10 Disorders of Sulfur Amino Acid Metabolism
Bridget Wilcken
10.1 Introduction
Disorders of sulfur amino acid metabolism include disorders of transsulfura- tion and disorders of the remethylation of homocysteine (Hcy) to methionine (Mudd et al. 2001; Rosenblatt and Fenton 2001). Disorders involving cystine – cystinuria and cystinosis – are dealt with elsewhere in the book. This introduc- tion identifies the individual disorders, the treatment aims, and the evidence, where it exists, for the different treatment modalities.
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Transsulfuration Disorders
Methionine adenosyltransferase I/III deficiency is rare and can be benign, but demyelination has been reported in some patients. Methionine levels are very high, but there is a deficiency of S-adenosyl methionine (SAM), and the aim of treatment is to elevate the latter, with anecdotal success (Surtees et al. 1991), and perhaps to reduce methionine levels. One case of adenosylhomocysteine hydrolase deficiency has recently been described, in which there was elevated methionine and SAM. (Mudd et al. 2003). The phenotype is still unclear. The need for treatment in this disorder is not yet substantiated, but there is in- creasing evidence that very high levels of methionine (over at least 1500 µ mol / l,
which may not occur in these disorders) can possibly cause cerebral edema (Yaghmai et al. 2002). Glycine N-methyl transferase deficiency also leads to ele- vated methionine and SAM levels, but also N-methyl glycine (see below; Mudd et al. 2001).
Cystathionine beta synthase (C β S) deficiency, classic homocystinuria, results
in elevated levels of circulating Hcy and methionine, S-adenosylmethionine
and S-adenosyl homocysteine, and reduced circulating cystathionine and cys-
teine (Mudd et al.). C β S deficiency is associated with lens dislocation, skeletal
and intellectual problems, and increased risk of thromboembolism. While the
pathophysiology of C β S is not fully understood, the main goal of treatment is
to lower Hcy levels in plasma while maintaining methionine within or above
the normal range, with cysteine within the normal range (Fig. 10.1). There are
few data to suggest optimal treatment targets for any of the analytes to obtain
good outcomes, and in practice it is very difficult to achieve a normal level of
plasma total homocysteine (tHcy) in all but a very few patients.
Untreated patient
B
6100 mg bd for 2 weeks, measure tHcy, then add folate 5mg/day for 2 weeks
tHcy < 60 µmol/l tHcy decreased, but >60 µmol/l tHcy unchanged
B
6-Responsive B
6-partially responsive B
6- nonresponsive
tHcy<20 µmol/l tHcy >20 µmol/l
Consider betaine and/or protein restriction plus amino acid supplement
(Methionine-free)
Consider betaine and/or protein restriction plus amino acid supplement
(Methionine-free)
Add: betaine 3 g bd and protein restriction plus amino acid supplement
(Methionine-free)
Monitor amino acid levels 3-6 monthly or monthly (children); adjust diet, supplement, and betaine, to keep tHcy levels as low as possible, and preferably below 60 µmol/l
Fig. 10.1. Cystathionine β -synthase deficiency: flow chart for institution of treatment and monitoring of homocysteine levels (tHcy, total homocysteine)
The outcome in 158 patients treated for up to 18 years has recently been reported (Yap et al. 2001a). Those patients responsive to pyridoxine (vitamin B
6; see below) maintain tHcy levels of < 60 µ mol / l (reference < 15 µ mol / l), while
B
6-nonresponsive patients have levels usually > 80 µ mol / l. Treatment regimens
vary somewhat. There is a substantial decrease in thromboembolic episodes
from the number expected in untreated patients. In a subset of patients whose
Introduction 107 treatment has been standardized and similar to that described below, the same clinical outcome has been seen (Wilcken et al. 1983). In patients with neona- tal diagnosis and treatment, there is also evidence of improved outcome, with avoidance of intellectual deficit and dislocation of the lens with free homocys- teine (fHcy) levels maintained at usually < 19 µ mol / l (Yap et al. 2001b).
Several strategies are used to lower Hcy levels (Mudd et al.):
• The methionine load is reduced by a low-protein diet combined with a me- thionine-free amino acid mixture, containing supplemented cysteine.
• Transsulfurationcanbeincreasedinsomepatientsbyusingpharmacological doses of the cofactor vitamin B
6.
• Remethylation can be increased both by the folate cycle, using folate and vitamin B
12medication, and by betaine methyl transferase, using betaine medication (Wilcken et al. 1983, 1985).
