Neuronal ceroid lipofuscinosis

INTRODUCTION — The neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal diseases characterized by progressive neurodegeneration and intracellular accumulation of autofluorescent lipopigment.

This topic will review the NCLs.

TERMINOLOGY AND CLASSIFICATION

History and eponyms — The first description of an NCL in the western medical literature was by Stengel [1], who described a childhood-onset disorder with blindness and progressive dementia. A similar clinical entity was described by Batten in 1903 and included the first description of neuropathology: "cerebral degeneration with macular changes" [2]. Similar reports were made by Spielmeyer [3] and Vogt [4] in 1905. This disorder has come to be known as juvenile NCL, Batten-Spielmeyer-Vogt disease, or simply Batten disease. Shortly thereafter, Janský [5] and Bielschowsky [6] described a similar disorder with "late infantile" onset, which became known as late infantile NCL or Janský-Bielschowsky disease. Kufs later described an adult-onset disease with similar pathology but lacking visual impairment [7], eventually called adult-onset NCL or Kufs disease. In the 1970s, an infantile-onset form was reported by Haltia [8] and Santavuori [9], which became known as infantile NCL or Haltia-Santavuori disease.

Classic forms — The NCLs were originally diagnosed based on clinical features and ultrastructural abnormalities found with electron microscopy and were grouped into four classic forms:

●Infantile NCL (Haltia-Santavuori disease)

●Late infantile NCL (Janský-Bielschowsky disease)

●Juvenile NCL (Batten-Spielmeyer-Vogt disease, or simply Batten disease)

●Adult NCL (Kufs disease)

Each of the four classic forms was formerly thought to have distinct ultrastructural findings, with granular osmiophilic deposits in infantile NCL, curvilinear profiles in late infantile NCL, fingerprint bodies in juvenile NCL, and rectilinear profiles in adult NCL [10]. However, as the genetic basis of each NCL emerged and genetic testing became standard, it is now apparent that the relationship between genotype or NCL type and ultrastructural features is not specific.

Over time, investigators have described additional forms of NCL with clinical features similar to those of the four classic forms.

Definition and modern classification — With new proposed NCL genes and an expanding number of associated clinical entities, it became necessary to develop a clear definition of NCL: "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" [11].

NCL experts now recommend primary disease classification by gene or protein (eg, CLN1 disease or PPT1 deficiency) and secondary classification by age at onset and clinical features. A more extensive proposed classification system includes seven axes: 1) affected gene (CLN gene symbol), 2) mutation diagnosis, 3) biochemical phenotype, 4) clinical phenotype, 5) ultrastructural features, 6) level of functional impairment (descriptive or using a universally recognized scoring system), and 7) other remarks (additional genetic, environmental, or clinical features) [12].

Although comprehensive, the seven axis system is impractical for regular clinical use; the authors suggest axes 1 (gene or protein) and 4 (clinical phenotype) for clinical practice [12].

Despite efforts to standardize nomenclature, multiple interchangeable terms remain in use. Thus, Batten disease may be used to refer specifically to CLN3 disease or as an umbrella term for all NCLs. Infantile NCL (INCL) may be used interchangeably with CLN1 disease; late infantile NCL (LINCL) may be used interchangeably with CLN2 disease; and juvenile NCL (JNCL) may be used interchangeably with CLN3 disease. Several forms may be referred to as variant late infantile NCL (vLINCL). In what follows, we will adhere to the classification system proposed by Williams and Mole [12].

PATHOPHYSIOLOGY — Abnormal intracellular storage materials accumulate in all NCL disorders, comprised of a mixture of lipids and proteins. The main storage material composition includes saposins in CLN1, CLN10, and CLN11 diseases, with mitochondrial adenosine triphosphate (ATP)-synthase subunit C in most forms including CLN11 disease [13]. There is typically early, regional glial activation and functional impairment preceding neuronal loss [14,15]. Though NCL genes are expressed widely outside of the nervous system in various tissues, disease manifestations primarily derive from central nervous system dysfunction. There appears to be both regional and cell-type specific selective vulnerability to NCL protein deficiency, with early retinal degeneration as a prominent feature in some forms and later or no known involvement of the retina in others. The thalamus and cerebellum are affected early in many NCL forms [16].

Distinct inclusion patterns (fingerprint, curvilinear profiles, granular osmiophilic deposits) are found in multiple tissues, including skin, rectal tissue, brain, and smooth muscle (picture 1). Inclusion patterns, once thought to represent distinct forms of NCL, are now recognized to have overlap across genetic etiologies, and multiple inclusion patterns can be observed within a single genetic cause [17-19]. Emerging knowledge suggests interactions between certain NCL genes [20-23]. In CLN3 disease, an additional pathologic finding of vacuolated lymphocytes (picture 2) can be an important clue to diagnosis [24].

