Keywords
CLN2 disease - neuronal ceroid lipofuscinosis - language development - enzyme replacement
therapy - cerliponase alfa
Introduction
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease; OMIM # 204500) is a rare pediatric neurodegenerative disorder caused by mutations in TPP1, resulting in tripeptidyl peptidase 1 (TPP1) enzyme deficiency, build-up of lysosomal
storage materials, and progressive neuronal loss.[1]
[2]
[3]
[4]
Seizures are generally recognized as the first presenting symptom of CLN2 disease,
occurring between the ages of 2 and 4 years, but emerging data show that language
delay may precede this, being evident from as early as 18 months of age.[2]
[4]
[5]
[6] Early language delay has been shown to be an initial sign of late-infantile classical
CLN2 disease in up to 83% of affected children (dementia in childhood (DEM-CHILD)
cohort), frequently preceding the onset of more overt symptoms.[2] By the age of 5 years, patients will lose almost half of the verbal abilities they
had at diagnosis.[2]
Motor dysfunction may also be an early manifestation, commonly presenting as ataxia
or clumsiness.[2] Functional decline is universally rapid and predictable for those with the classical
late-infantile phenotype, leading to dementia, loss of the abilities to walk and talk,
and blindness. CLN2 disease is usually fatal by mid-adolescence.[1]
[5]
[6]
[7]
[8]
Diagnostic delays of up to 20 months are common in CLN2 disease because of its scarcity,
nonspecific presentation, and a diagnostic test that is not always part of standard
laboratory screens.[8]
[9]
In 2017, both the U.S. Food and Drug Administration and the European Medicines Agency
granted approval of cerliponase alfa, a recombinant intraventricular TPP1 enzyme replacement
therapy (ERT), as a treatment for CLN2 disease. By helping replace deficient TPP1,
the build-up of lysosomal storage materials is minimized, slowing further neuronal
damage and decline in both motor and language function.[10]
[11] The availability of treatment that can potentially prolong the quality and quantity
of life demands an immediate increase in the awareness of CLN2 disease among health
care professionals (HCPs).
The identification of language delay in children presenting with a first seizure is
a red flag that could help diagnose CLN2 disease in its earliest stages. Literature
reports on language delay in CLN2 disease are limited despite the increasing recognition
of this trait as an early hallmark. By collating current knowledge of the language
features of CLN2 disease, we aim to provide a call to action for HCPs to consider
CLN2 disease during differential diagnosis for all children with a language delay
and/or first seizures, to support early identification and prompt intervention.
Methods
A group of experts on CLN2 disease met to discuss the types of language deficits commonly
seen in clinical practice. This manuscript communicates their experiences, and uses
patient cases to illustrate features of language delay in children with CLN2 disease.
Retrospective, anonymized data from patient records are included (ethics committee
approval was not required), and all data are from patients who received a diagnosis
of CLN2 disease according to published expert diagnostic recommendations.[9] Ages at first words, first use of two-/three-word phrases, and first use of full
sentences were analyzed, and age at first seizure and language scores at initiation
of ERT were assessed using the CLN2 disease clinical rating scale.[12] The authors confirm that informed consent was taken from all the participants.
Results
Based on our experiences of caring for patients with CLN2 disease (see cases in [Table 1] and [Supplementary Fig. S1], available in the online version), language abilities vary during the early stages
of CLN2 disease prior to treatment initiation. Verbal ability ranges from broadly
age appropriate to mild but detectable deficits or no speech at all.
Table 1
Case studies
|
Case
|
Age at first words (mo)
|
Age at first use of two-/three-word phrases (mo)
|
Age at first use of full sentences (mo)
|
Age at first seizure (mo)
|
Language score at initiation of ERT (score and age)[a]
|
|
1
|
9
|
24
|
Not achieved
|
38
|
Score 3 at 46 mo
|
|
2
|
8
|
24
|
Not achieved
|
48
|
Score 2 at 48 mo
|
|
3
|
8–9
|
Not recorded prior to ERT initiation
|
Not achieved
|
38
|
Score 2 at 44 mo
|
|
4
|
7
|
24
|
36
|
59
|
Score 2 at 60 mo
|
|
5
|
6
|
36
|
Not achieved
|
38
|
Score 2 at 42 mo
|
|
6
|
10–12
|
36
|
Not achieved
|
41
|
Score 2 at 57 mo
|
|
7
|
6
|
Not measured prior to ERT initiation
|
Not achieved
|
–
|
Score 1 at 100 mo
|
|
8
|
14
|
Not achieved
|
Not achieved
|
36
|
Score 2 at 56 mo
|
|
9
|
Not achieved
|
Not achieved
|
Not achieved
|
36
|
Score 0 (nonverbal) at 58 mo
|
|
10
|
12
|
36
|
Not achieved
|
44
|
Score 1 at 70 mo
|
|
11
|
12
|
24
|
54
|
44
|
Score 2 at 48 mo
|
|
12
|
15
|
Not achieved
|
Not achieved
|
32
|
Score 1 at 52 mo
|
|
13
|
Not clearly reported
|
Not achieved
|
Not achieved
|
36
|
Score 1 at 54 mo
|
|
14
|
12
|
30
|
Not achieved
|
35
|
Score 2 at 54 mo
|
|
15
|
Not clearly reported
|
42
|
Not achieved
|
36
|
Score 2 at 47 mo
|
|
16
|
14
|
42
|
Not achieved
|
36
|
Score 2 at 43 mo
|
|
17
|
18
|
36
|
Not achieved
|
45
|
Score 1 at 53 mo
|
|
18
|
9
|
24
|
Not achieved
|
35
|
Score 3 at 39 mo
|
|
19
|
14
|
Not achieved
|
Not achieved
|
43
|
Score 3 at 51 mo
|
|
20
|
8
|
18
|
42
|
38
|
Score 1 at 51 mo
|
|
21
|
12
|
24
|
Not achieved
|
35
|
Score 1 at 45 mo
|
|
22
|
11
|
23
|
Not achieved
|
31
|
Score 2 at 52 mo
|
|
23
|
12
|
Not achieved
|
Not achieved
|
42
|
Score 2 at 48 mo
|
|
Median (range)
|
11.5 (6–18)
|
24 (18–42)
|
42 (36–54)
|
38 (31–59)
|
–
|
Abbreviation: ERT, enzyme replacement therapy.
Note: The table details the language development of patients cared for by the authors.
Cases 1 to 7 were from Bambino Gesù Children's Hospital, Rome, Italy; cases 8 to 16
were from Great Ormond Street Hospital, London, United Kingdom; and cases 17 to 23
were from University Medical Center Hamburg-Eppendorf, Hamburg, Germany. All data
included were collected prior to or at the initiation of enzyme replacement therapy
(ERT).
a Cases were assessed using the CLN2 disease clinical rating scale. This scale is based
on the Hamburg and Weill Cornell scales and examines motor, language, and visual functions,
and seizures. Each category is scored from 0 to 3 (3 in the language category equates
to normal function), with a score from 0 to 12 for the full scale.[12]
The cases illustrate that timing of first words is broadly age appropriate (9–12 months),
but progression to short phrases and longer combinations is limited.[13] Speaking in two- to three-word phrases, which is expected to occur at 18 to 24 months
in the general population,[13] was not achieved in six patients and occurred after the expected age in seven patients.
Of these seven patients, two (cases 15 and 16) had first seizures after the children
would have been expected to be speaking in two- to three-word phrases, indicating
that a language abnormality was present prior to seizures. The ability to form sentences,
expected at 36 to 48 months in the general population,[13] is severely affected, with 87% (20/23) of our cases not achieving this milestone.
Only three patients had a language domain score of 3 (normal function) at initiation
of ERT, and eight patients had a score of 0 or 1, further emphasizing the extent of
language regression, and the need for practitioners to specifically enquire about
language development in children presenting with a first seizure.
In our experience, stagnation of language is common, with affected children often
having difficulty in acquiring new vocabulary. As they get older, children with CLN2
disease may speak more slowly and with reduced clarity compared with their peers.
It has been observed in some centers that receptive skills can be maintained for longer
than expressive skills, but this is not a universal finding, and the current data
are limited.[14]
It is likely that, as with children in the general population, the ability to recognize
images outweighs the ability to verbally describe the image (when their cognitive
resources and visual functions allow). Nonverbal communication, such as eye contact
and body language, tends to be preserved for longer than structured language abilities.
In addition to the disease process itself, there are other factors that may affect
a child's capacity to speak, understand, and communicate. Side effects of antiseizure
medication, therapeutic rehabilitation programs, frustrations, and family coping strategies
may each have a significant impact on communication abilities.
Discussion
While the cases in this manuscript illustrate the language delays seen in patients
with CLN2 disease, identifying children with language delay who may have CLN2 disease
remains a challenge for several reasons.
Seizures continue to be the most frequently reported presenting symptom,[2] perhaps because they may necessitate more immediate medical intervention than language
delay. Mild delay in language development may be assumed to be within normal parameters.
Specifically querying developmental milestones in language (beyond the timing of the
first words) at seizure presentation might detect language delay before more severe
regression.
