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Spinocerebellar ataxia recessive type 7 due to novel compound heterozygous variants in TPP1: First report from India

      Highlights

      • This report highlights the rare and atypical phenotype spinocerebellar ataxia autosomal recessive type 7 of TPP1 deficiency.
      • This is the first case of SCAR7 belonging to Indian ethnicity with novel compound heterozygous variants in TPP1 gene.
      • SCAR7 should be considered in patients with childhood onset spastic ataxic syndrome of relatively slow progression.

      Keywords

      Spinocerebellar ataxia, autosomal-recessive-7 (SCAR7) is an atypical and rare phenotype of deficiency of tripeptidyl peptidase-I (TPP1) enzyme, a lysosomal exopeptidase that sequentially removes tripeptides from the N-terminus of proteins. SCAR7 is characterized by a childhood to adolescent onset ataxia, with or without pyramidal signs, posterior column involvement, tremor, and nystagmus, with pontocerebellar atrophy on imaging [
      • Gardner E.
      • Bailey M.
      • Schulz A.
      • Aristorena M.
      • Miller N.
      • Mole S.E.
      Mutation update: review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease.
      ]. This report describes a first case of SCAR7 from India with a novel frameshift truncating variant (p.Phe397SerfsTer30) in compound heterozygous state with a missense variant (p.Pro479Ala) in TPP1 gene.

      1. Case report

      A 17-year-old girl, presented with tremulousness in bilateral upper-limbs of one year duration, followed by progressive imbalance while walking for 10months and slurring of speech for 6months. Tremulousness was more during reaching towards an object and with fine activity, intermittent in a posture and absent at rest. There was no history suggestive of cognitive impairment, seizures, cranial nerve deficits, weakness, sensory abnormality or other system involvement. She was born of consanguineous parentage (Fig. 1A) , with normal perinatal and developmental history. The video was taken after written informed consent for online publication and dissemination.
      Fig. 1
      Fig. 1A-Pedigree of the patient. B-MRI brain of the patient showing diffuse cerebellar atrophy. C- Sanger sequencing chromatogram of the patient and the mother showing variants TPP1:c.1190delT (orange arrow) and TPP1:c.1435C>G (blue arrow) in compound heterozygous state in the patient and variant TPP1:c.1190delT (orange arrow) in heterozygous carrier state with wild type at TPP1:c.1435C (green arrow) in the mother. AAO- age at onset, wt-wild-type. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
      On examination, she had cognitive impairment (MMSE-20/30), normal visual acuity and fundus, normal range of eye movements, saccadic dysmetria, broken pursuit, gaze-evoked horizontal nystagmus and mild cerebellar dysarthria (Video-e1, segment-1,2). Cerebellar signs were present in the form of intention tremor of bilateral upper-limbs, impaired finger-nose and heel-shin test, dysdiadokokinesia (video-e1, segment-3) and spastic ataxic gait with impaired tandem (Video-e1, segment-4) (Scale for the assessment and rating of ataxia-12/40). In addition, spasticity and brisk reflexes were noted in bilateral lower-limbs, with normal power and plantar response. Rest of the examination was normal.
      Routine blood workup for acquired ataxia and nerve conduction study was normal. Latencies of bilateral visual and lower limb somatosensory evoked potentials were prolonged. MRI of the brain revealed diffuse cerebellar atrophy (Fig. 1B). Exome sequencing was performed and annotated variants were filtered based on genotype quality score, zygosity and read depth. Frequency filters and ACMG classifiers were used to narrow down to potentially significant variants. Hereditary ataxia panel [containing 420 genes] was utilized to further narrow down to the most probable disease-causing variants. This yielded two compound-heterozygous variants in TPP1 gene. A novel single base-pair deletion variant (Variant-1, chr11:g.6636749delA;c.1190delT;p.Phe397SerfsTer30;NM_000391.4) in exon-10 and a missense variant (Variant-2, chr11:g.6636213G>C;c.1435C>G;p.Pro479Ala;NM_000391.4) in exon-12. The variant-1 has not been previously reported in gnomAD database whereas variant-2 observed in 3 individuals of South-Asian descent (population allele frequency-0.00009799) in heterozygous state according to the gnomAD database and has been previously reported in ClinVar database as a variant of unknown significance. Variant-1 results in frameshift with premature truncation of protein. Variant-2 results in amino-acid substitution at position 479 with a CADD score of 25.8. This variant falls in the serine-rich region of catalytic domain peptidase-S53 and is close to the catalytic active site p.Ser475 that forms the catalytic triad Ser475-Glu272-Asp360. The native amino-acid proline at p.479 is highly conserved across species and multiple in-silico computational analysis of the variant predicts it to be disease causing. However, there is a small physiochemical difference between proline and alanine. The variants were confirmed by Sanger sequencing (Fig. 1C). Variant-1 was found in heterozygous carrier state in the patient's mother while Variant-2 was absent (Fig. 1C). Father's sample was not available for sequencing. The variants were deduced to be in compound-heterozygous trans state. The variants were classified as pathogenic (Variant-1:PVS1,PM2,PP3) and likely pathogenic (Variant-2:PM1,2,3,PP2,3) according to the ACMG guidelines. The patient was diagnosed as SCAR7, antispastic medication was adjusted along with neurorehabilitation and genetic counselling of the family.

