Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants
Abstract Background Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late‐infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult‐onset retinal dystrophy. Clas...
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Wiley
2024-08-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.2505 |
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| author | Sigurd Dobloug Ulrika Kjellström Glenn Anderson Emily Gardner Sara E. Mole Jayesh Sheth Andreas Puschmann |
| author_facet | Sigurd Dobloug Ulrika Kjellström Glenn Anderson Emily Gardner Sara E. Mole Jayesh Sheth Andreas Puschmann |
| author_sort | Sigurd Dobloug |
| collection | DOAJ |
| description | Abstract Background Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late‐infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult‐onset retinal dystrophy. Classic late‐infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non‐syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. Methods Here we present longitudinal studies on four adult‐onset patients who were biallelic for four MFSD8 variants. Results Two unrelated patients who presented with adult‐onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. Conclusions Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8‐related disease, adult‐onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy. |
| format | Article |
| id | doaj-art-a5dd1973fd084228a9cd7051f8edf816 |
| institution | OA Journals |
| issn | 2324-9269 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj-art-a5dd1973fd084228a9cd7051f8edf8162025-08-20T01:59:26ZengWileyMolecular Genetics & Genomic Medicine2324-92692024-08-01128n/an/a10.1002/mgg3.2505Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variantsSigurd Dobloug0Ulrika Kjellström1Glenn Anderson2Emily Gardner3Sara E. Mole4Jayesh Sheth5Andreas Puschmann6Department of Neurology Helsingborg General Hospital Helsingborg SwedenLund University, Skåne University Hospital, Ophthalmology Lund SwedenDepartment of Histopathology Great Ormond Street Hospital London UKGreat Ormond Street Institute of Child Health University College London London UKGreat Ormond Street Institute of Child Health University College London London UKFoundation for Research in Genetics and Endocrinology Institute of Human Genetics Ahmedabad IndiaLund University, Skåne University Hospital, Neurology Lund SwedenAbstract Background Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late‐infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult‐onset retinal dystrophy. Classic late‐infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non‐syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. Methods Here we present longitudinal studies on four adult‐onset patients who were biallelic for four MFSD8 variants. Results Two unrelated patients who presented with adult‐onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. Conclusions Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8‐related disease, adult‐onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.https://doi.org/10.1002/mgg3.2505ataxiaCLN7MFSD8NCL7neuronal ceroid lipofuscinosisretinal degeneration |
| spellingShingle | Sigurd Dobloug Ulrika Kjellström Glenn Anderson Emily Gardner Sara E. Mole Jayesh Sheth Andreas Puschmann Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants Molecular Genetics & Genomic Medicine ataxia CLN7 MFSD8 NCL7 neuronal ceroid lipofuscinosis retinal degeneration |
| title | Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants |
| title_full | Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants |
| title_fullStr | Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants |
| title_full_unstemmed | Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants |
| title_short | Maculopathy and adult‐onset ataxia in patients with biallelic MFSD8 variants |
| title_sort | maculopathy and adult onset ataxia in patients with biallelic mfsd8 variants |
| topic | ataxia CLN7 MFSD8 NCL7 neuronal ceroid lipofuscinosis retinal degeneration |
| url | https://doi.org/10.1002/mgg3.2505 |
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