Five forms of NCL are due to defects in soluble lysosomal proteins: CLN1 disease due to palmitoyl protein thioesterase-1 deficiency, CLN2 disease due to tripeptidyl peptidase-1 deficiency, CLN5 disease due to bis(monoacylglycero)phosphate (BMP) deficiency [25], CLN10 disease due to cathepsin D deficiency, and CLN13 due to cathepsin F deficiency.

All other known forms of NCL are caused by defects in lysosomal, endoplasmic reticulum, or cytoplasmic vesicular transmembrane proteins [26,27].

Though the specific pathways underlying involvement in protein dysfunction, lysosomal storage, and neuronal death are still being investigated, putative roles in cellular function include regulation of lysosomal acidification [28,29], lysosomal sorting [30], regulation of autophagy [31], calcium homeostasis, and galactosylceramide transport [32], along with other cellular homeostasis functions [16,27].

Other diseases have been identified that show evidence of intracellular ceroid lipofuscin accumulation. Debate remains as to whether these are indeed true NCLs [33].

GENETICS — At least 13 different genetic forms of NCL have been identified and assigned a "CLNx" number. Genetic forms of NCL are summarized in the table (table 1). With the exception of CLN4 disease, the NCLs are recessive disorders.

As we gain more knowledge about the spectrum of disease associated with NCLs, it has become apparent that causative gene and specific pathogenic variants do not always predict phenotype. In addition, though there are general phenotypic patterns, including age at onset, which guide the diagnostic approach, age at onset does not necessarily predict genotype. There is also now an established association between haploinsufficiency of the progranulin (GRN) gene and adult-onset frontotemporal dementia, which may be relevant for family genetic counseling [13,34].

EPIDEMIOLOGY — Collectively, NCLs are the most prevalent neurodegenerative disorders of childhood [11]. However, the individual NCLs are rare conditions, epidemiologic studies are limited, and prevalence estimates vary from country to country, in part due to founder effects for certain disease forms.

In Europe, where the majority of epidemiologic studies have been conducted, incidence estimates range from 0.6 per 100,000 in Italy to 13.6 per 100,000 in Newfoundland [35-37]. Collectively, NCLs have an estimated prevalence of 1 per 1 million people in the United States [38], 1.2 per 1 million people in Italy [36], and as high as 1 per 100,000 people in Scandinavian regions [38]. In Latin America, CLN2 and CLN3 diseases represent the most prevalent NCL forms [39]. Worldwide, as the number of recognized NCL types has increased and as the approach to diagnostic testing has evolved, there is a need for updated assessment of the incidence and prevalence of NCL disorders.

CLINICAL MANIFESTATIONS

Shared features — The NCLs share features of a progressive clinical course with vision loss, dementia, epilepsy, movement disorders, and storage of ceroid lipofuscin in neurons. Despite similar features, each NCL is a distinct biologic entity and differs from other NCLs in age at onset, specific clinical features, rate of progression, or a combination of these factors [40].

Individual genetic forms

●CLN1 disease – The CLN1 gene codes for palmitoyl-protein thioesterase-1 (PPT1), a soluble lysosomal protein [41]; pathogenic variants in CLN1 are generally associated with classic infantile NCL. In classic infantile-onset CLN1 disease, following a period of normal-appearing development, there is rapid developmental regression between 6 and 24 months of age, combined with seizures, myoclonus, ataxia, and visual failure [42]. Visual failure usually occurs by age 2 years with optic atrophy, retinal changes, and early extinction on the electroretinogram. Signs and symptoms progress to a state of severe spasticity and decreased level of consciousness; lifespan is severely shortened.

Some pathogenic variants in CLN1 can cause later onset disease with more extended disease courses. All forms of childhood-onset CLN1 disease progress to premature death, though typically, the later the symptom onset, the more protracted the course. Late infantile CLN1 disease begins between two and four years of age. There is visual and cognitive decline followed by development of ataxia and myoclonus [43,44]. Juvenile CLN1 disease, also referred to as "juvenile NCL with granular osmiophilic deposits," typically presents between the ages of 5 and 10 years, with cognitive decline followed by epilepsy, motor decline, and vision loss [44,45]. There are case reports of a rare adult-onset form, beginning with cognitive decline and depression, followed by ataxia, parkinsonism, and vision loss [46,47].

In terms of genotype-phenotype correlations, pathogenic variants predicted to cause severe truncation or loss of protein are more likely to be associated with infantile-onset disease [44,48].

●CLN2 disease – The CLN2 gene codes for tripeptidyl peptidase-1 (TPP1), a soluble lysosomal protein, and is associated with the classic late infantile-onset form of NCL [49]. CLN2 disease is more homogeneous than CLN1 disease in age at onset and clinical phenotype, though some variability still exists. Classic late infantile CLN2 disease presents between two and four years of age [50]. Typically, there is speech delay, developmental plateau, or loss of developmental milestones beginning in the second year of life, followed by the development of refractory epilepsy [51]. Seizures are polymorphic and include myoclonic, tonic, atypical absence, and tonic clonic. Over time, ataxia, refractory nonepileptic myoclonus, and spastic quadriparesis develop. Due to substantial cognitive impairment, vision loss may be less obvious than in other forms of NCL. Retinal degeneration is most apparent in the macula, but there is no "cherry red spot" [52]. Electroretinograms and visual-evoked potentials are abnormal.

