Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028738 (nystagmus)
 7,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na+/K+ -ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.
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PMID:A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs. 1545 25

Episodic ataxia type 2 is an autosomal dominant paroxysmal cerebellar ataxia characterized by acetazolamide-responsive recurrent attacks with interictal nystagmus. This disease is caused by mutations (mainly truncating mutation) within the alpha1(A) subunit of P/Q type voltage-dependent calcium channel gene, CACNA1A. Further researches would establish the genotype/phenotype correlation and clarify the mechanism of this disorder.
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PMID:[Episodic ataxia type 2]. 1577 63

Late onset cerebellar ataxia can be caused by several genetic mutations but a large percentage of patients remain undiagnosed. Thirty-eight patients with onset of slowly progressive, pure cerebellar ataxia >or=40 years-of-age were identified from a large ataxia database. Their clinical findings and quantitative oculomotor tests were reviewed; all were screened for SCA1, SCA2, SCA3, SCA6, SCA8, SCA14, and the Fragile X premutation (FMR1). All 47 exons of CACNA1A were screened for mutations. Genetic analysis uncovered a mutation in 11 patients. The SCA6 mutation was present in 8 patients (repeats 22-23). Three additional genetic mutations were found: SCA1 (42 repeats), SCA3 (66 repeats), and SCA8 (121 repeats). Patients without identified genetic mutations were characterized by 1) a later age of onset, 2) truncal without extremity ataxia, 3) and down beat nystagmus. Although only a third of these idiopathic late onset ataxia patients had a positive family history, this homogeneous syndrome probably represents a yet to be identified genetic disorder.
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PMID:Late-onset pure cerebellar ataxia: differentiating those with and without identifiable mutations. 1610 27

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6.
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PMID:Meiotic CAG repeat instability in spinocerebellar ataxia type 6: maternally transmitted elongation in a presumed sporadic case. 1631 Aug 5

Episodic ataxia type 2 (EA 2) is a rare neurological disorder of autosomal dominant inheritance resulting from dysfunction of a voltage-gated calcium channel. It manifests with recurrent disabling attacks of imbalance, vertigo, and ataxia, and can be provoked by physical exertion or emotional stress. In the spell-free interval, patients present with central ocular motor dysfunction, mainly downbeat nystagmus. A slow progression of cerebellar signs accompanied by a slight atrophy of midline cerebellar structures is commonly observed during the course of the disease. EA 2 is caused most often by the loss of function mutations of the calcium channel gene CACNA1A, which encodes the Ca(v)2.1 subunit of the P/Q-type calcium channel and is primarily expressed in Purkinje cells. To date, more than 30 mutations have been described. Two effective treatment options have been established for EA 2: acetazolamide (ACTZ), which probably changes the intracellular pH and thereby the transmembraneous potential, and 4-aminopyridine (4-AP), a potassium channel blocker. Approximately 70% of all patients respond to treatment with ACTZ, but the effect is often only transient. In an open trial, 4-AP prevented attacks in five of six patients with EA 2, most likely by increasing the resting activity and excitability of the Purkinje cells. These findings were confirmed by experiments in animal models of EA 2. Many aspects of the pathophysiology (e.g., induction of the attacks) and treatment of EA 2 (e.g., mode of action of ACTZ and 4-AP) still remain unclear and need to be addressed in further animal and clinical studies.
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PMID:Episodic ataxia type 2. 1739 37

Hemiplegic migraine (HM) is a rare variety of migraine with aura characterized by the presence of a motor weakness during the aura. Hemiplegic migraine has two main forms according to the familial history: patients with at least one first- or second-degree relative who has aura including motor weakness have familial hemiplegic migraine (FHM); patients without such familial history have sporadic hemiplegic migraine (SHM). The prevalence of HM is one in 10,000 with FHM and SHM being equally frequent. Typical HM attacks include a motor weakness that is always associated with other aura symptoms, the most frequent being sensory, visual and speech disorders. In addition, basilar-type symptoms occur in up to 70% of the patients. Severe attacks may occur in FHM as well as in SHM with prolonged hemiplegia, confusion, coma, fever and seizures. The clinical spectrum also includes permanent cerebellar signs (nystagmus, ataxia, dysarthria) and less frequently various types of seizures and intellectual deficiency. FHM is the only variety of the autosomal dominant migraine and all three know genes encode ion-transporters. A genetic diagnosis is now possible by screening the three known genes involved in FHM (CACNA1A, ATP1A2 and SCNA1). Prognosis is usually good. Treatment is similar to approaches used in other varieties of migraine with aura, excepted for triptans that are contraindicated in MHF/MHS. Based on new pathophysiological insight, preventive treatments by various antiepileptic agents seem promising.
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PMID:[Familial and sporadic hemiplegic migraine]. 1840 71

We describe a family with an R1668W mutation in the CACNA1A gene who presented with a broader clinical spectrum and more variable features than previously reported. The mother had a pure progressive cerebellar ataxia of late onset with downbeat nystagmus, whereas her daughter suffered from episodic ataxia, hemiplegic migraine, and progressive cerebellar ataxia with horizontal gaze-evoked and rebound nystagmus. In both patients, treatment with acetazolamide was ineffective and worsened baseline ataxia, whereas flunarizine ameliorated episodic symptoms. Our report highlights profound phenotypic variability that can be associated with CACNA1A mutations and adds important therapeutic considerations.
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PMID:Progressive cerebellar ataxia with variable episodic symptoms--phenotypic diversity of R1668W CACNA1A mutation. 1843 43

Autosomal dominant episodic ataxia type 2 (EA2) results from mutations of the CACNA1A gene. We describe EA2 with unusual features in a father and daughter with a novel CACNA1A mutation coding for Y248C. Both patients showed severe cerebellar atrophy in MRI and clinical signs of progressive spinocerebellar atrophy type 6. Most disabling were the very frequent episodes of ataxia with migraine (with aura in the father and without aura in the daughter) and nystagmus in our patients. Additionally, they suffered from ictal hyperhidrosis with acute hypothermia of the extremities. Lastly, the father presented with interictal chronic diarrhea not associated to a known primary gastrointestinal disorder. Both ictal hyperhidrosis and interictal diarrhea ameliorated upon acetazolamide intake, the typical treatment for EA2. The significance of these findings is discussed and the phenotype correlated to previously reported cases.
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PMID:Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation. 1860 18

Clinical examinations and mutational analyses were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.
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PMID:Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family. 1867 Jul 97

Episodic ataxia type 2 is a rare autosomal dominant disease characterized by recurrent attacks of vertigo and cerebellar ataxia. The disease was caused by mutations in the CACNA1A gene, on chromosome 19p. We perform a mutational screening in a group of 43 unrelated patients. Forty-two patients presented episodes of disequilibrium and ataxia, and one child was studied because of the occurrence of episodic torticollis. The genetic analysis showed 15 mutated patients (35%). In 13 cases we found novel CACNA1A gene mutations, including missense, protein truncating, and aberrant splicing mutations. Two truncating mutations lead to the uppermost premature stop so far reported, challenging recent hypotheses on dominant negative effect. In patients without CACNA1A mutations, molecular testing for CACNB4 gene mutations excluded this genetic subtype. Clinical features of mutated subjects mostly confirmed previous sign and symptoms associated with EA2, including paroxysmal torticollis and mental retardation. CACNA1A mutated patients have an earlier age at onset, interictal nystagmus, and abnormalities of ocular movements. A review of all CACNA1A mutations so far reported showed that they are mainly located downstream exon 18. Our data substantially increase the number of the described CACNA1A mutations, and propose clinical and molecular criteria for a more focused genetic screening.
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PMID:Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. 2012 25


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