Managing CLN2 disease: a treatable neurodegenerative condition among other treatable early childhood epilepsies

Figures & data

Table 1. Symptoms and diagnostic features of childhood epilepsy syndromes with pharmacological or dietary treatments

Disorder/group of disorders	Neurological symptoms	Diagnostic features	Treatment
PDE [14–17]	Seizures, dystonia, increased startle response, irritability, intellectual disability and developmental delay	Electroencephalography (EEG) Diffuse slowing Generalized bursts of polyspike slow waves Focal or generalized sharp waves Hypsarrhythmia Focal or multifocal discharges Magnetic resonance imaging (MRI) Hemispheric hypoplasia or atrophy Cerebellar or cortical dysplasia Intracerebral hemorrhage Periventricular hyperintensity Urinary, plasma and cerebrospinal fluid (CSF) metabolite, amino acid, and neurotransmitter level abnormalities	Acute intravenous pyridoxine, followed by long-term oral or enteral pyridoxine A lysine-restricted diet may be an addition to pyridoxine therapy to improve seizure control and psychomotor development Some patients may have seizures that respond to folinic acid
Cerebral folate deficiency [14,18–22]	Seizures, psychomotor regression, and behavioral symptoms	MRI Demyelination defects and cerebellar atrophy Low levels of methyltetrahydrofolate in CSF	Oral and/or intrathecal folinic acid, which is most effective if started in early childhood
Cerebral creatine deficiency syndromes [14,23] L-Arginine:glycine amidinotransferase (AGAT) deficiency Guanidinoacetate methyltransferase (GAMT) deficiency Creatine transporter 1 (CT1) deficiency (X-linked)	Seizures, developmental delay movement disorders, language deficits, and behavioral symptoms	MRI Globus pallidus involvement (GAMT deficiency) Magnetic resonance spectroscopy Absence of brain creatine peak	Dietary supplements for seizures and movement disorders in AGAT deficiency (oral creatine) and GAMT deficiency (oral creatine, arginine, and ornithine) Antiepileptic drugs (AEDs) for seizures in CT1 deficiency
GLUT1 deficiency [14,24–27]	Seizures (absence before 4 years of age; myoclonic and other types; developmental delay; movement disorders; language deficits; cognitive deficits; and microcephaly)	Low levels of glucose in CSF and normal levels of lactate in CSF	Ketogenic diet for seizures, movement disorders, and cognitive deficits, which is most effective if initiated early in the disease

GLUT1, glucose transporter 1; PDE, pyridoxine-dependent epilepsy.

Table 2. Common misdiagnoses associated with the nonspecific symptoms of CLN2 disease

Symptoms Disorder(s)	Epilepsy	Language deficits	Motor impairment	Visual impairment	Developmental delay	Behavioral issues	Intellectual disabilities, cognitive deficits, or dementia	Brain abnormalities on MRI
Cerebral palsy [40]	✓	✓	✓	✓	✓	✓	✓	✓
Other NCLs [2,32,33]	✓ Age of onset varies by subtype	✓	✓ Tremor, falls, hypotonia	✓	✓ Regression	-	✓ Regression	✓ Cerebral or cerebellar atrophy
Dravet syndrome [41–43]	✓ Occurs from infancy Common initial status epilepticus	✓	Ataxia, hypotonia	✓	✓	✓ Autism, attention deficit hyperactivity disorder, aggression, irritability	✓	-
GLUT1 deficiency [14,24]	✓ Occurs from infancy	✓	✓ Hypotonia, spasticity, dystonia, ataxia, movement disorders	-	✓	-	✓	-
Myoclonic astatic epilepsy (MAE or Doose syndrome) [44,45]	✓ Occurs from early childhood or infancy	-	-	-	-	-	✓	-
Chromosomal abnormalities [46–51]	✓	✓	✓	-	✓	✓	✓	-
Mitochondrial disorders [52,53]	✓	✓	✓	✓	✓	✓	✓	✓
Angelman syndrome [54,55]	✓	✓	✓	-	✓	✓	✓	-
Autism spectrum disorder [56,57]	✓	✓	-	-	-	✓	✓	-
Other inherited metabolic disorders with accumulated cellular material^a [58–62]	✓	✓	✓	✓	✓ Regression	✓	✓ Regression	✓ Periventricular abnormalities, hyperintensities, demyelination

^aIncluding leukodystrophies, lipid storage disorders, mucopolysaccharidoses, and peroxisomal disorders. GLUT1, glucose transporter 1; MRI, magnetic resonance imaging; NCL, neuronal ceroid lipofuscinosis.

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