There is also increasing evidence that autism spectrum disorder (ASD) may be associated
with inborn errors of metabolism (IEM) such as the neuronal ceroid lipofuscinosis
family of disorders that includes CLN2 disease.[15] ASD is rarely seen in isolation in IEM disorders, and as such, the presence of other
symptoms with ASD should alert clinicians to the potential for patients to have such
a disorder.[15] Further, a retrospective analysis of 59 children with ASD reported that 44% also
had epilepsy, and a second study found that 75% of children with ASD had language
impairments before starting kindergarten.[16]
[17] With ASD estimated to occur in 1% of the population, and this overlap with epilepsy
and language impairment, ASD assessments and clinics may provide a further opportunity
to identify patients with CLN2 disease. To avoid diagnostic delays, we recommend that
if any symptoms of CLN2 disease (such as language delay or seizures) are identified
during ASD assessment, genetic testing for CLN2 disease be performed.
Assessing the language abilities of patients with CLN2 disease presents multiple complex
challenges. It inevitably takes time to connect and successfully interact with children
who have a short attention span, communication difficulties, and, as a result, significant
levels of frustration. To optimize engagement, the child should be in a comfortable,
familiar environment with few distractions.
Early language delays are frequently initially identified by parents, and childcare
and educational providers, as well as HCPs. Depending on the health care system, children
with suspected language delays may be assessed by speech and language therapists,
neurologists, psychologists, and other HCPs using a range of informal tools, and standardized
developmental and language assessments. Parent-reported outcomes and home videos can
also be a useful part of the overall assessment as they provide real-life information
about children's abilities. There is no universally accepted rating method for early
language delay, and the choice is influenced by regional differences and professional
preferences.
Although a language disorder would not formally be diagnosed before the age of 3 years,
if a child has not progressed to use word combinations and has a vocabulary of less
than 50 words at the age of 2 years, they should be considered for referral for support
and for speech and language intervention and monitoring.[13]
Red Flags for Raising Suspicion of CLN2 Disease
Red Flags for Raising Suspicion of CLN2 Disease
Based on our experience and the cases in this article, it is our recommendation that
CLN2 disease be considered in children presenting with any of these “red flag” features:
Information on other features that could raise suspicion of CLN2 disease may have
already been obtained during the diagnostic workup through magnetic resonance imaging
(MRI) and electroencephalography (EEG), and could include subtle cerebellar or cerebral
atrophy, or white matter hyperintensities on MRI, or background abnormalities or a
photoparoxysmal response on EEG.[8]
[18]
[19]
[20] When clinical suspicion of CLN2 disease is raised, the next steps in the diagnostic
process would incorporate analyses of TPP1 enzyme activity and TPP1 genotype as outlined in the 2016 expert recommendations for early detection and laboratory
diagnosis of CLN2 disease.[9]
Our recommendations to support the early identification of language delay and testing
for CLN2 disease are summarized in [Table 2].
Table 2
Summary of recommendations to support the early identification of language delay
|
Recommendations
|
|
Investigate language milestones beyond timing of first words as achievement of this
milestone may be age appropriate
|
|
If any symptoms of CLN2 disease (such as language delay or seizures) are identified
during ASD assessment, carry out enzyme activity/genetic testing for CLN2 disease
|
|
During language assessments, ensure that children are in a comfortable, familiar environment
with few distractions
|
|
Consider parent-reported outcomes as part of the overall assessment as they provide
real-life information about children's abilities
|
|
If a child has not progressed to use word combinations and has a vocabulary of less
than 50 words at the age of 2 years, consider for referral for support and for speech
and language intervention and monitoring
|
|
Keep in mind the “red flag” features of CLN2 disease, including slowing or stagnation
of language skills, other developmental impairments, seizures of unknown origin, and
clumsiness or ataxia
|
Abbreviations: ASD, autism spectrum disorder; CLN2, neuronal ceroid lipofuscinosis
type 2.
Conclusion
A greater understanding of the types of language deficits that occur in CLN2 disease
could support early identification of the disease, enabling provision of appropriate
care and support. We consider these deficits to include limited progression to full
sentences, a lack of vocabulary explosion, and language stagnation.
While emerging data show that language delay frequently precedes seizures in CLN2
disease,[2] identifying early language deficits continues to be a challenge, primarily because
of the considerable variability in which children typically develop their language
abilities during infancy when CLN2 disease first presents. A language delay may have
been noticed by parents or other childcare, educational, and health care providers,
and the child may be awaiting or receiving assessments and support. But if the potential
for a diagnosis of CLN2 disease is not realized, diagnostic delays may continue until
more well-known symptoms, such as seizures, become apparent. During this time, the
affected child may lose a significant proportion of their verbal and motor capabilities
that could have been maintained with appropriate treatment.
With the increasing recognition that language delay is a hallmark of early CLN2 disease
and that an approved treatment, if started early, can significantly slow disease progression,[10] it is our opinion that clinicians should routinely assess language milestones in
children with any of the “red flag” features outlined in this article.
This would improve patient outcomes through reduced diagnostic delay, earlier treatment
with ERT, and prompt involvement and support from the multidisciplinary team.
