Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome.

BACKGROUND: This study investigated a girl with Leigh syndrome born to first-cousin parents of Pakistani descent with an isolated respiratory chain complex I deficiency in muscle and fibroblasts. Her early development was delayed, and from age 2 years she started losing motor abilities. Cerebral MRI showed basal ganglia lesions typical of Leigh syndrome. METHODS AND RESULTS: A genome-wide search for homozygosity was performed with the Affymetrix GeneChip 50K Xba array. The analysis revealed several homozygous regions. Three candidate genes were identified, and in one of the genes, NDUFA12, a homozygous c.178C→T mutation leading to a premature stop codon (p.Arg60X) was found. Western blot analysis showed absence of NDUFA12 protein in patient fibroblasts and functional complementation by a baculovirus system showed restoration of complex I activity. CONCLUSION: NDUFA12 mutations are apparently not a frequent cause of complex I deficiency, since mutations were not found by screening altogether 122 complex I deficient patients in two different studies. NDUFA12 encodes an accessory subunit of complex I and is a paralogue of NDUFAF2. Despite the complete absence of NDUFA12 protein, a fully assembled and enzymatically active complex I could be found, albeit in reduced amounts. This suggests that NDUFA12 is required either at a late step in the assembly of complex I, or in the stability of complex I.

Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 2nd Edition, 2012.

Headache and facial pain are among the most common, disabling and costly disorders in Europe. Correct diagnosis and treatment is important for achieving a high quality of care. As a national organisation whose role is to educate and advocate for the needs of patients with primary headaches, the Danish Headache Society has set up a task force to develop a set of guidelines for the diagnosis, organisation and treatment of the most common types of headaches and for trigeminal neuralgia in Denmark. The guideline was published in Danish in 2010 and has been a great success. The Danish Headache Society decided to translate and publish our guideline in English to stimulate the discussion on optimal organisation and treatment of headache disorders and to encourage other national headache authorities to produce their own guidelines. The recommendations regarding the most common primary headaches and trigeminal neuralgia are largely in accordance with the European guidelines produced by the European Federation of Neurological Societies. The guideline provides a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organised in Denmark. This description is followed by individual sections on the characteristics, diagnosis, differential diagnosis and treatment of each of the major headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular problems regarding headache in children and headache in relation to female hormones and pregnancy are described.

Familial hemiplegic migraine type 1 associated with parkinsonism: a case report.

Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered.

Coexisting typical migraine in familial hemiplegic migraine.

OBJECTIVE: In contrast to patients with migraine with aura (MA) and migraine without aura (MO), most patients with familial hemiplegic migraine (FHM) do not report migraine-like attacks after pharmacologic provocation with glyceryl trinitrate (GTN), a donor of nitric oxide. In the present study, we examined patients with FHM without known gene mutations and hypothesized that 1) GTN would cause more migraine-like attacks in patients with FHM compared to controls, and 2) GTN would cause more migraine attacks in patients with FHM with coexisting MA or MO compared to the pure FHM phenotype. METHODS: The study design was a balanced provocation study. Twenty-three patients with FHM and 11 healthy controls received a continuous IV infusion of 0.5 mug/kg/min GTN over 20 minutes. RESULTS: We found no difference in the incidence of migraine-like attacks comparing all patients with FHM (30%) to controls (9%) (p = 0.15). Patients with FHM with coexisting MA or MO reported more migraine attacks after GTN (55%) than patients with the pure FHM phenotype (8.3%) (p = 0.02). Compared to healthy controls, more patients with FHM with coexisting MA or MO reported migraine-like attacks than controls (p = 0.03), whereas the FHM group with the pure FHM phenotype did not (p > 0.05). CONCLUSIONS: Compared to patients with migraine with aura (MA) and migraine without aura (MO), patients with familial hemiplegic migraine (FHM) without known gene mutations display a reduced sensitivity to nitric oxide. A subset of patients with FHM with coexisting nonhemiplegic migraine is more sensitive than controls. These data extend our previous findings that pathophysiologic pathways in FHM may differ from those of MO and MA.

Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype.

OBJECTIVE: The neuropeptide calcitonin gene-related peptide (CGRP) is a migraine trigger that plays a crucial role in migraine pathophysiology, and CGRP antagonism is efficient in the treatment of migraine attacks. Familial hemiplegic migraine (FHM) is a dominantly inherited subtype of migraine with aura associated with several gene mutations. FHM shares many phenotypical similarities with common types of migraine, indicating common neurobiological pathways. We tested the hypothesis that the FHM genotype confers a CGRP hypersensitive phenotype. METHODS: We included 9 FHM patients with known mutations in the CACNA1A and ATP1A2 genes and 10 healthy controls. All subjects received i.v. infusion of CGRP (1.5 microg/min). We recorded headache intensity on a verbal rating scale and vascular changes in the middle cerebral artery and the superficial temporal artery. RESULTS: CGRP infusion did not induce an aura in any of the participants. The incidences of reported migraine and migraine-like headache were not different in the two groups, with 22% (2 of 9) reporting migraine in the patient group and 10% (1 of 10) reporting migraine-like headache in the control group (95% CI -0.31 to 0.55; p = 0.58). Headache severity and intensity were not different between the groups. CONCLUSIONS: Familial hemiplegic migraine (FHM) patients do not show hypersensitivity of the calcitonin gene-related peptide (CGRP)-cyclic adenosine 3',5'-monophosphate pathway, as characteristically seen in migraine patients without aura. This indicates that the pathophysiologic pathways underlying migraine headache in FHM may be different from the common types of migraine and questions whether CGRP antagonists would be effective in the treatment of FHM patients.

The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura.

Epidemiological studies indicate that migraine with typical aura (MA) has a major genetic component but the genes for MA have not been identified. However, the autosomal dominantly inherited familial hemiplegic migraine (FHM) is often caused by mutations in the CACNA1A or ATP1A2 genes. The aim of the study was to investigate if the CACNA1A or ATP1A2 genes are involved in MA with an apparently autosomal dominant mode of inheritance. From a clinic population diagnosed by a trained physician we recruited 34 extended families (comprising 174 MA patients) with an apparently autosomal dominant mode of inheritance of MA. We performed a linkage analysis of 161 of 174 MA patients and 79 unaffected relatives using a framework marker set of 44 markers for chromosome 1 and 22 markers for chromosome 19. Linkage analysis was made with a non-parametric or autosomal dominant parametric model, either allowing for heterogeneity or not, using an affected only analysis. We identified no linkage to CACNA1A and ATP1A2 loci on chromosome 19 or 1, respectively. Additionally, at least two patients from each family and 92 healthy, unrelated controls were selected for a sequence analysis. We sequenced the 48 exons of CACNA1A and the 23 exons of ATP1A2, including promoter and flanking intron sequences. No polymorphism was identified in the CACNA1A or ATP1A2 genes with a strong correlation to MA. Our study shows that the CACNA1A or ATP1A2 genes are probably not involved in MA. To identify the genes involved in the common forms of migraine, future genetic studies should focus on MA and migraine without aura (MO) and not FHM.

Basilar-type migraine: clinical, epidemiologic, and genetic features.

BACKGROUND: It remains uncertain whether basilar-type migraine (BM) is a subtype of migraine with typical aura (MTA) or a distinct phenotype or genotype. OBJECTIVE: To analyze the symptomatology, familial distribution, and genotype of BM. METHODS: The authors recruited 105 families comprising 362 patients with MTA or BM (International Classification of Headache Disorders-1 criteria). Among these patients, 38 patients from 29 families had BM. In 12 of the families with BM with an apparently dominant inheritance the authors sequenced all exons of the CACNA1A (chromosome 19) and ATP1A2 (chromosome 1) genes responsible for most cases of the autosomal dominantly inherited familial hemiplegic migraine and performed a linkage analysis of chromosome 1 and 19 with a nonparametric or autosomal dominant parametric model using an affected only analysis. RESULTS: BM occurred in 10% (38/362) of patients with MTA. The basilar-type aura had a median duration of 60 minutes and comprised vertigo 61%, dysarthria 53%, tinnitus 45%, diplopia 45%, bilateral visual symptoms 40%, bilateral paresthesias 24%, decreased level of consciousness 21%, hypacusia 21%, and ataxia 5%. The relative frequency of the individual basilar-type symptoms was not different from patients with hemiplegic migraine from a previous study. The patients with BM were equally distributed among the 105 families with MTA (p = 0.37). The attacks of MTA were identical in families with or without BM. No causative mutations and no linkage was identified. CONCLUSIONS: Basilar-type aura seemingly may occur at times in any patient with migraine with typical aura. There is no firm clinical, epidemiologic, or genetic evidence that BM is an independent disease entity different from MTA.

Implications of clinical subtypes of migraine with aura.

OBJECTIVE: To compare the clinical characteristics of familial hemiplegic migraine (FHM), sporadic hemiplegic migraine (SHM), and nonhemiplegic migraine with aura (NHMA) and further, to compare subtypes of NHMA. BACKGROUND: To discover distinct underlying genetic and pathophysiological mechanisms it is crucial to drive clinical subdivision of migraine with aura as far as possible. The documentation of subtypes of migraine with aura depends on the clinical characteristics as the genetic mechanisms are unknown except for the dominantly inherited FHM. METHODS: Patients with FHM, SHM, or familial NHMA were recruited from specialist practice and diagnosed according to the International Classification of Headache Disorders (ICHD) in a validated interview by a physician. Patients with hemiplegic migraine had a physical and neurological examination. Patients with population-based NHMA from a previous Danish study were used for comparison. RESULTS: We recruited 147 patients with FHM, 105 with SHM, and 362 with familial NHMA. FHM and SHM had similar aura and headache characteristics. Patients with FHM and SHM were more likely to experience two or more aura symptoms (100% vs. 31%, P < .0001), they more often had prolonged aura symptoms, they almost always had a headache associated with the aura (93% vs. 58%, P < .0001), and they more frequently had basilar-type symptoms (69% vs. 10%, P < .0001) than patients with population-based NHMA. Patients with familial NHMA were more likely to experience two or more aura symptoms than patients with population-based NHMA (61% vs. 32%, P < .0001). Within the subtypes of NHMA, patients with typical aura with migraine headache had an earlier age at onset (20 +/- 10 vs. 23 +/- 13 years, P= .044) and a higher co-occurrence of migraine without aura (43% vs. 22%, P= .002) than patients with typical aura with nonmigraine headache. CONCLUSIONS: The present study proves that distinct subtypes of migraine with aura exist. It further underlines the phenotypic differences between the different subtypes of migraine with aura which likely are caused by different etiological mechanisms. In future studies FHM, SHM, and NHMA therefore should be analyzed as separate entities and patients with NHMA may be stratified by ICHD-2 subtype of NHMA.