As with CLN1 disease, children with onset of CLN2 disease after the age of four years tend to have a milder course with more prominent ataxia and less prominent epilepsy [53,54]. Later onset is typically associated with reduced levels, but not absence, of functional TPP1 enzyme [53]. An even later onset variant has been called autosomal recessive spinocerebellar ataxia 7 (SCAR7) based on the absence of epilepsy and vision loss, but this entity has now been shown to be caused by TPP1 deficiency due to pathogenic variants in CLN2 [55,56].

●CLN3 disease – The CLN3 gene encodes a lysosomal transmembrane protein of unknown function and is associated with the classic juvenile-onset form of NCL. There appears to be less phenotypic heterogeneity for CLN3 disease than in other forms of NCL; a single phenotype predominates [57,58]. The typical age at onset in CLN3 disease is between four and seven years, with vision loss that rapidly progresses from normal vision to functional blindness over the course of approximately one year. Light-dark perception may be retained for several years. Vision loss is followed by cognitive decline, behavioral problems, epilepsy, and parkinsonism [59-61]. CLN3 disease is also accompanied by a characteristic severe, stuttering dysarthria that usually develops after age 10 years. Females have slightly later onset of vision loss but also more rapid progression than males [59,62]. Cardiac conduction and structural abnormalities have been reported in older individuals [63,64].

Less common phenotypes of CLN3 disease include:

•Protracted CLN3 disease, characterized by slower progression, milder symptoms, or later onset of salient disease features compared with classic CLN3 disease [65,66].

•Nonsyndromic retinal dystrophy but without other clinical features of an NCL [67].

•Autophagic vacuolar myopathy with cardiomyopathy, retinal dystrophy, and relative cognitive and motor function preservation [68].

●CLN4 disease – CLN4 disease, an adult-onset NCL, is due to pathogenic variants in the DNAJC5 gene that codes for a cysteine string protein [69,70]. This is the only known autosomal dominant form of NCL. CLN4 disease is also known as "Parry disease," named after the family in which it was first described [71]. Clinical features include ataxia, progressive dementia, seizures, and myoclonus, typically starting after 30 years of age. There is no vision loss associated with CLN4 disease.

●CLN5 disease – CLN5 disease is a "variant" late infantile-onset form of NCL. The term "variant late infantile" has been used to distinguish forms with early childhood onset from classic late infantile CLN2 disease. CLN5 disease is sometimes referred to as the "Finnish variant" due to its initial description in Finland [72], but it is not limited to individuals with Finnish heritage [73]. The CLN5 protein is a soluble lysosomal glycoprotein of unknown function. The age at onset in CLN5 disease varies from 2 to 17 years, with a median of 5 years [73,74]. In a European cohort of 15 children with CLN5 disease, impaired learning and cognition were the most common early symptoms. Seizures occurred relatively late (median age 8 years). Other clinical features include psychomotor regression, ataxia, and visual failure, which may be a presenting sign. Atypical forms, with onset of vision loss, ataxia, and cerebellar atrophy in adulthood, have also been reported [75].

●CLN6 disease – There are several phenotypes associated with CLN6 mutations. CLN6 disease was initially described as another variant late infantile-onset NCL [76]. Pathogenic variants in the CLN6 gene have also been shown to cause classic late infantile-onset NCL and adult-onset type A Kufs disease [17,77]. The CLN6 protein is a transmembrane protein of unknown function. Like other "variant" late infantile-onset NCLs, the age at onset of childhood CLN6 disease is highly variable, ranging from 18 months to 8 years. Seizures are an early feature in CLN6 disease, occurring before five years in >60 percent of patients. Early vision loss is reported in 50 percent of patients with CLN6 disease, but vision loss is not ubiquitous in late infantile CLN6 disease [78]. Additional clinical features include developmental delay, dysarthria, and ataxia [76,79]. There is rapid symptom progression, and death usually occurs between 5 and 12 years of age in early childhood-onset forms.

As noted above, pathogenic variants in CLN6 have been shown to cause autosomal recessive type A Kufs disease. Kufs disease has been subclassified as types A and B [33]. Type A begins with a progressive myoclonic epilepsy with later development of dementia and ataxia. In one series of 20 individuals with type A Kufs disease due to pathogenic variants in CLN6, the mean age at onset was 28 years (range 12 to 51 years) following a period of normal development. The initial symptom is typically refractory myoclonic seizures [17]. Visual symptoms are atypical in type A Kufs due to CLN6 pathogenic variants. Ataxia leading to impaired walking, variable dementia, and dystonia may follow the onset of epilepsy; life span is shortened.

