Introduction
Methods
cblC | cblD-MMA/HC | cblF | cblD-HC | cblE | cblG | MTHFR deficiency | |
---|---|---|---|---|---|---|---|
Number of reported cases | 169 | 16 | 13 | 5 | 20 | 25 | 148 |
Eating disorders/failure to gain weight | |||||||
Small for gestational age | + | ++ | (+) | ||||
Feeding difficulties, failure to thrive | +++ | ++++ | +++ | +++ | ++++ | ++ | |
Nervous system | |||||||
Decreased consciousness +/− apnoea | ++ | (+) | +++ | +++ | +++ | ||
Seizures | +++ | ++++ | ++ | (++) | +++ | +++ | +++ |
Ataxia | + | (++) | (+) | ++ | ++ | ||
Movement disorder and/or abnormal muscle tone | +++ | +++ | +++ | ++++ | +++ | ++++ | +++ |
Peripheral neuropathy/subacute degeneration of spinal cord | ++ | (+) | (++) | ++ | ++ | ++ | |
Hydrocephalus | ++ | ++ | ++ | ++ | |||
Visual impairment (retinopathy, optic atrophy) | +++ | ++ | +++ | ++ | ++ | + | |
Developmental disorder/ cognitive impairment | +++ | +++ | ++++ | ++++ | ++++ | ++++ | ++++ |
Behavioural/mental disorders | ++ | ++ | ++++ | (+) | ++ | ||
Microcephaly | ++ | ++++ | ++ | + | ++ | ||
Blood and bone marrow | |||||||
Megaloblastic anaemia | ++ | ++ | +++ | +++ | ++++ | ++++ | + |
Pancytopenia/neutropenia | ++ | +++ | ++ | + | |||
Recurrent severe infections | (+) | ++ | |||||
Kidneys | |||||||
Haemolytic uraemic syndrome | ++ | ++ | ++ | (+) | |||
Glomerulopathy | + | (+) | |||||
Tubulointerstitial nephropathy | + | ||||||
Cardiopulmonary | |||||||
Cardiac malformation | + | +++ | |||||
Cardiomyopathy | ++ | ||||||
Interstitial pneumonia | + | ||||||
Pulmonary hypertension | + | ||||||
Vascular | |||||||
Stroke | (+) | (+) | + | ||||
Venous thrombosis/ embolism | + | (+) | + | ||||
Malformations | |||||||
Facial dysmorphism | + | (+) | |||||
Skeletal deformity | (+) | + | |||||
Gastrointestinal | |||||||
Cheilitis/gastritis | +++ | ||||||
Liver steatosis | + | ++ | |||||
Skin | |||||||
Dermatitis/rash/hyperpigmentation | + | ++ | + | ||||
Other | |||||||
Hydrops fetalis | + | ||||||
Metabolic acidosis and/or hyperammonaemia | + | ||||||
Temperature instability/hypothermia | + | (+) |
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Which clinical signs are characteristic and allow timely diagnosis (Outcome: timely clinical diagnosis; this outcome is considered important)
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Which biochemical parameters allow timely and valid diagnosis? (Outcome: valid, timely laboratory diagnosis; this outcome is considered important)
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How can we prevent death and avoid/treat severe organ damage (Outcome: survival, severe organ complications; this outcome is considered critical)
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How can we prevent or treat eye disease and neurocognitive impairment? (Outcome: visual and neurocognitive function; this outcome is considered critical)
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Are you confident that the benefits outweigh the harms/burden or vice versa?
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Is there high, moderate or low quality evidence? Please consider:
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Risk of bias
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Study design
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Directness and consistency of results
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Magnitude of effect
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Dose–response gradient
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Publication bias
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Are you confident that the recommendation meets typical values and preferences of the target population (e.g. patients, parents)?
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Are the resources worth the expected net benefit following the recommendation?
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Overall strength of recommendation: weak or strong?
Which clinical signs are characteristic for remethylation defects and allow for timely diagnosis?