      2. Discussion

      Extremely low or absent TPP1 enzyme activity results in a classical late-infantile neuronal ceroid lipofuscinosis (CLN2) disease characterized by the onset of neurodevelopmental regression at 2–4 years of age, with onset of seizures, cognitive impairment, language difficulties, visual loss, spasticity, ataxia, and eventually death by the second decade [
      • Dy M.E.
      • Sims K.B.
      • Friedman J.
      TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.
      ]. A minority of patients, with a higher residual TPP1 activity, can have atypical presentation with later onset, and a protracted course (juvenile CLN2). Rarely, patients with TPP1 deficiency can present without seizures and variable phenotype.
      Breedveld et al., in 2004, reported a non-consanguineous Dutch family with a childhood-onset, slowly progressive, autosomal-recessive spinocerebellar ataxia (later referred to as SCAR7), with pyramidal signs, posterior column involvement, and postural tremor. Neuroimaging showed atrophy of cerebellum, vermis, pons and medulla and based on the genome-wide linkage study the responsible gene was mapped to chromosome band 11p15 [
      • Breedveld G.
      • Van Wetten B.
      • te Raa G.
      • Brusse E.
      • van Swieten J.
      • Oostra B.
      • et al.
      A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15.
      ]. In 2013, TPP1 was identified as the causative gene in this family and in an unrelated patient with SCAR7 phenotype [
      • Sun Y.
      • Almomani R.
      • Breedveld G.J.
      • Santen G.W.
      • Aten E.
      • Lefeber D.J.
      • et al.
      Autosomal recessive spinocerebellar ataxia 7 (SCAR 7) is caused by variants in TPP1, the gene involved in classic late‐infantile neuronal ceroid lipofuscinosis 2 disease (CLN 2 disease).
      ]. Further, TPP1 genetic abnormality was identified in a patient with childhood onset progressive ataxia, neurocognitive impairment without pyramidal signs [
      • Dy M.E.
      • Sims K.B.
      • Friedman J.
      TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.
      ]; in a patient with complex hereditary spastic paraplegia who had past history of seizure with progressive spastic paraplegia, bulbar palsy, dystonic neck posturing and severe cognitive problems [
      • Kara E.
      • Tucci A.
      • Manzoni C.
      • Lynch D.S.
      • Elpidorou M.
      • Bettencourt C.
      • et al.
      Genetic and phenotypic characterization of complex hereditary spastic paraplegia.
      ] and in a family with childhood onset autosomal-recessive dystonia-parkinsonism, cognitive impairment, ataxia, pyramidal signs without seizures [
      • Di Giacopo R.
      • Cianetti L.
      • Caputo V.
      • La Torraca I.
      • Piemonte F.
      • Ciolfi A.
      • et al.
      Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: clinical, molecular and biochemical characterization in three sibs.
      ]. The phenotype observed in the current report was more akin to SCAR7.
      The heterogenous phenotypic spectrum observed with TPP1 deficiency can be partly explained by the TPP1 activity and on the combination of TPP1 variants [
      • Dy M.E.
      • Sims K.B.
      • Friedman J.
      TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.
      ,
      • Sun Y.
      • Almomani R.
      • Breedveld G.J.
      • Santen G.W.
      • Aten E.
      • Lefeber D.J.
      • et al.
      Autosomal recessive spinocerebellar ataxia 7 (SCAR 7) is caused by variants in TPP1, the gene involved in classic late‐infantile neuronal ceroid lipofuscinosis 2 disease (CLN 2 disease).
