Treating status epilepticus in adults. / Behandling av status epilepticus hos voksne.

This clinical review examines the treatment of status epilepticus, a condition in which epileptic seizures are prolonged and pose a significant risk of brain damage and death. International guidelines recommend the use of benzodiazepines as first-line treatment, and these should be administered promptly and in appropriate doses. Second-line treatment involves the use of high-dose anti-seizure medications to stop and prevent seizures. If seizure activity persists, general anaesthesia should be administered as soon as possible. All neurological hospital departments should have established and rehearsed protocols for treating status epilepticus.

A woman in her sixties with epilepsy and syncope. / En kvinne i 60-årene med epilepsi og synkope.

BACKGROUND: A woman in her sixties had been diagnosed with generalised epilepsy twenty years earlier. The diagnosis was confirmed by EEG, and an MRI scan revealed hippocampal sclerosis, which is not uncommon in patients with epilepsy. Treatment with carbamazepine was initiated. CASE PRESENTATION: Due to a rise in the patient's cholesterol, carbamazepine was replaced with oxcarbazepine. At a follow-up, the patient reported a recent episode with loss of consciousness. Unstable epilepsy was suspected and the oxcarbazepine dose increased. The patient had had a minor stroke shortly before the check-up. As part of the diagnostic workup, a 24-hour ECG was performed. On removal of the apparatus, the patient described an episode with loss of consciousness that same morning. The ECG showed asystole at that point in time due to total AV block. A pacemaker was implanted, and the patient has had no episodes since. INTERPRETATION: The patient retrospectively reported recurrent episodes with loss of consciousness over many years. The diagnosis of epilepsy was convincing, but was the heart condition linked to her epilepsy, her medication or was it a separate entity? When seizures become more frequent or change character in a previously stabilised patient with epilepsy, it is important to look for non-epileptic causes, and cardiac arrhythmias should be high on the list.

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties.

OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability. INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.

Life satisfaction in women with epilepsy during and after pregnancy.

OBJECTIVE: The aim of this study was to investigate life satisfaction in women with epilepsy during and after pregnancy. METHODS: The study was based on the Norwegian Mother and Child Cohort Study, including 102,265 women with and without epilepsy from the general population. Investigation took place at pregnancy weeks 15-19 and 6 and 18months postpartum. Women with epilepsy were compared with a reference group without epilepsy. RESULTS: The proportion of women with epilepsy was 0.6-0.7% at all three time points. Women with epilepsy reported lower life satisfaction and self-esteem both during and after pregnancy compared with the references. Single parenting correlated negatively with life satisfaction in epilepsy during the whole study period. Epilepsy was associated with lower levels of relationship satisfaction and higher levels of work strain during pregnancy and lower levels of self-efficacy and satisfactory somatic health 18months postpartum. Adverse life events, such as divorce, were more common in women with epilepsy compared with the references, and fewer women with epilepsy had a paid job 18months postpartum. SIGNIFICANCE: Reduced life satisfaction associated with epilepsy during and after pregnancy showed that, even in a highly developed welfare society, women with epilepsy struggle. Mothers with epilepsy and their partners should be examined for emotional complaints and partnership satisfaction during and after pregnancy. Validated screening tools are available for such measures.

Depression and anxiety in women with epilepsy during pregnancy and after delivery: a prospective population-based cohort study on frequency, risk factors, medication, and prognosis.

OBJECTIVE: To assess incidence, prevalence, risk factors, and prognosis of peripartum depression and anxiety in a prospective study of women with epilepsy. METHOD: Pregnancies in women with epilepsy (n=706) were compared to pregnancies in all women without epilepsy (n=106,511) including women with specified nonepileptic chronic diseases (n=8,372) in the Norwegian Mother and Child Cohort Study. The database was linked to the Medical Birth Registry of Norway. Depression and anxiety were assessed with validated questionnaires five times from the second trimester to 36 months after delivery. Blood was drawn for analysis of antiepileptic drug (AED) concentrations. RESULTS: Women with epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than women without epilepsy (18.9% and 14.8%, respectively, p<0.001 for both comparisons) and women with other chronic diseases (23.1% and 18.4%, respectively, p=0.03 and 0.01). Women using AEDs during pregnancy were especially at risk regardless of AED type. The risk further increased with the use of multiple AEDs and with high doses and/or plasma levels. Risk factors associated with peripartum depression and/or anxiety in the epilepsy cohort were high seizure frequency, a history of physical and/or sexual abuse, adverse socioeconomic factors, previous loss of a child, AED use, unplanned pregnancy, and prepregnancy depression and/or anxiety. The recovery rate 3 years after delivery was lower for women with epilepsy with a history of depression/anxiety or physical/sexual abuse than for women without epilepsy. Depressed women with epilepsy were less frequently treated with antidepressive drugs during pregnancy than women without epilepsy. SIGNIFICANCE: Women with epilepsy frequently have depression and anxiety during and after pregnancy. Patients at risk should be identified before delivery as depressive symptoms could be undertreated in this group.

