Laboratory Abnormalities in Ambulatory Patients With Myotonic Dystrophy Type 1

Background  Myotonic dystrophy type 1 (DM1) is the most prevalent form of adult muscular dystrophy worldwide. Although well known for the classic manifestations of myotonia, weakness, and early cataracts, it has broad effects on multiple organ systems.

Objective  To analyze and compile the laboratory abnormalities of 126 adult patients with DM1.

Design  Laboratory data obtained before treatment were compiled and include values for 45 different laboratory tests and 2860 total studies.

Setting  University hospital.

Patients  One hundred twenty-six medically healthy, mild to moderately affected, ambulatory patients with DM1 and good venous access enrolled in one of 12 major DM1 clinical trials at a university hospital from 1975 to 2005.

Results  Of the 2860 laboratory studies, results for 470 (16.4%) were outside their reference ranges. Of the 45 types of laboratory tests studied, 41 demonstrated abnormal findings. The relative frequency of an abnormally elevated laboratory value was greater than 50% in several tests, including levels of hemoglobin A_1c, follicle-stimulating hormone, luteinizing hormone in men, and γ-glutamyltransferase and creatine kinase in women. In addition, levels of lactate dehydrogenase in men and hemoglobin in women were abnormally high or low in more than 50% of the test results evaluated.

Conclusion  There is a high frequency of abnormal laboratory values in DM1 that may form a basis for early screening and monitoring and provide insight into the spectrum of tissues involved in this disease.

Myotonic dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy in the world, affecting 5 to 20 of every 100 000 people.¹ Myotonic dystrophy type 1 is an autosomal dominant disorder caused by an unstable trinucleotide repeat expansion on chromosome 19q13.3.^2-4 The classic main features of DM1 are myotonia, weakness, and early cataracts (<50 years of age), although other organ systems are frequently involved, including the heart, brain, skin, reproductive organs, gastrointestinal tract, and endocrine system.⁵ The multiple tissue involvement in DM1 is often reflected by varied abnormal laboratory values in this disease. The frequency of the occurrence of these abnormal test results is unknown, because a large-scale evaluation of routine baseline laboratory values in mild to moderately affected patients with DM1 (hereafter referred to as DM1 patients) has not been performed.

An evaluation of routine laboratory abnormalities in ambulatory, mildly symptomatic DM1 patients is important in 4 regards. First, in a disease with such phenotypic variability, it provides a baseline estimate of the associated multitissue manifestations. Second, it provides information that may be used to direct a practitioner who encounters abnormal values toward the clinical diagnosis of DM1. Third, it expands our view of the physiological dysfunction seen in DM1. Fourth, it suggests potential subclinical organ dysfunction that may need to be followed up by practitioners over time for potential worsening. Herein we compile the laboratory abnormalities of 2860 separate studies from 126 ambulatory DM1 patients.

The laboratory data were collected from 126 ambulatory DM1 patients. Inclusion criteria were (1) the diagnostic criteria for DM1 as set by Griggs and Wood (1989)⁶; (2) age 18 to 60 years; (3) volunteer status for 1 of 12 DM1 clinical trials from the Neuromuscular Disease Center, University of Rochester, Rochester, NY, from 1975 to 2005; (4) the ability to ambulate independently (cane, walker, or orthoses allowed); and (5) good venous access.

In addition to meeting diagnostic criteria for DM1, 45 of the 126 patients had DNA test results positive for a CTG repeat elongation (mean number of repeats, 593; range, 169-1731). The patients came from multiple social, ethnic, and regional backgrounds. In many cases, multiple sets of laboratory data were obtained on the same patient during subsequent visits. In this analysis, only the results of the baseline laboratory testing, before enrollment in clinical research studies, were tabulated. Each initial baseline blood draw was performed with the patient in a fasting state. Each patient was observed at a clinical research center for a minimum of 10 hours before his or her blood was drawn to ensure that a true fasting state was achieved. Overall, the patient population represented early to midstage DM1 and did not include individuals with congenital DM1. Patients were excluded from the original clinical trials if they fit any of the following criteria:

• Known cancer (excluding benign skin cancer or pilomatricoma)

• Active or symptomatic disease of the heart, liver, kidney, pancreas, intestine, or hematologic system

• Known epilepsy

• Active tobacco use (smoking or chewing) up to 2 days before the study

• Use of any antidiabetic, antimyotonic, antiepileptic, anticoagulant, or corticosteroid medication

• Younger than 18 years

• Older than 60 years

• Known to be pregnant or lactating

• Known neuromuscular disease other than DM1

• Alcohol or other drug abuse within 3 months of the enrollment

• Inability to give consent

Each patient underwent multiple laboratory studies, although none underwent all 45 separate tests. The data were divided into male and female study groups. In instances where standard laboratory ranges were based on menstrual staging (ie, levels of follicle-stimulating hormone and luteinizing hormone), the reference range was broadened to include all possible premenstrual and postmenopausal values. The reference laboratory ranges used in our analysis were based on the current standardized test reference ranges at Strong Memorial Hospital Clinical Laboratories, Rochester. These ranges are set through varied methods, including local volunteer testing and outside data accumulation. Data for this study were collected from 92 men and 34 women. No patient's data were excluded from this study on the basis of abnormal initial blood test results. Men outnumbered women in part because the clinical trials required easy venous access or involved the administration of testosterone or growth hormones, which produce masculine features in women. The effects of the menstrual cycle on insulin action precluded some women with DM1 from participating in certain clinical trials. The laboratory tests are included in Table 1 and Table 2 in order from highest to lowest percentage of abnormal values by sex and include the standard deviation, reference ranges, average value, and total number of patients studied.

Of the 2860 laboratory studies performed, DM1 patients had 470 abnormal laboratory values. Male DM1 patients had abnormal laboratory values in 38 of 45 categories; female patients, in 36 of 44 categories. In men with DM1, 8 separate tests had abnormal laboratory values in more than 30% of the men tested. These included levels of lactate dehydrogenase (LD), hemoglobin A_1c, follicle-stimulating hormone, luteinizing hormone, total serum cholesterol, mean corpuscular hemoglobin, γ-glutamyltransferase (GGT), and serum triglycerides. In women with DM1, 11 of 44 categories had abnormal laboratory values in more than 30% of the women tested. These included levels of GGT, creatine kinase, hemoglobin, triglycerides, serum cholesterol, albumin, serum creatinine, LD, aspartate aminotransferase, testosterone, and mean corpuscular hormone. Some of the abnormal laboratory values were consistently elevated (ie, GGT and creatine kinase levels), whereas others were consistently low (ie, albumin and serum creatinine levels). For some tests (ie, LD and testosterone levels), abnormal values were sometimes elevated and at other times in the low range.

Certain laboratory tests showed no abnormalities. No abnormalities were demonstrated for levels of prostate-specific antigen, triiodothyronine (in men), mean cell hemoglobin concentration (in men), or several portions of the differential white blood cell count. However, the total white blood cell counts were often low (17 [22%] of 79 DM1 patients), and the mean corpuscular hemoglobin level was often elevated (26 [33%] of 79 DM1 patients).

Our tabulated data add to prior studies of abnormal laboratory values in DM1. Two previous studies of serum testosterone levels in DM1 reported decreased levels. One reported a decrease in the average testosterone level of 42 DM1 patients compared with control subjects.⁷ A second study showed that 4 of 26 DM1 patients had a baseline low testosterone level.⁸ In our population, 14 (26%) of 53 DM1 patients undergoing testing had abnormal levels of testosterone. However, of the 14 with abnormal testosterone levels, 7 had elevated levels, and 7 had low levels. In 1997, Kinoshita et al⁹ reported baseline low calcium levels in 13 DM1 patients. We found that 6 (8%) of 79 DM1 patients undergoing testing had low calcium levels; however, when corrected for albumin levels, all calcium levels were within the reference range. Past studies of liver enzyme levels reported elevations in 35 (66%) of 53 DM1 patients, and elevated GGT levels in 11 (65%) of 17 patients with DM1.^10,11 Likewise, our patients demonstrated abnormal values in all liver enzyme levels tested; however, only 15 (45%) of 33 DM1 patients undergoing testing had elevated GGT levels. Finally, in 1989, Moorjani et al¹² observed elevated plasma triglyceride and very low-density lipoprotein cholesterol levels in DM1 patients compared with controls. We observed that 24 (41%) of 58 DM1 patients undergoing testing had elevated total serum cholesterol levels, and 11 (33%) of 33 had elevated triglyceride levels. The difference in the percentage of abnormal laboratory values between our patient population and the populations in the other studies may to a large degree relate to our inclusion of only ambulatory, mild to moderately affected individuals without other severe underlying disease. Further studies are necessary to confirm this possible explanation.

It is evident that DM1 is associated with abnormal laboratory results. To our knowledge, this is the first report to summarize a collection of a wide range of abnormal laboratory values from a large population of ambulatory DM1 patients. Because our study population excluded DM1 patients with other underlying diseases, our data likely underestimate the amount of laboratory abnormalities in DM1 patients in the community. These data reinforce the principle that DM1 is a multisystem disease. In addition, these data may serve as a reference for physicians monitoring the laboratory data of DM1 patients through routine care and implementation of new pharmacological therapeutics. We also expect that serial measurement of abnormal laboratory values can be used to further define the disease and promote research.

Early screening and treatment of hypercholesterolemia, hypertriglyceridemia, hyperglycemia, and thyroid abnormalities may prove beneficial in DM1 patients, given the frequency of these abnormalities. Likewise, correction of low serum testosterone values may increase the decreased muscle mass in DM1 patients.¹³

There is a relatively frequent appearance of abnormally elevated liver enzyme levels (GGT, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and LD) in DM1. It has been speculated that the etiology of these elevations is from a cell membrane defect affecting the contractility of bile ductules,¹⁰ although more studies are needed to tie the genetic abnormalities of DM1 to these putative membrane defects. An alternative interpretation is that the elevation of GGT levels represents dysfunction of the hepatocyte, and that the elevation of aspartate aminotransferase, alanine aminotransferase, and LD levels is caused by abnormal skeletal muscle in DM1. The clinical and pathophysiologic significance of the elevation of hepatic enzymes remains uncertain. At present, it seems prudent to consider these specific abnormal laboratory values as subclinical indicators of potential organ dysfunction and to monitor hepatic enzyme levels serially when patients receive medications that depend on metabolic clearance by the liver. The 24 (30%) of 79 DM1 patients with low albumin levels may also have a subclinical alteration in the function of hepatocytes and/or ductal cells. Nutritional deficiency secondary to poor eating habits, dysphagia, or abnormal absorption are also etiologic possibilities. If abnormal absorption is the cause of low albumin levels in DM1, an adjustment in diet may provide benefit.

More studies are needed to evaluate the significance of the numerous laboratory abnormalities of DM1 to determine the best opportunities for treatment.

Correspondence: Chad R. Heatwole, MD, Neuromuscular Disease Center, Strong Memorial Hospital, University of Rochester, 601 Elmwood Ave, PO Box 673, Rochester, NY 14642 (chad_heatwole@urmc.rochester.edu).

Accepted for Publication: February 21, 2006.

Author Contributions: Dr Heatwole had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Heatwole, Miller, and Moxley. Acquisition of data: Heatwole, Martens, and Moxley. Analysis and interpretation of data: Heatwole, Miller, and Moxley. Drafting of the manuscript: Heatwole and Moxley. Critical revision of the manuscript for important intellectual content: Heatwole, Miller, Martens, and Moxley. Statistical analysis: Heatwole and Martens. Obtained funding: Moxley. Administrative, technical, and material support: Heatwole and Moxley. Study supervision: Heatwole and Moxley.

Acknowledgment: We thank Robert Griggs, MD, Charles Thornton, MD, William Kingston, MD, and all the patients and staff who participated in the trials that made this study possible.