ID:
C0751523
Disease or Syndrome
There is inconclusive evidence to precisely define the duration of the seizure; however, based on current evidence an operational threshold of 10 minutes is appropriate as beyond this a seizure is likely to be more prolonged. The individual may or may not be aware or in coma.
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.

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