      ]. Absent or extremely low TPP1 activity often result in severe classical CLN2 while a higher residual TPP1 activity result in later onset juvenile CLN2 with protracted course. The residual enzyme activity is higher in patients with SCAR7, dystonia-parkinsonism and spastic-ataxic phenotypes [
      • Dy M.E.
      • Sims K.B.
      • Friedman J.
      TPP1 deficiency: rare cause of isolated childhood-onset progressive ataxia.
      ]. In addition, biallelic variants in TPP1 gene are often null/null in classical CLN2, whereas the variants are often less severe in juvenile CLN2 and other atypical phenotypes [
      • Sun Y.
      • Almomani R.
      • Breedveld G.J.
      • Santen G.W.
      • Aten E.
      • Lefeber D.J.
      • et al.
      Autosomal recessive spinocerebellar ataxia 7 (SCAR 7) is caused by variants in TPP1, the gene involved in classic late‐infantile neuronal ceroid lipofuscinosis 2 disease (CLN 2 disease).
      ]. Early diagnosis of TPP1 deficiency is important as disease-specific therapy by enzyme replacement is approved and available for CLN2 in United states of America and Europe. Cerliponase-alfa is a recombinant-human TPP1 given biweekly as intraventricular infusion via a reservoir. Significant reduction in decline of both motor and language function was observed in patients with CLN2. However, it is yet to be approved for SCAR7 phenotype amd is still not available in India [
      • Schulz A.
      • Ajayi T.
      • Specchio N.
      • de Los Reyes E.
      • Gissen P.
      • Ballon D.
      • et al.
      Study of intraventricular cerliponase alfa for CLN2 disease.
      ].
      In conclusion, this report highlights the first case of SCAR7 from India with novel compound heterozygous variants in TPP1 gene. SCAR7 should be considered in patients with childhood onset spastic ataxic syndrome of relatively slow progression.

      Author roles

      Vikram V Holla contributed in acquisition and interpretation of the data and in writing the first draft of the manuscript. Prashant Phulpagar performed experiments associated with validation of the variants and in review and critique of the manuscript. Shreyasi Jha contributed in acquisition of the data and review and critique of the manuscript. Gautham Arunachal performed exome sequencing analysis and contributed in review and critique of the manuscript. Pramod Kumar Pal, Babylakshmi Muthusamy, and Ravi Yadav contributed in acquisition and interpretation of the data and in review and critique of the manuscript.

      Statement regarding the journal's ethical publication guidelines

      We confirm that we have read the journal's position on issues involved in the ethical publication and affirm that this work is consistent with those guidelines. We also confirm that the patient has given written informed consent for the publication of the videos.

      Source of funding

      This work was partly supported by a research grant provided by Department of Biotechnology (DBT), Government of India ( BT/PR26428/MED/12/783/2017 ).

      Financial disclosure and conflict of interest

      VVH, PP, SJ, GA, PKP, BM, and RY have no financial disclosures or any conflicts of interest to report relevant to this article.

      Declaration of competing interest

      The authors report no financial interests or conflict of interests.

      Acknowledgement

      None.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:
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