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In 2009 an updated nomenclature was proposed for NCL, summarised below.
Why was the nomenclature updated?
The previous NCL nomenclature was adopted in 1969 when the name 'neuronal ceroid lipofuscinosis' was used for the first time. This was 25 years before the first NCL genes were identified. Since then many NCL genes have been identified, and it is now known that the NCLs show genetic heterogeneity (mutations in different genes may result in similar clinical disease phenotype), allelic heterogeneity (different mutations within the same disease gene may result in very different clinical disease phenotypes) and can be phenotypically heterogeneous even within the same family (the same mutation in the same disease gene may result in differing clinical symptoms and rates of disease progression).
The nomenclature was therefore reviewed, assessing its accuracy and appropriateness. The overriding reason for classification of a disease is to provide a definition for subtypes that is universally understood. A general definition of an NCL disorder is: A progressive degenerative disease of the brain and, in most cases, the retina, in association with intracellular storage of material that is morphologically characterized as ceroid lipofuscin or similar. A disease nomenclature or diagnostic classification system should also provide information about prognosis and guide treatment choices. It should be of value for clinicians responsible for diagnosis and treatment, diagnostic laboratories, research scientists, patients and families, and supporting health and education professionals.
Nomenclature 1969-2009
In this period, NCLs were classified according to the age at onset of symptoms: infantile, late infantile, juvenile and adult. These were given the common abbreviations INCL, LINCL, JNCL and ANCL. In some countries they were also known by their eponyms, according to who originally described them, e.g. Haltia-Santavuori, Jansky-Bielschowsky, Spielmeyer-Vogt or Batten disease and Kufs disease. The existence of variants became increasingly recognised, such as a late infantile variant, particularly in Finland, and early juvenile in the UK and other countries. The term 'Batten disease' was used both to refer only to NCL cases of juvenile onset, and to the complete collection of NCL conditions.
Nomenclature 2009 to date
The updated nomenclature is an axial diagnostic classification system similar to those used for the epilepsies and for mental health disorders in children (ICD-10).The use of eponyms is discouraged. Although clinically the term NCL disorders is preferred as an overall description, families and those who support them, including fundraisers, require a term that is easy to use, and the already adopted term 'Batten disease' fits this purpose, and can be continued in this context. The proposed axial nomenclature system for NCL disorders is as follows:
Axis 1: Affected gene
For example: CLN1, CLN2, CLN3 etc.
Axis 2: Mutation diagnosis - this includes, where possible, the disease causing mutations on both disease chromosomes, using internationally standardized notation. It may also include information regarding the predicted effect of the gene product for example: a truncation mutation predicted to result in a short non-functional protein.
Axis 3: Biochemical phenotype (enzymopathy or deficiency of membrane protein etc.)
For example: CTSD, PPT1 or TPP1 deficiency. Enzyme results may be included with reference ranges and type of tissue studied.
Axis 4: Clinical phenotype (gives an indication of age of onset and possible disease course)
For example: Congenital, infantile, late infantile, juvenile, adult onset.
Axis 5: Ultrastructural features particularly important for those cases where no positive diagnostic biochemical or genetic information is available. Should include the specimen type studied (e.g. skin, rectum, conjunctiva) and may include cell types affected.
For example: GROD, CL, RL, FP (tissue)
Axis 6: Functionality - this may be a description of current level, and ultimately may use a universally recognized clinical scoring system, for example the Hamburg scales and the Unified Batten Disease Rating Scale (UBDRS).
Axis 7: Other remarks of possible medical relevance (e.g. additional disabilities, genetic or environmental effects that may affect disease onset and progression).
The diagnostic classification gives a pedigree of information with the option to omit some of the information, e.g. Axes 5, 6 and 7 may not be necessary or useful in the majority of cases.
An abbreviated system is useful in clinical practice, e.g. combining Axes 1 and 4 only such as infantile CLN1disease and juvenile CLN3 disease.
