Objective: We report a case of a Cortical Basal Syndrome (CBS) due to heterozygous Granulin (GRN) mutation who develops a lysosomal storage pathology characterized by autofluorescent ceroid-lipofuscine-like muscle deposits.

Background: Pathogenic mutations in GRN mostly create null alleles resulting in haploinsufficiency of the protein and being a frequent cause of autosomal-dominant forms of Frontotemporal degeneration with TDP-43-immunoreactive inclusions (FTLD-TDP43) as well as the most common genetic cause of CBS phenotype. Total deficiency of secreted PRGN induces lysosomal dysfunction leading to the neuronal ceroid lipofuscinoisis (NCL type IV).

Methods: A 48-year-old man with a progressive asymmetrical parkinsonism unresponsive to levodopa, ptosis and hearing loss underwent neuropsychological evaluation, Cerebral magnetic resonance imaging (MRI), Cerebral SPECT with 99m Tc-HMPAO, CSF and genetic analysis and, in the suspicion of a mitochondrial syndrome, a muscle biopsy.

Results: Clinical and instrumental data confirmed a FTDL syndrome characterized by atypical parkinsonism CBD-like due to a heterozygous GRN mutation (GRN met1 – g.2T> C, rs63751006). Cerebrospinal and plasmatic levels of PGRN confirmed halved levels compared to healthy controls. Muscle biopsy disclosed slight myopathic changes with few vacuoles, autofluorescent cytoplasmic granules and increased acid phosphatase activity; electron microscopy showed lipofuscine and ceroid-lipofuscine-like deposits.

Conclusions: PGRN deficiency can uniquely produce, due to the residual protein activity, adult onset NCL and FTDL. Indeed, previous studies on GRN mutations have suggested a phenotypic overlap between FTD and lysosomal storage disorders. Moreover, pathological marker proteins characteristic for NCL/lysosomal impairment were found in brains of FTLD-TDP-43/GRN patients. We report that, in FTDL due to a heterozygous GRN mutation, a muscle accumulation of abnormal ceroid lipofuscine like deposits resembling the neuronal inclusions typical of NCL was documented. Thus, our findings support the hypothesis that lysosomal storage disorders and GRN-associated FTLD share common features.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/muscle-ceroid-lipofuscine-like-deposits-in-a-patient-with-ftd-due-to-a-progranulin-mutation/