Objectives Hyperekplexia is predominantly caused by mutations in the α-1 subunit of the inhibitory glycine receptor (GLRA1). Three quarters of cases show autosomal-recessive inheritance.
Methods We carefully ascertained reports of ethnicity from our hyperekplexia research cohort. These were compared with all published cases of hyperekplexia with an identified genetic cause. Ethnicities were subgrouped as Caucasian, Asian, Arabic, Turkish, Jewish or Afro-American.
Results We report the ethnicity of 90 cases: 56 cases from our service augmented by 34 cases from the literature. Homozygous deletions of exons 1 to 7 are predominantly seen in people with Turkish backgrounds (n=16/17, p<0.001). In contrast, the dominant point mutation R271 is seen in people of Asian, Caucasian and African-American heritage (n=19) but not in people with Arab or Turkish ethnicities (p<0.001).
Conclusions Self-declared ethnicity can predict gene-screening outcomes. Cultural practices influence the inheritance patterns and a Caucasian founder is postulated for R271 mutations.
- Paediatric Neurology
- Movement Disorders
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Hyperekplexia is a rare genetically stratified neurological disorder characterised by hypertonia and triggered startle attacks. Classic (hereditary) hyperekplexia is a glycine synaptopathy caused by recessive and dominant mutations in the α1 and β-subunits of the inhibitory glycine receptor (GlyR; GLRA1 and GLRB)1 ,2 and the presynaptic glycine transporter 2 (GlyT2; SLC6A5).3 Symptoms are present at birth, and the phenotype includes recurrent apnoea attacks and developmental delay and intellectual disability in some.4 The majority of cases with a known genetic cause harbour mutations within GLRA1, which was the first gene identified in hyperekplexia.1 ,5
The clinical features of hyperekplexia were initially described in large Northern European families creating an ascertainment bias favouring autosomal-dominant inheritance. However, many hyperekplexia cases were seemingly ‘sporadic’, with no family history, until the importance of recessive inheritance was recognised.6 ,7 In the gene-screening process, we noted a variation in the pattern of gene mutation: we wanted to ascertain whether there were ethnic biases in the pattern of GLRA1 mutations. By detecting ethnic clustering of genotypes or inheritance patterns, we could plan targeted sequencing for specific populations. This may be especially important in regions with limited healthcare provision.
Cases were drawn from two sources: (i) primarily published and unpublished cases from our research group at Swansea University4 ,5 ,8 and (ii) a comparison cohort of published cases from the literature. Our screening process, referral criteria and review procedure are described elsewhere.8 ,9 Cases with GLRA1 mutation(s) referred to our service were identified and the clinicians were contacted. A single proband was studied per family. We designed a proforma to standardise the clinical information and to acquire an updated clinical report. Ethnicity data were also crosschecked against medical records where available. All cases underwent parental testing and segregation analyses, when possible, to confirm the inheritance pattern.
PubMed was searched using the terms ‘hyperekplexia’, ‘hyperexplexia’, ‘startle’, ‘GLRA1’. Additional articles were identified using the citation database Scopus and by contacting authors active in the field. Where information was not available from the papers, we contacted the authors directly. The clinician report of ethnicity was used; typically this was a self-reported ethnicity. To compare patterns of gene mutations, we used six broad groups of ethnicity—Caucasian, Asian, Arabic, Turkish, Jewish and Afro-American. The χ2 test with Yate's correction was used. Mutations were divided into three recessive patterns (deletion; homozygous; compound heterozygous) and dominant into two groups (point mutations at R271, and the remainder).
Ninety cases with a known ethnicity were identified. Our research project yielded 56 cases with a proven genetic diagnosis where the ethnicity was established (see online supplementary table). The literature review identified a further 49 cases with a genetic diagnosis of hyperekplexia, and from of this data set we were able to identify the ethnicity in 69% of families (n=34). In order of occurrence the ethnicity frequencies were Caucasian (37.8%), Turkish (27.8%), Asian (15.5%), Arabic (13.3%), Jewish (4.4%) and African-American (1.1%). Sixty-one (68%) had recessive GLRA1 hyperekplexia mutations (table 1).
Deletion of exons 1 to 7 of GLRA1
Of the 25 cases that were identified as Turkish, 16 (70%) were homozygous for a specific large deletion (exons 1 to 7). Only one individual with this deletion did not declare an immediate Turkish or Turkish Kurd background (16/17, p<0.001). Ninety-six per cent of Turkish cases had a recessive hyperekplexia.
