title: Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency.
abstract: OBJECTIVE
  Experimental treatment with substrate replacement was successfully performed in single cases with molybdenum cofactor deficiency type A. The objective of this study was to quantitate the yet undefined natural history in untreated patients to ultimately benefit knowledge in experimental treatments in the future.
  
  
  METHODS
  Systematic analysis of published cases with molybdenum cofactor deficiency. The main outcome measures were survival, initial cardinal disease features at onset, and diagnostic delay.
  
  
  RESULTS
  The median survival for the overall population was 36 months. Initial cardinal disease features at onset were seizures (72%) as well as feeding difficulties (26%) and hypotonia (11%). In addition, developmental delay (9%), hemiplegia (2%), lens dislocation (2%), and hyperreflexia (1%) were reported. The median age at onset of the disease was the first day of life; the median age at diagnosis was 4.5 months. The median time to diagnosis (diagnostic delay) was 89 days.
  
  
  CONCLUSIONS
  Molybdenum cofactor deficiency has its onset during the neonatal period and infancy. There is considerable diagnostic delay. Although seizures were the most frequent initial cardinal sign, molybdenum cofactor deficiency should be considered as a differential diagnosis in patients presenting with hypotonia, developmental delay, or feeding difficulties. The survival data will inform further natural-history and therapeutic studies.
authors.affiliation: Pediatric Psychopharmacology, Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Konstantin
authors.identifier: http://orcid.org/0000-0002-5322-7140
authors.initials: K
authors.lastname: Mechler
authors.affiliation: Department of Clinical Research, School of Nursing, College of Health and Human Services, University of North Carolina at Wilmington, Wilmington, North Carolina, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Mountford
authors.affiliation: Pediatric Neurology and Center for Rare Disorders, Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: Pediatric Neurology and Center for Rare Disorders, Center for Pediatric and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Markus
authors.identifier: http://orcid.org/0000-0002-5054-5741
authors.initials: M
authors.lastname: Ries
mesh_terms: D002658:Developmental Disabilities / Q000503:physiopathology; D006429:Hemiplegia / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007906:Lens Subluxation / Q000503:physiopathology; D008664:Metal Metabolism, Inborn Errors / Q000175:diagnosis / Q000503:physiopathology; D009123:Muscle Hypotonia / Q000503:physiopathology; D035583:Rare Diseases / Q000175:diagnosis / Q000503:physiopathology; D012021:Reflex, Abnormal; D012640:Seizures / Q000503:physiopathology