Exposure to antiepileptic drugs in utero and child development: a prospective population-based study.

PURPOSE: Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an effect on early child development. METHODS: From mid-1999 through December 2008, children of mothers recruited at 13-17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 children), and mothers reported on their child's motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months (44,147 children) of age. The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate supplementation, and child congenital malformation or low birth weight. KEY FINDINGS: A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1% vs. 2.9%; OR 2.0, 95% confidence interval [CI] 1.1-3.7) and autistic traits (3.5% vs. 0.9%; OR 2.7, CI 1.1-6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5% vs. 3.3%; OR 2.2, CI 1.1-4.2), sentence skills (11.2% vs. 4.8%; OR 2.1, CI 1.2-3.6), and autistic traits (6.0% vs. 1.5%; OR 3.4, CI 1.6-7.0). The drug-exposed children also had increased risk of congenital malformations (6.1% vs. 2.9%; OR 2.1, CI 1.4-3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range. SIGNIFICANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.

Psychiatric comorbidity and social aspects in pregnant women with epilepsy - the Norwegian Mother and Child Cohort Study.

OBJECTIVE: The objective of this study was to investigate psychiatric disease and social aspects in young women with epilepsy before and during pregnancy. METHOD: The study included self-reported data from 106,935 pregnancies. RESULTS: Seven hundred eleven women reported having epilepsy, and 45.9% of them were using antiepileptic drugs (AEDs). Compared to the reference group, self-reported eating disorders and depression were increased in the untreated epilepsy group before pregnancy. Both AED-treated and untreated women with epilepsy reported higher depression scores as assessed by the Hopkins Symptom Checklist, and the Lifetime Major Depression scale was increased in AED-treated women. Antiepileptic drug treatment was linked to low income (27.4% vs. 18.4%, p<0.001) and no income (5.5% vs. 2.6%, p=0.001). Low educational level was associated with epilepsy in AED-treated and untreated women (50.5%, p<0.001 and 46.9%, p<0.001 vs. 32.2%), as was unemployment due to disability (7.9%, p<0.001 and 6.5%, p<0.001 vs. 1.5%) and single parenting (4.4%, p=0.016 and 4.5%, p=0.007 vs. 2.4%). No difference was found for smoking, alcohol use, or narcotic use. CONCLUSION: Symptoms of depression were associated with epilepsy both during and before pregnancy. Epilepsy was linked to eating disorders before pregnancy. Unemployment, single parenting, and low educational level were linked to epilepsy in young pregnant females. Efforts aiming at treatment and screening for psychiatric comorbidity in pregnant women with epilepsy are important in the follow-up of these patients.

Mitochondrial diseases and epilepsy.

The mitochondrial respiratory chain is the final common pathway for energy production. Defects affecting this pathway can give rise to disease that presents at any age and affects any tissue. However, irrespective of genetic defect, epilepsy is common and there is a significant risk of status epilepticus. This review summarizes our current understanding of the epilepsy that occurs in mitochondrial disease, focusing on three of the most common disorders: mitochondrial myopathy encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy and ragged-red fibers (MERRF), and polymerase gamma (POLG) related disease. In addition, we review the pathogenesis and possible treatment of these disorders.

[Glioma-associated epilepsy]. / Epilepsi ved gliom.

