Abstract
Objectives:
To describe the clinical and neurophysiologic patterns of patients with neuronal ceroid lipofuscinoses associated with CLN6 mutations.
Methods:
We reviewed the features of 11 patients with different ages at onset.
Results:
Clinical disease onset occurred within the first decade of life in 8 patients and in the second and third decades in 3. All children presented with progressive cognitive regression associated with ataxia and pyramidal and extrapyramidal signs. Recurrent seizures, visual loss, and myoclonus were mostly reported after a delay from onset; 7 children were chairbound and had severe dementia less than 4 years from onset. One child, with onset at 8 years, had a milder course. Three patients with a teenage/adult onset presented with a classic progressive myoclonic epilepsy phenotype that was preceded by learning disability in one. The EEG background was slow close to disease onset in 7 children, and later showed severe attenuation; a photoparoxysmal response (PPR) was present in all. The 3 teenage/adult patients had normal EEG background and an intense PPR. Early attenuation of the electroretinogram was seen only in children with onset younger than 5.5 years. Somatosensory evoked potentials were extremely enlarged in all patients.
Conclusions:
In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature.
Neuronal ceroid lipofuscinoses (NCLs) are a family of hereditary diseases causing progressive neuronal degeneration and often retinal dystrophy. Clinically, there are variable associations of loss of cognitive skills, progressive visual impairment, refractory epilepsy, and movement disorders, presenting at different ages with varying time courses.
The neuropathologic marker is the intracellular storage of abnormal autofluorescent lipopigments, which accumulate in neurons and in other cells, characterized by electron microscopy as granular osmiophilic deposits (GRODs), curvilinear profiles (CPs), or fingerprint profiles (FPs). Classically, the coupling of onset age with specific neuropathologic patterns resulted in 4 main groupings: infantile, typically associated with GRODs; late-infantile (LINCL) associated with CPs; juvenile, associated with FPs; and adult (Kufs disease) with mixed neuropathologic patterns. Besides typical forms, many variants were recognized and the identification of molecular genetic abnormalities opened new prospects for NCL characterization, but also pointed to the problem of matching specific mutations with definite NCL phenotype.1 This led to development of a new NCL classification based on several axes, including clinical, morphologic, and genetic data.2
Mutations in CLN6, encoding a protein of unknown function localized to the endoplasmic reticulum, were first identified in families denoted as variant LINCL (vLINCL).3,4 Recently, other mutations of the same gene were found in patients with the recessive adult form of NCL known as Kufs disease.5–7 We describe here the spectrum of clinical and neurophysiologic features associated with mutations of CLN6 in a series of 11 patients, in order to identify common features that could suggest the diagnosis.
METHODS
We performed a retrospective analysis of patients with NCL and known mutations of CLN6, observed between 1990 and 2014 at a single center.
We evaluated their clinical histories to detect initial, intermediate, and late symptoms of the disease. We considered as “earliest” the symptom occurring within 6 months from the recognition of neurologic abnormalities, as “intermediate” symptoms emerging between 6 months and 4 years, and “late” those emerging after 4 years (see table 1).
Table 1.
Patients with NCL and known mutations of CLN6
We evaluated the neurophysiologic and imaging findings obtained in proximity to the disease onset (0–2 years) and those obtained after a follow-up lasting 4 to 13 years.
EEG, somatosensory evoked potentials (SEPs), flash-evoked visual potentials, and electroretinogram (ERG) were performed according to standard procedures8 as is our standard protocol in evaluating patients with putative progressive neurologic disorders. All patients or their parents signed the informed consent for all procedures performed in the study, including genetic evaluation.
The amplitude of N20-P25 SEP component was regarded as “giant” when exceeding 25 µV (normative laboratory values: 5.1 ± 2.4 µV). ERG was recorded using surface electrodes, with flashes administered at 0.5 Hz, 1 J. Flash-evoked visual potentials were recorded in the same session of ERG recording, from O1 and O2 referred to Fz; N1-P1 potentials exceeding 10 µV and N2-P2 potentials exceeding 30 μV were regarded as giant.
Ultrastructural examination of skin, lymphocytes, and CNS was done as previously reported.9 All of the specimens were evaluated at the C. Besta Institute (M.M.), with the exception of the rectal biopsies (patients 9 and 10), which were performed in other hospitals.
