Objective: To describe an atypical late onset phenotypical presentation of a homozygous TPP1 mutation with complex movement disorders.

Background: TPP1 mutations, lead to deficiency of tripeptidyl peptidase 1, and are associated with neuronal ceroid lipofuscinoses type 2 (CLN2). The classic phenotype usually presents around 2-4 years of age, with language delay and epilepsy, followed by rapidly progressive ataxia, cognitive and motor disfunction. Atypical phenotypes, include a juvenile form, that starts around 6-10 years of age, with epilepsy as the first symptom, but with a protracted disease course, and spinocerebellar ataxia recessive type 7 (SCAR7), which has a later onset and mainly ataxic features.

Method: Case Report.

Results: A 38-year-old Brazilian man, started at age of 9 years, with handwriting difficulty (dystonia) and frequent falls. After one year, his gait became clearly unsteady, and he started developing speech problems; symptoms were slowly progressive, and after some years of disease, he developed dysphagia, as well as cognitive complaints. He never had any visual or hearing impairment, however, during his adolescence, he had generalized tonic-clonic seizures related to febrile episodes, due to aspiration pneumonias. Regarding his family history, he had consanguineous parents (first degree cousins), and he was the second child of an offspring of 4, with 2 of his 3 sisters presenting with similar symptoms. His neurological examination disclosed severe dysarthria (cerebellar speech), saccadic pursuit on eye examination, generalized dystonia (constant left laterocollis, associated with truncal dystonia with internal rotation of the right leg and right arm flexion more evident during gait), action myoclonus in the upper limbs, appendicular and axial ataxia, head titubation, and normal tendon reflexes with down going plantar reflex. He had normal laboratorial findings; his brain CT disclosed cerebellar atrophy. His ophthalmological exam was unremarkable. His initial genetic panel for ataxia was negative and his whole exome sequencing disclosed homozygous TPP1 mutation.

Conclusion: TPP1 mutations usually leads to a classical phenotype of CLN2, we report a late onset atypical phenotype of the disease, with the complex movement disorders and a slower progressive course as the main features.

References: 1. Chen ZR, Liu DT, Meng H, Liu L, Bian WJ, Liu XR, Zhu WW, He Y, Wang J, Tang B, Su T, Yi YH. Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation. Seizure. 2019 Jul;69:180-185. doi: 10.1016/j.seizure.2018.08.027. Epub 2018 Sep 2. PMID: 31059981.
2. Sampaio LPB, Manreza MLG, Pessoa A, Gurgel-Giannetti J, Coan AC, Júnior HVL, Embiruçu EK, Henriques-Souza AMM, Kok F. Clinical management and diagnosis of CLN2 disease: consensus of the Brazilian experts group. Arq Neuropsiquiatr. 2023 Mar;81(3):284-295. doi: 10.1055/s-0043-1761434. Epub 2023 Apr 14. PMID: 37059438; PMCID: PMC10104757.
3. Liu RH, Wang XY, Jia YY, Wang XC, Xia M, Nie Q, Guo J, Kong QX. Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7: A case report. World J Clin Cases. 2023 Sep 26;11(27):6618-6623.
4. Sun Y. Almomani R. Breedveld G.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). Hum. Mutat. 2013; 34: 706-713

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MDS Abstracts - https://www.mdsabstracts.org/abstract/complex-movement-disorders-in-late-onset-tpp1-gene-mutation-atypical-neuronal-ceroid-lipofuscinosis-type-2/