BACKGROUND: Epileptic seizures are a common symptom in patients with primary brain tumours of the glioma type. The paper presents a discussion of epileptogenesis, choice of medication and follow-up of these patients. METHOD: The article is based on a search in PubMed and selection of articles based on the authors' discretionary judgement and clinical experience with this patient group. RESULTS: Epileptic seizures are a common symptom of glioma, particularly the low-grade types. The background to glioma-associated epilepsy is multifactorial, and the molecular biological characteristics of the tumour probably play a central part in the epileptogenesis. Effective treatment of epileptic seizures is of great importance to the quality of life of the glioma patient. Seizure frequency and the effectiveness of anti-epileptic treatment vary, and some patients require treatment with several anti-epileptic drugs. Surgical and oncological treatment of the tumour will also often reduce the frequency of seizures. CONCLUSION: As a general rule, antiepileptics without enzyme-inducing properties and with low protein-binding should be preferred for glioma patients. This will reduce the risk of interactions with chemotherapy or steroid therapy. Patients with brain tumours are particularly vulnerable to the effects on wakefulness, moods and cognition, and this should be borne in mind in the choice of medication and in follow-up. Haematological status should be monitored particularly closely when there is concomitant use of chemotherapy and antiepileptic drugs that may affect the bone marrow function.

Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes.

Mutations in the catalytic subunit of the mitochondrial DNA-polymerase gamma cause a wide spectrum of clinical disease ranging from infantile hepato-encephalopathy to juvenile/adult-onset spinocerebellar ataxia and late onset progressive external ophthalmoplegia. Several of these syndromes are associated with an encephalopathy that characteristically shows episodes of rapid neurological deterioration and the development of acute cerebral lesions. The purpose of this study was to investigate the nature, distribution and natural evolution of central nervous system lesions in polymerase gamma associated encephalopathy focusing particularly on lesions identified by magnetic resonance imaging. We compared radiological, electrophysiological and pathological findings where available to study potential mechanisms underlying the episodes of exacerbation and acute cerebral lesions. We studied a total of 112 magnetic resonance tomographies and 11 computed tomographies in 32 patients with polymerase gamma-encephalopathy, including multiple serial examinations performed during both the chronic and acute phases of the disease and, in several cases, magnetic resonance spectroscopy and serial diffusion weighted studies. Data from imaging, electroencephalography and post-mortem examination were compared in order to study the underlying disease process. Our findings show that magnetic resonance imaging in polymerase gamma-related encephalopathies has high sensitivity and can identify patterns that are specific for individual syndromes. One form of chronic polymerase gamma-encephalopathy, that is associated with the c.1399G > A and c.2243G > C mutations, is characterized by progressive cerebral and cerebellar atrophy and focal lesions of the thalamus, deep cerebellar structures and medulla oblongata. Acute encephalopathies, both infantile and later onset, show similar pictures with cortical stroke-like lesions occurring during episodes of exacerbation. These lesions can occur both with and without electroencephalographic evidence of concurrent epileptic activity, and have diffusion, spectroscopic and histological profiles strongly suggestive of neuronal energy failure. We suggest therefore that both infantile and later onset polymerase gamma related encephalopathies are part of a continuum.

Neuropsychological Performance 1 Year After Status Epilepticus in Adults.

OBJECTIVES: Status epilepticus (SE) may lead to or worsen cognitive dysfunction. Few studies have evaluated magnitude and profile of cognitive dysfunction in patients after SE. Characterization of cognitive deficits may be important for rehabilitation and follow-up. We assessed cognitive function in a consecutive, non-selected group of relatively healthy survivors with a comprehensive neuropsychological test battery. METHODS: A total of 33 patients (24 men, 9 women; mean age 54,9 years, mean education 11,8 years) were tested 1 year after SE with Wechsler Adult Intelligence Scale Fourth edition (WAIS-IV), Rey Auditory Verbal Learning Test, subtests from the Wechsler Memory Scale-Revised, Phonemic and Semantic word list generation, and the Halstead-Reitan Battery. Premorbid IQ was estimated with a Norwegian version of the National Adult Reading Test (NART). Results were compared to published norms. Regression analyses and independent groups t-tests were performed to assess the influence of background variables. RESULTS: Mean performance generally was about one standard deviation below average. Full scale IQ (WAIS-IV) was significantly reduced compared to estimated premorbid IQ (NART). Negative influence on cognition of brain lesions visible on computed tomography or magnetic resonance imaging and duration of SE >30 min was shown by group comparisons. CONCLUSIONS: SE represents a marker for possible cognitive dysfunction, and follow-up with neuropsychological assessment and cognitive rehabilitation seems warranted in most patients. Complex problem-solving abilities with high general sensitivity to brain impairment showed the most prominent reduction. Otherwise, no specific profile of domain affection was found. Structural brain lesions and duration of SE over 30 min represent risk factors for cognitive deficit.

Pregnancy, delivery, and outcome for the child in maternal epilepsy.

PURPOSE: To investigate pregnancy, delivery, and child outcome in an unselected population of women with both treated and untreated epilepsy. METHODS: In the compulsory Medical Birth Registry of Norway, all 2,861 deliveries by women with epilepsy recorded from 1999-2005 were compared to all 369,267 nonepilepsy deliveries in the same period. RESULTS: The majority (66%, n = 1900) in the epilepsy group did not use antiepileptic drugs (AEDs) during pregnancy. A total of 961 epilepsy-pregnancies were exposed to AEDs. Compared to nonepilepsy controls, AED-exposed infants were more often preterm (p = 0.01), and more often had birth weight <2,500 g (p < 0.001), head circumference <2.5 percentile (p < 0.001), and low Apgar score (p = 0.03). Small-for-gestational-age (SGA) infants (<10 percentile) occurred more frequently in both AED-exposed (p = 0.05) and unexposed (p = 0.02) epilepsy-pregnancies. Frequency of major congenital malformations (MCMs) was 2.8% (n = 81) in the epilepsy group versus 2.5% in controls (p = 0.3). Increased risk for MCMs could be demonstrated only for exposure to valproate (5.6%, p = 0.005) and AED polytherapy (6.1%, p = 0.02). Neonatal spina bifida was not significantly increased, but was a major indication for elective pregnancy termination among women with epilepsy. Cesarean section was performed more often in maternal epilepsy, regardless of AED-exposure (p < 0.001). DISCUSSION: Adverse pregnancy and birth outcome in women with epilepsy is mainly confined to AED-exposed pregnancies, although some risks are associated also with untreated epilepsy. The risk for congenital malformations was lower than previously reported. This could be due to a shift in AED selection, folic acid supplement, or possibly reflect the true risks in an unselected epilepsy population.

POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection.

The epileptic semiology of 19 patients (from 15 families) with mitochondrial disease due to mutations in the POLG1 gene is presented. The patients were either homozygous for the 1399G > A (p.A467T) or 2243G > C (p.W748S) mutations or compound heterozygotes for these two mutations. While the clinical features have been reviewed, detailed analysis of their epilepsy is presented for the first time. Irrespective of genotype, patients developed an epileptic syndrome with initial features of occipital lobe epilepsy. Occipital seizure phenomena included flickering coloured light, sometimes persisting for weeks, months or even years, ictal visual loss, horizontal/vertical nystagmus or oculoclonus, dysmorphopsia, micro-/macropsia and palinopsia. Most patients developed simple partial seizure phenomena with motor symptoms suggesting frontal lobe seizure initiation or spread. Simple and complex partial seizures, clonic- and/or myoclonic seizures with epilepsia partialis continua and frequent convulsive status epilepticus were observed in this syndrome that appears to be a symptomatic and secondary generalized or multifocal epilepsy with focal occipital predilection. The mean age of seizure presentation was 18.4 years (6-58 years). All patients developed status epilepticus and 11 patient deaths were, all related to prolonged convulsive status epilepticus, including two with liver failure apparently precipitated by treatment with sodium valproate.

Neuropsychological performance in patients with POLG1 mutations and the syndrome of mitochondrial spinocerebellar ataxia and epilepsy.

Mutations in the catalytic subunit of polymerase gamma (POLG1) produce a wide variety of neurological disorders including a progressive ataxic syndrome with epilepsy: mitochondrial spinocerebellar ataxia and epilepsy (MSCAE). Our earlier studies of patients with this syndrome raised the possibility of more prominent right than left hemisphere dysfunction. To investigate this in more detail, eight patients (six women, two men; mean age: 22.3 years) were studied. All completed an intelligence test (Wechsler Adult Intelligence Scale; WAIS), and four were also given memory tests and a comprehensive neuropsychological test battery. Patients with MSCAE showed significant cognitive dysfunction. Mean Verbal IQ (84.3) was significantly better than Performance IQ (71.8) (t=5.23, P=0.001), but memory testing and neuropsychological testing failed to detect a consistent unilateral dysfunction. Further studies are needed to define the profile and development of cognitive symptoms in this disorder.

De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features.

