title: Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: "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.
authors.forename: Dana
authors.initials: D
authors.lastname: Craiu
authors.affiliation: Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania. Electronic address: octaviadragostin@yahoo.com.
authors.forename: Octavia
authors.initials: O
authors.lastname: Dragostin
authors.affiliation: Pediatric Neurology Clinic, Research Department, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania. Electronic address: dica_denisa@yahoo.com.
authors.forename: Alice
authors.initials: A
authors.lastname: Dica
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland. Electronic address: dhoffman@wp.pl.
authors.forename: Dorota
authors.initials: D
authors.lastname: Hoffman-Zacharska
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland. Electronic address: monika.gos@imid.med.pl.
authors.forename: Monika
authors.initials: M
authors.lastname: Gos
authors.affiliation: "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.
authors.forename: Alexandra Eugenia
authors.initials: AE
authors.lastname: Bastian
authors.affiliation: Ultrastructural Pathology Lab., 'Victor Babes' National Institute of Pathology, 99-101 Spl. Independentei, 050096 Bucharest 5, Romania. Electronic address: mgherghiceanu@yahoo.com.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gherghiceanu
authors.affiliation: 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.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: Centogene AG, Schillingallee 69, 18057 Rostock, Germany. Electronic address: Nahid.Nahavandi@centogene.com.
authors.forename: Nahid
authors.initials: N
authors.lastname: Nahavandi
authors.affiliation: "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.
authors.forename: Mihai
authors.initials: M
authors.lastname: Craiu
authors.affiliation: "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.
authors.forename: Catrinel
authors.initials: C
authors.lastname: Iliescu
mesh_terms: D017668:Age of Onset; D001259:Ataxia / Q000209:etiology; D001766:Blindness / Q000209:etiology; D002648:Child; D002658:Developmental Disabilities / Q000209:etiology; D018450:Disease Progression; D004569:Electroencephalography; D005260:Female; D006579:Heterozygote; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000503:physiopathology*; D010290:Parents; D015518:Rett Syndrome / Q000503:physiopathology*; D012640:Seizures / Q000209:etiology
chemical_list: C522398:MFSD8 protein, human; D026901:Membrane Transport Proteins
keywords: Ataxia; Blindness; CLN7; Compound heterozygous; IRDA; MFSD8; Rett like onset