Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation

Abstract

Mutations in exons 21 and 20 of the DMNT1 gene have been associated with two multisystem neurodegenerative diseases that involve central and peripheral nervous system ADCADN (Autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy) and HSAN 1E (Hereditary Sensory and Autonomic Neuropathy IE). We describe a new case of ADCADN that was referred to us in the suspicion of secondary narcolepsy. A 44-year-old female with personal and familiar longstanding history of progressive bilateral sensorineural deafness, and sensitive cerebellar ataxia, presenting with brief episodes of falls while laughing and excessive diurnal somnolence. Clinical and neurophysiological evaluations reveled signs of cerebellar, pyramidal, peripheral, cognitive involvement, and optical atrophy. A 48-hour continuous polysomnography (PSG) and Multiple Sleep Latency Test at first evaluation revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency without sleep onset REM periods (SOREMPs). Normal level of cerebrospinal fluid (CSF) hypocretine 1 was detected. Given the reminiscence with DNMT 1 spectrum a direct sequencing of exons 20 and 21 of the DNMT1 gene was performed revealing the p.Glu575Lys mutation in exon 21 in the proband and her mother. During the 4 years of follow-up her walking ability declined, she became more somnolent and repeated PSG documented REM sleep latency shortening, and finally the evidence of de novo spontaneous SOREMPs, although normal CSF hrct-1 at second revaluation. This case highlights the progressive course of disease although a full-blown picture of classical narcolepsy type 1 was never reached.

Citation:

Postiglione E, Antelmi E, Pizza F, et al. Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation. J Clin Sleep Med. 2020;16(1):143–147.

INTRODUCTION

DNA methyltransferase 1 gene (DNMT1) encodes for the major enzyme involved in genomic methylation patterns. DNMT1 mutations are the cause of two discrete hereditary entities,^1,2 autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCA-DN) with mutations in exon 21, and hereditary sensory and autonomic neuropathy (HSAN1E) with mutations in exon 20, respectively. HSAN1E² has a prominent peripheral nervous system involvement, whereas ADCA-DN³ a prominent central nervous system involvement, with cerebellar ataxia and narcolepsy with cataplexy. Clinical evidence seems to challenge the former classification suggesting that the phenotypes of patients carrying mutations in the two DNMT1 exons may largely overlap.^4–7 Both of these methylopathies indeed may present with wide involvement of the nervous system, including optic atrophy, narcolepsy, peripheral neuropathy, and behavioral and cognitive aspects, together with a multisystemic involvement. Particularly, sleep complaints have been reported in both conditions, even rarely characterized by means of instrumental and serological investigations (Table 1).

Table 1.

Instrumental and serological investigation in patients with DNMT1 mutation complaining of sleep disorders reported in the literature.

Here, we describe a new Italian case of DNMT1 syndrome, belonging to unreported kindred and carrying a mutation in exon 21 of DNMT1. The patient was referred to our narcolepsy center because of suspicion of a secondary narcolepsy, presenting with cerebellar ataxia, deafness, cataplexy and excessive daytime sleepiness (EDS). However, the biological and neurophysiological hallmarks of type 1 narcolepsy, namely low levels of cerebrospinal fluid hypocretin-1 (CSF hcrt-1) and sleep-onset rapid eye movement periods (SOREMPs), are lacking.

REPORT OF CASE

A 44-year-old female was referred to our narcolepsy center because of EDS and falls to the ground elicited by laughing. Since she was 39 years old, the patient reported a feeling of paroxysmal tingling and progressive lower limbs weakness often leading to falls to the ground, triggered by laughter. Since age 43 years, she has experienced disrupted nocturnal sleep and tendency to fall asleep during the day. Past medical history revealed a 15-year history of progressive asymmetrical bilateral sensorineural deafness leading to bilateral cochlear implants. She also reported, since her early 40s, gait instability, upper limb tremor, nocturnal cramps, lower limb pain and numbness, urinary urgency, and femoral chondromalacia.

Family history disclosed the recurrence of similar clinical manifestations in the patient’s mother, in whom bilateral sensorineural hypoacusia developed during her 20s and who had a progressive gait disorder in her 40s, along with cognitive decline and personality changes. She also experiences falls trigged by emotions. Sleep complaints were not reported nor investigated. She died at age 55 years after the progression of symptoms left the patient bedridden.

Results of clinical investigations are reported in Table 2.

Table 2.

Diagnostic and follow-up investigations.

Briefly, investigations disclosed a sensory peripheral neuropathy, bilateral sensorineural deafness, and optic atrophy. Neuropsychological evaluation showed executive dysfunction and mild cognitive multidomain impairment with depressed mood.

Brain magnetic resonance imaging showed a mild diffuse brain and cerebellar atrophy, and multiple hyperintensities on T2 and fluid-attenuated inversion recovery-weighted sequences in cortical-subcortical areas. Brain positron emission tomography scan with fludeoxyglucose (¹⁸F) confirmed a diffuse and irregular decreased metabolic activity in cerebral parenchyma, with a prominent cerebellar involvement.

As far as sleep complaints were concerned, 48 hours of continuous polysomnography (PSG) and the Multiple Sleep Latency Test (MSLT) revealed a normal sleep structure with frequent diurnal sleep episodes and a pathological sleep latency (7’12”), without SOREMPs. Lumbar puncture showed a normal biochemical and cytological cerebrospinal fluid (CSF) profile, with neurodegeneration markers within the normal value (Tau, pTau, and beta amyloid), and normal CSF level of hcrt-1 (270 pg/mL). Human leukocyte antigen was negative for DQB1*06:02, that is the haplotype linked to narcolepsy.

The complex clinical symptoms (sensorineural deafness, peripheral neuropathy, cerebellar ataxia optic atrophy), psychiatric changes (depression), mild cognitive impairment, and cataplexy were reminiscent of DNMT 1 spectrum. This was confirmed by an exome and direct sequencing of exons 20 and 21 of the DNMT1 gene that revealed the p.Glu575Lys mutation in exon 21. The presence of the mutation was also found in the patient’s mother.

According to the International Classification of Sleep Disorders, Third Edition,⁸ hypersomnia due to a medical disorder was diagnosed and the patient started modafinil treatment up to the dose of 200 mg/d with an initial relevant improvement. Over that time, the patient acquired copy strategies to prevent or minimize cataleptic spells, to the extent that no additional treatment was needed. However, sleepiness worsened at 1-year follow-up despite modafinil dosage increase. EDS was also objectively documented at subsequent follow-up investigations (up to 4 years) and documented rapid eye movement sleep latency shortening, and the evidence of de novo spontaneous SOREMPs on repeated PSG (Figure 1). Nonetheless, SOREMPs were still lacking on MSLT, and repeated CSF hcrt-1 level was in a normal range. Walking abilities also progressed and gait become restricted to few meters with necessity of double support, due to worsening imbalance.

Figure 1. Evolution of hypnograms during the 4 years of follow-up.

Second day and second night of 48-hour continuous polysomnography. Grays boxes = off-recording. Sleep staging is depicted on the y axis (R = rapid eye movement, W = wakefulness, 1 = stage N1 sleep, 2 = stage N2 sleep, 3 = stage N3 sleep). Time recording is depicted on the x axis (hh:mm). During the follow-up, increased daytime sleep is observed and reduced latency to rapid eye movement sleep (arrow).

DISCUSSION

We reported an ADCA-DN phenotype due to a mutation in exon 21. The patient experienced central and peripheral degenerative nervous system involvement. It should be noted that the course and presentation of sleep symptoms and signs was progressive and variable, presenting close to disease onset with an uncommon isolated cataplexy, lacking the SOREMPs typical of narcolepsy type 1. The general conditions progressed over time, and SOREMPs become visible with nighttime PSG and during spontaneous daytime napping. Repeated CSF hrct-1 remained within the normal range.

The reported case brings to mind two important “take-home messages” in relation to methylopathies.

First, even though mutation of exon 21 has been linked to ADCA-DN phenotype, our patient experienced a spectrum of symptoms that was in between HSAN1E and ADCA-DN phenotypes, further confirming the clinical overlap between these two methylopathies, as previously suggested.^4–7

Another important issue concerns the progressive nature of DNMT1 mutation-related diseases. In our patient, the severity of symptoms and signs of central hypersomnia progressed along the disease course, without never reaching the full-blown picture of classic type 1 narcolepsy, as frequently seen in secondary narcolepsy.

Indeed, when we first observed the patient she was experiencing cataplectic spells; nevertheless, neurophysiological and biochemical investigations did not confirmed all the criteria for narcolepsy; that is, no SOREMPs and normal CSF hrct-1 level. However, subsequent evaluations showed the appearance of SOREMPs, although not detected by the MSLT. The presence of episodes of clear-cut cataplexy with normal level of CSF-hcrt1, and the absence of SOREMPs, highlights the possible involvement of alternative neurotransmitter pathways, other than the hypocretin system, in the cataplexy physiopathology. This could be true especially in secondary cases of narcolepsy with more widespread central nervous system involvement, in contrast with the selective massive destruction of dorsolateral hypothalamus of primary narcolepsy, mirroring what was reported in gelastic cataplexy of Niemann-Pick type C, or in other forms of secondary cataplexy.^9,10

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Work for this study was performed at IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. The authors report no conflicts of interest.

ABBREVIATIONS

ADCAN-DN

autosomal Dominant Cerebellar Ataxia with Deafness and Narcolepsy

CSF hcrt-1

cerebrospinal fluid hypocretin-1

DNMT1, DNA

methyltransferase 1

HSAN1E

hereditary Sensory and Autonomic Neuropathy

MSLT

Multiple Sleep Latency Test

PSG

polysomnography

SOREMPs

sleep onset rapid eye movement periods