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1.
Ophthalmic Genet ; 42(5): 612-614, 2021 10.
Article in English | MEDLINE | ID: mdl-33949289

ABSTRACT

Background: Duane retraction syndrome and arthrogryposis multiplex congenita have an incidence of approximately 1:1500-1:3000 live births. However, the association of these two entities with a Marcus-Gunn might be a rare and, until now, under-recognized clinical presentation of the Wieacker-Wolff Syndrome.Patient and methods: We report a 7-year-old female with dysmorphic features, global developmental delay, arthrogryposis multiplex congenita (AMC), Duane retraction syndrome (DRS), and unilateral Marcus Gunn jaw winking.Results: Whole Exome Sequencing showed a de novo premature stop codon in ZC4H2. Extensive genetic and metabolic work was negative otherwise and Brain MRI showed delayed non-specific myelination abnormalities. She continues to have significant delays but does not have regression, seizures or other neurological complications. She has required a multidisciplinary approach for the management of her multiple contractures.Conclusion: This case confirms ZC4H2 as a cause of syndromic DRS and extends the ZC4H2 phenotype to include Marcus Gunn jaw winking.


Subject(s)
Apraxias/diagnosis , Arthrogryposis/genetics , Blepharoptosis/genetics , Contracture/diagnosis , Duane Retraction Syndrome/genetics , Genetic Diseases, X-Linked/diagnosis , Heart Defects, Congenital/genetics , Intracellular Signaling Peptides and Proteins/genetics , Jaw Abnormalities/genetics , Muscular Atrophy/diagnosis , Mutation , Nervous System Diseases/genetics , Nuclear Proteins/genetics , Ophthalmoplegia/diagnosis , Reflex, Abnormal/genetics , Apraxias/genetics , Arthrogryposis/diagnosis , Blepharoptosis/diagnosis , Child , Codon, Nonsense , Contracture/genetics , Duane Retraction Syndrome/diagnosis , Female , Genetic Diseases, X-Linked/genetics , Heart Defects, Congenital/diagnosis , Humans , Jaw Abnormalities/diagnosis , Magnetic Resonance Imaging , Muscular Atrophy/genetics , Nervous System Diseases/diagnosis , Ophthalmoplegia/genetics , Exome Sequencing
2.
BMJ Case Rep ; 13(12)2020 Dec 15.
Article in English | MEDLINE | ID: mdl-33323420

ABSTRACT

Hyperekplexia is an exaggerated startle to external stimuli associated with a generalised increase in tone seen in neonates with both sporadic and genetic predisposition. This is an uncommon neurological entity that is misdiagnosed as seizure. A 28-days-old infant was admitted to us with characteristic intermittent generalised tonic spasm being treated as a seizure disorder. The infant had characteristic stiffening episode, exaggerated startle and non-habituation on tapping the nose. Hyperekplexia was suspected and confirmed by genetic testing (mutation in the ß subunit of glycine was found). Initial improvement was seen with the use of clonazepam, which was not sustained. At the age of 4.5 years, the child is still having neurobehavioural issues like hyperactivity and sensory hyper-responsiveness. Usually, hyperekplexia is benign in nature. We report a case of hyperekplexia with non-sense mutation in the ß subunit of GlyR gene having abnormal neurodevelopmental findings at 4.5 years.


Subject(s)
Hyperekplexia/diagnosis , Hyperekplexia/genetics , Mutation, Missense/genetics , Receptors, Glycine/genetics , Anticonvulsants/therapeutic use , Child, Preschool , Clonazepam/therapeutic use , Diagnosis, Differential , Diagnostic Errors , Humans , Hyperekplexia/physiopathology , Hyperkinesis/genetics , Hyperkinesis/physiopathology , Infant, Newborn , Male , Reflex, Abnormal/genetics , Reflex, Startle/genetics
4.
Neurology ; 95(21): e2866-e2879, 2020 11 24.
Article in English | MEDLINE | ID: mdl-32913013

ABSTRACT

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.


