The third case report a patient with primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome de novo variant mutations in the CACNA1D gene

Semenova, N.A.; Ryzhkova, OP; Строкова, Т.В.; Taran, N. N.

doi:10.17116/jnevro201811812149

Cited by 21 publications

(15 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Primary aldosteronism was not reported in the first case of congential HH affected by a CACNA1D variant G403D [15]. Three individuals with CACNA1D variants G403D, I750 M and V259Ahad primary aldosteronism but, despite transient short episodes of postnatal hypoglycemia, did not require long-term diazoxide treatment [10,14]. Therefore our case is the first in a patient with both endocrine disorders, emphasizing the importance of early tests for primary aldosteronism in patients with syndromes affected by CACNA1D variants.…”

Section: Discussionmentioning

confidence: 75%

“…Since primary aldosteronism was also described in three previous patients carrying pathogenic CACNA1D de novo variants [10,14] we also screened the patient for heart disease and hyperaldosteronism. Echocardiography showed a slightly hypertrophic left ventricle with minimal aortic insufficiency.…”

Section: Resultsmentioning

confidence: 99%

“…Some patients also present with endocrine symptoms at birth which guide early diagnosis and intervention. So far three cases (variants G403D, I750 M, V259A) with a syndrome presenting with congenitial primary aldosteronism have been described also associated with seizures and neurological abnormalities (PASNA, OMIM # 615474; 10,14). Postnatal transient hypoglycemia with fast recovery upon treatment was also reported in these patients.…”

Section: Introductionmentioning

confidence: 88%

See 2 more Smart Citations

A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia

Alemany

Grau²,

Macián

et al. 2020

Channels

View full text Add to dashboard Cite

Congenital hyperinsulinemic hypoglycemia is the most frequent cause of persistent and recurrent hypoglycemia in the first years of life and in many patients rare genetic variants can be identified. Recently a case of congenital hyperinsulinemic hypoglycemia and a severe neurodevelopmental syndrome due to a mutation in the voltage-gated Cav1.3 Ca 2+ channel CACNA1D gene has been reported which required long-term treatment with diazoxide. This suggested CACNA1D variants as a potential cause for this condition. Here we support this observation by presenting the case of a female child with congential hyperinsulinemic hypoglycemia and primary hyperaldosteronism, aortic insufficiency, pronounced developmental delay, muscle hypotonia, and facial dysmorphias but without seizures. Sequencing of the exome of the child and its parents identified a novel de novo CACNA1D missense mutation p.L271 H, replacing a highly conserved residue in a functionally relevant region of the voltagegated Cav1.3 Ca 2+ channel. The patient was treated with diazoxide and nifedipine with adequate control of glucose metabolism and blood pressure, and with improvement in muscle tone. Our findings further confirm the pathogenic role of CACNA1D for congentital hyperinsulinemic hypoglycemia and primary aldosteronism. Moreover, we provide evidence that the dihydropyridine Ca 2+ channel blocker nifedipine, although not considered a first-line treatment for congenital hyperinsulinism, may be beneficial to control blood pressure and neurological symptoms in patients with CACNA1D mutations.

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

See 1 more Smart Citation

A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia

Alemany

Grau²,

Macián

et al. 2020

Channels

View full text Add to dashboard Cite

show abstract

“…Very recently identified de novo mutation V259A has been reported in another severely affected individual, a 1-year-old male with seizures, global developmental delay and primary aldosteronism [19]. So far this mutation has not been functionally characterized.…”

Section: Discussionmentioning

confidence: 99%

“…We [14][15][16] and others [17][18][19][20] have recently provided accumulating evidence that de novo missense mutations in the pore-forming α 1 -subunit of Cav1.3 LTCCs (CACNA1D) confer high risk for neurodevelopmental disorders in humans. Symptoms range from ASD with (mutations A749G, Q547H [14,20];) and without (G407R [14]) intellectual disability to more severely affected patients with seizures, muscle hypotonia, and global developmental delay (V401L [15]).…”

Section: Introductionmentioning

confidence: 99%

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

et al. 2020

View full text Add to dashboard Cite

Background: There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 Ltype Ca 2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely diseasecausing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods: For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results: Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~13-17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca 2+-levels during action potential-like stimulations, characteristic for gain-offunction changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca 2+-channel blocker isradipine by 3-4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca 2+-channel blockers.

show abstract

CACNA1D-Related Channelopathies: From Hypertension to Autism

Ortner

2023

Handbook of Experimental Pharmacology

View full text Add to dashboard Cite

The third case report a patient with primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome de novo variant mutations in the CACNA1D gene

Cited by 21 publications

References 17 publications

A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia

A de novo CACNA1D missense mutation in a patient with congenital hyperinsulinism, primary hyperaldosteronism and hypotonia

Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

CACNA1D-Related Channelopathies: From Hypertension to Autism

Contact Info

Product

Resources

About