Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy.
BACKGROUND
The cblC defect is a rare inborn error of intracellular cobalamin metabolism. Biochemical hallmarks are elevated homocysteine and low methionine in plasma accompanied by methylmalonic aciduria. Due to the heterogeneous clinical picture, patients with the late-onset form of the disease (onset >12 months) come to the attention of diverse medical specialists, e.g. paediatricians, neurologists, nephrologists, psychiatrists or haematologists. The report reviews the published clinical data and adds three new cases to raise awareness for this severe but often treatable disease.


METHODS
The Pubmed and the Cochrane databases were searched for clinical reports on cblC patients and three unreported cases are presented to illustrate the clinical spectrum.


RESULTS
Reports on 58 cases (30 females, 22 males, 6 = no information) and the three new cases underlined the clinical heterogeneity of the disease. Time between first symptoms and diagnosis ranged from three months to more than 20 years. Haemolytic uraemic syndrome and pulmonary hypertension were main presenting symptoms in preschool children. In older children/adolescents, psychiatric symptoms, cognitive impairment, ataxia and myelopathy were frequently observed while thromboembolic events and glomerulopathies were almost exclusively seen in adults. Brain atrophy, white matter lesions and myelopathy were frequently encountered. The majority of patients showed marked biochemical and clinical response to treatment with parenteral hydroxocobalamin combined with oral betaine, folate, carnitine and rarely methionine. The course was less favourable in late treated or untreated patients.


CONCLUSIONS
The late-onset cblC defect is a rare disease and unfortunately, diagnosis is often delayed. Raising awareness for this disorder can significantly improve patients' outcome and perspective by timely initiation of targeted treatment. Newborn screening (NBS) for the cblC defect might be of benefit especially for late-onset patients since treatment seems efficient when initiated before irreversible organ damage. In general, inborn errors of metabolisms should be considered in unexplained medical cases at any age, especially in patients with multisystemic disease. More specifically, total homocysteine in plasma and methylmalonic acid in urine/plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.
Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. martina.huemer@kispi.uzh.ch.|Radiz - Rare Disease Initiative Zürich, University Zürich, Zürich, Switzerland. martina.huemer@kispi.uzh.ch.|Department of Pediatrics, LKH Bregenz, Bregenz, Austria. martina.huemer@kispi.uzh.ch.
Martina
M
Huemer
Clinic for Pediatrics I; Inherited Metabolic Disorders, Innsbruck Medical University, Innsbruck, Austria. sabine.scholl-buergi@uki.at.
Sabine
S
Scholl-Bürgi
Divisions of Nephrology and Transplantation, Geneva University Hospitals, Geneva, Switzerland. Karine.Hadaya@hcuge.ch.
Karine
K
Hadaya
Pediatric Nephrology & Metabolism, Children's Hospital, University of Geneva, Geneva, Switzerland. ilse.kern@hcuge.ch.
Ilse
I
Kern
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. Ronny.Beer@i-med.ac.at.
Ronny
R
Beer
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. Klaus.Seppi@i-med.ac.at.
Klaus
K
Seppi
Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. Brian.fowler@kispi.uzh.ch.
Brian
B
Fowler
Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. Matthias.baumgartner@kispi.uzh.ch.|Radiz - Rare Disease Initiative Zürich, University Zürich, Zürich, Switzerland. Matthias.baumgartner@kispi.uzh.ch.
Matthias R
MR
Baumgartner
Clinic for Pediatrics I; Inherited Metabolic Disorders, Innsbruck Medical University, Innsbruck, Austria. daniela.karall@i-med.ac.at.
Daniela
D
Karall
D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008764:Methylmalonic Acid / Q000097:blood*; D015997:Neonatal Screening; D010088:Oxidoreductases; D055815:Young Adult
D002352:Carrier Proteins; D008764:Methylmalonic Acid; C508359:MMACHC protein, human; D010088:Oxidoreductases