36 Other Metabolic Disorders
Georg F. Hoffmann, Nenad Blau
36.1 Introduction
Trimethylaminuria, also called fish-odor syndrome, is an autosomal recessive disorder characterized by a distinctive smell of rotten fish emanating from the urine, breath, and skin. It is caused by a deficient trimethylamine-oxidizing system resulting in accumulation of trimethylamine, a tertiary amine, which is volatile and responsive for the offensive smell (Mitchell 1996; Rehman 1999).
Dimethylglycinuria was described in 1999 in an adult with “fish-odor syn- drome,” muscular fatigue, and raised serum creatine kinase (Molenaar et al.
1999).
Sjögren-Larsson syndrome is a neurocutaneous disorder caused by a defi- ciency of the microsomal enzyme fatty aldehyde dehydrogenase catalyzing the oxidation of medium- and long-chain fatty aldehydes to their corresponding acids. Clinically it is characterized by the triad congenital ichthyosis, spastic di- or quadriplegia, and mental retardation (Willemsen et al. 2001a). Retinal changes (“glistening white dots”), pruritus, and severe speech disturbance with pseudobulbar dysarthria are also part of the clinical spectrum.
Hypophosphatasia is a metabolic bone disease causing defective mineraliza-
tion of the skeleton and teeth. The clinical spectrum is very wide, ranging from
perinatally lethal forms (“the boneless fetus”), rickets-like disease in infants
and children, to an exclusively dental form in adults (Whyte 2001).
382 Other Metabolic Disorders
36.2 Nomenclature
No. Disorder (symbol) Definitions/comment Gene symbol OMIM No.
36.1 Trimethylaminuria Fish-odor syndrome FMO3 602079
36.2 Dimethylglycinuria Fish-odor syndrome DMGDHD 605849
36.3 Hypophosphatasia Phosphoethanolaminuria TNSALP 146300
241500 241510
36.4 Sj¨ogren-Larsson syndrome ALDH 270200
36.3 Treatment
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36.1 Trimethylaminuria
Management of trimethylaminuria is not always easily accomplished. Treatment involves counseling and dietary adjustments. The latter include avoidance of choline-rich products (egg yolk, liver, kidney, legumes, soybeans, peas as well as fish, including shellfish). The reduced intake may reduce the excretion of trimethylamine and consequently the odor. The additional restriction of milk has proved useful in some cases. Some individuals have trimethylaminuria that is not responsive to dietary management. Occasionally, a short course of metronidazole, neomycin and lactulose can suppress production of trimethy- lamine by reducing the activity of gut microflora. In some patients, soaps with a pH value 5.5–6.5 have been reported to reduce the odor dramatically. They act by retaining secreted trimethylamine (a strong base) in a less-volatile salt form (Mitchell 1996; Rehman 1999).
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36.2 Dimethylglycinuria
The intensity of the odor in dimethylglcine dehydrogenase deficiency increases with physiological stress, such as illness, as well as during times of increased physical activity. No treatment strategy has as yet been established.
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36.3 Hypophosphatasia
A variety of medical treatments to improve osteomalacia in hypophosphata- sia have been tried. In general results have not been beneficial or long-lasting (Whyte 2001). Assessment of therapy is hampered by the low numbers of pa- tients and the uncertain natural course of disease, which includes spontaneous improvements.
Supplementation of vitamin D and/or mineral should be avoided, unless
obvious deficiencies have been documented. In hypophosphatasia circulating
levels of Ca, P, and vitamin D are generally not low, and hypercalcemia and hy-
Alternative Therapies/Experimental Trials 383
percalciuria will be worsened by supplementation. In contrast, dietary intake of calcium often needs to be restricted in generalized infantile disease. Chloroth- iazide has successfully improved hypercalcemia, hypercalciuria, and chronic bone demineralization in infantile hypophosphatasia (Girschick et al. 1999).
Treatment with synthetic calcitonin may be needed to control hypercalcemia (Barcia et al. 1997).
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36.4 Sjögren-Larsson Syndrome
Therapy for Sjögren-Larsson syndrome rests in an interdisciplinary approach between dermatology, neurology, and orthopedics. Ichthyosis and pruritus can be treated with topical lubrications as well as with oral retinoids (Willemsen et al. 2001a).
Epilepsy is usually responsive to conventional antiepileptics. Spasticity is often troublesome and early, and consequent physical therapy is a cornerstone of therapy. If necessary different neuropharmacological drugs can be used to ameliorate severe spasticity, such as baclofen and benzodiazepines. Injections of botulinum toxin and intrathecal baclofen administration have also been tried with anecdotal success, but no data are available in the literature.
Dangers/Pitfalls
In children the benefit of administration of retinoids has to be weighted against potential side-effects on the developing skeleton. Growth has to be carefully and regularly monitored clinically as well as radiologically.
Teratogenic actions of retinoids are a major concern in women of childbearing age.
36.4 Alternative Therapies/Experimental Trials
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36.3 Hypophosphatasia
Enzyme replacement has been repeatedly attempted by infusions of different
alkaline phosphatases, e. g., from patients with Paget bone disease, with disap-
pointing physiological as well as clinical responses. There is a single report of
clinical and radiological improvement following haploidentical bone marrow
transplantation (Whyte 2001).
384 References
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36.4 Sjögren-Larsson Syndrome
A fat-modified diet enriched with medium-chain fatty acids has been tried without convincing clinical success (Maaswinkel-Mooij et al. 1994; Auada et al.
2002). Conceptionally, it could only exert a positive effect, if started in early childhood.
Recently, promising results could be obtained in an experimental trial using Zileuton, an inhibitor of the synthesis of leukotriene B
4(Willemsen et al. 2001b).
References
1. Auada MP, Taube MBP, Collares EF, et al. (2002) Sjögren-Larsson syndrome: biochemical defects and follow up in three cases. Eur J Dermatol 12:263–266
2. Barcia JP, Strife CF, Langman CB (1997) Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization. J Pediatr 130(5):825–828
3. Girschick HJ, Seyberth HW, Huppertz HI (1999) Treatment of childhood hypophos- phatasia with nonsteroidal antiinflammatory drugs. Bone 25(5):603–607
4. Maaswinkel-Mooij PD, Brouwer OF, Rizzo WB (1994) Unsuccessful dietary treatment of Sjögren-Larsson syndrome. J Pediatr 124:748–750
5. Mitchell SC (1996) The fish-odor syndrome. Perspect Biol Med 39(4):514–526
6. Molenaar SH, Poggi-Bach J, Engelke UF, et al. (1999) Defect in dimethylglycine dehy- drogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin Chem 45:459–464
7. Rehman HU (1999) Fish odor syndrome. Postgrad Med J 75(886):451–452
8. Whyte MP (2001) Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The metabolic and molecular bases of inherited disease, 8th edn, vol IV. McGraw-Hill, New York, pp 5313–5329
9. Willemsen MA, Ijlst L, Steijlen PM, Rotteveel JJ, Jong JG de, Domburg PH van, May- atepek E, Gabreels FJ, Wanders RJ (2001a) Clinical, biochemical and molecular genetic characteristics of 19 patients with the Sjögren-Larsson syndrome. Brain 124:1426–1437 10. Willemsen MA, Rotteveel JJ, Jong JG de, Wanders RJ, Ijlst L, Hoffmann GF, Mayatepek E (2001b) Defective metabolism of leukotriene B4in the Sjögren-Larsson syndrome. J Neu- rol Sci 183:61–67
