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Methylmalonacidurie

Formen, Diagnostik und Therapie

Methylmalonic aciduria

Classification, diagnosis and therapy

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Summary

Congenital methylmalonic aciduria (MMA) is a metabolic disorder inherited by an autosomal recessive trait. The metabolic block is located in the catabolic pathway of propionyl-CoA to succinyl-CoA.

Biochemically, four enzymatic defects have been recognized, i.e.:

  1. 1.

    Methylmalonyl-CoA racemase.

  2. 2.

    Methylmalonyl-CoA mutase apoenzyme.

  3. 3.

    Synthesis of desoxyadenosyl-cobalamine.

  4. 4.

    Disturbance at an earlier level of cobalamine metabolism which causes defective synthesis of both vitamin B12-coenzymes.

These four enzymatic defects express themselves in three ways: non-vitamin B12-dependent MMA (defects 1 and 2); vitamin B12-dependent MMA (defect 3); MMA associated with homocystinuria (defect 4).

The various forms of MMA cannot be distinguished clinically from one another. The disorder manifests itself during the first few days to weeks of life. Principal symptoms and signs are: anorexia, vomiting, muscular hypotonia and metabolic acidosis.

The diagnosis is established by determination of methylmalonic acid in plasma, cerebrospinal fluid and urine, as well as by assay of enzyme activities in leukocytes, liver tissue or cultured fibroblasts (from biopsied skin). A prenatal diagnosis is feasible by the examination of cultured amnion cells, amniotic fluid and maternal urine.

Therapy of non vitamin B12-dependent MMA calls for reduction of protein intake, particularly that of precursors of methylmalonic acid, such as methionine, threonine, isoleucine and valine. The treatment of vitamin B12-dependent forms is accomplished by i.m. injection of high doses of vitamin B12.

No definite statement can be made as yet with regard to long-term prognosis and normalcy of mental development in treated children.

Zusammenfassung

Die kongenitale Methylmalonacidurie (MMA-urie) ist eine angeborene Stoffwechselkrankheit mit autosomal recessivem Erbgang. Der Block liegt im Abbau von Propionyl-Coenzym A (CoA) zu Succinyl-CoA.

Es sind 4 biochemische Defekte beschrieben:

  1. 1.

    Methylmalonyl-CoA Racemase.

  2. 2.

    Methylmalonyl-CoA Mutase Apoenzym.

  3. 3.

    Desoxyadenosylcobalamin-Synthese.

  4. 4.

    Störung auf einer früheren Stufe des Cobalaminstoffwechsels, die zu einem Defekt in der Synthese der beiden Vitamin B12-Coenzyme führt.

Diesen 4 Defekten lassen sich 3 klinische Formen zuordnen: die nicht Vitamin B12 abhängige MMA-urie (Defekt 1 und 2), die Vitamin B12 abhängige MMA-urie (Defekt 3) und die MMA-urie mit Homocystinurie (Defekt 4).

Vom klinischen Bild her sind die verschiedenen Formen nicht zu unterscheiden. Die Krankheit manifestiert sich in den ersten Lebenstagen oder -wochen. Leitsymptome sind Trinkschwäche, Erbrechen, Muskelhypotonie und metabolische Acidose.

Die Diagnostik erfolgt durch Bestimmung der Konzentration von MMA in Plasma, Liquor und Urin und die Bestimmung der Enzymaktivität in Leukocyten, Leber oder Fibroblasten-Kulturen aus Hautbiopsie-Material. Eine pränatale Diagnostik aus Amnion-Zellkulturen, Amnion-Flüssigkeit und mütterlichem Urin ist möglich.

Die Therapie der nicht auf Vitamin B12-ansprechenden Formen erfolgt durch eine Reduktion der Proteinzufuhr, besonders der Vorstufen von MMA, der Aminosäuren Methionin, Threonin, Isoleucin und Valin. Die Vitamin B12-abhängigen Formen werden mit i.m. Injektion hoher Dosen Vitamin B12 behandelt.

Über die Prognose in Bezug auf eine normale geistige Entwicklung kann noch keine abschließende Aussage gemacht werden.

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Abbreviations

CoA:

Coenzym A

Cbl:

Cobalamin

OH-Cbl:

Hydroxycobalamin

dA-Cbl:

Desoxyadenosyl cobalamin

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  1. Department für Kinderheilkunde der Universität Ulm, Germany

    Dorothea Leupold

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Leupold, D. Methylmalonacidurie. Klin Wochenschr 55, 57–63 (1977). https://doi.org/10.1007/BF01469083

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