Iron Therapy May Improve Sleep Quality in Young Angelman Patients

Sleep disturbances in people with Angelman syndrome may be at least partly associated with iron deficiency, according to a small study in the U.S.

The data also showed that supplementation with the mineral, which also is naturally present in many foods, improved the sleep quality of children with Angelman, as reported by their parents, supporting the treatment’s potential effectiveness at managing sleep problems in this patient population.

Further research is needed to confirm these findings and to better understand the mechanisms behind iron deficiency in Angelman patients, the researchers said.

The study, “Iron Deficiency and Its Role in Sleep Disruption in Patients With Angelman Syndrome,” was published in the Journal of Child Neurology.

Angelman syndrome is a complex genetic condition mainly caused by mutations in the maternal copy of the UBE3A gene. This gene provides instructions for making the enzyme UBE3A, which is thought to play a key role in the normal development and function of the nervous system.

“Up to 80% of Angelman syndrome patients have sleep initiation and maintenance difficulties,” researchers wrote, adding that such problems “can be stressful to patients and caregivers alike.”

However, the underlying mechanisms of Angelman-associated sleep disruption remain poorly understood.

Patients may have sleep-onset insomnia, multiple night awakenings, and long periods of remaining awake.

These disruptions may be related to several factors, such as epileptic seizures (a common symptom of the disease), the effects of anti-seizure medications, changes in the production patterns of the sleep hormone melatonin, UBE3A deficiency in particular areas of the brain, environmental factors, and inadequate sleep hygiene.

Notably, iron deficiency has been shown to contribute to sleep problems. But whether it is a contributing factor in Angelman patients is unknown.

Now, researchers at the Mayo Clinic in Rochester, Minn., evaluated whether sleep disturbances in people with Angelman were associated with iron deficiency.

The demographic and clinical data of 19 children and adolescents (10 boys and nine girls) with Angelman syndrome and sleep complaints, who were followed at the clinic between 2013 and 2017, were retrospectively analyzed. The patients’ mean age was 6.2 years, with a range from 8.4 months to 16.7 years, and most (89%) had seizures and were receiving anti-seizure treatment.

A total of 57 age- and sex-matched individuals — at a 3-to-1 ratio, or three for each patient — without the disease or any medical condition that could affect iron levels were included in the study as healthy controls.

Problems in falling and staying asleep were the most common sleep complaint (95%) among the Angelman patients, followed by periodic limb movement disorder (37%) and obstructive sleep apnea (32%).

Fifteen 15 of these patients underwent a sleep study, which showed poor sleep efficiency in 13 (87%) of them, and high periodic limb movement (PLM) index in nine (60%). The PLM index is the number of periodic leg movements per hour of total sleep time.

The team first compared the blood levels of ferritin — a protein that represents the main form of iron stored in the body’s cells — of the Angelman patients with those of the healthy controls.

Results showed that the children and adolescents with Angelman had lower mean ferritin levels compared with unaffected individuals (19.9 micrograms/L vs. 27.8 micrograms/L), but this difference did not reach statistical significance.

However, 15 patients (79%) had iron deficiency — identified as ferritin levels lower than 24 micrograms/L — and the children and adolescents with Angelman were found to be four times more likely to have iron deficiency than the healthy controls.

The team then assessed the effects of iron supplementation in the sleep quality of the patients with this genetic disorder.

Iron therapy was recommended to 17 patients (89%), including all of those with a high PLM index. Nine patients received oral iron supplementation, while four received intravenous (into-the-vein) iron therapy; the remaining four were given both oral and into-the-vein treatment.

Follow-up data was available for 12 (71%) of these patients (seven with high PLM index and five without), with parents reporting sleep improvements in all of them. Notably, data from an additional sleep study after iron therapy showed that PLM was resolved in a girl with a previously high PLM index.

Available follow-up ferritin data from eight patients showed that ferritin levels were increased by a mean of 24 micrograms/L following iron supplementation.

These findings suggested that “sleep difficulties in Angelman syndrome, though multifactorial, may in part be related to iron deficiency,” the researchers wrote, adding that treating disease-related sleep problems with oral or into-the-vein iron “may be helpful in improving subjective sleep quality.”

The team hypothesized that the potential link between Angelman syndrome and iron deficiency may be directly associated with UBE3A dysfunction, as it is known to interact with another enzyme involved in the regulation of iron metabolism.

Further studies are needed to clarify this and to better assess the therapeutic benefit of iron supplementation in this patient population, they concluded.