LMOD3 Gene Variant Identified in Hypersomnolence Case With Potential Kleine-Levin Syndrome

Kleine-Levin syndrome is rare and difficult to diagnose, especially when symptoms are atypical. Recent research points to LMOD3 variations as a potential diagnostic marker if confirmed by further research.

Kleine-Levin syndrome (KLS), a rare sleep disorder that is difficult to diagnose, can have debilitating effects on patients but does not have any known biomarkers. A case report published in Sleep Medicine identified a variant of the LMOD3 gene in a possible case of atypical KLS that might hold diagnostic potential if further research confirms its utility.

KLS is characterized by hypersomnolence, cognitive issues, psychiatric disturbances, and reduced inhibition, but there are no known biomarkers or etiology associated with it. Diagnosis is based on patient history, and familial cases are rare. The associated periods of hypersomnolence can last from days to months, and there is significant variation between patients.

In the case report, a female patient and her family had an unclassified, periodic central disorder of hypersomnolence (CDH). The female patient started having hypersomnolence episodes in 2001 after muscle weakness led to a fall during a minor viral infection, several days after which she started sleeping through days and nights. She also had trouble waking up for meals, leading to weight loss.

Three weeks later, her hypersomnolence improved, but she still suffered from excessive daytime sleepiness (EDS) and sleep attacks. On the Epworth sleepiness scale, (ESS) she reported 20 points (out of 24) in 2002 and 8 points in 2004. Modafinil and antidepressants did not resolve the symptoms, and neuropsychological examination showed results within normal ranges. She dropped out of school due to issues related to the symptoms.

The patient’s symptoms were milder between 2004 and 2018, she retrospectively reported. In this time, episodes would only occur 2 or 3 times per year and were sometimes associated with stress or menstruation. EDS was a persistent issue between episodes of hypersomnolence.

In 2018, her hypersomnolence and associated symptoms worsened and were persistent between hypersomnolence episodes. Her symptoms improved in 2020 as her psychosocial health improved on bupropion treatment and counseling.

In this case, members of the patient’s maternal family were also positive for hypersomnolence and psychiatric conditions, including her mother, who reported EDS since childhood and experienced periods of long sleep duration that lasted up to months. Her mother also experienced periods of insomnia. The patient’s aunt and great-grandmother also had similar symptoms, and her grandfather had paranoid schizophrenia. The patient’s 2 siblings and father had no signs of any sleep-wake disorder.

The patient was initially referred to the study authors as a potential case of narcolepsy, but testing ruled out that suspicion. Idiopathic hypersomnia (IH) was another potential diagnosis, but the patient’s symptom fluctuations were not characteristic of IH. A long-term electroencephalography in 2002 showed that the patient got 8 to 10 hours of nocturnal sleep and that there was no daytime sleep propensity, despite a reported ESS of 17.

Given the discrepancies between subjective reported symptoms and objective findings in tandem with worsening symptoms at stressful times, hypersomnia associated with a psychological condition was also considered. But the patient was within normal ranges on psychosocial testing, and therefore the patient was diagnosed with atypical KLS and familial periodic hypersomnia.

The LMOD3 gene was sequenced in all family members due to the uncertainty of the patient’s diagnosis and based on recent findings that KLS could be associated with LMOD3 gene variants. The patient, her mother, and her asymptomatic sister all showed a proline for histidine substitution at the codon 552 on LMOD3, while her father and brother did not carry the variant.

This variant was reported in 2 sporadic cases of KLS previously, leading to suspicions that LMOD3 variants are pathogenic for KLS. Although study authors note that more research on larger groups is needed to confirm diagnostic potential of variants on LMOD3, this case was diagnosed as an atypical form of familial KLS.

“We recommend further systematic research on CDH and KLS and the assessment of the LMOD3 gene variants in a case-control study with patients having a clear KLS diagnosis,” study authors concluded. “There is a strong need for biomarkers allowing an earlier and accurate diagnosis of KLS.”

Reference

Wenz E, Tafti M, Bassetti CLA. LMOD3 gene variant in familial periodic hypersomnolence. Sleep Med. Published online February 28, 2022. doi:10.1016/j.sleep.2022.02.019