Kufs type B (ie, CLN13) is characterized by dementia with cerebellar and/or extrapyramidal motor symptoms and has been attributed to pathogenic variants in the cathepsin F (CTSF) gene [80], as reviewed below in CLN13.

●CLN7 disease – CLN7 disease is another "variant" late infantile-onset NCL, which is sometimes called the "Turkish" variant due to its initial description in Turkish families [81]. However, it is not limited to individuals with Turkish ancestry [82]. The CLN7 protein is a lysosomal membrane protein that belongs to the "major facilitator" superfamily of transporter proteins (major facilitator superfamily domain-containing 8 protein), and the encoding gene is MFSD8. Age at onset is typically between two and seven years. Seizures are typically an early sign, followed by motor decline, myoclonus, dementia, and vision loss.

Pathogenic variants in MFSD8 have also been shown to cause a nonsyndromic, retinal rod-cone dystrophy with severe macular involvement. The specific pathogenic variants p.Glu336Gln and p.Met454Thr appear to be responsible for this phenotype [83].

●CLN8 disease – CLN8 disease is caused by pathogenic variants in the CLN8 gene encoding a transmembrane protein of the endoplasmic reticulum of unknown function. There are two recognized forms of the disease, but these may fall on a spectrum rather than representing two distinct phenotypes [84]. The first is a "variant" late infantile NCL that was initially described in Turkish families [85] but has also been reported in other ethnic groups [86,87]. Age of onset is usually 5 to 10 years; patients initially present with seizures followed by progressive motor and cognitive decline. Vision loss also occurs. The second form of CLN8 disease has been referred to as "Northern epilepsy," a form of progressive myoclonus epilepsy [88,89]. It is also characterized by seizures with cognitive and motor decline but without vision loss.

●CLN9 disease – CLN9 disease was proposed as a distinct entity with a juvenile-onset NCL that was not CLN3 disease in two Serbian sisters and two German brothers [90]. A specific gene was not identified, and subsequently, it was determined that these individuals had pathogenic variants in CLN5 [91]. Thus, CLN9 disease has not been confirmed to be a distinct entity.

●CLN10 disease – CLN10 disease can manifest as a severe congenital form of NCL or as a juvenile-onset form. CLN10 disease is caused by pathogenic variants in the lysosomal aspartic protease cathepsin D gene (CTSD) [92]. The congenital phenotype is the earliest onset form of NCL. It presents in the neonatal period with microcephaly, severe brain atrophy, absence of neonatal reflexes, and respiratory insufficiency. Infants with CLN10 disease rarely survive more than a few days. The juvenile-onset phenotype of CLN10 disease is characterized by onset of a progressive ataxia between ages 7 and 15 years, with associated pigmentary retinopathy and progressive cognitive decline. A sensory axonal neuropathy has also been described in some individuals [93].

●CLN11 disease – CLN11 disease is due to pathogenic variants in the progranulin (GRN) gene [34]. Heterozygous pathogenic variants in GRN are a major cause of frontotemporal lobar degeneration in adults, but homozygous pathogenic variants have been reported to cause a younger adult-onset NCL. Initially described in two siblings, the age at onset was in their early 20s with progressive vision loss and seizures, followed by ataxia, cognitive decline, and retinal dystrophy. A subsequent case series has expanded the phenotype to include age at onset as young as seven years [34,94].

●CLN12 disease – CLN12 disease is better known as Kufor-Rakeb syndrome (or PARK9). It was initially described in a consanguineous Jordanian family [95]. The clinical features include the parkinsonian features of masklike face, rigidity, and bradykinesia but without tremor. Spasticity, supranuclear upgaze paresis, and dementia are present in most affected individuals [96]. Age at onset is in early adolescence; symptoms progress rapidly. Kufor-Rakeb syndrome is caused by loss-of-function pathogenic variants in a predominantly neuronal P-type ATPase gene, ATP13A2 [97,98]. Description of typical NCL pathology in a family with pathogenic variants in ATP13A2 led to the alternative classification as CLN12 disease [99].

●CLN13 disease – CLN13 disease is due to pathogenic variants in the CTSF gene that codes for cathepsin F. Pathogenic variants in CTSF appear to account for the majority of cases of adult-onset NCL of the type B Kufs phenotype [80,100]. Type B Kufs is characterized by dementia with cerebellar and/or extrapyramidal motor symptoms. Onset is typically in early adulthood.

●CLN14 disease – CLN14 disease is due to pathogenic variants in the KCTD7 gene that codes for the potassium channel tetramerization domain-containing protein 7 [101]. It is characterized by rapidly progressive neurodegeneration with onset of intractable myoclonic seizures before age 2 years accompanied by developmental regression. This condition has also been classified as a progressive myoclonic epilepsy (EPM3) [102], but, as intracellular accumulation of autofluorescent lipopigment storage material has been identified in some affected individuals [101], it has been designated as CLN14. Ultrastructural findings on skin biopsies are variable, but the clinical features are generally consistent across reports.