Subject(s)
Cerebellar Ataxia/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/genetics , Hemiplegia/genetics , Mutation/genetics , Optic Atrophy/genetics , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Adolescent , Adult , Cerebellar Ataxia/metabolism , Cerebellar Ataxia/therapy , Child , Child, Preschool , Cohort Studies , Female , Foot Deformities, Congenital/metabolism , Foot Deformities, Congenital/therapy , Hearing Loss, Sensorineural/metabolism , Hearing Loss, Sensorineural/therapy , Hemiplegia/diagnosis , Hemiplegia/therapy , Humans , Infant , Male , Middle Aged , Optic Atrophy/metabolism , Optic Atrophy/therapy , Phenotype , Seizures/therapy , Young Adult
5.
Am J Med Genet C Semin Med Genet ; 184(3): 611-617, 2020 09.
Article in English | MEDLINE | ID: mdl-32914532

ABSTRACT

To report ophthalmic findings of patients without colobomas, and with a clinical and molecular diagnosis of CHARGE Syndrome. Retrospective study of ophthalmic findings in 67 CHARGE patients-clinically confirmed diagnosis with positive CHD7 mutation-seen in the Ophthalmology department of Cincinnati Children's Hospital Medical Center between January 1, 2008 through September 25, 2018. Criteria for inclusion in this study was absence of any form of a coloboma in either eye. In our cohort, all patients had a positive CHD7 mutation, in addition to a clinical diagnosis. 19.4% (13/67) of CHARGE patients did not have a coloboma in either eye. 69.2% (9/13) had strabismus, 76.9% (10/13) had a refractive error that warranted refractive correction, 23.1% (3/13) had amblyopia, 38.5% (5/13) had nasolacrimal duct obstruction, 30.8% (4/13) had dry eye syndrome and exposure keratopathy, 15.4% (2/13) had ptosis, 15.4% (2/13) had blepharitis, 15.4% (2/13) had Cortical Visual Impairment, 7.7% (1/13) of patients had optic nerve drusen, 7.7% (1/13) had Marcus Gunn Jaw Winking, and 7.7% (1/13) with an eyelid nevus. There are numerous ophthalmic findings in individuals with CHARGE Syndrome without colobomas. No study to date has evaluated the ophthalmic findings in CHD7 positive CHARGE patients without colobomas. These findings need to be assessed and treated to ensure optimal vision in the CHARGE patient population. Absence of coloboma does not rule out a diagnosis of CHARGE syndrome, and if there is a clinical suspicion, clinical confirmation then genetic testing would be warranted.


Subject(s)
Blepharoptosis/genetics , CHARGE Syndrome/genetics , Coloboma/genetics , Heart Defects, Congenital/genetics , Jaw Abnormalities/genetics , Lacrimal Duct Obstruction/genetics , Nervous System Diseases/genetics , Reflex, Abnormal/genetics , Adolescent , Blepharoptosis/complications , Blepharoptosis/pathology , CHARGE Syndrome/complications , CHARGE Syndrome/pathology , Child , Child, Preschool , Coloboma/complications , Coloboma/pathology , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Female , Heart Defects, Congenital/complications , Heart Defects, Congenital/pathology , Humans , Infant , Jaw Abnormalities/complications , Jaw Abnormalities/pathology , Lacrimal Duct Obstruction/complications , Lacrimal Duct Obstruction/pathology , Male , Mutation/genetics , Nasolacrimal Duct/metabolism , Nasolacrimal Duct/pathology , Nervous System Diseases/complications , Nervous System Diseases/pathology , Optic Nerve/metabolism , Optic Nerve/pathology
6.
Neurology ; 95(21): e2912-e2923, 2020 11 24.
Article in English | MEDLINE | ID: mdl-32873692

ABSTRACT

OBJECTIVE: To determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses. METHODS: In this case-control study, we included 457 individuals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 individuals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR. RESULTS: Massive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800-1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7-137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found. CONCLUSIONS: A biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.


Subject(s)
Cerebellar Ataxia/genetics , Replication Protein C/genetics , Adult , Age of Onset , Case-Control Studies , Female , Humans , Male , Microsatellite Repeats , Peripheral Nervous System Diseases/genetics , Reflex, Abnormal/genetics , Replication Protein C/metabolism , Vestibular Diseases/diagnosis , Vestibular Diseases/genetics , Vestibular Diseases/metabolism
9.
PLoS One ; 15(6): e0234394, 2020.
Article in English | MEDLINE | ID: mdl-32574176

ABSTRACT

In the BACHD mouse model of Huntington's disease (HD), deletion of the N17 domain of the Huntingtin gene (BACHDΔN17, Q97) has been reported to lead to nuclear accumulation of mHTT and exacerbation of motor deficits, neuroinflammation and striatal atrophy (Gu et al., 2015). Here we characterized the effect of N17 deletion on dorsolateral striatal medium spiny neurons (MSNs) in BACHDΔN17 (Q97) and BACWTΔN17 (Q31) mice by comparing them to MSNs in wildtype (WT) mice. Mice were characterized on a series of motor tasks and subsequently whole cell patch clamp recordings with simultaneous biocytin filling of MSNs in in vitro striatal slices from these mice were used to comprehensively assess their physiological and morphological features. Key findings include that: Q97 mice exhibit impaired gait and righting reflexes but normal tail suspension reflexes and normal coats while Q31 mice do not differ from WT; intrinsic membrane and action potential properties are altered -but differentially so- in MSNs from Q97 and from Q31 mice; excitatory and inhibitory synaptic currents exhibit higher amplitudes in Q31 but not Q97 MSNs, while excitatory synaptic currents occur at lower frequency in Q97 than in WT and Q31 MSNs; there is a reduced total dendritic length in Q31 -but not Q97- MSNs compared to WT, while spine density and number did not differ in MSNs in the three groups. The findings that Q31 MSNs differed from Q97 and WT neurons with regard to some physiological features and structurally suggest a novel role of the N17 domain in the function of WT Htt. The motor phenotype seen in Q97 mice was less robust than that reported in an earlier study (Gu et al., 2015), and the alterations to MSN physiological properties were largely consistent with changes reported previously in a number of other mouse models of HD. Together this study indicates that N17 plays a role in the modulation of the properties of MSNs in both mHtt and WT-Htt mice, but does not markedly exacerbate HD-like pathogenesis in the BACHD model.


Subject(s)
Huntingtin Protein/genetics , Huntington Disease/genetics , Action Potentials , Animals , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Dendrites/pathology , Disease Models, Animal , Excitatory Postsynaptic Potentials , Female , Humans , Huntingtin Protein/chemistry , Huntingtin Protein/physiology , Huntington Disease/pathology , Huntington Disease/physiopathology , Lameness, Animal/genetics , Lameness, Animal/physiopathology , Male , Mice , Mice, Mutant Strains , Mice, Transgenic , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/physiology , Neurons/pathology , Neurons/physiology , Protein Domains , Reflex, Abnormal/genetics , Reflex, Abnormal/physiology , Sequence Deletion
10.
Hum Mol Genet ; 29(9): 1568-1579, 2020 06 03.
Article in English | MEDLINE | ID: mdl-32356556

ABSTRACT

The translocase of outer mitochondrial membrane (TOMM) complex is the entry gate for virtually all mitochondrial proteins and is essential to build the mitochondrial proteome. TOMM70 is a receptor that assists mainly in mitochondrial protein import. Here, we report two individuals with de novo variants in the C-terminal region of TOMM70. While both individuals exhibited shared symptoms including hypotonia, hyper-reflexia, ataxia, dystonia and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset. Both individuals were undiagnosed despite extensive genetics workups. Individual 1 was found to have a p.Thr607Ile variant while Individual 2 was found to have a p.Ile554Phe variant in TOMM70. To functionally assess both TOMM70 variants, we replaced the Drosophila Tom70 coding region with a Kozak-mini-GAL4 transgene using CRISPR-Cas9. Homozygous mutant animals die as pupae, but lethality is rescued by the mini-GAL4-driven expression of human UAS-TOMM70 cDNA. Both modeled variants lead to significantly less rescue indicating that they are loss-of-function alleles. Similarly, RNAi-mediated knockdown of Tom70 in the developing eye causes roughening and synaptic transmission defect, common findings in neurodegenerative and mitochondrial disorders. These phenotypes were rescued by the reference, but not the variants, of TOMM70. Altogether, our data indicate that de novo loss-of-function variants in TOMM70 result in variable white matter disease and neurological phenotypes in affected individuals.


Subject(s)
Genetic Predisposition to Disease , Leukoencephalopathies/genetics , Mitochondrial Membrane Transport Proteins/genetics , Nervous System Diseases/genetics , Age of Onset , Ataxia/genetics , Ataxia/pathology , Child , Dystonia/genetics , Dystonia/pathology , Female , Humans , Leukoencephalopathies/pathology , Male , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria/pathology , Mitochondrial Precursor Protein Import Complex Proteins , Muscle Hypotonia/genetics , Muscle Hypotonia/pathology , Nervous System Diseases/pathology , Reflex, Abnormal/genetics
11.
Muscle Nerve ; 62(2): 266-271, 2020 08.
Article in English | MEDLINE | ID: mdl-32363625

ABSTRACT

BACKGROUND: Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease. METHODS: Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples. RESULTS: A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients. CONCLUSIONS: Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.