All 12 Arabic and all 4 Jewish cases had homozygous GLRA1 mutations. The majority of GLRA1 hyperekplexia is caused by homozygous mutations (68%)—20% are large deletions (above) and the remainder are accounted for by infrequently recurring private mutations. The exception to this is the dominant Y202X genotype, which recurs in Pakistani and Jordanian kindreds.
Dominant inheritance is the norm in Caucasian cases (62%) but seen in under 7% of non-Caucasians with hyperekplexia. The dominant R271 mutation demonstrates a striking ethnic disparity. Both Japanese families, 21/34 of Caucasian cases and a single African-American kindred had hyperekplexia due to mutation of an arginine residue at point 271. This is the single most frequently occurring point mutation and causes a dominant hyperekplexia. In contrast, dominant R271 has not been reported in people with Arabic, Israeli or Turkish ethnicities (p<0.001). The non-R271 dominant mutations followed a similar pattern, except that there were four Asian and a single Turkish case.
This is the first review of hyperekplexia ethnicities and describes the novel finding that ethnicity can predict GLRA1 genotype and subsequently estimate the mode of inheritance. Recessive GLRA1 is associated with a broader phenotype of apnoeas and developmental delay than autosomal-dominant GLRA1 hyperekplexia.4 There are limitations inherent in estimating ethnicity and we recognise these. Self-declared ethnicity may not be fully accurate for a multitude of reasons including a subjective feeling of national identity, non-paternity and failing to recognise or appreciate mixed heritage in previous generations. These limitations, however, should only make it more difficult to find the associations we present. A full picture of regional and ethnic differences will only be possible with greater clinical recognition and genetic testing in all healthcare settings.
Hyperekplexia has been genetically identified in many populations, but has not yet been described in anyone of Slavic or Polynesian heritage, although one clinical case from Papua New Guinea has been described.10 This is more likely to reflect local healthcare resources than a genuine absence of hyperekplexia in any specific ethnicity. A single family of African-American heritage has been diagnosed—the first with any identifiable links with Africa.11 In addition, we can now report two siblings of North-African Jewish heritage. The genotype of the African-American family would suggest either a de novo mutation or that the family has some Caucasian ancestry.
There appears to be three clusters of cases: first, Caucasian cases predominate (38%).12 This can be partially explained by referral bias due to the proximity of local tertiary testing centres, and a healthcare setting that facilitates diagnosis and referral for testing. However, the first pedigrees were Northern European and so there may well be a greater frequency of cases in these populations too. The high frequency of R271 mutations, predominantly in Caucasian peoples, does raise the possibility of a founder mutation effect. The alternative hypothesis, that the R271 amino acid site is vulnerable to de novo mutagenesis, should produce more ethnically disparate cases.
The second cluster is from Turkey: of the 23 Turkish cases, 8 are specifically described as Kurdish, there is also one Iraqi Kurdish family identified. Kurds appear to be of greater risk due to the presence of a common large deletion allele; a founder effect is recognised.13 ,14 Seven families have been identified from Pakistan, two of which are specifically of Kashmiri origin. The Asian cases show the same varied causes as white Caucasian cases, in contrast to Arabic and Jewish families where homozygosity, enhanced by consanguinity, is the sole cause. Transplanted populations appear at increased risk—driven by culturally determined patterns of marriage.
We recently described the clinical features of hyperekplexia associated with GLRB mutations.2 Their reported ethnicities make an interesting comparison, 5/10 cases are of Indian origin, only two are Caucasian and there was the first kindred with Chinese ethnicity. We predict that hyperekplexia is recognised clinically in India and only a minority of cases get referred for genetic testing; however, the disproportionate number of Indian cases with GLRB mutations is as yet unexplained. There are also regionally specific startle syndromes that await genetic characterisation such as the ‘Jumping Frenchmen of Maine’ and ‘Latah’. These do not resemble hyperekplexia phenotypically, however, and are thought to have a predominantly psychogenic aetiology.15
Hyperekplexia demonstrates clear regional and ethnic variation but it is likely to also be present but under-recognised in populations where it is less prevalent. This is of importance for targeting genetic testing in resource poor settings, and for genetic counsellors when estimating recurrence risks.
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Files in this Data Supplement:
- Data supplement 1 - Online supplement
Contributors RHT: drafted/revised manuscript, data analysis, acquisition of data, study design. CGJD, SEW, CLH and SKC: revised manuscript and acquisition of data. MIR: hyperekplexia research programme lead, revised manuscript, study design and obtained funding.
Funding This work was supported by grants from the Waterloo Foundation (to MIR) and NISCHR (Wales Epilepsy Research Network to MIR and RHT).
Competing interests None.
Ethics approval Hyperekplexia study approved by South West Wales 07/WMW02/24.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We have added a supplementary table with the genotypes studied.
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