The clinical presentation of myoadenylate deaminase deficiency stems from the absence of the enzyme that facilitates the conversion of adenosine monophosphate (AMP) to inosine monophosphate (IMP) and ammonia (NH3) as a byproduct [1] [2]. As this process plays an important role in the generation of energy, the vast majority of patients reports symptoms that are related to exercise and physical activity [1] [3] [4]. Skeletal muscle pain (myalgia, which is sometimes be accompanied by cramping), frequent reports of fatigue, and weakness are the principal complaints [1] [3] [4] [5] [6]. Virtually any skeletal muscle can be affected - the facial muscles, the upper and lower extremities, or even a generalized presentation may be seen, and atrophy might also be reported [4] [6]. The duration of symptoms is quite long before the diagnosis is made, as up to 10 years may pass before clinical suspicion is raised [1] [3] [4] [5] [6]. An atypical presentation of constant muscle pain without an exertional association has been noted in rare cases [6]. The prevalence of myoadenylate deaminase deficiency is high: between 1-2% of the population is established to suffer from mutations that produce this effect. The deficiency shows an autosomal recessive pattern of inheritance with a very broad phenotypic range [2]. Furthermore, other neuromuscular diseases may be concomitantly present [2] [3], which is why the diagnosis of myoadenylate deaminase deficiency may not be easy to make.

• Fatigue

  The individuals with MDD fatigued after performing only 28% as much work as their non-MDD counterparts. Muscle biopsies were obtained from the four MDD patients and the eight non-MDD patients at rest and following exercise to the point of fatigue. [doi.org]

  People who do experience symptoms typically have fatigue, muscle pain (myalgia), or cramps after exercise or prolonged physical activity (exercise intolerance). [ghr.nlm.nih.gov]

  leading to central fatigue [ 2 ]. [omicsonline.org]

• Chills

  A 10 ml blood sample was collected into pre-chilled, heparinized tubes and centrifuged immediately (200 g for 5 min), and plasma lactate concentration was determined using an enzymatic analyser (Yellow Springs Instruments, YSI 23L, Yellow Springs, OH, [ncbi.nlm.nih.gov]

  When muscle is sufficiently chilled, the paramyotonia disappears, and the muscle is flaccid and paralyzed. [sites.google.com]

• Intravenous Administration

  Intravenous administration rates were 83, 167, and 222 mg/kg/h, which were well tolerated but oral administration of more than 200 mg/kg/h caused diarrhea. [ncbi.nlm.nih.gov]

• Delayed Speech Development

  In "secondary" MADA deficiency, the clinical findings have been variable with delayed motor development, hypotonia, cardiomyopathy, delayed speech development, and generalized weakness. [ncbi.nlm.nih.gov]

• Myalgia

  A diagnosis of tension myalgia or myofascial-type pain is often considered when no objective findings are seen in the evaluation. [ncbi.nlm.nih.gov]

  CONCLUSION: MAD deficiency must be ruled out in every patient with exertional myalgia and increased CK which normalizes when asymptomatic. [pesquisa.bvsalud.org]

• Muscle Weakness

  This report concerns two unrelated males; one had sarcoidosis, sarcoid myopathy and muscle weakness, and the other had exercise-induced weakness and myalgia. [ncbi.nlm.nih.gov]

  Woman with Leg Weakness and Atrophic Muscle Fibers on Biopsy 554 Case 89A A Woman with Muscle Weakness and a Skin Rash 559 Case 90 A Man with Muscle Pains 567 Case 91 An Older Woman with Progressive Muscle Weakness 572 Case 92 An HIVInfected Man with [books.google.com]

  The lack of AMP deaminase activity can result in fatigue, muscle weakness or pain, or other muscle problems in some people with AMP deaminase deficiency. It is not known why some people with this condition do not experience symptoms. [ghr.nlm.nih.gov]

• Muscle Cramp

  In contrast, 35 unrelated patients presenting with exercise-related muscle cramps or pains showed normal histochemical MAD activity. [ncbi.nlm.nih.gov]

  Myoadenylate deaminase deficiency (MAD) constitutes the most common genetically determined enzymatic defect of the skeletal muscle (2% of the population), however, it causes clinical symptoms such us exercise-related muscle cramps and pain in quite a [neurologia.com]

• Exercise-induced Muscle Pain

  A 55 years old patient suffering from exercise-induced muscle pain and stiffness due to primary myoadenylate deaminase deficiency has been successfully treated with D-ribose since 1984: single doses of 4 grams administered at the beginning of exercise [ncbi.nlm.nih.gov]

  muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. [semanticscholar.org]

  Hübner Summary A 55 years old patient suffering from exercise-induced muscle pain and stiffness due to primary myoadenylate deaminase deficiency has been successfully treated with D-ribose since 1984: single doses of 4 grams administered at the beginning [doi.org]

  Observations on two brothers with exercise-induced muscle pain. J Neurol Sci 53:125–136 Google Scholar 19. Heffner RR (1980) Myoadenylate deaminase deficiency. J Neuropathol Exp Neurol 39:360 Google Scholar 20. [link.springer.com]