General clinical patterns of remethylation disorders
Age specific patterns of remethylation disorders
Neonates (0–28 days) |
Encephalopathy |
Lethargy, apnoea |
Feeding difficulties |
Muscular hypotonia |
Seizures |
Nystagmus |
Anaemia/thrombocytopenia or pancytopenia, megaloblastosis |
Haemolytic uremic syndrome |
Cardiomyopathy |
Hydrocephalus |
Pulmonary hypertension |
Infants (1–12 months) |
Growth failure/poor weight gain |
Acute progressive encephalopathy/apnoea |
Chronic encephalopathy |
Muscular hypotonia |
Developmental disability/regression |
Seizures |
Recurrent acute behavioural changes/lethargy |
Visual inattention/Nystagmus |
Anaemia/thrombocytopenia or pancytopenia, megaloblastosis |
Haemolytic uremic syndrome |
Pulmonary hypertension |
Children (1–12 years) |
Chronic Encephalopathy |
Muscular hypotonia or spasticity |
Developmental disability/regression or dementia |
Seizures |
Neuropsychiatric disturbance/personality changes |
Intermittent acute behavioural changes/lethargy |
Acute progressive encephalopathy/apnoea |
Subacute degeneration of the cord |
Paraesthesia |
Incontinence |
Ataxia/spasticity |
Progressive limb weakness (legs>arms) |
Haemolytic uremic syndrome |
Thromboembolic events |
Recurrent venous thrombosis |
Pulmonary thromboembolism |
Cerebrovascular events |
Pulmonary hypertension |
Adolescents and adults (>12 years) |
Chronic encephalopathy |
Developmental disability/regression or dementia |
Neuropsychiatric disturbance |
Personality changes |
Intermittent acute behavioural changes/lethargy |
Acute progressive encephalopathy |
Subacute degeneration of the spinal cord |
Paraesthesia |
Incontinence |
Ataxia/spasticity |
Progressive limb weakness (legs>arms) |
Thromboembolic events |
Recurrent venous thrombosis |
Pulmonary thromboembolism |
Cerebrovascular events |
Pulmonary hypertension |
Clinical patterns specific for combined remethylation disorders (cblC, cblD-MMA/HC, cblF, cblJ)
Clinical patterns specific for isolated remethylation disorders (cblD-HC, cblE, cblG)
Clinical patterns specific for MTHFR deficiency
Clinical differential diagnosis
Affecting cobalamin availability |
Nutritional inadequacy (maternal vitamin B12 deficiency/vegan diet) |
Intestinal malabsorption (e.g. genetic disorders such as Imerslund-Graesbeck syndrome gastric intrinsic factor deficiency; autoimmune or parasitic disease; short gut syndrome) |
Disturbed binding and cellular uptake (e.g. TC deficiency) |
Disturbance of intracellular metabolism (nitrous oxide) |
Affecting folate availability |
Nutritional inadequacy (maternal deficiency/dietary inadequacy) |
Intestinal malabsorption (acquired/genetic) |
Disturbed binding and cellular uptake of folate (autoimmune/genetic) |
Disturbance of intracellular metabolism (antifolate drugs, MTHFD1 deficiency) |
Other diseases with a combination of haematological and neurological symptoms |
Severe iron deficiency |
Infectious diseases (e.g. CMV/EBV/HHV6/HPVB19/HIV1) |
Leukaemia/myeloproliferative disorders |
Myelodysplastic syndromes |
Disorders affecting the mitochondrial respiratory chain (e.g. Pearson syndrome) |
UMP synthase deficiency (orotic aciduria) |
Thiamine transporter (SLC19A2) defect |
Branched chain organic acidaemia such as methylmalonic or propionic acidaemia |
Lysinuric protein intolerance |
Macrocytosis or macrocytic anaemia | MMA | Met | Total vitamin B12 | Folate | |
---|---|---|---|---|---|
cblC cblD-MMA/HC | + or − | ↗ | ↘↘ to nl | nl | nl |
cblF/cblJ | + | ↗ | ↘↘ to nl | nl | nl |
cblE/G | + | nl | ↘↘ to nl | nl | nl |
cblD-HC | + or − | nl | ↘↘ to nl | nl | nl |
MTHFR | – | nl | ↘↘ to nl | nl | nl or ↘ |
Vitamin B12 deficiency or malabsorption | + | ↗ | ↘ to nl | ↘↘ | nl |
Folate deficiency or malabsorption | + | nl | ↘ to nl | nl | ↘↘ |
HCFC1 (cblX) | + or − | ↗ or nl | ↘↘ to nl | nl | nl |
CBS deficiency | – | nl | nl-↗ | nl | nl |
TC deficiency | + | ↗ | ↘↘ to nl | nl (↘) | nl |
MTHFD1 deficiency* | + | nl | ↘↘ to nl | nl | nl |
Which parameters allow valid and timely laboratory diagnosis?
