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Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy.

Huemer M, Scholl-Bürgi S, Hadaya K, Kern I, Beer R, Seppi K, Fowler B, Baumgartner MR, Karall D - Orphanet J Rare Dis (2014)

Bottom Line: 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.More specifically, total homocysteine in plasma and methylmalonic acid in urine/plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.

View Article: PubMed Central - PubMed

Affiliation: Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. martina.huemer@kispi.uzh.ch.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Number of patients and age at onset for main clinical symptoms in 39 patients with the late-onset cblC defect. * Each column represents one patient.
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Fig3: Number of patients and age at onset for main clinical symptoms in 39 patients with the late-onset cblC defect. * Each column represents one patient.

Mentions: Information on age at disease onset was available for 39 symptomatic patients (mean 15 years; median 12 years, range 1.3-44 years) [Figure 2]. The frequency of symptoms differs markedly over the lifespan. Age specific patterns of the disease are depicted in Figure 3. HUS (median age at onset 6; mean 7.8, range 1.25-20 yrs) and PAH (median age at onset 3; mean 4, range 1.25-14 yrs) were the most frequent symptoms in very young children. In older children/adolescents psychiatric symptoms (median age at onset 14; mean 21.6, range 10-42 yrs), ataxia/dysarthria (median age at onset 16; mean 20.8, range 4-44 yrs) and cognitive decline (median age at onset 17; mean 19, range 4-34 yrs) were most frequent; while in adults, in addition to cognitive decline and ataxia/dysarthria, thromboembolic events (median age at onset 29; mean 28.5, range 16-44 yrs), neuropathy/myelopathy (median age at onset 23; mean 27.3, range 12-44 yrs) and non-HUS renal disease (glomerulopathies) (median age at onset 39; mean 34.4, range 16-42 yrs) were dominant features.Figure 2


Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy.

Huemer M, Scholl-Bürgi S, Hadaya K, Kern I, Beer R, Seppi K, Fowler B, Baumgartner MR, Karall D - Orphanet J Rare Dis (2014)

Number of patients and age at onset for main clinical symptoms in 39 patients with the late-onset cblC defect. * Each column represents one patient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255922&req=5

Fig3: Number of patients and age at onset for main clinical symptoms in 39 patients with the late-onset cblC defect. * Each column represents one patient.
Mentions: Information on age at disease onset was available for 39 symptomatic patients (mean 15 years; median 12 years, range 1.3-44 years) [Figure 2]. The frequency of symptoms differs markedly over the lifespan. Age specific patterns of the disease are depicted in Figure 3. HUS (median age at onset 6; mean 7.8, range 1.25-20 yrs) and PAH (median age at onset 3; mean 4, range 1.25-14 yrs) were the most frequent symptoms in very young children. In older children/adolescents psychiatric symptoms (median age at onset 14; mean 21.6, range 10-42 yrs), ataxia/dysarthria (median age at onset 16; mean 20.8, range 4-44 yrs) and cognitive decline (median age at onset 17; mean 19, range 4-34 yrs) were most frequent; while in adults, in addition to cognitive decline and ataxia/dysarthria, thromboembolic events (median age at onset 29; mean 28.5, range 16-44 yrs), neuropathy/myelopathy (median age at onset 23; mean 27.3, range 12-44 yrs) and non-HUS renal disease (glomerulopathies) (median age at onset 39; mean 34.4, range 16-42 yrs) were dominant features.Figure 2

Bottom Line: 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.More specifically, total homocysteine in plasma and methylmalonic acid in urine/plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.

View Article: PubMed Central - PubMed

Affiliation: Division of Metabolic Diseases and Children's Research Center, University Children's Hospital Zürich, Zürich, Switzerland. martina.huemer@kispi.uzh.ch.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus