Nadine Pelzer

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

Genome-wide meta-analysis identifies new susceptibility loci for migraine

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Detection of interferon alpha protein reveals differential levels and cellular sources in disease

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFN&agr; in healthy donors, viral infection, and complex and monogenic interferonopathies. IFN&agr; protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFN&agr; levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFN&agr; protein indicated disease-specific mechanisms. Measurement of IFN&agr; attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.

Familial and Sporadic Hemiplegic Migraine: Diagnosis and Treatment

Opinion statementHemiplegic migraine (HM) is a rare subtype of migraine with aura, characterized by transient hemiparesis during attacks. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-II). Two types of HM are recognized: familial (FHM) and sporadic hemiplegic migraine (SHM). HM is genetically heterogeneous. Three genes have been identified (CACNA1A, ATP1A2, and SCN1A) but more, so far unknown genes, are involved. Clinically, attacks of the 3 subtypes cannot be distinguished. The diagnosis can be confirmed but not ruled out by genetic testing, because in some HM patients other, not yet identified, genes are involved. The presence of additional symptoms (such as chronic ataxia or epilepsy) may increase the likelihood of identifying a mutation. Additional diagnostics like imaging, CSF analysis, or an EEG are mainly performed to exclude other causes of focal neurological symptoms associated with headache. Conventional cerebral angiography is contraindicated in HM because this may provoke an attack. Because HM is a rare condition, no clinical treatment trials are available in this specific subgroup of migraine patients. Thus, the treatment of HM is based on empirical data, personal experience of the treating neurologist, and involves a trial-and-error strategy. Acetaminophen and NSAIDs often are the first choice in acute treatment. Although controversial in HM, triptans can be prescribed when headaches are not relieved sufficiently with common analgesics. An effective treatment for the severe and often prolonged aura symptoms is more warranted, but currently no such acute treatment is available. Prophylactic treatment can be considered when attack frequency exceeds 2 attacks per month, or when severe attacks pose a great burden that requires reduction of severity and frequency. In no strictly preferred order, flunarizine, sodium valproate, lamotrigine, verapamil, and acetazolamide can be tried. While less evidence is available for prophylactic treatment with topiramate, candesartan, and pizotifen, these drugs can also be considered. The use of propranolol in HM is more controversial, but evidence of adverse effects is insufficient to contraindicate beta-blockers.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1 , which was termed ‘retinal vasculopathy with cerebral leukodystrophy’. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud’s phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (± standard deviation) age at diagnosis was 42.9 ± 8.3 years and at death 53.1 ± 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 ± 10.6 years). Of them, 54% had mild Raynaud’s phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud’s phenomenon appear to be part of the clinical spectrum as well. Penetrance seems high. Because of the pathogenetic basis and the emerging clinical picture with systemic manifestations and conspicuous absence of leukodystrophy, we renamed the disease ‘retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations’. We propose diagnostic criteria to facilitate clinical recognition and future studies. * Abbreviations : AGS : Aicardi-Goutieres syndrome MC : mutation carrier RVCL(-S) : retinal vasculopathy with cerebral leukoencephalopathy (and systemic manifestations)

Two novel SCN1A mutations identified in families with familial hemiplegic migraine

Background Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes. Methods We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes. Results FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile1498) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe1661). Conclusions We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.

PRRT2 and hemiplegic migraine: A complex association

Hemiplegic migraine (HM) is a rare migraine subtype characterized by hemiparesis during the attack and is associated with at least 3 genes: CACNA1A, ATP1A2, and SCN1A.1 Recent reports suggested that the proline-rich transmembrane protein PRRT2 gene might be the fourth gene for HM.2 In the vast majority of cases, PRRT2 is associated with paroxysmal kinesigenic dyskinesia, benign familial infantile seizures (BFIS), or infantile convulsion choreoathetosis syndrome. In families with such a “typical PRRT2 phenotype,” HM was reported in a few PRRT2 mutation carriers. Most of these cases also had a “typical PRRT2 phenotype.”2 Vice versa, PRRT2 mutations were found in 5 out of over 200 index cases with HM; 2 of these 5 PRRT2 mutation carriers also had features of “typical PRRT2 phenotypes.”3,4

Familial hemiplegic migraine treated by sodium valproate and lamotrigine.