  Observations on two brothers with exercise-induced muscle pain. J Neurol Sci. 1982 Jan; 53(1):125-36. Conal C. Kar, PhD, Carl M. Pearson, MD. Muscle Adenylate Deaminase Deficiency. Report of six new cases. Arch Neurol. 1981 May; 38(5):279-81. [revistas.proeditio.com]

• Muscular Atrophy

  The diagnoses in the 13 patients were: polyneuropathy (n 5), infantile spinal muscular atrophy (n 3), congenital myopathy with type 2 fibre atrophy, facioscapulohumeral myopathy, polymyositis, myotonic dystrophy and hyperornithinaemia with gyrate atrophy [ncbi.nlm.nih.gov]

  He is currently involved in multiple clinical trials of novel genetic interventions for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy. [books.google.com]

  Spinal muscular atrophies: Amyotrophic lateral sclerosis (ALS), or motor neuron disease Infantile progressive spinal muscular atrophy Intermediate spinal muscular atrophy Juvenile spinal muscular atrophy Adult spinal muscular atrophy Inflammatory myopathies [hopkinsmedicine.org]

  MAD deficiency have been described in muscle biopsy of patients with polyneuropathy, infantile spinal muscular atrophy, congenita myopathy with type-2 fiber atrophy, facioscapulohumeral myopathy, polymyositis, dermatomyositis, myotonic dystrophy, limb-girdle [scielo.br]

  ADULT SPINAL MUSCULAR ATROPHY Age of onset: 18 to 50 years. Weakness in the tongue, hands or feet which slowly spreads to other parts of the body. A relatively mild form of spinal muscular atrophy, it has little impact on life expectancy. [mda.org.au]

• Withdrawn

  Blood was withdrawn 2, 5 10, and 15 min after exercise. For lactate and pyruvate measurement, 1 mL blood was withdrawn in a tube containing 2 mL perchloric acid 1M previously cooled to 0 C. [journals.plos.org]

• Areflexia

  67 An Elderly Woman with a Progressive Neuropathy 429 Case 68 A Young Woman with Difficulty Swallowing 433 Case 69 A Young Woman with Intermittent Weakness and a Positive Family History of Similar Problems 436 Case 70 A Woman with Muscle Weakness and Areflexia [books.google.com]

The diagnostic workup of myoadenylate deaminase deficiency should start with a thorough patient history that will reveal the symptoms and their duration, as well as onset and progression. Clinical suspicion can be raised when an association is made between exercise and the appearance of complaints, in which case a more detailed approach should be sought. Elevation of creatine kinase (CK) is nonspecific, but very frequently found in this patient population [3] [5]. One of the key laboratory tests that point to a deficiency of myoadenylate deaminase is the evaluation of lactate, pyruvate, and ammonia levels 10 minutes after resting from physical activity [1] [2] [5]. In this condition, the normal rise in lactate is typically not followed by elevations of ammonia [2]. To further solidify the diagnosis, a muscle biopsy that uses specific stains to determine enzymatic activity is recommended by some authors [2] [3] [4] [6]. As a definitive method, genetic studies that detect mutations in the MAD gene located on chromosome 1 may be employed [2] [3] [7].

• Ammonia Increased

  increase on forearm ischaemic testing that was 10 % of normal control values (with a normal lactate rise) plus heterozygous for the AMPD1 mutation as above, and no other neuromuscular disorder as ruled out by the screening process outlined below ( Fishbein [ncbi.nlm.nih.gov]

1. Rannou F, Uguen A, Scotet V, et al. Diagnostic Algorithm for Glycogenoses and Myoadenylate Deaminase Deficiency Based on Exercise Testing Parameters: A Prospective Study. PLoS One. 2015;10(7):e0132972.
2. Tarnopolsky MA, Parise G, Gibala MJ, Graham TE, Rush JWE. Myoadenylate deaminase deficiency does not affect muscle anaplerosis during exhaustive exercise in humans. J Physiol. 2001;533(Pt 3):881-889.
3. Teijeira S, San Millán B, Fernández JM, et al. Myoadenylate deaminase deficiency: clinico-pathological and molecular study of a series of 27 Spanish cases. Clin Neuropathol. 2009;28(2):136-142.
4. Abe M, Higuchi I, Morisaki H, Morisaki T, Osame M. Myoadenylate deaminase deficiency with progressive muscle weakness and atrophy caused by new missense mutations in AMPD1 gene: case report in a Japanese patient. Neuromuscul Disord. 2000;10(7):472-477.
5. Lim L, Palayer M, Bruneau A, et al. Myoadenylate deaminase deficiency: a frequent cause of muscle pain A case detected by exercise testing. Ann Biol Clin (Paris). 2017;75(4):445-449.
6. Ahmed A, Lowden MR. Chronic Non-Exertional Myalgia and Myoadenylate Deaminase Deficiency: a Possible Association. J Clin Med Res. 2009;1(1):56-57.
7. Morisaki T, Gross M, Morisaki H, Pongratz D, Zöllner N, Holmes EW. Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci U S A. 1992;89(14):6457-6461.