The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive hereditary disorders with progressive neuron degeneration. Traditionally, NCLs were classified into infantile NCL, classical late infantile NCL (LINCL), juvenile NCL, adult NCL, and several variant forms [1, 2]. Recent studies have advanced the classification of human NCLs into at least ten genetic forms (CLN1–CLN10), among which eight genes have been identified (CLN1–3, CLN5–8, CLN10; CLN4 and CLN9 to be defined). Mutations in two more genes, CLCN6 and SGSH, have also been identified in unusual NCL cases (http://www.ucl.ac.uk/ncl). CLN2 gene encodes tripeptidyl peptidase 1 (TPP1) [3]. Deficiency of TPP1 leads to the accumulation of autofluorescent lipopigments consisting of the subunit c of mitochondrial ATP synthase in lysosome, which results in typically clinical and pathomorphological features of LINCL [4]. Mutations in CLN2/TPP1, which are always homozygote or compound heterozygote, cause the majority cases of classical LINCL [1, 5]. Up to now, 72 mutations in CLN2/TPP1 have been found. Here, we report a novel splice site mutation in CLN2/TPP1 from a Chinese LINCL patient, which constitutes a compound heterozygous mutation in CLN2/TPP1 with another missense mutation.

The patient and her parents were examined at the present hospital. Exons and exon/intron boundaries of the CLN2/TPP1 (NM_000391.3) were PCR-amplified and sequenced.

Pedigree of the family is shown in Fig. 1a. The proband showed myoclonic seizures at 3.5 years as an initial symptom, which progressively aggravated and became intractable, with tonic–clonic seizures later. Progressive cognitive and neuromotor dysfunction, including prominent speech regression and ataxia, appeared gradually afterwards. Vision problems occurred recently (6 years). The video EEG revealed irregular and slow background activity with intermittent bursts of generalized, or occipital-dominant, spike-waves or poolyspike-waves. Synchronous myoclonic seizures occurred with the bursts of discharge on EEG. MRI demonstrated generalized encephalatrophy, remarkably in the cerebellum. Pathological examination of the biopsy tissue from right frontal lobe showed a typical pathological change of LINCL (Figs. 1b–e). The TPP1 activity measurement was not available. Based on the clinical and pathological findings, the patient was diagnosed as having LINCL.

Fig. 1
figure 1

Pedigree, pathological features, and mutation analysis of the family. a The pedigree of the family. II:2 is the proband. Her sibling showed similar symptoms and evolution from 2 years old, and died at 14 years (II:1). Her parents were asymptomatic. Written informed consent has been obtained from the family. b Degenerative and atrophic neurons in the cortex (light microscope, ×400). c Immature neurons mixed with other abnormal neurons in the cortex (light microscope, ×400). d Brown-black granules (white arrows) in neuron plasma shown by sliver staining (light microscope, ×400). e Numerous lipofuscinic pigments with curvilinear-like bodies in neurons (electron microscope, ×20,000). f Sequencing of CLN2/TPP1. Arrows indicate the heterozygous mutant nucleotides. Heterozygous mutations g.646G >A and c.1551 + 1G >A were detected in the mother and father, respectively, and both mutations appeared in the proband

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DNA sequencing identified a novel compound heterozygous mutation consisting of c.646G >A (p.Val216Met) and c.1551 + 1(IVS12 + 1)G >A in CLN2/TPP1 in the patient; heterozygous c.646G >A and c.1551 + 1G >A in her asymptomatic mother and father, respectively (Fig. 1f). Missense mutation c.646G >A has been identified in a patient with LINCL (http://www.ucl.ac.uk/ncl) previously; whereas splice site mutation c.1551 + 1G >A is a novel finding, which changed the invariant splice junction residue.

Previous studies have shown that splice site mutations in CLN2/TPP1 are common causes of LINCL [5]. It has been reported that patients with CLN2/TPP1 mutations have relatively homogenous clinical pictures, although missense mutations p.Arg447His, p.Ser153Pro, and p.Arg127Gln were shown to be associated with later onset age and more protracted courses [5, 6]. The present patient has the classic clinical and pathological features of LINCL, suggesting that mutation c.1551 + 1G >A may be similar in causative of LINCL as most of the CLN2/TPP1 mutations reported before. Although NCL cases were occasionally reported in China, there is no report showing its incidence or gene mutations. Further studies are required to know the frequency of c.1551 + 1G >A in Chinese LINCL patients.