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At a glance

It is an inherited or secondarily acquired disorder of muscle purine nucleotide metabolism. The clinical manifestations include exercise-induced myopathy, post-exertional muscle weakness or cramping, prolonged fatigue after exertion, and limping infant caused by benign congenital hypotonia. Generalized muscle pair is often manifested. There is evidence that patients with myoadenylate deaminase deficiency (and the carrier as well) may be at an increased risk of malignant hyperthermia (MH) when subjected to anesthesia.

Synonyms

Muscle Adenosine Monophosphate Deaminase Deficiency; MADA Deficiency; AMP Deaminase; Adenosine Monophosphate Deaminase Deficiency Type 1.

Incidence

This defect is specific to skeletal muscle and may be one of the most common genetic defects. The heterozygosity is believed to be 1 in 5. It is found in 2% of muscle biopsies of patient presenting with muscle weakness or poor exercise tolerance. It has equal sex distribution.

Genetic inheritance

The primary deficiency is transmitted as autosomal dominant. The AMPD1 gene encoding for muscle adenosine monophosphate deaminase (MADM) is located on chromosome 1. The mutant allele is frequent in white people. In secondary cases, the defect could be caused by a limitation in AMPD1 transcript availability. In those cases, the participation of the MADM deficit to the patient’s phenotype is unclear.

Pathophysiology

MADM is one of the three enzymes of the purine cycle. In the muscle, this cycle removes adenosine monophosphate (AMP) formed during exercise to favor formation of ATP from adenosine diphosphate (ADP), releases ammonia (NH3) and inosine monophosphate, stimulators of glycolysis and thus energy production, and produces fumarate, an intermediate of the citric acid cycle. This impaired muscular energy production during exercise seems to be the cause of the muscular dysfunction.

Diagnosis

Absence of elevation of plasma ammonia following exercise (as in normal subjects); activity of MADM is lower than 2% in inherited cases and between 2 and 15% in secondary cases. Onset is in childhood or adolescence in nearly 50% of cases.

Clinical aspects

In case of primary defect, postexercise symptoms are the main manifestations: early fatigue, cramps, or myalgias sometimes accompanied by myoglobinuria and increased creatine kinase following moderate to vigorous exercise. Administration of oral ribose could improve muscle strength and endurance.

Precautions before anesthesia

There are evidence that patients with myoadenylate deaminase deficiency (and the carrier as well) are possibly at an increased risk of MH when subjected to anesthesia. The risk is significant for rhabdomyolysis, but not as significant for MH as seen with other dystrophinopathies. Nevertheless, it is highly recommended to obtain a complete personal and familial history of previous anesthetics and possible complications related to MH. The association is mild, but nevertheless not negligible. In primary defects, check muscle strength and creatine ...

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