Examples
- Infantile NCL
A child presenting in infancy who has PPT1 deficiency and mutations in CLN1:
Short form: CLN1 disease, infantile (alternatively: infantile CLN1 disease or CLN1 disease, classic infantile)
Axis 1: CLN1
Axis 2: p.[Arg122Trp]+[Arg122Trp] (p.R122W homozygote)
Axis 3: PPT1 deficiency: white blood cells level 5 nmol/hr/mg protein (normal range 17-139)
Axis 4: infantile
Axis 5: GROD (rectum)
Axis 6: Hamburg LINCL score 1, gastrostomy dependent, seizures partially controlled on 3 anti-epileptic drugs, nonambulant, no speech, frequent chest infections.
Axis 7: Younger sibling affected.
- Juvenile NCL with GRODs
A child presents with visual failure and subsequently develops seizures and loses skills, is negative for vacuolated lymphocytes and has mutation in CLN1:
Short form: CLN1 disease, juvenile (alternatively: juvenile CLN1 disease)
Axis 1: CLN1
Axis 2: p.[Thr75Pro]+[Arg151X] (p.T75P/R151X heterozygote)
Axis 3: PPT1 deficiency: white blood cells level 12 nmol/hr/mg protein (normal range 17-139)
Axis 4: juvenile
Axis 5: GROD (skin)
Axis 6: Hamburg JNCL Score: 5 , UBDRS score: physical 47; seizure 12; behaviour 15
Axis 7: mild asthma, no additional difficulties or major health concerns
- Variant late infantile NCL, normal enzymes and no mutations identified so far:
Short form: NCL, late infantile variant (alternatively: variant late infantile disease)
Axes 1 and 2: no mutations found in coding region of CLN3, CLN6, CLN7, CLN8, CLCN6 by sequencing of genomic DNA
Axis 3: Normal CTSD, PPT1 and TPP1 on blood and fibroblast samples
Axis 4: late infantile variant
Axis 5: mixed FPP, RL and CVL (skin)
Axis 6: Hamburg LINCL score: 2
Axis 7: single parent
- Classical juvenile NCL:
Short form: CLN3 disease, juvenile (alternatively: juvenile CLN3 disease or CLN3 disease, classic juvenile)
Axis 1: CLN3
Axis 2: c.[462-677del+462-677del],1 kb del+1 kb del (homozygous for the 1 kb intragenic deletion)
Axis 3: not applicable
Axis 4: juvenile
Axis 5: FPP (skin)
Axis 6: Hamburg JNCL score: 1; UBDRS score: physical 78; seizure 20; behaviour 23.
Axis 7: In residential care setting
- Late infantile variant:
Short form: CLN8 disease, late infantile variant (alternatively: late infantile CLN8 disease)
Axis 1:CLN8
Axis 2: p.[Gly22fs]+[Gly22fs]
Axis 3:
Axis 4: late infantile
Axis 5:
Axis 6:
Axis 7:
- Epilepsy with progressive mental retardation (EPMR)
Short form: CLN8 disease, EPMR (alternatively: EPMR CLN8 disease)
Axis 1:CLN8
Axis 2: p.[Arg24Gly]+[Arg24Gly]
Axis 3:
Axis 4: EPMR
Axis 5:
Axis 6:
Axis 7:
- Adult onset NCL, genetically defined
Short form: CLN1 disease, adult (alternatively: adult CLN1 disease)
Axis 1: CLN1
Axis 2: p.[Cys45Tyr]+[Arg151X]
Axis 3: PPT1(0.09)
Axis 4: adult
Axis 5: GROD (rectum)
Axis 6:
Axis 7:
- Adult onset NCL, genetically defined
Short form: CLN5 disease, adult (alternatively: adult CLN5 disease)
Axis 1: CLN5 and CLCN6
Axis 2: CLN5:p.[Trp224]+[Tyr374Cys]+CLCN6:p.[Thr628Arg]
Axis 3: Normal CTSD, PPT1 and TPP1 on blood and fibroblast samples
Axis 4: adult
Axis 5: GROD and CL (skin)
Axis 6:
Axis 7: Father is heterozygote carrier of CLCN6 and CLN5 mutations
- Adult onset NCL, genetically undefined
Short form: NCL disease, adult (alternatively: adult NCL disease)
Axes 1 and 2: no mutations found in coding region of CLN3, CLN5, CLN6, CLN7, CLN8 by sequencing of genomic DNA
Axis 3: Normal CTSD, PPT1 and TPP1 on blood and fibroblast samples
Axis 4: adult
Axis 5: GROD and CL (skin)
Axis 6:
Axis 7: