Dana Craiu1, Octavia Dragostin2, Alice Dica3, Dorota Hoffman-Zacharska4, Monika Gos5, Alexandra Eugenia Bastian6, Mihaela Gherghiceanu7, Arndt Rolfs8, Nahid Nahavandi9, Mihai Craiu10, Catrinel Iliescu11. 1. "Carol Davila" University of Medicine Bucharest, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Discipline Pediatric Neurology, Romania; Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania. Electronic address: dcraiu@yahoo.com. 2. Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania. Electronic address: octaviadragostin@yahoo.com. 3. Pediatric Neurology Clinic, Research Department, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania. Electronic address: dica_denisa@yahoo.com. 4. Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland. Electronic address: dhoffman@wp.pl. 5. Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland. Electronic address: monika.gos@imid.med.pl. 6. "Carol Davila" University of Medicine Bucharest, Department II, Dental Medicine, Pathology Discpline, Romania; Pathology Lab., Colentina University Hospital, Sos Stefan cel Mare 19-21, Sector 2, 020125 Bucharest, Romania. Electronic address: aleca.bastian@yahoo.com. 7. Ultrastructural Pathology Lab., 'Victor Babes' National Institute of Pathology, 99-101 Spl. Independentei, 050096 Bucharest 5, Romania. Electronic address: mgherghiceanu@yahoo.com. 8. Albrecht-Kossel-Institute for Neurogenetics, Medical Faculty, University of Rostock, Gehlsheimerstrasse 20, 18157 Rostock, Germany; Centogene AG, Schillingallee 69, 18057 Rostock, Germany. Electronic address: Arndt.Rolfs@centogene.com. 9. Centogene AG, Schillingallee 69, 18057 Rostock, Germany. Electronic address: Nahid.Nahavandi@centogene.com. 10. "Carol Davila" University of Medicine Bucharest, Department of Pediatrics and Medical Genetics, Discipline Pediatrics, Romania; Pediatric II Clinic, "Alfred Rusescu" Clinical Pediatric Hospital, Institute of Mother and Child Health, B-dul Lacul Tei No. 120, Sector 2, Bucharest, Romania. Electronic address: mcraiu@yahoo.com. 11. "Carol Davila" University of Medicine Bucharest, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Discipline Pediatric Neurology, Romania; Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania. Electronic address: iliescu_catrinel@yahoo.com.
Abstract
BACKGROUND: We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION: A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS: MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION: NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.
BACKGROUND: We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION: A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS:MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION: NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.
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