Dysequilibrium Syndrome Research Articles

Interventions for preventing haemodialysis dysequilibrium syndrome.

Dialysis dysequilibrium syndrome (DDS) refers to neurological symptoms usually seen during or after new initiation or following reinitiation of haemodialysis (HD) after missing multiple sessions. DDS is associated with death and morbidity. We studied interventions aimed at preventing DDS. To evaluate the benefits and harms of different types of interventions for preventing DDS. We contacted the information specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 8 May 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. We included randomised controlled trials (RCTs) that compared any intervention against standard care, including individuals initiated on HD, regardless of age. Two authors independently determined study eligibility, assessed quality and extracted data. Data were collected on methods, interventions, participants, and outcomes (DDS incidence, severe DDS, death, adverse events). Risk ratios (RR) and confidence intervals (CI) were calculated. Study quality was assessed using the Cochrane Risk of Bias 2 (ROB2) tool. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We included two RCTs, enrolling 32 adult participants. Interventions included were slow dialysis, sodium modelling, standard sodium dialysate, and high sodium dialysate. The risk of bias was of some concern to high risk of bias in both studies. Slow dialysis compared to sodium modelling (1 study, 15 participants) may result in little to no difference in DDS, severe DDS, and death (low certainty evidence) and has uncertain effects on adverse events (RR 1.33, 95% CI 0.15 to 11.64; very low certainty evidence). Standard sodium dialysate compared to high sodium dialysate (1 study, 17 participants) has uncertain effects on the incidence of DDS (RR 0.07, 95% CI 0.00 to 1.12), severe DDS (RR 0.47, 95% CI 0.02 to 10.32), and adverse events (RR 0.29, 95% CI 0.08 to 1.02) (very low certainty evidence). In HD patients, sodium modelling, compared to slow dialysis, may result in little to no difference in DDS and death (low certainty evidence) and has uncertain effects on adverse events (very low certainty evidence). The evidence is very uncertain for the effect of high-sodium dialysate and standard sodium dialysate on DDS, death and adverse events (very low certainty evidence).

Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.

Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interventions for preventing haemodialysis dysequilibrium syndrome

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: This review aims to look at the benefits and harms of interventions for preventing HD DDS.

Impact of COVID-19 Pandemic on a Multidisciplinary Approach to Reverse Phenotyping: A Case Report on Prenatal Diagnosis of CAMRQ Type 4 Syndrome

Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 (CAMRQ4) is a heterogenous group of genetic disorders that have been grouped based on their shared clinical features. CAMRQ4 should be suspected in patients presenting with ataxia, mental retardation, hypotonia, microcephaly, choreoathetoid movements or chorea, ophthalmoplegia, and global developmental delay, even if brain magnetic resonance imaging appears to be normal. We describe a family for whom reverse phenotyping played a crucial role in achieving the correct diagnosis of CAMRQ4 in the index child and prenatal diagnosis for the subsequent pregnancy. We describe the multidisciplinary approach that was followed during the pandemic, ensuring that the family was appropriately guided and informed.

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4.

BackgroundCerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early‐onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non‐progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified.MethodsFollowing the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR‐based Sanger sequencing.ResultsA novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand‐binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP‐binding domain.ConclusionOur findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype‐phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.

Turkish family with Dysequilibrium syndrome with a novel mutation in the VLDLR gene.

Background: A very few diseases are reported caused due to cerebellar hypoplasia and neuronal migration defects like pachygyria. Cerebellar Ataxia, mental retardation, and Dysequilibrium Syndrome 1 (DES) (OMIM # 224050) are one among such group of diseases. DES is caused due to a homozygous mutation in the VLDLR gene involved majorly in neuronal migration. Case Presentation: Two members (siblings) from a Turkish family presented with neuromotor developmental delay, moderate learning disability, delayed psychosocial development and strabismus complaints. Whole exome sequencing (WES) was performed as consanguinity existed between the parents and specific pre-diagnosis could not provide a satisfactory conclusion for the patients. WES revealed a homozygote novel mutation in the VLDLR gene. Conclusion: Evaluation of WES data resembled a process of finding a needle in a haystack; therefore, the present study recommended clinical information and anamnesis to be very important in understanding and interpreting the WES result.

Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome

Low density lipoprotein receptor (LDLR) family members are involved in signaling in the developing brain. Previously we have reported that missense mutations in the Very Low Density Lipoprotein Receptor gene (VLDLR), causing Dysequilibrium syndrome (DES), disrupt ligand-binding, due to endoplasmic reticulum (ER) retention of the mutants. We explored the degradation routes of these VLDLR mutants in cultured cells. Our results indicate that VLDLR mutants are retained in the ER for prolonged periods which could be facilitated by association with the ER-resident chaperone calnexin. The mutants were prone to aggregation and capable of eliciting ER stress. The VLDLR mutants were found to be degraded predominantly by the proteasomal pathway, since ubiquitinated VLDLR was found to accumulate in response to proteasomal inhibition. Further, the mutants were found to interact with the ER degradation adaptor protein SEL1L. The degradation of VLDLR wild type and mutant were delayed in CRISPR/Cas9 edited SEL1L knock-out cells which was reversed by exogenous expression of SEL1L. In summary, ER retention of pathogenic VLDLR mutants involves binding to calnexin, elevated ER stress, and delayed degradation which is dependent on SEL1L. Since core LDLR family members share common structural domains, common mechanisms may be involved in their ER processing.

Characterization of a novel zebrafish (Danio rerio) gene, wdr81, associated with cerebellar ataxia, mental retardation and dysequilibrium syndrome (CAMRQ).

BackgroundWDR81 (WD repeat-containing protein 81) is associated with cerebellar ataxia, mental retardation and disequilibrium syndrome (CAMRQ2, [MIM 610185]). Human and mouse studies suggest that it might be a gene of importance during neurodevelopment. This study aimed at fully characterizing the structure of the wdr81 transcript, detecting the possible transcript variants and revealing its expression profile in zebrafish, a powerful model organism for studying development and disease.ResultsAs expected in human and mouse orthologous proteins, zebrafish wdr81 is predicted to possess a BEACH (Beige and Chediak-Higashi) domain, a major facilitator superfamily domain and WD40-repeats, which indicates a conserved function in these species. We observed that zebrafish wdr81 encodes one open reading frame while the transcript has one 5′ untranslated region (UTR) and the prediction of the 3′ UTR was mainly confirmed along with a detected insertion site in the embryo and adult brain. This insertion site was also found in testis, heart, liver, eye, tail and muscle, however, there was no amplicon in kidney, intestine and gills, which might be the result of possible alternative polyadenylation processes among tissues. The 5 and 18 hpf were critical timepoints of development regarding wdr81 expression. Furthermore, the signal of the RNA probe was stronger in the eye and brain at 18 and 48 hpf, then decreased at 72 hpf. Finally, expression of wdr81 was detected in the adult brain and eye tissues, including but not restricted to photoreceptors of the retina, presumptive Purkinje cells and some neurogenic brains regions.ConclusionsTaken together these data emphasize the importance of this gene during neurodevelopment and a possible role for neuronal proliferation. Our data provide a basis for further studies to fully understand the function of wdr81.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-015-0229-4) contains supplementary material, which is available to authorized users.

Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome

Dysequilibrium syndrome (DES, OMIM 224050) is a genetically heterogeneous condition that combines autosomal recessive non-progressive cerebellar ataxia with mental retardation. The subclass dysequilibrium syndrome type 1 (CAMRQ1) has been attributed to mutations in the VLDLR gene encoding the very low density lipoprotein receptor (VLDLR). This receptor is involved in the Reelin signaling pathway that guides neuronal migration in the cerebral cortex and cerebellum. Three missense mutations (c.1459G>T; p.D487Y, c.1561G>C; p.D521H and c.2117G>T; p.C706F) have been previously identified in VLDLR gene in patients with DES. However, the functional implications of those mutations are not known and therefore we undertook detailed functional analysis to elucidate the cellular mechanisms underlying their pathogenicity. The mutations have been generated by site-directed mutagenesis and then expressed in cultured cell lines. Confocal microscopy and biochemical analysis have been employed to examine the subcellular localization and functional activities of the mutated proteins relative to wild type. Our results indicate that the three missense mutations lead to defective intracellular trafficking and ER retention of the mutant VLDLR protein. This trafficking impairment prevents the mutants from reaching the plasma membrane and binding exogenous Reelin, the initiating event in Reelin signaling. Collectively, our results provide evidence that ER quality control is involved in the functional inactivation and underlying pathogenicity of these DES-associated mutations in the VLDLR.