About half of all C β S patients are very responsive to pharmacological doses of vitamin B
6, and this treatment alone will substantially reduce plasma Hcy levels. All of these patients will eventually become folate depleted on treatment, and probably also B
12depleted, and they need these vitamins in addition. A few patients are partially responsive to B
6. Most B
6-responsive patients cannot achieve a normal level of Hcy on B
6, folate, and B
12treatment alone, although the levels obtained evidently result in a greatly improved outcome. Addition of diet and methionine-free amino acid supplement, if tolerated, will result in near-normal tHcy levels in most patients. B
6-nonresponsive patients need betaine in addition to folate, vitamins B
12, and B
6, and a low-protein diet with a methionine-free amino acid supplement (Wilcken et al. 1983). Usually only patients diagnosed as neonates are fully compliant with diet and the amino acid supplement.
γ -Cystathionase deficiency appears to be a benign disorder, needing no treatment (Mudd et al.).
Sulfite oxidase deficiency occurs both as an isolated disorder and, combined with xanthine oxidase deficiency, as a molybdenum cofactor disorder. This severe disorder usually causes intractable seizures and death. No treatment has been successful except in late-onset cases, which may respond to a diet low in protein and an amino acid mixture without methionine or cystine (Touati et al.
2000).
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Remethylating Defects
5,10-Methylene tetrahydrofolate reductase (MTHFR) deficiency is associated
with elevated circulating Hcy but low or low-to-normal levels of methionine, and
there is much clinical heterogeneity, with symptoms including gait disturbance,
intellectual deficits, and sometimes isolated thromboembolic episodes. Treat-
ment regimens aim at lowering Hcy while raising methionine and S-adenosyl
methionine levels, but clinical benefit is not clear, and several aspects of treat-
ment remain experimental. Key aspects of treatment include oral folates, be- taine and/or methionine, vitamin B
12, and riboflavin (Rosenblatt and Fenton;
Fowler 1998). Homozygosity for a common polymorphism in the MTHFR gene, 667C>T, confers a slightly increased risk of thromboembolism, especially where dietary folate is low.
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Disorders of Cobalamin Metabolism
Disorders of cobalamin metabolism and transport are associated with moder- ately high levels of circulating Hcy but, as above, low or low-to-normal plasma methionine. Deficiencies may affect hydroxocobalamin, resulting in combined functional deficiencies of methylmalonyl CoA mutase (CblC, CblD, and CblF) or methyl cobalamin alone, (CblE and CblG), resulting in a functional de- ficiency of methionine synthase. All these disorders can be associated with developmental delay, and to a varying degree, psychiatric disturbance, mega- loblastosis, and other problems. Treatment aims are to increase methionine and S-adenosyl methionine levels into the normal range and to reduce plasma Hcy (and methylmalonic acid in CblC, -D, and -F). Initial treatment with in- tramuscular vitamin B
12is certainly life-saving in cases presenting in infancy, and early treatment clearly improves the outcome. Other treatment modalities, including folates and betaine, are probably important, but their clinical efficacy has not been studied systematically (Rosenblatt and Fenton).
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Adverse Effects of Specific Treatments
• Vitamin B
6: doses > 400 mg daily have been associated with peripheral neu- ropathy (Bendeich and Cohen 1990).
• Betaine: accidental inhalation of the powder has been reported to cause very serious pulmonary problems.
• Methionine levels: very high plasma levels, > 1500 µ mol / l may possibly be
associated with cerebral edema, although this is uncertain (Mudd et al. 2001).
Nomenclature 109 10.2 Nomenclature
No. Disorder/deficiency Definition/comment Gene symbol OMIM No.
10.1.1 Methionine adenosyl transferase I/III
Hepatic form MAT1A 250850
10.1.2 S-Adenosylhomocysteine hydrolase
One case, with myopathy AHCY 180960
10.1.3 Glycine
N-methyltransferase
Possibly benign GNMT 606664
10.2 Cystathionine β -synthase CBS 236200
10.2.1 Cystathionine β -synthase Pyridoxine-responsive form CBS 236200 10.2.2 Cystathionine β -synthase Pyridoxine intermediate form CBS 236200 10.2.3 Cystathionine β -synthase Pyridoxine-nonresponsive form CBS 236200
10.3 γ -Cystathionase Appears benign CTH 219500
10.4.1 Molybdenum cofactor deficiency
Sulfite oxidase plus xanthine and aldehyde oxidase deficiencies
MOCS1 MOCS2
252150
10.4.2 Sulfite oxidase Isolated SUOX 272300
10.5 5,10-Methylene
tetrahydrofolate reductase
MTHFR 236250
10.5.1 5,10-Methylene
tetrahydrofolate reductase severe
MTHFR 236250
10.5.2 5,10-Methylene
tetrahydrofolate reductase thermolabile variant
Common in most populations, benign in presence of adequate folate intake
MTHFR, 667C > T
236250
10.6 Methionine synthase Functional defect
10.6.1 Cobalamin E defect Methionine synthase reductase CblE 236270
10.6.2 Cobalamin G defect Defects within methionine synthase CblG 250940 10.7 Methylmalonyl mutase and
methionine synthase
Functional defect
10.7.1 Cobalamin C defect Cytosolic reduction of hydroxocobalamin CblC 277400 10.7.2 Cobalamin D defect Cytosolic reduction of hydroxocobalamin CblD 277410
10.7.3 Cobalamin F defect Lysosomal transport CblF 277380
10.3 Treatment
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10.1.1 Methionine adenosyltransferase I/III deficiency
No. Symbol Age Medication/diet Dosage
10.1.1 MAT I/III All ages? S-Adenosyl
methionine
aa
Treatment reported in one patient with MAT I/III, with restoration of normal CSF
S-adenosylmethionine levels and remyelination seen on magnetic resonance image (MRI)
(Surtees et al. 1991)
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10.1.2 S-Adenosyl hydrolase deficiency
Only one patient with this disorder has been reported. Treatment with methio- nine restriction, phosphatidyl choline and creatine appear to have improved myopathy (Mudd et al. 2003).