EVALUATION AND DIAGNOSIS — For the child presenting with developmental regression or concern for neurodegenerative disease, efficiently achieving an accurate, early diagnosis, if possible, is important for guiding treatment decision making, anticipatory guidance, family planning, bringing to a close the diagnostic odyssey, connecting to disease-specific support groups, and determining eligibility for clinical trials [103].

When to suspect NCL — There are several clusters of signs and symptoms that suggest an NCL diagnosis:

●Developmental regression affecting infants and children

●Refractory epilepsy plus neurologic symptoms at any age

●Vision loss (especially retinopathy) plus neurologic symptoms at any age

●Progressive ataxia with cerebellar atrophy at any age

NCLs are one of the most prevalent causes of pediatric dementia [104,105] (see "Intellectual disability in children: Evaluation for a cause"). In a study of 300 individuals with childhood-onset ataxia with cerebellar atrophy, 18 percent had an NCL diagnosis [106].

It is important to include CLN2 disease in the growing list of treatable neurologic disorders of childhood, making ascertainment of an NCL diagnosis, when present, critically important.

Some children with NCL are first diagnosed with autism spectrum disorder, and some children with an NCL diagnosis have hand stereotypies reminiscent of Rett syndrome or FOXG1 disorders [107]. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis" and "Rett syndrome: Genetics, clinical features, and diagnosis".)

Brain imaging — When infants or children present with global developmental delay or developmental regression, we suggest early brain imaging, especially in the setting of seizures, abnormal neurologic examination findings, and/or macrocephaly or microcephaly [108-111]. Brain magnetic resonance imaging (MRI) is likely to have greater diagnostic yield compared with head computed tomography (CT) in this context and has the added benefit of avoiding radiation exposure. While imaging alone is nonspecific and is insufficient for establishing an NCL diagnosis, it may provide important clues that suggest a neurodegenerative condition is present, especially when cerebral and cerebellar atrophy are observed, which has been reported in most NCLs [17,112].

Of note, while diffuse cerebellar atrophy is an eventual universal finding in infantile-onset CLN1 disease [19,112,113], conventional brain MRI may be normal in children with CLN3 disease younger than age 10 years; cerebral atrophy becomes evident in adolescence followed by cerebellar atrophy [114]. Thalamic T2 hypointensity has been reported in several NCLs including CLN1, CLN2, CLN3, CLN5, and CLN7; this finding may also be observed in other neuronal lysosomal diseases [19,113,115].

The NCLs are primarily considered grey matter disorders, but white matter abnormalities have been described in CLN2 [116] and CLN3 [117].

Genetic testing — Genetic testing is the primary path to diagnosis for most individuals. When there is high suspicion for a specific NCL (eg, concern for CLN3 disease in a child with rapidly progressive vision loss and mild cognitive impairment at five years of age), single gene sequencing and deletion/duplication analysis may be appropriate.

In most cases, the clinical suspicion is more likely to be for NCLs as a group, a genetic form of epilepsy, or for a neurodegenerative disorder broadly. In these cases, it may be more appropriate to pursue panel-based, next-generation sequencing with deletion/duplication analysis for NCLs using NCL gene panels, epilepsy gene panels, or lysosomal disease gene panels, depending on the level of diagnostic certainty [118]. A broad-based approach to diagnosis is often needed due to overlapping symptom presentations.

Whole exome sequencing is increasingly used as a tool in the diagnostic evaluation of children with complex neurologic conditions. This approach may also yield a specific NCL diagnosis. However, some limitations apply. Large deletions and duplications may be missed by this approach, evaluation of variants of unknown significance may be challenging (given the rarity of these disorders), and confirmatory testing with enzyme analysis (for CLN1 and CLN2 disease) or tissue biopsy (to evaluate for lysosomal storage) may be required for diagnosis in certain cases.

The NCL Mutation and Patient Database is an additional resource for clarifying the nature of variants of unknown significance. In cases where the suspicion for an NCL disorder is very high and only a single pathogenic variant is found in an NCL gene, intronic pathogenic variants may also be explored in conjunction with an experienced geneticist [119]. There are also isolated case reports of NCLs due to uniparental disomy [120]. In the setting of a sibling with known genetic diagnosis, testing may begin with targeted analysis for the same pathogenic variant. Where insurance coverage and cost represent barriers to testing, there are an increasing number of industry-sponsored comprehensive epilepsy and lysosomal disease next-generation sequencing panels available at no financial cost to the patient.

Other studies — Enzyme testing, once a first-line diagnostic test for CLN1 and CLN2 disease, increasingly represents a secondary line of diagnostic or confirmatory testing. Similarly, tissue biopsy with electron microscopic analysis was once considered first-line in the diagnostic approach for all NCLs, but it, too, now represents a means of confirming or excluding an NCL diagnosis when genetic testing results are uncertain or inconclusive. Tissue sampling from the skin is most common; conjunctiva and rectal tissues constitute additional sources [18].

As in other complex neurodegenerative disorders, a thorough ophthalmologic examination may be beneficial, even in the absence of known vision loss. Evidence of early retinopathy in the setting of developmental regression may point to NCLs as a class of disorders. Electroretinography may be helpful to further assess retinal involvement in some settings.

While epilepsy is a common feature in NCLs, electroencephalography findings are generally nonspecific. It has been suggested that photosensitivity to low-frequency photic stimulation (1 to 5 Hz) may be a hallmark of NCL disorders, but this has not been studied extensively across NCLs [17,121,122].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for dementias of childhood is broad and includes genetic, metabolic, and inflammatory etiologies. Other neuronal lysosomal diseases, leukoencephalopathies, mitochondrial diseases, and peroxisomal disorders should be considered in children presenting with developmental regression with or without epilepsy.

The British Paediatric Surveillance Unit launched the progressive intellectual and neurologic deterioration study in 1997, tracking occurrence and diagnosis of neurodegenerative conditions of childhood [104,105]. In the 2019 analysis from this ongoing study, the most common diagnoses in a cohort of 1819 children with symptoms and signs of neurodegeneration were late infantile NCL, mucopolysaccharidosis type III, metachromatic leukodystrophy, Rett syndrome, adrenoleukodystrophy, juvenile NCL, Krabbe disease, Tay-Sachs disease, Niemann Pick type C, and Sandhoff disease [105]. Many of these conditions are primarily white matter diseases and lack prominent epilepsy combined with retinal degeneration. More than 190 different diagnoses were found in the cohort, confirming that the differential diagnosis can be expansive.

●Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder that results in accumulation of very long-chain fatty acids (VLCFAs) in all tissues. ALD consists of a spectrum of phenotypes (including childhood cerebral forms, adrenomyeloneuropathy, and primary adrenal insufficiency) that vary in the age and severity of clinical presentation. Female carriers often develop myelopathy and polyneuropathy during adulthood. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

●Krabbe disease is an autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC). The pathologic changes in the peripheral and central nervous system (globoid cell formation and decreased myelin) are hypothesized to result from the toxic nature of accumulated psychosine, which cannot be degraded because of the GALC deficiency. Most patients present with symptoms within the first six months of life; approximately 10 percent present later in life, including adulthood. A peripheral motor sensory neuropathy occurs in all patients, but the early-onset forms are dominated by symptoms related to central nervous system dysfunction. Infantile onset disease is associated with irritability, developmental delay or regression, limb spasticity, axial hypotonia, absent reflexes, optic atrophy, and microcephaly. Seizures and tonic extensor spasms eventually appear. Typically there is rapid regression to a decerebrate condition and death in most cases before two years of age. (See "Krabbe disease".)

●Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disease caused by pathogenic variants in the arylsulfatase A gene (ARSA). In a few patients, a variant form of MLD is caused by pathogenic variants in the prosaposin gene (PSAP). The late infantile form of MLD presents from age six months to two years; early signs include regression of motor skills, gait difficulty, ataxia, hypotonia, extensor plantar responses, optic atrophy, and peripheral neuropathy. The juvenile form of MLD presents between 3 and 16 years of age with gait disturbance, intellectual impairment, ataxia, upper motor neuron signs, and a peripheral neuropathy. Seizures may occur. Adult onset MLD (age 17 or older) is usually heralded by dementia and behavioral difficulties. (See "Metachromatic leukodystrophy".)

●The mucopolysaccharidoses (MPS) are lysosomal diseases caused by the deficiency of enzymes required for the stepwise breakdown of glycosaminoglycans (GAGs). Fragments of partially degraded GAGs accumulate in the lysosomes, resulting in cellular dysfunction and clinical abnormalities. MPS type III (Sanfilippo syndrome) is caused by a deficiency of one of four enzymes involved in the degradation of heparan sulfate, leading to its accumulation. All forms have autosomal recessive inheritance. An MPS disorder should be suspected in a child with coarse facial features, hepatosplenomegaly, and bone disease (dysostosis multiplex), with or without central nervous system (CNS) abnormalities. MPS type III is characterized primarily by progressive CNS degeneration. Hepatosplenomegaly, while characteristic of MPS disorders, is not observed in NCL conditions. (See "Mucopolysaccharidoses: Clinical features and diagnosis".)

●Niemann-Pick disease type C (NPD-C) is caused by pathogenic variants of the NPC1 and NPC2 genes that result in impaired cellular processing and transport of low-density lipoprotein (LDL) cholesterol. NPD-C can present from the perinatal period until late adulthood. Most patients with NPD-C have disease onset in middle to late childhood, typically with cerebellar symptoms, slow cognitive deterioration, vertical supranuclear gaze palsy, and progressive dystonia, dysarthria, and dysphagia. (See "Overview of Niemann-Pick disease".)

●Rett syndrome (RTT) is a rare neurodevelopmental disorder that occurs almost exclusively in females. In the majority of patients with typical or atypical RTT, the disorder is caused by pathogenic variants in the MECP2 gene. A minority of patients have atypical RTT caused by pathogenic variants in CDKL5 or FOXG1 genes. With typical RTT, patients initially develop normally and then experience loss of speech and purposeful hand use and onset of stereotypic hand movement and gait abnormalities. Deceleration of head growth can be one of the first signs, beginning as early as two to three months of age. Additional manifestations can include seizures, autistic features, intermittent breathing abnormalities, autonomic nervous system dysfunction, cardiac abnormalities, and sleep disturbances. Atypical RTT encompasses variants of RTT that have many but not all of the clinical features of typical RTT. (See "Rett syndrome: Genetics, clinical features, and diagnosis".)

MANAGEMENT

Supportive care — In general, the principles of management for individuals with NCL disorders follow the principles of symptomatic management for developmental and neurologic conditions based on common practice.

●Pharmacologic strategies – There are some pharmacologic strategies commonly used for management of neurologic sequelae of NCL.

•Epilepsy – For patients with NCL and epilepsy, antiseizure medications that may be helpful include valproate, lamotrigine, topiramate, and levetiracetam, recognizing that this is not a precise or exhaustive list, and that epilepsy in this setting is often resistant to treatment [123]. The mood stabilizing effect of valproate is a potential advantage for patients with juvenile NCL who may have psychotic symptoms. However, in one small series, valproate-induced hyperammonemic encephalopathy developed in 4 of 14 patients (29 percent) with juvenile NCL who were treated with valproate, suggesting an increased risk compared with other populations [124]. Agitation is a possible adverse effect of topiramate and levetiracetam. Topiramate may be started at a low dose (0.5 mg/kg per day) in patients with NCL and titrated slowly to minimize other adverse effects, which include cognitive impairment and language disturbance [123]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Overview of the management of epilepsy in adults".)

•Spasticity – For patients with NCL, our preferred treatment option for spasticity is baclofen, although high doses are often required [123]. Benzodiazepines are an alternative, and may be preferred as a first choice for patients with dyskinesia. Tizanidine is also an option. Botulinum toxin injections can be helpful for relieving focal or segmental spasticity.

•Movement disorders – Treatment of movement disorders in the NCLs may be difficult due to the complexity of movement disorder combinations and often treatment-refractory symptoms. Movement disorders that do not affect patient function, safety, or comfort need not be treated. For debilitating myoclonus, potentially useful treatments include benzodiazepines, levetiracetam, zonisamide, and piracetam [123].

One report described two sisters with CLN3 disease who developed dystonic storm (ie, status dystonicus, a life-threatening condition characterized by acute worsening of dystonia and complicated by bulbar weakness, progressive impairment of respiratory function, and metabolic derangements including rhabdomyolysis and acute kidney injury); abnormal movements improved after one sister was treated with bilateral pallidotomy and the other with bilateral pallidotomy followed by deep brain stimulation [125]. (See "Hyperkinetic movement disorders in children", section on 'Status dystonicus'.)

•Mood and behavior disorders – Caution should be used when considering dopamine D2 receptor antagonists for treatment of mood and behavior in CLN3 disease due to risk for inducing or worsening the parkinsonism associated with the disease. Quetiapine may be a better choice due to low D2 receptor affinity.

•Cognitive regression – There are no direct pharmacologic strategies for management of cognitive regression, though therapeutic supports for management of mood and behavior can be essential.

•Cardiac disorders – As supportive care improves and life expectancy lengthens in NCLs, a cardiac phenotype in these disorders is increasingly recognized. Providers should be aware of cardiac conduction abnormalities observed with increasing age in CLN1, CLN2, and CLN3 diseases [63,126,127] and cases of cardiomyopathy [126,128]. In the author's clinical experience, some practitioners and families opt for pacemaker placement when symptomatic cardiac arrhythmias reduce the quality of life.

A number of agents have shown no definite evidence of therapeutic benefit in patients with NCL, including cysteamine and N-acetylcysteine (CLN1 disease) [129], mycophenolate mofetil (CLN3 disease) [130], flupirtine (CLN3 disease) [131], melatonin (CLN3 disease) [132], antioxidants (CLN3 disease) [133], antiparkinsonian medications (CLN3 disease) [134], central nervous system stem cell transplantation (CLN1 and CLN2 disease) [135], and intermittent prednisolone (CLN3 disease) [136].

●Nonpharmacologic interventions – Nonpharmacologic interventions for patients with NCL are a critical aspect of disease management, including prevention of complications. These interventions may include physical, occupational, vision, and speech therapies; use of adaptive devices; nutritional supports; diet modification; good sleep hygiene; family and caregiver support; and palliative care integration starting early in the disease course [103,137].

Disease-modifying therapy for CLN2 — For patients with symptomatic CLN2 disease who are age 3 years and older, we recommend treatment with recombinant human cerliponase alfa [138]. This drug is a proenzyme form of human TPP1, which is deficient in patients with CLN2 disease. It administered into the cerebrospinal fluid via the lateral ventricles. It represents the first disease-modifying therapy for any NCL.