Mutations in genes involved in Ras signalling cause Noonan syndrome and other disorders characterised by growth disturbances and variable neuro-cardio-facio-cutaneous features. We describe two sisters, 46 and 31 years old, who presented with dysmorphic features, hypotonia, feeding difficulties, retarded growth and psychomotor retardation early in life. The patients were initially diagnosed with Costello syndrome, and autosomal recessive inheritance was assumed. Remarkably, however, we identified a germline HRAS mutation (G12A) in one sister and a germline KRAS mutation (F156L) in her sibling. Both mutations had arisen de novo. The F156L mutant K-Ras protein accumulated in the active, guanosine triphosphate-bound conformation and affected downstream signalling. The patient harbouring this mutation was followed for three decades, and her cardiac hypertrophy gradually normalised. However, she developed severe epilepsy with hippocampal sclerosis and atrophy. The occurrence of distinct de novo mutations adds to variable expressivity and gonadal mosaicism as possible explanations of how an autosomal dominant disease may manifest as an apparently recessive condition.

Cognitive function after status epilepticus versus after multiple generalized tonic-clonic seizures.

OBJECTIVES: Status epilepticus (SE) is considered a risk for cognitive impairment. Studies have indicated that SE cause more cognitive decline than multiple lifetime generalized tonic clonic (GTC) seizures. The aim of the study was to investigate whether patients suffering from SE or from multiple lifetime GTC seizures have cognitive dysfunction, and if the disabilities differ between these groups. MATERIALS AND METHODS: Patients suffering from SE were evaluated shortly after the clinical post-ictal phase and again after one year. Their follow-up results were compared to results from patients with ≥10 GTC seizures and a group of control subjects. Tests from Cambridge Neuropsychological Test Automated Battery (CANTAB) were used. Motor Screening Test (MOT) assessed motor speed, Delayed Matching to Sample (DMS) and Paired Associates Learning (PAL) assessed memory, and Stockings of Cambridge (SOC) assessed executive function. Estimated premorbid IQ and radiologically visible brain lesions were controlled for in adjusted results. Outcome measures were z-scores, the number of standard deviations a score deviates from the mean of a norm population. Negative z-scores indicate poor performance. RESULTS: After the clinical post-ictal phase, performances of SE patients were poor on all domains (n = 46). Mean z-scores with 95% confidence intervals were below zero for tests of psychomotor speed, executive thinking times and memory. Both SE patients at follow-up (n = 39) and patients with multiple GTC seizures (n = 24) performed poorer than controls (n = 20) on tests of memory. These group differences remained significant after covariate adjustments. SE patients at follow-up scored below patients with multiple GTC seizures on tests of psychomotor speed (mean difference -0.59, P = 0.020), but after adjusting for covariates this difference was no longer significant. CONCLUSIONS: Our data do not allow a firm conclusion as to whether SE is a more pronounced risk factor for cognitive dysfunction than repeated generalized tonic clonic seizures. In both patient groups, memory and learning dysfunction remained significant after adjusting for estimated premorbid IQ and structural brain lesions.

The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases.

We studied 26 patients belonging to 20 families with a disorder caused by mutations in the POLG gene. The patients were homozygous for 1399 G/A or 2243 G/C (giving the amino acid changes A467T and W748S, respectively) or compound heterozygotes for these two mutations. Irrespective of genotype, the patients exhibited a progressive neurological disorder usually starting in their teens and characterized by epilepsy, headache, ataxia, neuropathy, myoclonus and late onset ophthalmoplegia. However, major differences in survival were seen depending on genotype, with compound heterozygotes having a significantly shorter survival time than patients homozygous either for the A467T or W748S (P = 0.006). Epilepsy occurred in 22 of the 26 patients and in the majority of these there was an occipital EEG focus. Episodes of both generalized and focal motor status epilepticus were common and highly resistant to treatment, even with generalized anaesthesia. Status epilepticus was the recorded cause of death in 9 of 11 patients. Liver failure was the sole cause of death in two patients and evolved terminally in six others, all but one of whom were being treated with sodium valproate. Two patients underwent liver transplantation, but only one survived. Delayed psychomotor development and subsequent cognitive decline also occurs. This study demonstrates the clinical spectrum of a disorder that combines features of Alpers' syndrome and a later onset mitochondrial spinocerebellar ataxia with epilepsy and headache. Patients with this disorder are at high risk of death from status epilepticus and from liver failure, if exposed to sodium valproate. Each mutation appears capable of producing a disorder that is recessively inherited, although we also find evidence in one patient suggesting that heterozygotes may manifest. Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect.