A family of episodic ataxia type 2: no evidence of genetic linkage to the CACNA1A gene

Episodic ataxia type 2 (EA2) has been reported to result from mutations in the CACNA1A gene, located on chromosome 19p13. We describe a family with episodic ataxia, clinically indistinguishable from EA2, that was not caused by CACNA1A gene mutation. The proband is an 11-year-old boy, who has had 6 cerebellar ataxic attacks since 8 years of age. His attacks occurred almost monthly, lasting for 2 to 3 days. He was treated successfully with acetazolamide. His identical twin, mother and grandmother developed ataxic attacks at age 10, 34, and 50, respectively. The symptoms in his grandmother improved gradually without medication. His mother and identical twin took acetazolamide with a good response. We examined the CACNA1A gene for this family but did not detect any mutations. Furthermore, there was no evidence of genetic linkage between the CACNA1A gene and the symptomatic patients in this family. This suggests that the cause of EA2 can be heterogeneous, that is, defects of genes other than CACNA1A might be the cause of EA2.     

Mapping the gene for acetazolamide responsive hereditary paryoxysmal cerebellar ataxia to chromosome 19p

Acetazolamide responsive hereditary paroxysmal cerebellar ataxia(APCA) is a rare autosomal dominant disorder characterized byattacks of cerebellar ataxia and dysarthria with normal or nearnormal neurologic function between attacks. A genome-wide searchusing polymorphic di- and tri-nucleotide repeats was initiatedand the APCA locus was found to be linked to the short arm ofchromosome 19 in two large kindreds. The microsatellite markerUT705 was found to be linked to the APCA locus with two pointanalysis yielding a maximum lod score of 8·20 at     

Suicidal ideation and suicide attempts in panic disorder and attacks

Panic disorder, which is found in about 1.5 percent of the population at some time in their lives, includes recurrent episodes of sudden, unpredictable, intense fear accompanied by symptoms such as palpitations, chest pain, and faintness. Panic attacks, which do not meet these diagnostic criteria fully, are two to three times more prevalent. Since panic symptoms can mimic those of other medical disorders, patients with these symptoms use medical services frequently. To determine the risk of suicidal ideation and suicide attempts in panic disorder and attacks, we studied a random sample of 18,011 adults drawn from five U.S. communities. Subjects who had panic disorder, as compared with other psychiatric disorders, had more suicidal ideation and suicide attempts, with an adjusted odds ratio for suicide attempts of 2.62 (95 percent confidence interval, 1.83 to 3.74). The odds ratio was 17.99 (95 percent confidence interval, 12.18 to 26.58) when the group with panic disorder was compared with subjects who had no psychiatric disorder. Twenty percent of the subjects with panic disorder and 12 percent of those with panic attacks had made suicide attempts. These results could not be explained by the coexistence of major depression or of alcohol or drug abuse. We conclude that panic disorder and attacks are associated with an increased risk of suicidal ideation and suicide attempts. Physicians working in general medical settings and emergency departments should be alert to this problem.     

Allogeneic bone marrow transplantation in mevalonic aciduria

Mevalonic aciduria is a rare, inborn error of isoprene biosynthesis characterized by severe, periodic attacks of fever and inflammation, developmental delay, ataxia, and dysmorphic features. This autosomal recessive disease is caused by a mutation in the mevalonate kinase gene that severely reduces mevalonate kinase activity. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic bone marrow transplantation from an HLA-identical sister who was a heterozygous carrier of the mutant gene. We observed sustained remission of febrile attacks and inflammation during a 15-month follow-up period.     

Management of pregnancy in hereditary angioedema in a resource constrained setting: Our experience at Chandigarh,North India

Hereditary angioedema (HAE) is a rare genetic disorder distinguished clinically by recurrent episodes of non-pruritic swelling. Although pregnancy has been considered a trigger, it may have variable effect on frequency of attacks of HAE. C1-inhibitor (C1-INH) is the treatment of choice for management of HAE during pregnancy. However, because of non-availability of C1-INH therapy in developing countries, fresh-frozen plasma (FFP) and tranexamic acid remain the drugs of choice in pregnancy for treatment of acute attacks and for prophylaxis respectively. There is paucity of data on outcome of pregnancy with patients with HAE from developing countries such as India where all the first line medications are not available.A retrospective review was done including four HAE patients who conceived (with a total of 9 pregnancies). Our results suggest that frequency of attacks may increase during pregnancy especially during second trimester and post-delivery (during breastfeeding). However, HAE attacks are rare at the time of delivery.In resource limited settings, treatment with FFP/tranexamic acid needs to be individualised.     

Recurrent herpes zoster myelitis.

