Sudden Unexpected Death with Rare Compound Heterozygous Variants in PRICKLE1
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neurogenetics (2019) 20:39–43 https://doi.org/10.1007/s10048-018-0562-8 SHORT COMMUNICATION Sudden unexpected death with rare compound heterozygous variants in PRICKLE1 Yukiko Hata1 & Koji Yoshida2,3 & Naoki Nishida1 Received: 29 October 2018 /Accepted: 8 December 2018 /Published online: 18 December 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Progressive myoclonus epilepsy-ataxia syndrome (EPM5) is an autosomal recessive form of progressive myoclonus epilepsy that has been associated with a homozygous missense mutation in PRICKLE1. We report a 23-year-old male who died shortly after refractory convulsion and respiratory failure. Autopsy showed unilateral hippocampal malformation without significant neuronal loss or gliosis. Genetic analysis that targeted both epilepsy and cardiac disease using next-generation sequencing revealed two variants of PRICKLE1. Additional investigation showed that the patient’s father (p.Asp760del) and mother (p.Asp201Asn) each had a mutation in this gene. The present case shows that EPM5 can also be caused by compound heterozygous mutations. Keywords Compound heterozygous mutation . Hippocampus . Neuropathology . PRICKLE1 . Progressive myoclonus epilepsy . Sudden death Introduction Here we report the autopsy of a young man with a complex heterozygous mutation in PRICKLE1 whodiedsuddenly Progressive myoclonus epilepsy (PME) is a complex of neu- without medical treatment antemortem. rodegenerative diseases that show action myoclonus, epileptic seizures and progressive neurologic decline as core clinical features. The genetics and presentation of PME are varied, Case description making the diagnosis of specific forms of PME without ge- netic investigation particularly challenging [1]. One of the PMEs, progressive myoclonus epilepsy-ataxia syndrome type At midnight, a 23-year-old, male construction worker experi- 5 (EPM5), is an autosomal recessive form that has been asso- enced a sudden loss of consciousness with convulsions while ciated with a homozygous missense mutation in PRICKLE1 driving home after a karaoke party. His colleagues called the [1, 2]. Neuropathological reports of PMEs are rare, and our emergency services, and he was transferred to a general hos- literature survey has not found any such reports for EPM5. pital. On admission, his Glasgow Coma Scale score was 100. He continuously experienced convulsions and unstable respi- ratory conditions despite being in intensive care, and he died Electronic supplementary material The online version of this article 5 h after admission. The absence of structural abnormalities (https://doi.org/10.1007/s10048-018-0562-8) contains supplementary and disease was confirmed by biochemical examination of the material, which is available to authorized users. blood and radiological examination that included a computed tomography scan of his general body during intensive care. * Naoki Nishida He had neither been diagnosed nor received any medical [email protected] treatment of any kind throughout his life; however, his col- 1 Department of Legal Medicine, Graduate School of Medicine and leagues and friends had witnessed him having convulsive at- Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, tacks several times over the last year, and these convulsions Toyama 930-0194, Japan were witnessed three times in the last month. According to his 2 Department of Neurology, Toyama University Hospital, friends, all the previous convulsions they had witnessed disap- Toyama, Japan peared spontaneously within a short interval. Furthermore, the 3 Department of Neurology, Hyogo Cardiovascular Center, convulsions occurred at around midnight when the proband Himeji, Japan was in a fatigued state or had consumed alcohol. His parents 40 Neurogenetics (2019) 20:39–43 have no significant clinical history. They lived with him until Carlsbad, CA, USA) for the patient and his parents. Detailed 4 years ago but had never witnessed these convulsive attacks. methods are shown in our previous report [4]. Variants were Medicolegal autopsy showed some mild bruising and abra- called within the coding exons and ± 2 bp into the introns sion of the face and extremities. Bone fractures and injuries of using Ingenuity Variants Analysis (QIAGEN, California, the muscle and internal organs were not found. USA). All variants with a minor allele frequency (MAF) ≥ Dextromethorphan and diprophylline, which are present in 1.0% among the East Asian population were filtered using the over-the-counter cough medicine, were detected in his blood Genome Aggregation Database (gnomAD; http://gnomad. at non-lethal concentrations [3] of 0.63 and 5.5 μg/mL, re- broadinstitute.org). All the examined genes are listed in spectively. Alcohol was not detected in the blood and urine. Supplemental Table 1. The brain weighed 1451 g. Besides mild symmetrical As the results, NGS newly identified two variants of oedematous swelling, the left-sided hippocampus showed a PRICKLE1, and subsequent analysis of the family members more upright and globular appearance with vertical alignment showed that the father (p.Asp760del) and mother of the subiculum (Fig. 1a–c) when compared with two age- (p.Asp201Asn) each had a mutation in this gene (Fig. 2a, b; matched male autopsy cases (Fig. 1d, e). In the present case, Table 1)[6]. In the commonly used gnomAD, 15 alleles in the density of neurons in the CA1 region of the hippocampus over 282,752 were identified for pAsp760del and only three in was slightly lower than in the age-matched control cases (Fig. 251,342 were identified for p.Asp201Asn. p.Asp201Asn and 1f–h). Gliosis was not evident in the cerebrum, cerebellum, or p.Asp760del in PRICKLE1 are in the LIM zinc-binding 2 brain stem based on Holzer’s staining (Fig. 1i) and immunohis- domain and just before the serine-rich domain, respectively. tochemistry for glial fibre-associated protein (clone ZCG 29, These amino acids are completely conserved among verte- Nichirei Tokyo, Japan). The heart and other organs did not brate species (Fig. 2c) [5]. We applied four different in silico show any abnormal findings. predictive algorithms (CADD, Polyphen-2, SIFT, and After obtaining written informed consent from his parents, Mutation Taster), which revealed that both variants may be next-generation sequencing (NGS) of 146 epilepsy-related pathogenic as shown in Table 1. Possible pathogenic variants genes and 73 inherited cardiac disease-related genes was per- related to cardiovascular disease-related genetic variant were formed using an Ion PGM system (Life Technologies, not detected. Fig. 1 Pathological findings ab for the present case. a, b Gross appearance showing deformity of the left hippocampus. c–e Low-power view of the hippocampus of the present case (c) and the control cases (d, 25-year-old suicide case; e, 22-year-old traffic accident case). The arrow indicates the vertical alignment of the e subiculum. f–h Moderate-power cd* * view of the CA1 region of (c–e). * The asterisks indicate medial geniculate nuclei. i Holzer’s staining of the hippocampus. Significant gliosis was not evident. Scale bars, 2 mm (c–e, i), 200 μm(f–h) fgh i Neurogenetics (2019) 20:39–43 41 a b I 12 - / Asp760del Asp201Asn / - II.1 II I.1 1 Asp201Asn / Asp760del I.2 c 100 200 300 400 500 600 700 800 Q96MT3-PRICKLE1_Human (Pricle-like protein 1) 831 aa 14-122 124-189 189-249 249-313 655-682 761-772 816-821 Motif PET LIM1 LIM2 LIM3 Arg/His-rich Ser-rich Poly-Lys p.D201N p.D760del H.sapiens (NP_001138355.1) 191 C S A C D E I I F A D E C T E A E G R H W 750 R F LG L Y G E D D D S W C S S S - S S S P.troglodytes (XP_001166831.1) 187 C S A C D E I I F A D E C T E A E G R H W 746 K F F G L Y G E E D D S W C S T S - S S S M.mulatta (XP_002798581.1) 191 C S A C D E I I F A D E C T E A E G R H W 751 R F L G L Y G E D D D S W C S S S T S S S C.lupus (XP_005637023.1) 191 C S A C D E I I F A D E C T E A E G R H W 750 R F L G L Y G D D D D S W C S S S - T S S B.taurus (NP_001096004.1) 191 C S A C D E I I F A D E C T E A E G R H W 750 R F L G L Y G E D D D S W C S S S - S S S M.musculus (NP_001028389.1) 191 C S A C D E I I F A D E C T E A E G R H W 750 R F L G L Y G E D D D S W C S S S - S S S R.norvegicus (NP_955428.1) 198 C S S C D E I I F A D E C T E A E G R H W 724 R F T R L Y - - E - D D W C S T C S S S S G.gallus (XP_416036.2) 191 C S A C D E I I F A D E C T E A E G R H W 751 R F L G L Y G E D D D S W C S S T - S S S D.rerio (NP_899185.2) 191 C S A C D E I I F A D E C T E A E G R H W 751 K F L G L Y G E D E D S W C S T C S S S S X.tropicalis (NP_001016939.1) 191 C S A C D E I I F A D E C T E A E G R H W 751 R F L G L C G E D D D S W C S S S - T S S Consensus * * : * * * * * * * * * * * * * * * * * * : * * : * .