Biochemical metabolites
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Elevated plasma tHcy is the hallmark of remethylation disorders. We strongly recommend that investigations in patients with a suspected remethylation disorder should start with the measurement of total homocysteine in blood. We recommend the blood sample for tHcy to be centrifuged within an hour and kept at +4° or frozen until analysis. Immunoassays or chromatographic methods are suitable for tHcy measurement. (Quality of the evidence: moderate)
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We strongly recommend against measuring free homocysteine instead of total homocysteine. (Quality of the evidence: moderate)
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We strongly recommend that in the case of high total homocysteine, plasma and urine samples for determination of MMA, methionine, folate and vitamin B12 are to be obtained before treatment is started. (Quality of the evidence: moderate)
Differential diagnosis of biochemical parameters
Enzymatic studies
cblC | cblD-MMA/HC | cblF | cblJ | cblD-HC | cblE | cblG | MTHFR | |
---|---|---|---|---|---|---|---|---|
Direct enzyme assay (tissues) | no | no | no | no | no | yes | yes | yes |
fib/leuc/amn | fib/leuc/amn | fib/leuc/amn | ||||||
Indirect enzyme assays | ||||||||
Propionate incorporation | ↘ | ↘ | ↘ | ↘ | nl | nl | nl | nl |
MTHF incorporation | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | nl |
Formate incorporation into serine | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | nl or ↗ |
Formate incorporation into methionine | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ |
AdoCbl biosynthesis | ↘ | ↘ | ↘ | ↘ | nl | nl | nl | nl |
MeCbl biosynthesis | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ | ↘ |
Gene |
MMACHC
1
|
MMADHC
2
|
LMBRD1
3
|
ABCD4
4
|
MMADHC
2
|
MTRR
5
|
MTR
6
|
MTHFR
7
|
Chromosome location | 1p34.1 | 2q23.2 | 6q13 | 14q24.3 | 2q23.2 | 5p15.31 | 1q43 | 1p36.22 |
Mode of inheritance | AR | AR | AR | AR | AR | AR | AR | AR |
OMIM | 609831 | 611935 | 612625 | 603214 | 611935 | 602568 | 156570 | 607093 |
Molecular genetic analysis
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We strongly recommend diagnostic confirmation by molecular genetic analysis and/or direct or indirect enzyme assays in cultured skin fibroblasts (or lymphocytes) in experienced laboratories. (Quality of the evidence: moderate)
Prenatal diagnosis
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If prenatal diagnosis is considered in individual cases we recommend to perform molecular genetic analysis from chorionic villi or amniotic fluid samples given that mutations in the index case and carrier status in the parents have been identified (Quality of the evidence: low)
Feasibility and impact on outcome of newborn screening (NBS) for combined remethylation disorders
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We strongly recommend early treatment in patients with the cblC defect as it improves survival, corrects haematological abnormalities and may prevent HUS and hydrocephalus. However, early treatment has little influence on eye disease and unclear impact on neurocognitive outcome (Quality of the evidence: moderate)
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We strongly recommend to obtain plasma for determination of serum vitamin B12 before treatment is started in cases identified by NBS as part of studies to exclude maternal vitamin B12 deficiency. (Quality of the evidence: moderate)
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We recommend use of C3 acylcarnitine and the C3/C2 ratio as primary markers to screen for early onset cblC defect. (Quality of the evidence: moderate)
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We suggest consideration of C17 acylcarnitine as a promising primary marker to screen for early onset cblC defect. (Quality of the evidence: low)
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We strongly recommend performing second tier testing using tHcy and MMA to improve specificity and to differentiate the defects from other disorders. (Quality of the evidence: moderate)
Feasibility and impact on outcome of NBS for isolated remethylation disorders and MTHFR deficiency
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We strongly recommend early identification and treatment with betaine for MTHFR deficiency. Presymptomatic betaine treatment prevents severe neurological impairment (Quality of the evidence: high)
Disease course and outcome of combined remethylation disorders
Growth and physical features | Prenatal growth retardation and postnatal failure to thrive Dysmorphic facial features |
CNS | Microcephaly Hydrocephalus Developmental delay and/or regression; cognitive impairment ranging from executive dysfunction to severe mental retardation Neuropsychiatric disturbances, social withdrawal, personality changes, dementia Progressive encephalopathy Seizures Subacute combined degeneration of the spinal cord Peripheral neuropathy Leukoencephalopathy Cortical atrophy |
Eye | Nystagmus Maculopathy Progressive pigmentary retinopathy Optic atrophy Visual impairment/blindness |
Blood | (Macrocytic) anaemia Thrombocytopenia and/or neutropenia |
Vascular | Stroke Recurrent venous thrombosis Cor pulmonale or subclinical pulmonary thrombosis |
Renal | Haemolytic-uremic syndrome Glomerulopathy |
Heart | Congenital heart defects Left ventricular non-compaction Dilated cardiomyopathy Pulmonary hypertension |
Mortality
Renal disease and microangiopathy
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We recommend monitoring for all aspects of renal disease including arterial blood pressure in patients with cobalamin related remethylation disorders. (Quality of the evidence: low)
Vascular problems
