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Lactate dehydrogenase deficiency

Lactate dehydrogenase deficiency
Literature review current through: Jan 2024.
This topic last updated: Jan 21, 2022.

INTRODUCTION — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1,4-linked glucose, interrupted by a 1,6-linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).

There are a number of inborn errors of glycogen metabolism that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.

Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.

The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Glycogen serves as the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.

This topic will review lactate dehydrogenase (LDH) deficiency, sometimes called GSD type XI. An overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

OVERVIEW — LDH is involved in the interconversion of lactate and pyruvate, providing nicotinamide adenine dinucleotide (NAD+) for continued glycolysis in active muscle, and is needed for long-chain fatty acid oxidation in liver peroxisomes [1]. At least two isoforms exist, termed M (muscle) and H (heart):

The M isoform has a higher affinity for pyruvate than that of liver and generates L-lactate for gluconeogenesis by the liver. The M isoform is a product of the lactate dehydrogenase A (LDHA) gene, located at 11p15 [2-4].

The lactate dehydrogenase B (LDHB) gene that encodes the H isoform has been mapped to chromosome 12p12.2-p12.1 [5].

Defects in another isoform encoded by lactase dehydrogenase D (LDHD), located at 16q23, lead to D-lactic aciduria (MIM 245450) [6]. This D-lactate-specific isoform is thought to be important in methylglyoxal metabolism. However, despite a report of a patient with developmental delay, cerebellar ataxia, and transient hepatomegaly who had compound heterozygous pathogenic and likely pathogenic variants in the LDHD gene [7], the clinical significance of this enzymatic deficiency in neurologic disease still remains uncertain since an additional family-based case report only described hyperuricemia and gouty arthropathy associated with D-lactic acidemia [8]. Only L-lactate is typically measured in clinical laboratories, so an unexplained anion gap acidosis should prompt other investigations such as urine organic acid analysis. An acquired form of D-lactic acidosis causing acute encephalopathy is associated with short bowel syndrome due to bacterial overgrowth and increased D-lactate production [9], providing evidence for the potential neurotoxicity of D-lactate.

DEFICIENCY OF THE M ISOFORM — Deficiency of the skeletal muscle isoform/subunit of LDH (LDH M-subunit deficiency, MIM 612933), caused by mutations in the lactate dehydrogenase A (LDHA) gene (MIM 150000), results in childhood-onset myopathy, manifested by exercise intolerance, muscle stiffness following strenuous exercise, and myoglobinuria [4,5,10]. Frequent pains and uterine stiffness during pregnancy and the early stage of delivery have been reported in females with LDH M-subunit deficiency [4,11]. Some patients have skin eruptions (annually recurring acroerythema in the summertime, annular erythema, and pustular psoriasis-like lesions) [12-15]. Inheritance is autosomal recessive. Serum creatine kinase (CK) level is elevated in combination with a normal serum LDH level.

Diagnosis — The activity of LDH in red blood cells is reduced or absent. The forearm ischemic exercise test shows no rise in venous lactate but an excessive increase in pyruvate [16]. During episodes of myoglobinuria, high levels of serum CK contrast with low levels of serum LDH. Muscle biopsy with biochemical determination of LDH demonstrates low or absent enzyme activity. Molecular analysis of the LDHA gene may reveal various mutations [2,3,17]. In the era of next-generation sequencing, a muscle biopsy is not always needed, because the diagnosis can be made noninvasively with detection of mutations in the LDHA gene.

Therapy — There is no specific treatment for LDH deficiency. Pregnant individuals with known LDH deficiency have undergone cesarean births due to the risk of dystocia [4,11].

DEFICIENCY OF THE H ISOFORM — Deficiency of the H (heart) isoform of LDH (MIM 150100), caused by mutations in the lactate dehydrogenase B (LDHB) gene, appears to have no clinical consequences. Serum and red blood cell LDH levels are decreased, and, in one family, increased hemolysis was present [18]. However, in affected individuals, serum LDH concentration may not be increased in conditions in which elevations typically occur (such as myocardial infarction and liver damage), possibly leading to misdiagnosis.

SUMMARY

There are two isoforms of L-lactate dehydrogenase (LDH): the M (muscle) isoform and the H (heart) isoform. A third isoform that metabolizes D-lactate is not involved in carbohydrate metabolism. (See 'Overview' above.)

Deficiency of the M isoform of LDH results in childhood-onset myopathy, manifested by exercise intolerance, muscle stiffness following strenuous exercise, and myoglobinuria. Diagnosis is confirmed by muscle biopsy with low or absent LDH activity and/or detection of mutations in the lactate dehydrogenase A (LDHA) gene. There is no specific treatment. (See 'Deficiency of the M isoform' above.)

Deficiency of the H isoform of LDH appears to have no clinical consequences. (See 'Deficiency of the H isoform' above.)

  1. McClelland GB, Khanna S, González GF, et al. Peroxisomal membrane monocarboxylate transporters: evidence for a redox shuttle system? Biochem Biophys Res Commun 2003; 304:130.
  2. Hidaka K, Ueda N, Hirata I, et al. First case of missense mutation (LDH-H:R171P) in exon 4 of the lactate dehydrogenase gene detected in a Japanese patient. J Hum Genet 1999; 44:69.
  3. Sudo K. [Lactate Dehydrogenase M subunit deficiency]. Rinsho Byori 2002; 50:571.
  4. Miyajima H, Takahashi Y, Suzuki M, et al. Molecular characterization of gene expression in human lactate dehydrogenase-A deficiency. Neurology 1993; 43:1414.
  5. Tein I. Metabolic myopathies. Semin Pediatr Neurol 1996; 3:59.
  6. Monroe GR, van Eerde AM, Tessadori F, et al. Identification of human D lactate dehydrogenase deficiency. Nat Commun 2019; 10:1477.
  7. Kwong AK, Wong SS, Rodenburg RJT, et al. Human d-lactate dehydrogenase deficiency by LDHD mutation in a patient with neurological manifestations and mitochondrial complex IV deficiency. JIMD Rep 2021; 60:15.
  8. Drabkin M, Yogev Y, Zeller L, et al. Hyperuricemia and gout caused by missense mutation in d-lactate dehydrogenase. J Clin Invest 2019; 129:5163.
  9. McHale C, Keating E, O'Donovan H, Slattery E. D-lactic acidosis presenting as metabolic encephalopathy in a patient with short bowel syndrome. BMJ Case Rep 2021; 14.
  10. Kanno T, Maekawa M. Lactate dehydrogenase M-subunit deficiencies: clinical features, metabolic background, and genetic heterogeneities. Muscle Nerve Suppl 1995; 3:S54.
  11. Anai T, Urata K, Tanaka Y, Miyakawa I. Pregnancy complicated with lactate dehydrogenase M-subunit deficiency: the first case report. J Obstet Gynaecol Res 2002; 28:108.
  12. Nazzari G, Crovato F. Annually recurring acroerythema and hereditary lactate dehydrogenase M-subunit deficiency. J Am Acad Dermatol 1992; 27:262.
  13. Ito T, Aoshima M, Sugiura K, et al. Pustular psoriasis-like lesions associated with hereditary lactate dehydrogenase M subunit deficiency without interleukin-36 receptor antagonist mutation: long-term follow-up of two cases. Br J Dermatol 2015; 172:1674.
  14. Yue D, Zhu W, Zhao C. Exertional myalgia, contractures and annular erythema in a patient with muscle lactate dehydrogenase (LDH) deficiency. Neuromuscul Disord 2018; 28:59.
  15. Takeo N, Fujiwara S, Sakai T, et al. Hereditary lactate dehydrogenase M-subunit deficiency with late-developing pustular psoriasis-like lesions. J Dermatol 2016; 43:1429.
  16. Griggs R, Mendell J, Miller R. Metabolic myopathies. In: Evaluation and treatment of myopathies, Griggs R, Mendell J, Miller R (Eds), FA Davis Company, Philadelphia 1995. p.247.
  17. Maekawa M, Sudo K, Kanno T, Li SS. Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem Biophys Res Commun 1990; 168:677.
  18. Wakabayashi H, Tsuchiya M, Yoshino K, et al. Hereditary deficiency of lactate dehydrogenase H-subunit. Intern Med 1996; 35:550.
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