●Indication – Recombinant human cerliponase alfa was approved to slow the loss of ambulation in children age 3 years and older with symptomatic CLN2 disease [139].

●Efficacy – The efficacy of recombinant human cerliponase alfa was established in an open-label study of 23 children ages 3 to 16 years with CLN2 disease who were treated with intraventricular infusion of cerliponase alfa for at least 96 weeks and a historical control group of 42 patients with CLN2 disease [140]. Outcome was measured using the motor and language domains of the Hamburg CLN2 Clinical Rating Scale, where 0 represents no function and 3 represents normal function in each of the two domains, and aggregate scores range from 0 to 6.

Compared with historical controls, treated patients were less likely to decline in motor and language function, as measured by the median time until a 2-point decline in the combined motor-language score, a lower risk of an unreversed two-point decline in the combined motor-language score (hazard ratio 0.08; 95% CI 0.02-0.23), and a lower unadjusted mean rate of decline per 48-week period in the combined motor-language score (-0.27 for treated patients, compared with -2.12 for controls) [140]. An extension study with more than five years of follow-up found that treated patients continued to have slower decline of motor and language function compared with historical controls, with a lower risk of an unreversed 2-point decline or a score of 0 in the combined motor-language score (hazard ratio 0.14; 95% CI 0.06-0.33) [141].

●Dosing – Pretreatment with antihistamines with or without antipyretics or glucocorticoids is given 30 to 60 minutes prior to start of the infusion [142]. Cerliponase alfa 300 mg (10 mL) is given once every other week (followed by intraventricular electrolytes 2 mL, included in the administration kit) and infused at a rate of 2.5 mL per hour via a surgically implanted intracranial ventricular reservoir and infusion device. The first dose may be given five to seven days after device implantation. Aseptic technique must be strictly followed during preparation and administration [143]. Treatment should be managed by clinicians with expertise in intraventricular administration [144]. Since there is a risk of anaphylaxis, the drug should be given in a setting with appropriate facilities and medical support.

●Adverse effects – The most common adverse clinical effects with cerliponase alfa are pyrexia, electrocardiogram (ECG) abnormalities, vomiting, seizures, hypersensitivity, hematoma, headache, irritability, device-related infections, bradycardia, jittery feeling, and hypotension [141-143].

●Other – Replacement of the intraventricular access device is recommended prior to four years of use [142]. In longitudinal studies, breakdown of implanted intracranial ventricular reservoirs has been observed after 105 perforations, the number that would accrue over approximately four years of cerliponase alfa administration.

SUMMARY AND RECOMMENDATIONS

●The neuronal ceroid lipofuscinoses (NCL) are a group of lysosomal diseases characterized by progressive neurodegeneration.

●The NCLs were originally grouped into four classic forms:

•Infantile NCL (Haltia-Santavuori disease)

•Late infantile NCL (Janský-Bielschowsky disease)

•Juvenile NCL (Batten-Spielmeyer-Vogt disease, or simply Batten disease)

•Adult NCL (Kufs disease)

Over time, investigators have described additional forms of NCL with clinical features similar to those of the classic forms. NCL experts now recommend primary disease classification by gene or protein (eg, CLN1 disease or PPT1 deficiency) and secondary classification by age at onset and clinical features. (See 'Terminology and classification' above.)

●Abnormal intracellular storage materials accumulate in all NCL disorders, comprised of a mixture of lipids and proteins, morphologically characterized as ceroid lipofuscin. (See 'Pathophysiology' above.)

●At least 13 different genetic forms of NCL have been identified. Collectively, NCLs are the most prevalent neurodegenerative disorders of childhood [11]. However, the individual NCLs are rare conditions. (See 'Genetics' above and 'Epidemiology' above.)

●Though unified by common features of vision loss, dementia, movement disorders, and epilepsy, the neuronal ceroid lipofuscinoses (NCLs) represent a group of distinct conditions manifesting genetic heterogeneity and phenotypic pleiotropy. (See 'Clinical manifestations' above.)

●When infants or children present with global developmental delay or developmental regression, we suggest early brain imaging, especially in the setting of seizures, abnormal neurologic examination findings, and/or macrocephaly or microcephaly. Genetic testing is the primary path to diagnosis of NCL for most individuals. A broad-based approach is often needed and may include NCL gene panels, epilepsy gene panels, lysosomal disease gene panels, or whole exome sequencing. Enzymatic testing (for CLN1 or CLN2 disease) and/or skin biopsy to evaluate for lysosomal inclusions may serve as confirmatory strategies in the setting of inconclusive genetic testing, or when genetic testing is unavailable. (See 'Evaluation and diagnosis' above.)

●The approach to management is supportive for most NCLs. (See 'Supportive care' above.)

●For patients with CLN2 disease who are age 3 years and older, we recommend treatment with recombinant human cerliponase alfa (Grade 1B). (See 'Disease-modifying therapy for CLN2' above.)