Newly ID’d MECP2 Gene Mutation Linked to Congenital Rett Syndrome | Researchers Urge Testing for Respiration Issues in Such Circumstances

A new mutation has been found in the MECP2 gene — associated with most Rett syndrome cases — in a toddler with clinical features suggestive of congenital variant-like Rett syndrome, one of the most severe atypical forms of the disease.

The child had hypercapnia, or high carbon dioxide levels in the bloodstream, but this occurred only when she was sleeping, according to the case report. The researchers noted that these elevated levels were not caused by obstructive sleep apnea, a condition characterized by repeated obstruction to the airways during sleep.

“Such findings were never reported before in a child affected by Rett syndrome,” the researchers wrote in describing “the ventilatory and clinical management of this unique case.”

Additionally, the team suggested screening patients with congenital-like Rett syndrome via bedtime carbon dioxide and oxygen monitoring.

The report, “Hypoventilation and sleep hypercapnia in a case of congenital variant-like Rett syndrome,” was published in the Italian Journal of Pediatrics.

New mutation found in MECP2 gene

Rett syndrome, which almost exclusively affects girls, is characterized by neurological and motor problems that arise between 6 and 18 months of age.

Atypical forms of Rett syndrome occur when not all Rett diagnostic criteria are met.

There are several subtypes of atypical Rett, with some milder and others more severe than classic Rett syndrome. The most severe atypical form is congenital Rett syndrome, also known as the Rolando variant, which is caused by mutations in the FOXG1 gene. Notably, however, some clinicians now consider this disease a separate entity called FOXG1 syndrome.

While classic Rett leads to breathing problems, particularly when patients are awake, whether this symptom occurs in patients with atypical forms of the disorder is unclear.

In this study, researchers in Italy described the case of a 20-month-old girl with symptoms of congenital Rett syndrome. She had breathing problems that would occur exclusively during periods of sleep.

The child was born with low muscle tone, called hypotonia, but most tests came back normal. This included testing for Angelman syndrome and Prader-Willi syndrome, two genetic disorders.

By the age of 10 months, the girl showed a delay in motor skills. She couldn’t control her head properly or grasp objects. She fixed her gaze just for up to three minutes. Her height and head circumference also were below average for a child her age. Over the following months, her muscle tone worsened.

Using next-generation sequencing (NGS) — a genetic test that allows the sequencing of multiple genes — the team identified a de novo variant in the MECP2 gene that had never before been reported.

De novo mutations arise during embryonic development and are not inherited. The MECP2 gene provides instructions for a protein of the same name, which is important in regulating gene activity.

According to researchers, this child “shows a mutation encoding for a stop codon with a likely deep impairment in the protein function. Such type of mutation fits with the particularly severe clinical picture of the patient.”

A stop codon is a specific DNA sequence that essentially halts protein production in a cell.

“As our patient presents all the clinical presentation of Rolando variant, we consider she has a congenital variant-like Rett syndrome,” the team wrote.

Team recommends screening for similar patients

An X-ray taken after the genetic analysis confirmed that the toddler had extremely early-onset scoliosis, an abnormal sideways curvature of the spine.

During sleep, she also experienced hypoventilation — slow or shallow breathing that causes the body’s carbon dioxide level to rise — and periodic breathing. This was defined as pauses in breathing lasting longer than three seconds separated by less than 20 seconds of normal breathing. At night, her oxygen saturation levels would drop to below 90%, which is considered low.

The child did not have obstructive sleep apnea, defined as the absence of nasal airflow with continued chest movements for two or more breaths. Additionally, a pulse oximetry — a test that measures the oxygen level in the blood — and a capnography, which measures the partial pressure of carbon dioxide from the airway, were normal when she was awake.

She was put on non-invasive ventilation (NIV) to help her breathe during bedtime. After optimizing the system, a slight improvement in muscle tone and social interactions with her caregiver were observed.

Further assessments, including a polysomnography — a sleep study that records brain waves, oxygen levels in the blood, heart rate, and breathing — will be done after four months and every six months thereafter, the team said.

“To the best of our knowledge, this is the first case reporting [low oxygen blood levels] and persistent hypercapnia during sleep-time in a patient affected by a congenital form of [Rett syndrome],” the researchers wrote.

The team urged clinicians to be proactive in screening other patients with this variant.

“This single case suggests the need for a very early polygraph or at least pulse oximetry plus capnography in each patient affected by the congenital variant of Rett syndrome. Broadly speaking, we suggest considering NGS techniques to reach tricky diagnosis such as Rett syndrome with congenital features in hypotonic patients,” they concluded.