Cerebellar ataxia, mental retardation and dysequilibrium syndrome 1 (CAMRQ1) caused by an unusual constellation of VLDLR mutation

Cerebellar ataxia, mental retardation and dysequilibrium syndrome 1 (CAMRQ1) caused by an unusual constellation of VLDLR mutation

Challenges of diagnostic exome sequencing in an inbred founder population

Exome sequencing was used as a diagnostic tool in a Roma/Gypsy family with three subjects (one deceased) affected by lissencephaly with cerebellar hypoplasia (LCH), a clinically and genetically heterogeneous diagnostic category. Data analysis identified high levels of unreported inbreeding, with multiple rare/novel “deleterious” variants occurring in the homozygous state in the affected individuals. Step-wise filtering was facilitated by the inclusion of parental samples in the analysis and the availability of ethnically matched control exome data. We identified a novel mutation, p.Asp487Tyr, in the VLDLR gene involved in the Reelin developmental pathway and associated with a rare form of LCH, the Dysequilibrium Syndrome. p.Asp487Tyr is the third reported missense mutation in this gene and the first example of a change affecting directly the functionally crucial β-propeller domain. An unexpected additional finding was a second unique mutation (p.Asn494His) with high scores of predicted pathogenicity in KCNV2, a gene implicated in a rare eye disorder, retinal cone dystrophy type 3B. This result raised diagnostic and counseling challenges that could be resolved through mutation screening of a large panel of healthy population controls. The strategy and findings of this study may inform the search for new disease mutations in the largest European genetic isolate.

Disequilibrium syndrome caused by an unusual constellation of VLDLR mutations

Dysequilibrium syndrome (DES) is caused by an unusual constellation of VLDLR mutations. DES is an autosomal recessively inherited rare neurological disorder. DES is caused by mutations in the VLDLR gene encoding the VLDL receptor. To date, eight different mutations in the VLDLR gene have been described in seven families. The VLDL receptor is part of the reelin (RELN) pathway in neurons, directing neuronal migration and organization. Patients with DES are affected by cerebral ataxia and instable gait, intellectual disability, and epilepsy. Brain MRI of patients shows characteristic cerebellar vermis hypoplasia and impaired foliation.

A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion

BackgroundDysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. The condition has been classified into cerebellar ataxia, mental retardation and disequilibrium syndrome types 1 (CAMRQ1), 2 (CAMRQ2) and 3 (CAMRQ3) and attributed to mutations in VLDLR, CA8 and WDR81 genes, respectively. Quadrupedal locomotion in this syndrome has been reported in association with mutations in all three genes.MethodsSNP mapping and candidate gene sequencing in one consanguineous Omani family from the United Arab Emirates with cerebellar hypoplasia, moderate mental retardation, delayed ambulation and truncal ataxia was used to identify the mutation. In a second unrelated consanguineous Omani family, massively parallel exonic sequencing was used.ResultsWe identified a homozygous missense mutation (c.2117 G > T, p.C706F) in the VLDLR gene in both families on a shared affected haplotype block.This is the first reported homozygous missense mutation in VLDLR and it occurs in a highly conserved residue and predicted to be damaging to protein function.ConclusionsWe have delineated the phenotype associated with dysequilibrium syndrome in two Omani families and identified the first homozygous missense pathogenic mutation in VLDLR gene with likely founder effect in the southeastern part of the Arabian Peninsula.

Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.

Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans.

Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII

We define the neurological characteristics of familial cases from multiple branches of a large consanguineous family with cerebellar ataxia, mental retardation (MR), and dysequilibrium syndrome type 3 caused by a mutation in the recently cloned CA8 gene. The linkage analysis revealed a high logarithm of the odds (LOD) score region on 8q that harbors the CA8 in which a novel homozygous c.484G>A (p.G162R) mutation was identified in all seven affected members. The patients had variable cerebellar ataxia and mild cognitive impairment without quadrupedal gait. The brain MRI showed variable cerebellar volume loss and ill-defined peritrigonal white matter abnormalities. The Fluorodeoxyglucose Positron Emission Tomography (FDG PET) revealed hypometabolic cerebellar hemispheres, temporal lobes, and mesial cortex. This report expands the neurological and radiological phenotype associated with CA8 mutations. CA8 involvement should be considered in the differential diagnosis of other genetically unresolved autosomal recessive cerebellar ataxias.

Re-evaluation of the dysequilibrium syndrome

To re-evaluate middle-aged Swedish patients diagnosed with dysequilibrium syndrome (DES) in childhood and to compare their clinical and neuroimaging features to DES with VLDLR gene mutations (DES-VLDR). Six patients from five families underwent neurological examination and magnetic resonance imaging (MRI) of the brain. Blood samples from the patients were screened for serum carbohydrate-deficient transferrin (s-CDT; disialotransferrin). The very-low-density lipoprotein receptor (VLDLR) gene was sequenced. Five patients had non-progressive cerebellar ataxia (NPCA), dysarthria and short stature. Mental retardation and strabismus, characteristic for DES-VLDLR, were inconsistent among our patients. None of our patients had VLDLR mutations or MRI findings characteristic of DES-VLDLR. MRI findings were variable from a normal cerebellum to marked cerebellar hypoplasia or atrophy and signal intensity changes. One patient was diagnosed with congenital disorder of glycosylation type 1a (CDG-1a). DES was originally coined on mainly clinical grounds before MRI and specific genetic tests were available, both of which should be used to arrive at an appropriate diagnosis.

Mutations in VLDLR as a Cause for Autosomal Recessive Cerebellar Ataxia With Mental Retardation (Dysequilibrium Syndrome)

Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. Here, we report the first patient heterozygous for 2 novel mutations in VLDLR. An 18-month-old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. Magnetic resonance imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in 5 families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia, and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically, and molecularly well-defined genetic syndrome.

Treating seizures in renal and hepatic failure

INTRODUCTION: Renal and hepatic diseases cause seizures and patients with epilepsy may suffer from such diseases which change antiepileptic drugs (AEDs) metabolism. OBJECTIVES: To revise how seizures may be caused by metabolic disturbances due to renal or hepatic diseases, by their treatment or by comorbidities and how AEDs choice might be influenced by these conditions. RESULTS: Seizures arise in renal failure due to toxins accumulation and to complications like sepsis, hemorrhage, malignant hypertension, pH and hydroelectrolytic disturbances. Hemodialysis leads to acute dysequilibrium syndrome and to dementia. Peritoneal dialysis may cause hyperosmolar non-ketotic coma. Post-renal transplant immunosupression is neurotoxic and cause posterior leukoencephalopathy, cerebral lymphoma and infections. Some antibiotics decrease convulsive thresholds, risking status epilepticus. Most commonly used AEDs in uremia are benzodiazepines, ethosuximide, phenytoin and phenobarbital. When treating epilepsy in renal failure, the choice of AED remains linked to seizure type, but doses should be adjusted especially in the case of hydrosoluble, low-molecular-weight, low-protein-bound, low apparent distribution volume AEDs. Hepatic failure leads to encephalopathy and seizures treated by ammonium levels and intestinal bacterial activity reductions, reversal of cerebral edema and intracranial hypertension. Phenytoin and benzodiazepines are usually ineffective. Seizures caused by post-hepatic immunosupression can be treated by phenytoin or levetiracetam. Seizures in Wilson's disease may result from D-penicillamine dependent piridoxine deficiency. Porphyria seizures may be treated with gabapentin, oxcarbazepine and levetiracetam. Hepatic disease changes AEDs pharmacokinetics and needs doses readjustments. Little liver-metabolized AEDs as gabapentin, oxcarbazepine and levetiracetam are theoretically more adequate. CONCLUSIONS: Efficient seizures treatment in renal and hepatic diseases requires adequate diagnosis of these disturbances and their comorbidities besides good knowledge on AEDs metabolism, their pharmacokinetic changes in such diseases, careful use of concomitant medications and AEDs serum levels monitoring.

Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome

We have investigated a consanguineous Iranian family with eight patients who suffer from mental retardation, disturbed equilibrium, walking disability, strabismus and short stature. By autozygosity mapping we identified one region with a significant LOD score on chromosome 9(p24.2-24.3). The interval contains the VLDLR gene, which codes for the very low-density lipoprotein receptor. This protein is part of the reelin signalling pathway, which is involved in neuroblast migration in the cerebral cortex and cerebellum. A homozygous deletion encompassing VLDLR has previously been found to cause a syndrome of cerebellar ataxia and mental retardation associated with cerebellar hypoplasia in the Hutterite population known as dysequilibrium syndrome (DES). The reported deletion however, contains an additional brain expressed gene of unknown function, whose involvement in the aetiology of the phenotype could so far not be excluded. We screened the coding region of VLDLR for mutations in our patients and found a homozygous c.1342C>T nucleotide substitution, which leads to a premature stop codon in exon 10. This is the first report of a mutation in patients with DES that affects VLDLR exclusively, confirming the central role of the very low-density lipoprotein receptor in the aetiology of this condition.

Precipitation of long duration hypnic headaches after ACE inhibitor withdrawal

Sirs: Hypnic headache is a rare headache disorder characterised by recurrent attacks of pain occurring during sleep. Headaches tend to occur in the middle or later stages of the night and patients are abruptly awakened from sleep. We present an unusual case of an 84-year-old female who developed hypnic headaches, although lasting longer than classically described, after stopping her angiotensin converting enzyme (ACE) inhibitor. These resolved completely when the ACE inhibitor was re-started. An 84-year-old female had her ACE inhibitor (enalapril, 5 mg) and a benzodiazepine (flurazepam) stopped abruptly. She immediately developed a distinctive pattern of headache, which would wake her from sleep at 3 a. m. each night. The pain was bi-temporal and it would last approximately 10 hours. Paracetamol and ibuprofen were not effective, and indomethacin was not tried. There were no other symptoms associated with the headache; in particular there were no autonomic features. Her consumption of tea and coffee had not changed, and she did not drink alcohol. There was no previous history of headache and the only significant past medical history was hypertension for which she had been taking enalapril for four years. She had also taken flurazepam and chlordiazepoxide. The enalapril had been stopped by her general practitioner as her blood pressure was considered acceptable at approximately 150/85. Her daytime blood pressure off the enalapril did rise to approximately 180/100. Although we think it unlikely that this rise is significant enough to cause the headache, this does remain a possibility. Neurological and general physical examination was otherwise normal. A biochemical profile, full blood count and computed tomography head scan were normal. Benzodiazepine re-prescription for 2 months did not alleviate the headache, therefore her enalapril was restarted. Her headache responded immediately and one week after recommencing enalapril, her headache had completely resolved. There is general agreement that the mechanisms that underlie sleep regulation and nociception are fundamentally linked although the specific nature and underlying neurochemical processes are poorly defined [4]. The pathogenesis of hypnic headache as a specific sleep related headache, however, remains speculative. There is evidence for a role for the renin-angiotensin system (RAS) in the aetiology of some headache types. The ACE inhibitor lisinopril has been shown to have a prophylactic effect in migraine [5] and migraineurs with a DD genotype have both a higher ACE activity and frequency of attacks than other migraineurs [3]. It has also been shown that dialysis headache, where the headache is not related to blood pressure changes or a ‘dysequilibrium syndrome’, can improve after treatment with ACE inhibitors [2]. We feel that our case report suggests that the RAS may be implicated in the aetiology of hypnic headache. It is not clear how ACE inhibitors mediate the beneficial effect in migraine. Angiotensin II is a neuropeptide produced within the central nervous system (CNS) and may function as a neurotransmitter, influencing neurotransmission and excitability of neurons via glutaminergic and GABAergic neurons [3]. As well as inhibiting the conversion of angiotensin I to angiotensin II, ACE inhibitors also increase prostacyclin synthesis and inhibit the breakdown of bradykinin, encephalin and substance P. Hypnic headache is considered by many to be a rapid-eye movement (REM) sleep-phase phenomenon. In a meta-analysis of 71 cases of hypnic headache, four had headache during polysomnography, three emerging from REM sleep and one from slow wave sleep. The reason for the association with REM sleep is unknown, but it has been suggested that certain areas of the brain of fundamental importance to antinociception, for example the locus coeruleus, an area which is normally inactive during REM sleep, might be impaired [1]. This may perhaps provide a link with the RAS as this is one area of the brain in particular which has been demonstrated to possess high numbers of angiotension receptors [3]. In conclusion, a potential association between hypnic headache and the RAS is suggested. The posLETTER TO THE EDITORS