Clinical and genetic study of two patients with Zimmermann–Laband syndrome and literature review

Castori, Marco; Valiante, Michele; Pascolini, Giulia; Leuzzi, Vincenzo; Pizzuti, Antonio; Grammatico, Paola

doi:10.1016/j.ejmg.2013.08.004

Cited by 32 publications

(28 citation statements)

References 28 publications

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“…They were clinically assessed by experienced clinical geneticists and/or neurologists. Among them, five patients had previously been reported 5,12 .…”

Section: Methodsmentioning

confidence: 99%

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

et al. 2015

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Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltage-gated K(+) channel Eag1 (Kv10.1). Patch-clamp recordings showed strong negative shifts in voltage-dependent activation for all but one KCNH1 channel mutant (Gly469Arg). Coexpression of Gly469Arg with wild-type KCNH1 resulted in heterotetrameric channels with reduced conductance at positive potentials but pronounced conductance at negative potentials. These data support a gain-of-function effect for all ZLS-associated KCNH1 mutants. We also identified a recurrent de novo missense change in ATP6V1B2, encoding the B2 subunit of the multimeric vacuolar H(+) ATPase, in two individuals with ZLS. Structural analysis predicts a perturbing effect of the mutation on complex assembly. Our findings demonstrate that KCNH1 mutations cause ZLS and document genetic heterogeneity for this disorder.

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“…They were clinically assessed by experienced clinical geneticists and/or neurologists. Among them, five patients had previously been reported 5,12 .…”

Section: Methodsmentioning

confidence: 99%

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

et al. 2015

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“…The clinical history, including medical history and developmental course, seizure semiology, clinical examination, antiepileptic drugs treatment, EEG monitoring, and laboratory and neuroradiological data, was collected for nine cases with KCNH1-related disorders. Of the eight published cases, five had ZLS and three uncharacterized intellectual disability (Rauch et al, 2012;Castori et al, 2013;Campeau et al, 2014;Bramswig et al, 2015;Kortüm et al, 2015;Nair et al, 2015;Simons et al, 2015). A new case of a 12-month-old child with ZLS was also included.…”

Section: Methodsmentioning

confidence: 99%

Epilepsy in KCNH1‐related syndromes

Mastrangelo

Scheffer

Bramswig

et al. 2016

Epileptic Disorders

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Aim. KCNH1 mutations have been identified in patients with Zimmermann‐Laband syndrome and Temple‐Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Methods. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Results. Epilepsy was present in 7/9 patients. Both generalized and focal tonic‐clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Conclusions. Epilepsy is a key phenotypic feature in most individuals with KCNH1‐related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.

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“…It is genetically heterogeneous: Kortüm et al [] found KCNH1 or ATP6V1B2 mutations in eight of 24 patients. Castori et al [] reviewed 52 patients. Of these, three had ST [Chadwick et al, ; Holzhausen et al, ; Chacon‐Camacho et al, ], ranging from one to five in number.…”

Section: Exclusions Of Commonly Cited Syndromesmentioning

confidence: 99%

Syndromes with supernumerary teeth

Lubinsky

Kantaputra

2016

American J of Med Genetics Pt A

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While most supernumerary teeth are idiopathic, they can be associated with a number of Mendelian syndromes. However, this can also be a coincidental finding, since supernumerary teeth occur in 6% or more of the normal population. To better define this relationship, we analyzed the evidence for specific associations. We excluded conditions with a single affected patient reported, supernumerary teeth adjacent to clefts or other forms of alveolar disruption (as secondary rather than primary findings), and natal teeth, which can involve premature eruption of a normal tooth. Since, the cause of supernumerary teeth shows considerable heterogeneity, certain findings are less likely to be coincidental, such as five or more supernumerary teeth in a single patient, or locations outside of the premaxilla. We found only eight genetic syndromes with strong evidence for an association: cleidocranial dysplasia; familial adenomatous polyposis; trichorhinophalangeal syndrome, type I; Rubinstein–Taybi syndrome; Nance–Horan syndrome; Opitz BBB/G syndrome; oculofaciocardiodental syndrome; and autosomal dominant Robinow syndrome. There is also suggestive evidence of an association with two uncommon disorders, Kreiborg–Pakistani syndrome (craniosynostosis and dental anomalies), and insulin‐resistant diabetes mellitus with acanthosisnigricans. An association of a Mendelian disorder with a low frequency manifestation of supernumerary teeth is difficult to exclude without large numbers, but several commonly cited syndromes lacked evidence for clear association, including Hallermann–Streiff syndrome, Fabry disease, Ehlers–Danlos syndrome, Apert and Crouzon syndromes, Zimmermann–Laband syndrome, and Ellis–van Creveld syndrome. © 2016 Wiley Periodicals, Inc.

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Clinical and genetic study of two patients with Zimmermann–Laband syndrome and literature review

Cited by 32 publications

References 28 publications

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome

Epilepsy in KCNH1‐related syndromes

Syndromes with supernumerary teeth

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