Recurrent zoster myelitis is quite rare. We present a previously healthy 27-year-old woman who developed recurrent attacks of myelopathy shortly after the characteristic skin rashes of herpes zoster. Magnetic resonance imaging studies demonstrated each lesion in the spinal cord at the same segments as the skin lesions. She had two attacks at opposite sites at the same spinal cord level and complete recovery after being treated with intravenous acyclovir. We suspect that direct invasion of varicella zoster virus was the cause of recurrent myelopathy in our patient.     

Novel pregnancy‐triggered episodes of CAPOS syndrome

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM# 601338) is a rare autosomal dominant disorder characterized by episodic, fever‐induced ataxic encephalopathy in childhood with residual symptoms. All identified patients have the same heterozygous missense variant c.2452G>A (p.Glu818Lys) in the ATP1A3 gene, encoding Na⁺/K⁺ ATPase α3. We describe a large CAPOS pedigree with three generations of affected members, the first ascertained in the United States. Deafness, optic atrophy, and pes cavus were present in all three members of the family evaluated. In addition, one of the affected individuals experienced markedly worsening features during her three pregnancies and in the immediate postpartum period, a potential element of the natural history of CAPOS previously unreported. We conclude that the triggering factors and clinical spectrum of pathogenic ATP1A3 variants may be broader than previously described. Targeted sequencing of ATP1A3 should be considered in any patient presenting with cerebellar ataxia triggered by febrile illness, or pregnancy and delivery, especially in the presence of sensorineural hearing loss, optic atrophy, pes cavus, or early childhood history of acute encephalopathic ataxia. Prophylactic administration of acetazolamide or flunarizine may prevent acute episodes of ataxia or mitigate neurologic symptoms, although their efficacies have not been well studied.     

Phenotypic variability in two patients with tumor necrosis factor receptor associated periodic fever syndrome emphasizes a rare manifestation: Immunoglobulin A nephropathy

Tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) is caused by heterozygote mutations in TNFRSF1A, characterized by recurrent inflammatory attacks.In this report, we described two patients with different heterozygote mutations in TNFRSF1A. Patient 1, a 15-year-old male, had suffered from recurrent fever attacks accompanied by abdominal pain, eye manifestations, and myalgia with increased acute phase reactants since the age of 6-month. He had been unsuccessfully treated with colchicine for having familial Mediterranean fever without an identifiable MEFV mutation since the age of 4-year. At the age of 15 years, he was diagnosed with immunoglobulin (Ig) A nephropathy due to massive proteinuria and renal biopsy findings. Next generation sequencing revealed NM_001065.3: c.236C>T; p. (Thr79Met); T50M heterozygote mutation in TNFRFS1A. He was treated with methylprednisolone and cyclosporine for IgA nephropathy, thereafter with canakinumab for TRAPS. Patient 2, a 17-year-old female, had recurrent arthritis attacks accompanied by increased acute phase reactants for the last two months. She had neither fever attacks nor rashes or myalgia. Her physical examination was normal between attacks. Magnetic resonance imaging of both knees and ankles showed no signs of chronic arthritis. MEFV analyzes showed no mutation. Next generation sequencing revealed NM_001065.3: c.362G>A; p.(Arg121Gln); R92Q heterozygote mutation in TNFRFS1A. Arthritis attacks were treated successfully with ibuprofen thereafter.In conclusion, we wish to emphasize the diversity of the clinical manifestations between these two patients with distinct sequence variants in TNFRSF1A. Moreover, we presented a rare manifestation of TRAPS, IgA nephropathy.     

Ataxia telangiectasia with hepatocellular carcinoma in a 15-year-old girl and studies of her kindred

We studied a case of familial ataxia-telangiectasia in a 15-year-old girl who had a clinical history of cerebellar ataxia and recurrent pulmonary infections. She was found at autopsy to have a hepatocellular carcinoma, which has been described twice previously in the literature as occurring with this disorder. Family studies on the majority of her seven siblings (the product of one father and two mothers who were identical twins) showed one brother to have classic features of cerebellar ataxia, IgA deficiency, markedly elevated alpha-fetoprotein levels, and characteristic chromosomal abnormalities. This boy also died later of hepatocellular carcinoma in 1984. An affected sister had previously died of a respiratory tract infection.     