Background Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura that includes motor auras. Prophylactic treatment of FHM often has marginal effects and involves a trial-and-error strategy based on therapeutic guidelines for non-hemiplegic migraine and on case reports in FHM. Methods We assessed the response to prophylactic medication in an FHM family and sequenced the FHM2 ATP1A2 gene in all available relatives. Results A novel p.Met731Val ATP1A2 mutation was identified. Attack frequency was reduced significantly with sodium valproate monotherapy (n = 1) and attacks ceased completely with a combination of sodium valproate and lamotrigine (n = 2). Conclusions We report dramatic prophylactic effects of sodium valproate and lamotrigine in an FHM2 family, making these drugs worth considering in the treatment of other FHM patients.

Recurrent coma and fever in familial hemiplegic migraine type 2. A prospective 15-year follow-up of a large family with a novel ATP1A2 mutation.

Background Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2. Patients and methods After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated. Results A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed. Conclusion FHM should be considered in patients with recurrent coma and fever.

Heterozygous TREX1 mutations in early-onset cerebrovascular disease

We report on 100 patients suspected of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) [1] who were analyzed in our international CADASIL referral center, but in whom no NOTCH3 mutations were found. TREX1 was considered an excellent next disease gene candidate because of its link with Aicardi-Goutières syndrome (AGS) [3], the small vessel disease retinal vasculopathy and cerebral leukodystrophy (RVCL) [8], and (neuropsychiatric) systemic lupus erythematosus (SLE) [4–6]. Screening of our patient cohort yielded heterozygous TREX1 mutations in two patients with early-onset cerebrovascular disease. This expands the clinical spectrum of diseases associated with TREX1 mutations, and offers a differential diagnosis for CADASIL-like phenotypes. Patient A, a 53-year-old woman with a history of hypertension, hyperlipidemia and alcohol abuse presented with otherwise unexplained presenile dementia. MRI demonstrated basal ganglia and pontine lacunar infarcts and bilateral confluent white matter lesions (Fig. 1a–c). An extensive analysis for causes of dementia and stroke, including serum autoantibodies (ANCA, ANA) was negative. Her severe retinopathy was labeled as hypertensive. Severely demented, she died at the age of 55 of an aspiration pneumonia. Direct sequencing of the TREX1 gene detected a heterozygous mutation c.1079A[G; p.Tyr360Cys (p.Tyr305Cys on TREX1 isoform B). Patient B, a 42-year-old heavily smoking man with a past medical history including a splenic artery aneurysm at age 29, hypertension, hyperlipidemia and vascular claudication presented with progressive cognitive dysfunction. His family history was positive for (cardio)vascular disease. MRI showed a cortico-subcortical infarct in the right frontal lobe, ischemic lesions in the basal ganglia, brainstem and corpus callosum, and focal T2 white matter hyperintensities (Fig. 1d–f). Extensive diagnostic work-up did not reveal other causes for his cognitive decline. CSF showed a mononuclear pleocytosis with normal protein levels, but angiography was not suggestive of a cerebral vasculitis. CSF culture was negative and serum autoantibodies (ANCA, ANA, cardiolipines) were absent. He had a deep venous thrombosis in the leg at age 44. At age 46 and 47 he suffered from new brainstem infarcts. Direct sequencing detected a heterozygous TREX1 mutation c.506G[A; p.Arg169His (p.Arg114His on TREX1 isoform B). N. Pelzer J. Haan M. D. Ferrari A. M. J. M. van den Maagdenberg G. M. Terwindt (&) Department of Neurology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands e-mail: g.m.terwindt@lumc.nl