Alternative titles; symbols
ORPHA: 99845; DO: 0080108;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p25.1 | Myoglobinuria, acute recurrent, autosomal recessive | 268200 | Autosomal recessive | 3 | LPIN1 | 605518 |
A number sign (#) is used with this entry because of evidence that autosomal recessive recurrent acute myoglobinuria is caused by homozygous or compound heterozygous mutation in the LPIN1 gene (605518) on chromosome 2p25.
Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis associated with muscle pain and weakness and followed by excretion of myoglobin in the urine. Renal failure may occasionally occur. Onset is usually in early childhood under the age of 5 years. Unlike the exercise-induced rhabdomyolyses such as McArdle syndrome (232600), carnitine palmitoyltransferase deficiency (see 255110), and the Creteil variety of phosphoglycerate kinase deficiency (311800), the attacks in recurrent myoglobinuria no relation to exercise, but are triggered by intercurrent illnesses, commonly upper respiratory tract infections (Ramesh and Gardner-Medwin, 1992).
See 160010 for discussion of a possible autosomal dominant form of myoglobinuria.
Severe rhabdomyolysis is a major clinical feature of anesthetic-induced malignant hyperthermia (145600), an autosomal dominant disorder.
Christensen et al. (1983) studied the disorder in 3 brothers. Muscle carnitine palmitoyltransferase was normal. During exercise, serum creatine kinase rose markedly from only slightly elevated levels at rest. Precipitation of attacks seemed to be related to complete muscle glycogen depletion, indicating defective muscle lipid metabolism.
Ramesh and Gardner-Medwin (1992) described 2 families with familial paroxysmal rhabdomyolysis unrelated to exercise. In 1 family, a 3-month-old girl had a single attack of rhabdomyolysis. Her older brother died suddenly at the age of 4 years following a day-long illness. The parents were not consanguineous. The second family had 4 affected girls who were born of a Kuwaiti, Bedouin, first-cousin couple. The 2 oldest sisters died at the age of about 5 years with acute generalized muscle weakness and myoglobinuria.
Zeharia et al. (2008) 3 patients of Arab Muslim origin who developed recurrent episodes of myoglobinuria beginning at ages 2, 2, and 7 years, respectively. All were born at term and had normal birth and early psychomotor development. The episodes were invariably precipitated by febrile illnesses and lasted 7 to 10 days. Clinical features included generalized weakness, inability to walk, myalgia, and dark urine. Physical examination revealed marked sensitivity over the thighs and calf muscles without swelling, localized warmth, or redness. Muscle strength was markedly reduced, and the patellar and Achilles reflexes could not be elicited bilaterally. All patients had normal health between episodes.
Raaschou-Pedersen et al. (2019) reported studies of exercise without and with glucose supplementation in a 48-year-old man with autosomal recessive acute recurrent myoglobinuria with exercise intolerance and monthly rhabdomyolysis, compared with 2 control individuals. The mean fatty acid oxidation and palmitate oxidation rates were lower in the patient compared with controls, resulting in a lower fatty acid concentration in the patient than in controls during exercise. With an infusion of intravenous glucose, the patient's exercise duration increased from 36 to 60 minutes; with oral glucose, the increase was from 36 to 47 minutes. Self-rated exertion decreased with both intravenous and oral glucose supplementation.
Hed (1953) observed 3 affected brothers with myoglobinuria. Three other brothers and the parents were unaffected, suggesting autosomal recessive inheritance. Bowden et al. (1956) reported an affected brother and sister.
As preventive measures, Ramesh and Gardner-Medwin (1992) urged the avoidance of fasting, the prompt treatment of febrile illnesses with cooling measures and specific antibiotics where appropriate, and the consumption of high-energy drinks. Although excessive or very prolonged exertion should probably be avoided, normal childhood activities and a normal amount of exercise have not been shown to be harmful. Standard precautions against malignant hyperpyrexia should be taken in the event of anesthesia. Intravenous dextrose infusions are indicated before, during, and after surgery. The family should be informed of the nature of the condition and carry a card naming the disorder and outlining emergency treatment. The parents should be instructed in nasogastric tube feeding for emergency treatment when intravenous glucose is not available. Assisted ventilation may be required. Hyperkalemia may be a problem.
In affected members of an Arab Muslim family with recurrent myoglobinuria, Zeharia et al. (2008) identified a homozygous mutation in the LPIN1 gene (605518.0001). Five additional LPIN1 mutations (see, e.g., 605518.0002-605518.0005) were identified in 4 of 22 additional patients with recurrent rhabdomyolysis and myoglobinuria. The clinical course of these patients was essentially similar with normal early development and episodes of myoglobinuria precipitated by catabolic stress. All affected individuals developed normally between episodes. Zeharia et al. (2008) postulated that a defect in phosphatidic acid phosphatase may result in accumulation of lysophosphatidate and other lysophospholipids in muscle tissue, which may result in rhabdomyolysis during stress.
Raaschou-Pedersen et al. (2019) reported a 48-year-old man with acute recurrent myoglobinuria who was homozygous for a deletion of the entire last exon of the LPIN1 gene, which was identified by exome sequencing analysis.
Bowden, D. H., Fraser, D., Sackson, S. H., Walker, N. F. Acute recurrent rhabdomyolysis (paroxysmal myohaemoglobinuria). Medicine 35: 335-353, 1956. [PubMed: 13407337]
Christensen, T. E., Saxtrup, O., Hansen, T. I., Kristensen, B. H., Beck, B. L., Plesner, T., Krogh, I. M., Andersen, V., Strandgaard, S. Familial myoglobinuria: a study of muscle and kidney pathophysiology in three brothers. Danish Med. Bull. 30: 112-115, 1983. [PubMed: 6851679]
Farmer, T. A., Hammack, W. J., Frommeyer, W. B. Idiopathic recurrent rhabdomyolysis associated with myoglobinuria: report of a case. New Eng. J. Med. 264: 60-66, 1961. [PubMed: 13698231] [Full Text: https://doi.org/10.1056/NEJM196101122640202]
Hed, R. Myoglobinuria. Arch. Intern. Med. 92: 825-832, 1953. [PubMed: 13103836] [Full Text: https://doi.org/10.1001/archinte.1953.00240240061004]
Kahler, H. J. Die Myoglobinurien. Ergeb. Inn. Med. Kinderheilk. 11: 1-103, 1959.
Raaschou-Pedersen, D., Madsen, K. L., Stemmerik, M. G., Eisum, A. V., Straub, V., Vissing, J. Fat oxidation is impaired during exercise in lipin-1 deficiency. Neurology 93: e1433-e1438, 2019. [PubMed: 31492716] [Full Text: https://doi.org/10.1212/WNL.0000000000008240]
Ramesh, V., Gardner-Medwin, D. Familial paroxysmal rhabdomyolysis: management of two cases of the non-exertional type. Dev. Med. Child Neurol. 34: 73-79, 1992. [PubMed: 1544519] [Full Text: https://doi.org/10.1111/j.1469-8749.1992.tb08567.x]
Zeharia, A., Shaag, A., Houtkooper, R. H., Hindi, T., de Lonlay, P., Erez, G., Hubert, L., Saada, A., de Keyzer, Y., Eshel, G., Vaz, F. M., Pines, O., Elpeleg, O. Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood. Am. J. Hum. Genet. 83: 489-494, 2008. Note: Erratum: Am. J. Hum. Genet. 84: 95 only, 2009. [PubMed: 18817903] [Full Text: https://doi.org/10.1016/j.ajhg.2008.09.002]