Lack of association between the corticotrophin-releasing hormone receptor 2 gene and panic disorder

Panic disorder is classified as an anxiety disorder and affects 1-3% of the population. An individual suffering from such a disorder may experience unexpected recurrent panic attacks and fear of future attacks. Twin and family studies have pointed towards a strong heritability of the disorder. Stress response and anxiety are thought to be mediated, at least in part, by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway. To search for markers conferring genetic susceptibility to panic disorder, we typed three polymorphisms of the CRHR2 gene - CRHR2(CA), CRHR2(GT), and CRHR2(GAT) - in 466 individuals, 183 of whom had DSM-IV panic disorder. Seventy-five case-controls and 101 triad families plus 13 siblings were examined. Case-control association analyses using chi(2) tests yielded no difference in the distribution of the alleles. Linkage analysis using the Transmission Disequilibrium Test showed no preferential transmission of alleles for any of the three markers. Haplotype analysis indicated that allele 7 of CRHR2 (GAT) and 8 of CRHR2 (GT) are in almost complete linkage disequilibrium (P = 0.000 000 1). Although both neurobiology and chromosomal location point to the CHRH2 receptor gene as a candidate for panic disorder, our study indicates that the CRHR2 polymorphisms examined do not confer susceptibility to panic disorder. Further studies investigating additional polymorphisms in this gene and other components of the CRH signalling system may prove useful.     

De novo mutation in CACNA1A caused acetazolamide-responsive episodic ataxia

With the recent report of mutations in the calcium channel gene CACNA1A in two families with episodic ataxia type 2, we investigated a patient with nonfamilial episodic vertigo and ataxia responsive to acetazolamide for similar mutations. Single-strand conformation polymorphism (SSCP) analysis of exon 23 identified an extra band in the patient that was not present in other relatives or in normal controls. Exon 23 of the patient showed a spontaneous C to T substitution at position 4410 resulting in an early stop codon. Patients with nonfamilial episodic ataxia may respond to acetazolamide and may have mutations in CACNA1A. Am. J. Med. Genet. 77:298–301, 1998. © 1998 Wiley-Liss, Inc.     

A novel KCNA1 mutation identified in an Italian family affected by episodic ataxia type 1

Episodic ataxia type 1 (EA1) is a rare human neurological syndrome characterized by continuous myokymia and attacks of generalized ataxia that can be triggered by abrupt movements, emotional stress and fatigue. An Italian family has been identified where related members displayed continuous myokymia, episodes of ataxia, attacks characterized by myokymia only, and neuromyotonia. A novel missense mutation (F414C), in the C-terminal region of the K(+) channel Kv1.1, was identified in the affected individuals. The mutant homotetrameric channels were non-functional in Xenopus laevis oocytes. In addition, heteromeric channels resulting from the co-expression of wild-type Kv1.1 and Kv1.1(F414C), or wild-type Kv1.2 and Kv1.1(F414C) subunits displayed reduced current amplitudes and altered gating properties. This indicates that the pathogenic effect of this KCNA1 mutation is likely to be related to the defective functional properties we have identified.     

Muscle spasms as presenting feature of Nivelon-Nivelon-Mabile syndrome

Hedgehog acyltransferase gene (HHAT)-associated Nivelon-Nivelon-Mabile syndrome (NNMS) is a rare genetic disorder of multiple system involvement with microcephaly, central nervous system malformations, skeletal dysplasia, and 46,XY sex reversal. Other variable and inconsistent features reported in this disorder are muscle spasms, facial dysmorphism, prenatal onset growth restriction, microphthalmia, and holoprosencephaly. This is the sixth postnatal reported patient with biallelic variants in HHAT gene, who presented with microcephaly, short stature, muscle hypertrophy, muscle spasms, and facial dysmorphism. The most prominent and presenting finding in this patient were muscle hypertrophy and muscle spasms which had a clinical response to phenytoin and acetazolamide treatment. Our report emphasizes the phenotypic variability of NNMS and further reiterates muscle spasms as an important clinical manifestation of this extremely rare condition.     

A patient homozygous for the SCA6 gene with retinitis pigmentosa

The present authors studied a 55-year-old-patient homozygous for the SCA6 gene who experienced frequent attacks of positional vertigo at 37 years of age with subsequent staggering gait and night blindness. Retinitis pigmentosa (RP), as well as cerebellar ataxia and vertical antidirectional nystagmus, were detected. The subject's parents were first cousins, and two of his three male cousins, whose parents were also first cousins, had RP without ataxia or nystagmus. The numbers of CAG repeats in the expanded alleles of the SCA6 gene found by molecular analysis were 21 and 21. The genetic results were negative for SCA1, SCA2, SCA3, SCA7 and dentatorubral pallidoluysian atrophy. The retinal degeneration in this patient is most likely to be secondary to a genetic disorder of autosomal or X-linked recessive inheritance rather than SCA6. Other reported cases of patients homozygous for the SCA6 gene are also reviewed.     

Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean family.

Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine (FHM) have been known as allelic disorders, which are caused by the alteration of the alpha1A voltage-dependent calcium channel subunit. Expansions of the CAG repeat in the CACNA1A gene on the short arm of the chromosome 19 induce SCA6, and point mutations in the same gene are responsible for EA2 and FHM. In recent studies, both SCA6 and EA2 have been concurrently found in families with 26 CAG repeats without previously reported point mutations either in coding sequences or in intron-exon junctions. We describe a Korean family with CAG26 repeats in the CACNA1A gene. Some of the affected family members had progressive ataxia typical of SCA6 whereas others had episodic vertigo responsive to acetazolamide typical of EA2. Our family support that SCA6 and EA2 are allelic disorders with a high phenotypic variability.     

C1 inhibitor deficiency: 2014 United Kingdom consensus document

C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organization.     

La communication intercellulaire par l’intermédiaire des jonctions gap : un nouveau mécanisme dans la physiopathologie de la migraine avec aura. Applications thérapeutiques

Migraine is a common, recurrent and disabling primary headache disorder, which affects up to 20% of the population. About a third of patients with migraine have attacks with aura, a focal neurological disturbance that manifests itself as visual, sensitive or motor symptoms. Cortical spreading depression, a wave of electrical activity that moves across the cerebral cortex through neuronal-glial cell gap junctions, would be involved in the triggering of migraine aura. Moreover, cortical spreading depression activates perivascular trigeminal afferents in the neocortex, that through central and peripheral reflex, cause inflammatory reaction in the meninges to generate the headache. Tonabersat, a novel benzopyran compound, was selected for clinical trial on the basis of its inhibitory activity on cortical spreading depression and neurogenic inflammation in animal models of migraine. Moreover, tonabersat inhibited trigeminal ganglion neuronal-glial cell gap junctions, suggesting that this compound could prevent peripheral sensitization within the ganglion. In clinical trial, tonabersat showed a preventive effect on attacks of migraine with aura but had no efficacy on non-aura attacks and in the acute treatment of migraine. In conclusion, neuronal-glial cell gap junctional intercellular communication seems to be involved in the pathophysiology of migraine with aura and is emerging as a new promising therapeutic target for prophylactic treatment of patients with chronic attacks.     

X-linked cerebellar ataxia

Three independent families showing X-linked recessive inheritance of a rare form of cerebellar ataxia are presented. The disease is clinically distinct from both Friedreich and Marie ataxias. The age of onset is between 16–21 years and the course is progressive until the age of 30 when further deterioration is arrested. The manifestations are predominantly cerebellar with minimal pyramidal and no posterior column affection. Intellectual functions remain unimpaired. A case of female Turner's who is also a victim of this disorder is presented.     

Endometriosis of the Appendix

Endometriosis is a well known cause of infertility. Endometriosis of the appendix is a very rare condition. To highlight this rare entity, we are reporting a case of a young lady who was admitted with recurrent attacks of lower abdominal pain associated with primary infertility. Preoperative diagnosis was acute appendicitis. Histopathological examination of the appendix revealed endometriosis. Endometriosis should be considered in the differential diagnosis of recurrent lower abdominal pain in young females especially with history of infertility.     

Paternal mosaicism and hereditary angioedema in a Taiwanese family.

BACKGROUND: Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of localized subcutaneous or submucosal edema. It is inherited in an autosomal dominant fashion and caused by a deficiency of C1 inhibitor (C1 INH). Most patients with HAE have an absolute deficiency of C1 INH (type I HAE), whereas the rest (approximately 15%) synthesize a dysfunctional C1 INH protein (type II HAE). Mosaicism is rare in HAE. OBJECTIVE: To describe the clinical manifestations, laboratory findings, and molecular genetic studies in a Taiwanese family with type I HAE with paternal mosaicism. METHODS: A family that included a 34-year-old man (index patient) and his 25-year-old brother who both had recurrent peripheral angioedema was evaluated. A younger sister had died of an unexplained cause at 18 years of age. We analyzed blood levels of C3, C4, and C1 INH and sequenced the SERPING] (C1NH) gene that codes for C1 INH in 5 family members, including the parents and 3 brothers. RESULTS: The 4 men in the family had a novel mutation c.3_73del, p.N1fsX34 in exon 3 of the C1INH gene, resulting in C1 INH deficiency. Although the father carried this mutant gene, he had normal serum levels of C1 INH. Based on quantitative analysis of allele dosage by DNA fragment analysis (GeneScan), the father was determined to have genetic mosaicism. CONCLUSION: Parental mosaicism is a possible explanation for normal C1 INH plasma concentrations in both parents despite clinically apparent HAE in the children.