CLN1 Disease (PPT1)

Infants with the classic form of CLN1 disease often demonstrate typical development until 6–12 months of age, when deceleration of head growth, hypotonia, myoclonus, refractory epilepsy, and vision loss develop. Early in the disease, MRI T2-weighted sequences demonstrate hypointense signal changes in the thalamus and basal ganglia and hyperintense periventricular signal changes [24, 25]. Progressive, generalized cerebral atrophy is noted until approximately 4 years of age, after which further MRI changes are minimal [24]. Across all presentations of CLN1 disease, prominent cerebellar volume loss is a key imaging feature. Prominent epileptic and non-epileptic myoclonus, starting between 12 months and 24 months of age, occurs almost universally in the classic infantile-onset form [26]. Additional movement disorders in early-onset forms, including chorea [27], are less commonly described. Death occurs in the late first or early second decade.

In addition to the classic infantile-onset form, CLN1 disease can present with later-onset forms, including a juvenile NCL-like form that begins with vision loss, as seen in CLN3 disease [28]. Myoclonus tends to be less prominent in these patients. This form is sometimes referred to as juvenile NCL with GRODS (granular osmiophilic deposits), based on the pattern of inclusions observed on electron microscopy.

CLN2 Disease (TPP1)

Prior to the onset of definitive symptoms, children with the classic form of CLN2 disease can demonstrate relatively typical development until age 2–4 years. Language delay may represent a prodromal symptom [29]. Following onset of refractory epilepsy, there is rapid deterioration of cognitive, motor, and visual skills, followed by a protracted period of markedly impaired motor and cognitive function, culminating in death at a median age of 10 years [30].

In the classic late-infantile-onset form of CLN2 disease, myoclonus and cerebellar ataxia represent the predominant movement phenotype [31]. Myoclonus may be epileptic or non-epileptic in nature, which can be challenging to distinguish on a clinical basis. Additional movement disorders, beyond myoclonus and ataxia, have been described in the classic disease as well as childhood onset forms of atypical or protracted forms CLN2 disease, including: dystonia [31], tremor [31], chorea [32], and parkinsonism/dystonia–parkinsonism, including freezing of gait [33], and akathisia [33]. There is a report of an exacerbation of the complex movement disorder phenotype in CLN2 disease in the setting of the administration of valproate in children, commonly used in the management of epilepsy. Two children presented acutely with worsening of the existing movement disorder, encephalopathy, hyperthermia, and elevated creatine kinase levels. All symptoms improved within 24 hours of withdrawal of the valproate therapy and there were no other suspected etiologies of the decompensation in the context of a thorough evaluation [34].

Recently, it has been recognized that bi-allelic missense mutations in TPP1 may also result in an adult-onset, predominantly ataxic, phenotype – spinocerebellar ataxia recessive type 7 (SCAR7). Vision loss, epilepsy, and overt cognitive dysfunction are not observed in this phenotype and storage-material findings can be absent [35]. A similar phenotype can present in childhood as reported by Dy et al., where bi-allelic TPP1 mutations resulted in progressive cerebellar dysfunction and static below-average cognitive skills in a 10-year-old girl [36].

CLN3 Disease (CLN3)

CLN3 disease is the most prevalent form of NCL and has the most uniform phenotype of the NCL disease spectrum [1]. Disease onset is typically at 4–8 years of age, with rapidly progressive vision loss representing the most common initial symptom [37]. Over the course of multiple years, children develop seizures, behavioral difficulties, cognitive changes, and motor impairment. Motor symptoms emerge around 11 years of age with loss of independent ambulation by late adolescence to early adulthood [38]. Initial motor abnormalities include rigidity, bradykinesia, and a shuffling gait (parkinsonism) [39]. As motor skills decline, speech impairment progresses until children become non-verbal. Prior to the loss of speech, the speech pattern in CLN3 disease is unintelligible and characterized by frequent stuttering and dysfluency. In late adolescence, cardiac conduction abnormalities emerge, manifesting primarily with bradyarrhythmias [40]. Hyperkinetic involuntary movements are less commonly described but may occur, including chorea, tics, stereotypies, and myoclonus [39, 41, 42]. Rarely, emergent movement disorder crises occur in CLN3 disease. Elkay et al. described two sisters with CLN3 disease who developed abnormal movements. One developed chorea at age 9 years and progressive gait difficulties leading to loss of ambulation at age 12 years when she developed progressive generalized dystonia. Despite treatment, she developed dystonic storm with hyperthermia and elevated creatinine kinase. The other sister developed progressive generalized dystonia at age 17 years, and eventually severe dystonic storm [41].

Parkinsonism, the most common motor abnormality in CLN3 disease, is thought to arise from dopamine dysfunction in the striatum. Single-photon emission CT images in patients with juvenile NCL and parkinsonism demonstrate decreased striatal dopamine transporter density, and positron emission tomography demonstrates reduced striatal dopamine D1 receptor binding [43, 44].

CLN4 Disease (DNAJC5)

CLN4 disease is the only currently known autosomal-dominant form of NCL [45]. Symptom onset is typically a presentation with cerebellar dysfunction around 30 years of age with later development of epilepsy, myoclonus, and dementia [46–48]. Visual function is preserved. Alternate presentations have been described, including cranial and neck dystonia without myoclonus [46], and syndromes of myoclonus epilepsy with parkinsonism [48].

CLN5 Disease (CLN5)

The classic CLN5 disease phenotype is often described as a variant late-infantile type of NCL (vLINCL). Juvenile-onset and adult-onset forms have also been described. Symptoms commence between 2 years and 7 years of age, with motor clumsiness or delay and inattention, followed by progressive vision loss, cognitive and motor regression, ataxia, myoclonus, and epilepsy, then premature death in early adulthood (second to fourth decade) [49]. The initial course is slow, evolving to the development of severe neuropsychiatric symptoms in the second decade, with most of a cohort of 15 reported children being bedridden within a decade of recognized onset [49]. In addition to ataxia and myoclonus, stereotypies may also occur.

More recently, an adult-onset CLN5 disease phenotype was described as an autosomal-recessive cerebellar ataxia syndrome with dementia [50]. This report contrasts with typical teaching of associating autosomal-dominant cerebellar ataxias with adult-onset and autosomal-recessive cerebellar ataxias with primarily childhood onset.

CLN6 Disease (CLN6)

CLN6 disease was initially classified as a variant of late-infantile NCL and presents between 18 months and 5 years of age [51]. It was later linked to teenage- and adult-onset (Kufs disease) forms as well [52–54]. Though adult-onset NCLs were initially attributed to CLN4 disease, CLN6 mutations are now recognized as the cause of the majority of adult-onset NCLs [3].

Although the phenotype of CLN6 disease is widely variable, a common early childhood presentation is with epilepsy in pre-school years, followed by the development of vision loss and ataxia along with cognitive regression [55, 56]. Hand-wringing stereotypies occur in a subset of patients [56]. Cerebral and cerebellar atrophy is characteristic. In early childhood-onset forms, death typically occurs in the second decade of life.

Mutations in CLN6 are responsible for the majority of autosomal-recessive Kufs disease. Unlike childhood-onset NCLs, Kufs disease does not typically include retinal involvement. Kufs disease has been traditionally divided into two forms, type A and type B. Type A Kufs disease is characterized by progressive myoclonic epilepsy. Type B Kufs disease is characterized by adult-onset dementia with co-occurring motor dysfunction. However, there is often an overlap between the type A and type B phenotypes. For example, patients with type A Kufs phenotype often have evidence of cognitive or motor dysfunction prior to the onset of seizures [52, 53]. Both action and epileptic myoclonus are common in these patients. Overall, prominent action myoclonus and ataxia represent the predominant movement disorders in adult-onset Kufs disease of both types (A and B). These features contribute to a slowly progressive loss of mobility in affected patients. Additional movement disorders have been described and present later, including dystonia and tremor [52].

Canafoglia et al. described the clinical and electrographic features of 11 patients with CLN6 disease [54]. Seven presented with a late-infantile phenotype; symptoms began between 3 years and 6 years of age. One child had a later onset at 8 years of age, and three had symptom onset in the second or third decade of life. All children demonstrated a constellation of cognitive abnormalities plus ataxia and refractory epilepsy, and cerebellar atrophy was common (n = 7). Cognitive symptoms were the most common first symptom for children in this cohort (n = 6). Other presentations included ataxia (n = 1) and extrapyramidal signs that were not fully described (n = 1). Within months of disease onset, all children had motor abnormalities, and these findings were followed by epilepsy and vision loss. Multifocal action myoclonus began at variable times in the course of disease. Of the five with extended follow-up, loss of ambulation occurred on average 3.5 years after disease onset. Three patients in this series had the type A Kufs phenotype, consistent with progressive myoclonus epilepsy [54]. Cortical myoclonus progressed over time and caused significant motor impairment. One patient, with onset of learning difficulties at 12 years and seizures at 17 years, was bedridden by age 26 years due to continuous myoclonus. Two patients demonstrated ataxia in the intermediate stage of the disease and two patients showed both pyramidal and extrapyramidal signs in the later disease stages. Loss of ambulation occurred several years after disease onset in two of the three patients. Cognitive decline, in contrast, was relatively slow. All adults had normal vision.

