Erythrokeratodermia With Ataxia

Giroux, Jean-Mario; Barbeau, A.

doi:10.1001/archderm.1972.01620110019005

Cited by 65 publications

(32 citation statements)

References 6 publications

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“…The allelic mutation p.L168F in ELOVL4 has recently been described in a French-Canadian SCA pedigree with EKV (SCA34; OMIM 133190) ( Figure 3C). 3,24 Our findings further confirmed that heterozygous missense mutations in ELOVL4 cause SCA. The previously reported French-Canadian family and our Japanese families are clinically similar in the cardinal clinical feature of slowly progressive cerebellar ataxia.…”

Section: Discussionsupporting

confidence: 81%

A Novel Mutation inELOVL4Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia

et al. 2015

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IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified.OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTSClinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURESResults of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing.RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCECombined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

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Section: Discussionsupporting

confidence: 81%

A Novel Mutation inELOVL4Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia

et al. 2015

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“…Erythrokeratodermia variabilis (n = 3), ataxia (n = 1), or a combination of both phenotypes (n = 11) was found in the mutation carriers; the others were unaffected. As previously described, 3 2 types of skin lesions can be distinguished. First, erythematous and hyperkeratotic plaques are most commonly observed over the dorsal aspects of the hands and feet, the elbows, the ankles, and the external ears.…”

Section: Clinical Manifestations Of Mutation Carriersmentioning

confidence: 87%

“…3 The skin lesions were typical of erythrokeratodermia variabilis (EKV, OMIM 133200), a heterogeneous group of diseases characterized by erythematous lesions and hyperkeratosis. The pure form of EKV has been associated 4 with mutations in 2 connexin genes, GJB3 and GJB4, on chromosome 1p35.1, but additional genes causing EKV remain to be identified.…”

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confidence: 99%

Expanding the Clinical Phenotype Associated WithELOVL4Mutation

et al. 2014

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IMPORTANCE The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described.OBJECTIVE To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTSA total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations.MAIN OUTCOMES AND MEASURES Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTSWe describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. CONCLUSIONS AND RELEVANCEWe report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome β-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.

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“…Netherton disease is ruled out by microscopically normal hair shafts. Although erythrokeratodermia variabilis has been reported in association with neurologic abnormalities (Giroux and Barbeau, 1972;Beare et al, 1972), development is usually normal and other congenital defects are rare. Finally, though the agents in the aflatoxin assay have been reported to be associated with microcephaly, cleft palate, and growth retardation in laboratory animals (Bassir and Adekunle, 1970;Elis and DiPaolo, 1967), this patient's presentation has not been seen.…”

Section: Discussionmentioning

confidence: 99%

New syndrome of congenital ichthyosis with neurologic abnormalities

Zunich¹,

1983

Am. J. Med. Genet.

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THE SYNDROMEMain manifestations. Migratory ichthyosiform rash, cleft palate, hypertelorism, bilateral retinal colobomata, large size, seizure disorder, and developmental delay.Prenatal history. Maternal work exposure to aflatoxin assay (aflatoxin, chloroform, toluene, and benzene) during first 4-6 weeks of gestation.Birth history. Forceps delivery without further complications. BW was 4.0 kg (95%), TBL was 53.5 cm (95%).Medical/surgical history. Appearance of ichthyosiform rash by 1 week. Onset of seizures at 9 months, aggravated by high environmental temperatures. Repair of cleft palate at 15 months.Family history. G2P1, 23-year-old Irish-Dutch mother and 26-year-old Polish father. No known relatives with similar or other birth defects. Healthy 4lh-year-old sister.Clinical examination at 3% years. Male. height 101.5 cm (90%), weight 18.6 kg (>95%), OFC 48.5 cm (5%). Inner canthal, outer canthal, and interpupillary distances > 97 % .Skin and hair (Fig. I). Large areas erythematous, ichthyotic plaques with sharp margins. Palms and soles thickened. Uninvolved areas of skin normal. Fine, sparse, blond hair in normal distribution.Head and face (Fig. 2). Brachycephaly. Epicanthal folds. Left ptosis and exotropia. Bilateral retinal colobomata. Flat nasal bridge with linear scar-like tissue

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Erythrokeratodermia With Ataxia

Cited by 65 publications

References 6 publications

A Novel Mutation inELOVL4Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia

A Novel Mutation inELOVL4Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia

Expanding the Clinical Phenotype Associated WithELOVL4Mutation

New syndrome of congenital ichthyosis with neurologic abnormalities

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