RESULTS
We included 11 patients from 10 families. Eight had a childhood onset (3–8 years) and 3 a teenage/adult onset (16–28 years). Nine were the only affected members of the family, and 2 children were brothers (patients 2 and 4); one child (patient 1) and one adult patient (9) had affected brothers not included in the series because of insufficient information. All children were first observed at the C. Besta Institute at the median age of 5.5 years; adults were observed at C. Besta Institute (patients 9 and 11) or Catania University (patient 10) at the median age of 29 years. Follow-up (from onset) lasted for 5 years for children and 22 years for adults (see table 1).
The 11 patients had a variety of CLN6 mutations (8 homozygous, 3 compound heterozygous) (table 1). The mutations have been previously described,5,10,11 with the exception of a novel mutation in patient 7.
Clinical data in children.
Early disease presentation.
In 7 children, the disease manifested between 3 and 5.5 years, while in the remaining case, onset was at 8 years (median 5.0 years). Cognitive abnormalities (table 1) were the earliest detected sign in 6 children, and defective language skills indicated a delay of language acquisition. Ataxia was the first detected sign in patient 4 who was repeatedly observed in the preclinical stages. In patient 8, with a relatively late onset, the disease presented with prominent extrapyramidal signs.
Seizures occurred at the onset in only one child, which appeared in the course of a febrile illness. Examination of the fundus oculi performed in 7 children (patients 1–7) did not reveal any abnormalities.
Intermediate and late stages.
A few months after disease onset, worsening motor defects became obvious in all children, including prominent ataxia (patients 1–5) or pyramidal and/or extrapyramidal signs (patients 6–8). Four children had a clinically detectable progressive visual decline (patients 1, 3, 4, and 7); the others apparently did not. Repeated examinations of the eye fundus consistently showed normal findings.
Seven children had seizure onset at these later stages: 2 had absence seizures more than 4 years from the disease onset. Multifocal myoclonus, elicited or enhanced by movements, occurred in 4 patients (2, 3, 6, and 7); the delay between disease onset and appearance of myoclonus ranged from 0.5 (patient 6) to 7 years (patient 7) at ages 5.5 to 12 years.
Three children (patients 4–6) were lost to follow-up. Among the 5 observed for at least 4 years (4.5–12) from onset, disease progression was fast with profound mental decline. Gait loss occurred at 7.8 ± 2.7 years (after 3.5 ± 1.7 years from the disease onset). Patient 8 with a delayed disease onset had a milder course and, after 4.5 years, still retained some verbal abilities (total IQ 37, verbal IQ 51, performance IQ 36), was able to walk despite prominent extrapyramidal signs, and had normal visual acuity and fundal examination.
Clinical data in teenage/adult patients.
The disease presented in the second (patients 9 and 10) or third decade. Patient 10 manifested poor learning ability since the age of 12 years, before the obvious appearance of seizures at age 17. All patients showed prominent myoclonic jerks with the characteristic of cortical myoclonus from the age of 16 to 28 years. Myoclonus progressively worsened, becoming a dominant symptom and causing severe motor impairment.
All 3 patients had generalized seizures. Patient 9 had myoclonic seizures with the characteristics of “vibrating” attacks, induced by voluntary movements or somatosensory and visual stimuli. She died at 47 years after the occurrence of repeated epileptic status. The other 2 patients, now aged 31 and 50 years, are still alive after 14 and 22 years from the onset of symptoms. Patient 10 was bedridden since age 26 years, with continuous myoclonic attacks induced by any movement attempt. Patient 11 has less than monthly tonic-clonic seizures sometimes induced by visual stimuli.
Gait loss, leading to wheelchair use, occurred 17 years after onset in patient 9 and 7 years after onset in patient 10, while patient 11 is still able to walk with help. Patients 9 and 10 developed moderate pyramidal and extrapyramidal signs. All 3 showed slow cognitive decline but remained able to speak until last follow-up, 13 to 25 years from onset.
MRI.
Six children (patients 2–7) were evaluated within 2 years from onset. Five children (patients 1, 2, 3, 7, and 8) were evaluated more than 4 years after the onset. All adults were evaluated more than 4 years from the onset.
At our first evaluation, cerebral cortical atrophy was already detectable in all patients, which was associated with white matter periventricular T2 hyperintensity in all except for one adult (patient 10). In addition, cerebellar atrophy was observed in 7 children (patients 1–7) and one adult (patient 11).
Morphologic diagnosis.
In children, skin biopsy showed storage material characterized by FPs and CPs (figure e-1, B and E, on the Neurology® Web site at Neurology.org). Lymphocyte evaluation showed storage material with more heterogeneous features (figure e-1, A and D; see table 1).
The storage material in adult patients in brain (figure e-1, C and F) or rectal biopsies was predominantly FPs. The histologic diagnosis in patient 9 was based on the finding obtained in a rectal biopsy of her brother (not included in the series). Skin evaluation was consistently negative in the 3 adults.
Neurophysiologic data.
Children.
EEG/polygraphy.
Shortly after clinical onset, all children showed a slow (theta-delta) and poorly organized EEG background. All had interictal EEG discharges of irregular, slow spike and waves (SWs) (at about 2.5 Hz) (figures 1A, 2A, and 3A), although clinical seizures were not reported.
Figure 1. EEG and ERG pattern in children.
EEG pattern in patient 3 close to disease onset: (A) wakefulness showing irregular spike-and-wave discharge; (B and C) abnormal light and deep EEG pattern. (D and E) Photoparoxysmal response evoked by slow and high-frequency IPS. (F) At the bottom, ERG pattern showing attenuated and inconsistent response. At the top, visual evoked potential showing increased P1. ERG = electroretinogram; IPS = intermittent photic stimulation.
Figure 2. EEG and SEP pattern at early and late stages in children.
Early (A) and late (B) EEG recorded in patient 2. Note in B the signal attenuation with persistence of frontal spike and wave associated with a myoclonic seizure. (C and D) SEP recorded at early and late stages. Note that N20-P25 and medium cortical components are giant and remained almost unchanged in the follow-up. SEP = somatosensory evoked potential.
Figure 3. PPR in children and adults.
Patient 8, EEG: atypical absence in A and peculiar PPR in B and C, consisting of fast waves 1:1 related with flashes. Patient 11, resting EEG showing small occipital spikes in D; PPR showing fast waves 1:1 related with flashes in E and F. Parietooccipital channels are magnified in insets. IPS = intermittent photic stimulation; PPR = photoparoxysmal response.
Sleep was already disorganized: light sleep showed an excessive rhythmic alpha-beta activity, while slow sleep showed diffuse delta waves with rare multifocal (either frontocentral or posterior) spikes (figure 1, B and C).
All children already showed photoparoxysmal responses (PPRs) at 15-Hz stimulation, while 3 (patients 3, 5, and 7) showed PPR also to lower frequency stimuli and 2 (patients 3 and 5) responded with 1:1 spike to 1-Hz stimuli (figure 1, D and E).
Four years after the disease onset, all children except patient 8 had an extremely slow and low-voltage EEG, and SW discharges became rare, often replaced by individual spikes with multifocal location (figure 2B).
Myoclonus could present either time-locked with SW, leading to a myoclonic seizure (figure 2B), or without any visible EEG correlate.
In contrast to the other children, patient 8 had preserved alpha-theta background 4 years after disease onset. Spontaneous epileptic paroxysms occurred during the EEG recording (figure 3A) and there was a marked PPR, similar to that seen in adult patients (figure 3, B and C).
Evoked responses.
ERG waves were attenuated from our first measurement in 6 children (nearly extinct in 3) (figure 1F). In patient 2, ERG was initially considered normal but became attenuated 2 years later. Patient 8, at our last observation 4.5 years from onset, had a normal ERG waveform.
Visual evoked potentials showed heterogeneous features: at our first observation, P1 component (latency: 66 milliseconds) was enlarged in patients 3 and 5 (33 and 156 µV) (figure 1F), while it became slightly enlarged 4 years after onset in patients 1 and 8 (20 and 26 µV).
SEP amplitude was giant in all patients with an average value of 45.3 ± 6.5 µV, with normal or minimally delayed N20 latency. The amplitude remained consistently enlarged during follow-up (figure 2, C and D).
Adults.
The EEG recorded at the average age of 28.6 ± 5.5 years (8.3 ± 4.0 years from onset) showed a preserved background organization with dominant frequencies at the lower limits of the alpha band. Brief discharges of S, SW, or fast activity rarely occurred on posterior derivations (see figure 3D). Myoclonus regularly occurred with active movements, and was associated with occipital spikes at the time of intermittent photic stimulation. Both jerks and occipital spikes followed with a 1:1 ratio the stimuli administered at 1 to 5 Hz (see figure 3E) and became extreme in response to higher-stimulus frequencies when EEG spikes tended to spread toward other EEG derivations (see figure 3F). Abnormal PPR persisted until the advanced disease stage. The 3 adult patients had normal ERG and visual evoked potentials, but giant SEPs were seen.
DISCUSSION
Recent data show that CLN6 mutation may cause severe neurologic disorders beginning in both childhood and adult life. We evaluated the present series of 11 patients with NCL and CLN6 mutations with the aim of describing the phenotypic spectrum of this disorder. Seven patients had a childhood onset; one had an intermediate or “juvenile” onset at 8 years. Moreover, among the 3 adults, all showing a typical progressive myoclonic epilepsy (PME) phenotype, one had learning disabilities detected at 12 years. The patient with disease onset at 8 years, together with the patient with cognitive impairment at 12 years, before the appearance of myoclonus and seizures, have an intermediate age at onset and suggest that CLN6 does not present at 2 explicit age peaks but may occur at different ages.
Clinical presentation of the children in this series, in agreement with other reports of patients with CLN6 mutations10,12–16 (see table e-1), included cognitive and motor regression, progressive cerebellar, pyramidal, and extrapyramidal signs, and seizures. In our children, cognitive regression was the most common presenting feature, often associated with ataxia. Moreover, the observation of delayed language skills preceding the overt presentation of the disease might suggest that mild defects in cognitive development could actually be the true presenting symptom in all. The following course of the disease was severe in all children and led to loss of independent gait at approximately 7 years.
It is important to note that in our patients, the ERG attenuation was an early and important feature suggesting the diagnosis of NCL. Although visual deficits were never an initial feature, and the examination of the fundus oculi never revealed specific pathologic findings, it is possible that the rapid and severe mental decline and motor impairments masked visual defects suggested by the impairment of ERG.17
Seizures were not an early feature but appeared during the intermediate or late disease stages; only one child had early seizures associated with a febrile illness. Seizures were mostly generalized myoclonic or tonic-clonic, while absences occurred in the late stage of the disease in only 2 children. Epilepsy onset was therefore later than observed in the “classic” late-infantile CLN2 form.18 Segmental myoclonus, enhanced by active movements, was present in a few children and resembles that seen with the adult CLN6-PME phenotype. This observation is further supported by the presence of extremely enlarged SEPs, which is a typical marker of PMEs.19
The child with onset at age 8 years (patient 8) had a milder phenotype.20 His onset age is at the upper limit of that described for vLINCL1 but the lack of retinal involvement prevents the inclusion as a typical juvenile NCL form.21 The prominent extrapyramidal phenotype without any evidence of myoclonus differs from the adult presentation, but the presence of giant SEPs and PPR in this patient confirms cortical hyperexcitability.
The clinical picture of our adult patients is in accord with the definition of PME,5 with cortical myoclonus as the most disabling symptom.22 All had normal vision and normal ERGs. All developed pyramidal and extrapyramidal signs in the advanced disease stages, a neurologic condition that is frequent in NCL6,7 but rare in the more common PME forms such as EPM1 and EPM2.22–24
Morphologic evaluation of skin biopsy in children showed typical storage materials with the characteristics of FPs, CPs as reported in vLINCL12,25,26 suggesting that cytoplasmic vacuoles containing mixed CPs and fingerprints are a common characteristic in children with CLN6 mutations. Leukocyte examination is less invasive, but even if suggestive of NLCs does not show a specific pattern and can be negative.
Of note, none of the 3 adult patients showed storage material in the skin, so morphologic diagnosis needed invasive biopsies (deep rectal or brain). The rectal biopsies showed FP or GRODs in 2 of these adults; however, the reliability of the findings obtained in rectal specimen was recently questioned.27 This confirms that neuropathologic diagnosis in adult patients can be challenging and underscores the value of advances in molecular diagnosis for putative adult NCL cases.5,28,29
Neurophysiologic findings revealed a link between the different age-dependent CLN6 phenotypes. “Giant” SEPs, assumed to be a typical and specific marker of patients with cortical myoclonus, were present both in patients with Kufs with obvious PME and in our CLN6 children, either in the presence or absence of myoclonus. This suggests that mutation of CLN6 predisposes to cortical hyperexcitability irrespective of (or prior to) myoclonus or seizures. Another neurophysiologic marker of cortical hyperexcitability was the presence of a prominent PPR. This is characteristic of LINCL30–33 and has been recently reported in vLINCL associated with CLN134 but not in patients with CLN8 mutation.35 Our observation indicates that PPR was “extreme” in patients with Kufs disease, with a typical finding of 1:1 photomyoclonic response to low-frequency stimulation (as previously described7), but prominent PPRs were also present since the earliest observation in all of our children, thus representing a consistent and “connecting” marker in the different phenotypes.