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10.1.3 Glycine N-methyl transferase deficiency Recently described. May be a benign disorder.
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10.2 Cystathionine β -synthase deficiency 10.2.1 C β S deficiency, pyridoxine responsive 10.2.2 C β S deficiency, pyridoxine intermediate
No. Symbol Age
(years)
Medication/diet Dosage Frequency Target plasma
Hcy
10.2.1 C β S-R > 2 Pyridoxine 50 mg Daily tHcy
< 20 µ mol / l
10.2.2 C β S-I 2–15 Folic acid 1–2 mg Daily
Diet and aminoacid supplement if required
aPyridoxine 50–100 mg Twice daily tHcy
< 60 µ mol / l
Over 15 Folic acid 5 mg Daily
Hydroxocobalamin, oral
b, from c. 5 years
1 mg Daily
Betaine, if indicated
c1.5–3 g Twice daily Diet and aminoacid
supplement if required
aPyridoxine 50–100 mg Twice daily tHcy
< 60 µ mol / l
Folic acid 5 mg Daily
Hydroxocobalamin, oral 1 mg Oral, daily Betaine, if indicated
c3 g Twice daily Aspirin, if indicated
d100 mg Daily
Vitamin C
eDaily
a
Protein-restricted diet and methionine-free supplement can be used in patients who cannot maintain target Hcy levels.
See schedule for C β S-NR patients, below. Modest protein restriction is recommended for all patients
b
Hydroxocobalamin could alternatively be given as an intramuscular injection, 1 mg, monthly. The optimal frequency of IMI hydroxocobalamin in C β S deficiency has not been determined
c
Betaine is indicated in all C β S-I patients, and in C β S-R patients who cannot maintain target levels of total homocysteine (tHcy) and cannot tolerate a formal low-protein diet with aminoacid supplementation
d
Aspirin is indicated if there are other thrombophilic factors present, such as factor V Leyden, or if there has been a thromboembolic event
e
Vitamin C has been shown to improve the impairment of nitric oxide-dependent vasodilatation that occurs in C β S-deficient
patients (Pullin et al. 2002)
Treatment 111
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10.2.3 C β S deficiency, pyridoxine-nonresponsive
No. Symbol Age
(years)
Medication/diet Dosage Frequency Target plasma
Hcy
10.2.3 C β S-NR > 2 Pyridoxine
a50 mg Daily tHcy
< 20 µ mol / l
Folic acid 2 mg c. Daily
Low-protein diet c.2 g / kg per day
Methionine-free amino acid supplement
With meals
2–15 Betaine 1.5–3 g Twice daily tHcy
< 60 µ mol / l
Pyridoxine
a50–100 mg Daily
Folic acid 5 mg Daily
Hydroxocobalamin, oral
bfrom c. 5 years
1 mg Daily
Low-protein diet Methionine-free amino acid supplement
With meals
Over 15 Betaine
c3–4.5 g Twice daily tHcy
< 60 µ mol / l
Pyridoxine
a50–100 mg Daily
Folic acid 5 mg Daily
Low-protein diet Methionine-free amino acid supplement
1 g / kg per day With meals
Hydroxocobalamin, oral 1 mg Daily
Aspirin, if indicated
d100 mg Daily
Vitamin C
eDaily
a
Pyridoxine appears to improve the response to betaine in some pyridoxine-nonresponsive patients, but its use in this situation has not been rigorously investigated
b
Hydroxocobalamin could alternatively be given as an intramuscular injection, 1 mg, monthly. The optimal frequency of IMI hydroxocobalamin in C β S deficiency has not been determined
c
Anecdotally, betaine has been given in much higher doses, with no evidence of adverse effect. There is no evidence of advantage in a daily dosage of greater than 150 mg / kg (Matthews et al. 2002)
d
Aspirin is indicated if there are other thrombophilic factors present, such as factor V Leyden, or if there has been a thromboembolic event
e
Vitamin C has been shown to improve the impairment of nitric-oxide-dependent vasodilatation that occurs in
C β S-deficient patients (Pullin et al. 2002)
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10.3 γ -Cystathionase deficency
This defect appears benign, and no treatment is indicated.