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The incidence of vascular complications is significantly reduced with appropriate treatment in late onset patients and may be prevented in early onset patients with remethylation disorders. (Quality of the evidence: moderate)
Neurocognitive and psychiatric problems
Ophthalmological problems
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As knowledge and awareness of visual dysfunction progression allows timely initiation of appropriate vision intervention programs and support, we recommend that every patient newly diagnosed with a remethylation disorder should receive an ophthalmological consultation independent of the age at diagnosis and severity of disease. (Quality of the evidence: low)
Disease course and outcome in isolated remethylation disorders (cblD-HC, cblE, cblG)
Mortality
Renal disease, microangiopathy and anaemia
Vascular problems
Neurocognitive and psychiatric problems
Disease course and outcome in MTHFR deficiency
Mortality
Vascular problems
Neurocognitive problems
The effects of treatment on clinical outcome
Impact of prenatal treatment on outcome
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We suggest that prenatal maternal treatment may be considered in a pregnancy with a fetus with proven cblC disease. (Quality of the evidence: low)
Improving the outcome in the acutely ill patient with a suspected or proven remethylation disorder
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We strongly recommend immediate treatment with parenteral cobalamin in suspected cases. (Quality of the evidence: moderate)
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We recommend consideration of betaine treatment as soon as hyperhomocysteinaemia is proven and normal/low methionine confirmed. (Quality of the evidence: moderate)
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We suggest consideration of additional enteral supplementation with folinic acid or L-methionine in individual cases. (Quality of the evidence: low)
Improving the outcome: long-term management of cobalamin-related combined and isolated remethylation disorders
Drugs with proven clinical effect | Treatments without proven clinical effect | To be avoided | |
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Cobalamin related remethylation disorders | OHCbl parenteral Betaine | Folate/folinic acid L-Carnitine Methionine* | Nitrous oxide Protein restriction |
MTHFR deficiency | Betaine | Folinic acid/ 5-Methylfolate* L-Carnitine Methionine* | Nitrous oxide Folic acid Protein restriction |
Cobalamin
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We strongly recommend using parenteral OHCbl in treating patients with the cblC defect and other cobalamin-related remethylation disorders. (Quality of the evidence: high)
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We recommend applying a starting dose of 1000 μg (1 mg) OHCbl daily given parenterally in patients with the cblC defect. This regime has also been applied in other cobalamin-related remethylation defects. (Quality of the evidence: low)
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We suggest that the minimum effective OHCbl dose and frequency of administration should be individually titrated. Escalating doses of OHCbl may result in biochemical improvement; however, significant clinical benefit remains to be proven. Frequency of administration of OHCbl ranges between daily and weekly without evidence of advantage of one over the other. (Quality of the evidence: low)
Betaine
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We recommend oral betaine treatment in cblC disease and other cobalamin-related remethylation disorders (Quality of the evidence: low)
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We suggest that the minimum effective betaine dose should be individually titrated to improve the levels of tHcy and methionine. (Quality of the evidence: low)
Side effects of treatment with cobalamin and betaine
Folates
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Results failed to demonstrate or exclude a beneficial or detrimental effect of folic and/or folinic acid as adjunctive therapy in patients with cblC disease and other cobalamin-related remethylation disorders. (Quality of the evidence: low)
Levocarnitine
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Results failed to demonstrate or exclude a beneficial or detrimental effect of oral carnitine as adjunctive therapy in patients with cblC disease and other cobalamin-related remethylation disorders. (Quality of the evidence: low)
Dietary restrictions
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We strongly recommend not to restrict protein in cblC disease and other remethylation disorders. (Quality of the evidence: moderate)
Amino acid supplementation
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Met is essential in patients with remethylation defects and we recommend maintaining its plasma levels in the normal range; if necessary this may be achieved by oral methionine supplementation. (Quality of the evidence: low)
Betaine
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We strongly recommend early treatment with betaine as it improves clinical outcome and prevents neurological deterioration in MTHFR deficiency. (Quality of the evidence: high)
Folates
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Results failed to demonstrate or exclude a beneficial or detrimental effect of folic or folinic acid or 5-CH3THF as adjunctive therapy to restore cellular and cerebral folate deficiency in MTHFR deficiency on clinical outcome. (Quality of the evidence: low).
Other substances
Improving clinical outcome: management of general anaesthesia in remethylation disorders
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We strongly recommend against the use of nitrous oxide in patients with remethylation disorders. (Quality of the evidence: high)