A major difference between childhood and adult onset was the involvement of the retina; the ERG was attenuated only in patients with an onset younger than 5.5 years, as also reported in the classic late-infantile form caused by CLN2 mutation and in juvenile Batten disease caused by CLN3 (and less frequently CLN1) mutation. Another age-related neurophysiologic difference is the characteristic and time course of EEG background disruption, moderate in adults and in our child with a delayed onset but extremely severe in younger children, reminiscent of that described in the infantile NCL36 and in the late-infantile form associated with CLN1 mutation.34
Certain clinical and neurophysiologic features link the different presentations of CLN6 despite the variability in age at onset. Giant SEPs were a consistent marker of both childhood and adult presentation, and a PPR was present in all patients and extremely marked in adult cases. All these features revealed enhanced cortical (or corticothalamic) excitability in CLN6. Neurophysiologic findings have rarely been systematically evaluated in series of patients with CLN6 mutations (see table e-1), but they appear to significantly orient the diagnostic workup. Indeed, the finding of giant SEPs is extremely rare in childhood and considered to be mostly associated with NCL.37 On the basis of our observations, the concurrent presence of PPR and giant SEPs in childhood can be a feature suggestive of NCL, to which attenuated ERG can add further confidence in indicating the likelihood of finding a CLN6 mutation.
Our data do not imply changes in the diagnostic algorithm necessary in suspected childhood NCLs,38 but they are valuable in proposing a pathophysiologic link between childhood onset and adult CLN6-LINCL, revealed by strong and early cortical hyperexcitability even in the presence of dissimilar clinical presentation, namely, in early disease stages.
In adult and adolescent patients presenting with prominent cortical myoclonus,5,39 CLN6 should be included in the genetic screening especially in the presence of extreme responses to intermittent photic stimulation at low and high frequencies (Kufs type A), since storage material is difficult to identify in skin, absent in lymphocytes, and problematic in rectal biopsy.26,27
Supplementary Material
GLOSSARY
- CP
curvilinear profile
- ERG
electroretinogram
- FP
fingerprint profile
- GROD
granular osmiophilic deposit
- LINCL
late-infantile neuronal ceroid lipofuscinosis
- NCL
neuronal ceroid lipofuscinosis
- PME
progressive myoclonic epilepsy
- PPR
photoparoxysmal response
- SEP
somatosensory evoked potential
- SW
spike and wave
- vLINCL
variant late-infantile neuronal ceroid lipofuscinosis
Footnotes
Supplemental data at Neurology.org
AUTHOR CONTRIBUTIONS
Dr. Canafoglia conceived the study, clinically evaluated the patients, analyzed neurophysiologic findings, discussed the results, and drafted and revised the manuscript. Dr. Gilioli clinically evaluated the patients, analyzed neurophysiologic findings, discussed the results, and drafted the manuscript. Dr. Invernizzi performed genetic studies and discussed the results. Dr. Sofia clinically evaluated the patients and discussed the results. Dr. Fugnanesi performed neuropathologic studies and discussed the results. Dr. Morbin evaluated neuropathology, discussed the results, and drafted and revised the manuscript. Dr. Chiapparini evaluated neuroradiology and discussed the results. Dr. Granata clinically evaluated the patients, discussed the results, and revised the manuscript. Dr. Binelli clinically evaluated the patients, evaluated EEG recordings, and discussed the results. Dr. Scaioli evaluated evoked potentials and discussed the results. Dr. Garavaglia evaluated the genetic findings and discussed the results. Dr. Nardocci clinically evaluated the patients, discussed the results, and revised the manuscript. Dr. Berkovic evaluated genetic findings, discussed the results, and revised the manuscript. Dr. Franceschetti conceived the study, clinically evaluated the patients, analyzed neurophysiologic findings, discussed the results, and drafted and revised the manuscript.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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