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10.4.1, 10.4.2 Molybdenum cofactor deficiency, and isolated sulfite oxidase deficiency
No. Symbol Age Medication Dose / kg Frequency Comment
10.4.1 MOCS1 Child Low-protein diet Reportedly useful in late-
presenting cases. No treat- ment effective in early pre- senting cases
10.4.2 SUOX Methionine + cysteine-free amino acid mixture
With meals Dextromethorphan
(NMDA receptor inhibitor)
12.5 mg
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10.5 5,10-Methylenetetrahydrofolate (MTHFR) deficiency
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No. 10.5.1 MTHFR deficiency, severe Symbol Age Medication Dosage Frequency Target
10.8.1 MTHFR 1–2 years Folic acid
a2 mg Daily Maximize MTHFR
activity
Methyl THF
bReplacement
Betaine – oral 150 mg / kg Twice
daily
To increase methionine and SAM
Hydroxocobalamin – oral
c0.5 mg Daily Cofactor for methionine synthase
Riboflavin
d5 mg Daily MTHFR cofactor
2 years to adult
Folic acid 5 mg Daily As above
Methyl THF if available
Betaine 3–4.5 G Twice
daily Hydroxocobalamin – oral 1 mg Daily
Riboflavin 5–10 mg Daily
a
Folinic acid, 7.5–15 mg daily may be tried instead, but is more expensive
b
Methyl THF may not be available, and there is little experience with this as a medication
c
Intramuscular hydroxocobalamin could be used instead, perhaps 1 mg monthly
d
A trial of riboflavin should be given. Dosages up to 50 mg / day are safe even for babies
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10.5.2 MTHFR 667C > T
Homozygosity for this thermolabile variant is common (10–20% or more in
many populations). Treatment is not indicated unless there has been a related
adverse event, when 2–5 mg folic acid is given daily.
Treatment 113
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10.6 Functional defects of methionine synthase 10.6.1 Cobalamin E defect
10.6.2 Cobalamin G defect
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10.7 Functional defects of methylmalonyl mutase plus methionine synthase 10.7.1 Cobalamin C defect
10.7.2 Cobalamin D defect 10.7.3 Cobalamin F defect
No: Symbol Age Medication
aDosage Comment
10.6.1 CblE 0–6 months Hydroxocobalamin, IMI 1 mg / day For CblC, D and F,
10.6.2 CblG Folic acid, oral 1 mg daily the mutase defect does
10.7.1 CblC Betaine, oral 250–500 mg not produce sufficient
10.7.2 CblD Twice daily methylmalonic acid to
10.7.3 CblF require specific treatment
other than B
1210.6.1 CblE 6 months– Hydroxocobalamin, IMI 1 mg twice weekly See footnote for CblF 10.6.2 CblG 5 years Hydroxocobalamin, oral
b1 mg / day
10.7.1 CblC Folic acid, oral 2 mg / day
10.7.2 CblD Betaine, oral 75 mg / kg per day
10.7.3 CblF Twice daily
10.6.1 CblE 5 years + Hydroxocobalamin, IMI 1 mg twice weekly 10.6.2 CblG Hydroxocobalamin, oral
b1 mg / day
10.7.1 CblC Folic acid, oral 5 mg / day
10.7.2 CblD Betaine, oral 75 mg / kg per day
10.7.3 CblF twice daily
a
There is evidence to support these medications, but the suggested dosage schedule for hydroxocobalamin does not have published data to support it.
b
Oral hydroxocobalamin is not indicated for use in CblF, as there is probably a transport defect also affecting ileal
transcytosis.
10.4 Follow-up/Monitoring
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10.2 Cystathionine β -synthase deficiency
Age Biochemical Frequency Clinical Frequency
0–5 years Plasma amino acids 1–3 monthly Outpatient visit 1–3 monthly Total homocysteine
5–16 years Total homocysteine 3-monthly Outpatient visit 3–6 monthly Plasma amino acids 3–6 monthly Bone mineral density Baseline, then every
3–4 years Serum B
12(unless on B
12) Yearly Opthalmology Yearly 16 years + Total homocysteine 6 monthly Outpatient and
other monitoring as indicated
6 monthly
Plasma amino acids 6 monthly
Lipids 2–3 yearly
Thrombophilic factors Once
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