Hypoglycemia in patients with congenital muscle disease

Hypoglycemia, defined as a blood glucose level below 60 mg/dl (3.3 mmol/L) in infants and children [1], has been reported sporadically in children with neuromuscular disease [2, 3]. Bruce et al. described two girls with spinal muscular atrophy type II (muscle mass only 10% of body weight) with recurrent, severe hypoglycemic episodes that went unrecognized until the girls became comatose and were found to have blood glucose levels of 30–34 mg/dl (1.7–1.9 mmol/L) and metabolic acidosis [2]. In one girl (case #2), hypoglycemia frequently developed in the morning after fasting overnight [2]. Shu et al. reported a similar case; a 7-year-old boy with congenital muscular dystrophy with hypoglycemic episodes both upon awakening and during the course of viral illnesses [3]. A 34-h fasting study in 9 boys with Duchenne muscular dystrophy did not precipitate hypoglycemia, however these patients demonstrated lower alanine levels [4], suggesting a decreased reserve of gluconeogenic substrate from muscle. Reports of hypoglycemia are equally rare among adults with neuromuscular disease [5, 6]. Importantly, the incidence of hypoglycemia among adults and children with neuromuscular disease has not been systematically investigated.

It has been proposed that low muscle mass in the context of muscle atrophy predisposes children with neuromuscular disorders to hypoglycemia. In healthy children, glucose levels can be maintained by hepatic glycogenolysis during periods of fasting for approximately 8–12 h [7]. As glycogen stores are depleted, however, amino acids derived from the breakdown of muscle tissue become essential substrates for hepatic gluconeogenesis [7]. In the glucose-alanine cycle, for example, alanine is released into the bloodstream by skeletal muscle and taken up by the liver [7]. There, it is converted to pyruvate which then enters the gluconeogenic pathway, creating glucose that can be shuttled back to muscle as an energy source [7]. Thus, when a patient with low muscle mass fasts or has increased energy requirements (e.g. during illness), he/she may be at risk for developing hypoglycemia due to inadequate gluconeogenic substrate from muscle. This risk is compounded in children because of their limited hepatic glycogen stores compared with adults [8, 9].

In this retrospective study, we identified 10 patients with a confirmed molecular or clinical and immunohistological diagnosis of congenital muscular dystrophy or congenital myopathy who experienced at least one episode of documented hypoglycemia. We report the frequency, common triggers, and symptoms associated with hypoglycemia episodes as well as any accompanying biochemical abnormalities available. We suggest that these patients deserve prompt evaluation of glucose levels when presenting with signs and symptoms of hypoglycemia and routine evaluation of glucose homeostasis.

An IRB-approved study announcement was distributed electronically to all members of the Congenital Muscle Disease International Registry (CMDIR) by CMDIR staff. Families who expressed interest in participating in this study were then directed to contact the investigator (LH) via e-mail and medical information release consents were secured to request and review participants’ medical records. Patients were included if they: 1) had an established clinical and molecular diagnosis of congenital muscular dystrophy or congenital myopathy (based on genetic testing and/or muscle biopsy), and 2) had a history of at least one documented episode of symptomatic hypoglycemia (defined as a blood glucose level < 60 mg/dL) between the ages of 1–10 years.

Of the 1702 patients registered in the CMDIR, 38 registrants had an established diagnosis of a congenital myasthenic syndrome and were not included. The remaining 1664 patients were contacted, and 17 families responded to the inquiry and were then contacted directly by the investigators. Of the 17 patients with congenital muscle disease, five did not meet inclusion/exclusion criteria because they reported isolated neonatal hypoglycemia or could not provide documentation of hypoglycemia. Two patients did not respond to further emails from the study staff. The remaining 10 patients were included in the review of records and were contacted for necessary clarifications. A flowchart of study recruitment for patients is shown in Fig. 1.

Anthropometric data was also obtained from age-, sex-, and BMI (body mass index)-matched patients with congenital muscular dystrophy without a history of hypoglycemia who were evaluated at the National Institutes of Health (NIH) as part of an IRB-approved natural history study (protocol 12-N-0095). Note that in patients with congenital muscle disease, as well as in other patients with joint contractures, standing height is approximated using ulnar length [10].

In this retrospective registry-based study, we report a cohort of 10 patients with genetically and/or pathologically confirmed forms of congenital muscle disease (congenital muscular dystrophies or congenital myopathies) who experienced at least one episode of hypoglycemia. We show that these hypoglycemic episodes are typically associated with clinical symptoms, ranging from increased fatigue to decreased alertness and are often associated with profound metabolic abnormalities consistent with a ketotic hypoglycemic state. Consistent with previous reports, these hypoglycemic episodes are typically triggered by prolonged periods of fasting or situations of increased glucose demand such as intercurrent illness or increased physical activity. Hypoglycemic episodes were recurrent and required aggressive treatment in most of the patients studied in this cohort.

There are multiple potential mechanisms by which patients with congenital muscle disease may be at risk for developing hypoglycemia. Decreased muscle mass is believed to account for the higher risk of hypoglycemia in patients with neuromuscular disease [5, 6]. Indeed, skeletal muscle is an essential source of amino acid substrate for gluconeogenesis during periods of prolonged fasting. While we did not have access to urine creatinine or DEXA data to estimate lean muscle mass, we did not find a strong association between hypoglycemia and BMI percentile. Further, as the majority of hypoglycemic episodes occurred in patients younger than 10 years-of-age and resolved over time, we suspect that the pathophysiology of hypoglycemia in CMD patients may overlap with that of idiopathic ketotic hypoglycemia in normal children [11].

There may also be disease-specific factors that predispose CMD patients to ketotic hypoglycemia. For example, LAMA2-related dystrophy is caused by a deficiency of laminin-211 (also known as merosin). It is of interest that laminin-211 is expressed not only in muscle tissue but also in the basement membrane of pancreatic insulin-producing beta cells [12, 13]. However, hyperinsulinism is typically associated with non-ketotic hypoglycemia and the majority of CMD patients had ketonuria. Another possibility is that the increased metabolic rate in pediatric patients with congenital muscle disease is contributory, as has been described in patients with Duchenne muscular dystrophy [14]. Future prospective studies in a larger patient cohort that include detailed biochemical parameters will be necessary to better understand the cause of hypoglycemia among patients with CMD.

The recruitment of patients to this study was limited by family initiative and engagement with the CMDIR and hence resulted in a low response rate. Since the small sample size and retrospective nature limits our conclusions, it will be necessary to further investigate the occurrence of hypoglycemia in patients with congenital muscle disease in a prospective study.

In conclusion, we report hypoglycemia as an important clinical occurrence in a cohort of 10 pediatric patients with congenital onset muscle disease. These patients appear to be more susceptible to hypoglycemia during early childhood, possibly due to low muscle mass resulting in inadequate gluconeogenic substrate. Thus, a glucose level should be checked in any patient who presents with an unexplained change in level of alertness, nausea and/or vomiting Specifically we recommend that (1) patients and their caregivers should monitor glucose levels during prescribed fasts (in preparation for surgery or other procedures requiring anesthesia) or during periods of illness when normal oral intake cannot be maintained; (2) first line providers should be aware of an apparent increased risk of hypoglycemic episodes in pediatric patients with congenital muscle disease and tailor diagnostic testing and fluid resuscitation protocols accordingly; and (3) providers should consider screening CMD patients for hypoglycemia with fasting glucose levels to identify those at risk.

Children with congenital muscle disease are at risk for episodes of ketotic hypoglycemia, often triggered by illness or fasting, which we postulate is related to low muscle mass and possible intrinsic muscle factors. Clinically, patients should be monitored closely for symptoms of hypoglycemia, be promptly evaluated and treated, and preventative measures should be considered.