Another series reported a similar progression of symptoms in adult-onset CLN6 disease (Kufs disease), including onset in early adulthood, action or stimulus-induced myoclonus, and a severe functional impact of myoclonus combined with dementia [57]. Eyelid myoclonia can be a component of the refractory epilepsy phenotype, and the disease in adults may also manifest with progressive ataxia [58].

CLN7 Disease (MFSD8)

Also originally categorized within the group Turkish variant LINCL (vLINCL), CLN7 disease is now recognized as a distinct entity, as is true for CLN6 and CLN8. Classic CLN7 disease begins in early childhood, between 3 years and 7 years of age, primarily presenting with developmental delay or regression and refractory epilepsy with polymorphic seizures [59–61]. Both cerebral and cerebellar atrophy are evident on brain imaging, although cerebellar atrophy is more prominent and progressive [59]. Ataxia and myoclonus represent the predominant movement disorders, appearing early in the disease course. In some series, loss of ambulation occurs within 2 years of ataxia onset [59, 62]. As with other NCLs, myoclonus may be epileptic or non-epileptic in nature. Stereotyped hand movements akin to those observed in Rett syndrome as well as dystonia have been reported [60, 62].

CLN8 Disease (CLN8)

There are two distinct phenotypes of CLN8 disease: (1) progressive epilepsy with intellectual disability (Northern epilepsy syndrome) and (2) variant late-infantile NCL (vLINCL). The vLINCL form of CLN8 disease is characterized by early-childhood onset and rapid, severe symptomatic progression. Initial presentation is typically with developmental delay and refractory myoclonic epilepsy in the toddler to pre-school years, combined with ataxia. Subsequently, vision loss progressing to blindness develops [63–65]. In one child, following a period of early-onset retinal dystrophy and possible seizures, parkinsonism developed, characterized by shuffling gait and problems initiating voluntary movements. Within 2 years, ambulation was lost and disabling dyskinesias developed [66]. In some, stereotyped hand movements occur, similar to those that may occur in CLN6 and CLN7 diseases [63]. Cerebral and cerebellar atrophy and diffuse white matter hyperintensity are also evident [63, 65–68].

CLN9 Disease

CLN9 disease has been proposed although not confirmed as a distinct entity.

CLN10 Disease (CTSD)

Mutations in CTSD that lead to cathepsin D deficiency may manifest as CLN10 disease [69], as either a congenital-onset or juvenile-onset NCL. In addition to the features described below, at least two cases of CLN10 disease, one with infantile onset and one with juvenile onset, have been reported to have associated hypertrophic cardiomyopathy [70].

In the congenital disease, presentation is characterized by microcephaly with severe brain atrophy, respiratory insufficiency, hypertonia, neonatal seizures, and jitteriness. Age at death ranges between hours and weeks of life. Although the concept of a congenital NCL was first described decades ago [71–76], only rare cases have been reported since then [77, 78]. Siintola et al. first described congenital NCL secondary to CTSD mutations in three siblings born to consanguineous parents, and one unrelated child without family history of consanguinity [79]. The affected infants were born at term with significant microcephaly, intractable epilepsy, and spasticity. One infant was reported to have jerky movements in utero, attributed to myoclonic seizures. Postnatal apnea was severe, and death occurred within 1–10 days of delivery. Dysmorphic features such as low-set ears were described. Prior to the identification of the gene, Sandbank described two siblings born with microcephaly and abnormal movements who progressed to death 24–48 hours after delivery [76]. These infants presented with hyperkinesis and tremors in the hands and legs. While these patients did not have a genetic diagnosis, CLN10 is likely based on the congenital onset of an NCL. Abnormal movements have not been reported in other cases of congenital NCL [71, 72, 75]. Congenital-onset CLN10 disease is presumed to be related to complete inactivation of CTSD enzyme activity.

One case of early-infantile NCL secondary to CTSD mutations has been described [70]. This patient presented with early acquired microcephaly and cerebral atrophy and a progressive intractable epilepsy. Hypertrophic cardiomyopathy developed in this child. Of note, abnormal movements were not described.

Juvenile NCL secondary to CTSD mutations presents with ataxia and retinitis pigmentosa. Steinfeld et al. described the first case of juvenile CLN10 disease in which the patient presented in early childhood with ataxia and vision changes [69]. Over the course of years, dementia, loss of speech, and retinal atrophy emerged. She was wheelchair-bound by 17 years of age and had significant intellectual disability. Hersheson et al. later described two consanguineous families with juvenile-onset symptoms secondary to homozygous CTSD mutations [80]. All affected individuals had ataxia, retinitis pigmentosa, and cognitive decline. In the first family, symptom onset was at 15 years of age for multiple family members, with ataxia as the presenting sign. In the second family, age of onset was 8 years. Sensory peripheral neuropathy and hypertrophic cardiomyopathy were also described in some individuals. On neuroimaging, cerebellar atrophy is a characteristic finding across congenital and juvenile ages at onset [80].

CLN11 Disease (GRN)

While heterozygous mutations in the progranulin gene (GRN) are a cause of frontotemporal dementia, homozygous loss-of-function mutations in GRN are a cause of adult-onset NCL. As seen in most childhood-onset NCLs, rapidly progressive vision loss is a key component of the disease phenotype in CLN11 disease, and epilepsy is variably present. The predominant movement disorder is mild to moderate ataxia, and myoclonus, palinopsia, and mild cognitive impairment are also present [81–83].

CLN12 Disease (ATP13A2)

Mutations in ATP13A2 are typically associated with a form of juvenile Parkinson disease associated with dementia (Kufor–Rakeb syndrome) [84] or hereditary spastic paraplegia (SPG78) [85]. ATP13A2 loss-of-function mutations have also been implicated in CLN12 disease [86]. Vacuolated lymphocytes may be seen in cases due to ATP13A2 mutations as they are in CLN3 disease, with ultrastructural findings similar to those observed in other forms of NCL. Rigidity and akinesia are the predominant movement disorders in this form of NCL, with some also demonstrating resting tremor, which is uncommon in CLN3 disease, the other NCL typically manifesting parkinsonism. Transient response to levodopa, at times with the development of dyskinesias has been reported [86]. In addition, uncommon with the parkinsonism observed in CLN3 disease, coexisting myoclonus and ataxia have been seen.

CLN13 Disease (CTSF)

While type A Kufs disease (adult-onset NCL) has been attributed to CLN4 or CLN6 disease, more recently, type B Kufs disease has been associated with mutations in CTSF, which encodes cathepsin F, a lysosomal enzyme [23, 87]. In cases reported to date, symptom onset is in the third or fourth decade of life. Ataxia and tremor along with other cerebellar symptoms such as dysarthria are common. These symptoms are followed by the development of dementia, although in some cases, cognitive symptoms or seizures are the presenting sign [23, 87]. Additional involuntary movements described in isolated cases include segmental myoclonus and perioral dyskinesias that are not further specified [23, 87]. The epilepsy of CLN13 disease is less refractory than in other NCL forms. Vision loss has not been reported. MRI brain scans are non-specific but may demonstrate diffuse cerebral and cerebellar atrophy [88].

CLN14 Disease (KCTD7)

Mutations in KCTD7 have previously been linked to progressive myoclonic epilepsy [89, 90]. CLN14 disease has been proposed [91], but has not been confirmed as an NCL. In addition to the progressive myoclonic epilepsy phenotype, there are patients reported with childhood onset of refractory epilepsy, developmental regression, non-epileptic myoclonus, ataxia, and vision loss, as typically seen in NCL disorders. Lysosomal storage, however, has been only variably present in tissue specimens [91, 92], raising questions around classification as an NCL disorder [14, 92, 93].

Symptomatic Treatments

A comprehensive review of symptomatic movement disorder treatment is beyond the scope of this chapter; recent reviews are available [94, 95]. Although no systematic studies are available, the following case reports or small series contain information that may be helpful in guiding treatment decisions.

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