Subject(s)
Brain Diseases/genetics , Loss of Function Mutation , Muscle Hypotonia/genetics , Muscle, Skeletal/pathology , Muscular Diseases/genetics , Protein Serine-Threonine Kinases/genetics , Psychomotor Disorders/genetics , Seizures/genetics , Adolescent , Brain/diagnostic imaging , Brain Diseases/diagnostic imaging , Child , Developmental Disabilities/genetics , Female , Homozygote , Humans , Leukoencephalopathies/diagnostic imaging , Leukoencephalopathies/genetics , Magnetic Resonance Imaging , Muscle Weakness/genetics , Muscle Weakness/pathology , Muscular Diseases/pathology , Protein Serine-Threonine Kinases/metabolism , Reflex, Abnormal/genetics , Severity of Illness Index , Siblings , Syndrome , Exome Sequencing
13.
Brain Dev ; 41(7): 625-629, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30904181

ABSTRACT

BACKGROUND: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome is a known ATP1A3-related disorder, but little has been elucidated regarding its pathophysiology. We now report two new patients, a Japanese boy and his mother with a pathogenic mutation (c.2452G>A) in ATP1A3, who were diagnosed with CAPOS syndrome. METHODS: After febrile illnesses at 7 months of age, and again at 22 months of age, the boy had a reduced level of consciousness, truncal ataxia and eye movement-disorders. The patient's 32-year-old mother may have experienced an episode of acute encephalopathy in her childhood and sustained sensorineural hearing loss. In the present study, we demonstrated chronological dynamic changes in cerebral blood flow (CBF) in the son, using serial single-photon emission computed tomography (SPECT). RESULTS: The serial CBF-SPECT findings using statistical methods showed progressive hyperperfusion in the frontal lobes, basal ganglia and thalamus, and hypoperfusion in the occipital and temporal lobes during the acute and subacute phases. Thereafter, the dynamic changes of CBF improved in the chronic but hypoperfusion in thalamus appeared to the chronic phase. CONCLUSION: The abnormal cortico-subcortical CBF may contribute to an acute encephalopathy-like condition in the acute stage of CAPOS syndrome. CAPOS syndrome is not often reported, and is possibly an under-recognized syndrome in clinically mild cases.


Subject(s)
Cerebellar Ataxia/physiopathology , Cerebrovascular Circulation/physiology , Foot Deformities, Congenital/physiopathology , Hearing Loss, Sensorineural/physiopathology , Optic Atrophy/physiopathology , Sodium-Potassium-Exchanging ATPase/genetics , Adult , Cerebellar Ataxia/genetics , Female , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/genetics , Humans , Infant , Male , Mutation , Optic Atrophy/genetics , Phenotype , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/metabolism , Tomography, Emission-Computed, Single-Photon/methods
14.
J Biol Chem ; 294(1): 269-280, 2019 01 04.
Article in English | MEDLINE | ID: mdl-30409907

ABSTRACT

The cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome is caused by the single mutation E818K of the α3-isoform of Na+,K+-ATPase. Here, using biochemical and electrophysiological approaches, we examined the functional characteristics of E818K, as well as of E818Q and E818A mutants. We found that these amino acid substitutions reduce the apparent Na+ affinity at the cytoplasmic-facing sites of the pump protein and that this effect is more pronounced for the lysine and glutamine substitutions (3-4-fold) than for the alanine substitution. The electrophysiological measurements indicated a more conspicuous, ∼30-fold reduction of apparent Na+ affinity for the extracellular-facing sites in the CAPOS mutant, which was related to an accelerated transition between the phosphoenzyme intermediates E1P and E2P. The apparent affinity for K+ activation of the ATPase activity was unaffected by these substitutions, suggesting that primarily the Na+-specific site III is affected. Furthermore, the apparent affinities for ATP and vanadate were WT-like in E818K, indicating a normal E1-E2 equilibrium of the dephosphoenzyme. Proton-leak currents were not increased in E818K. However, the CAPOS mutation caused a weaker voltage dependence of the pumping rate and a stronger inhibition by cytoplasmic K+ than the WT enzyme, which together with the reduced Na+ affinity of the cytoplasmic-facing sites precluded proper pump activation under physiological conditions. The functional deficiencies could be traced to the participation of Glu-818 in an intricate hydrogen-bonding/salt-bridge network, connecting it to key residues involved in Na+ interaction at site III.


Subject(s)
Adenosine Triphosphate/metabolism , Cerebellar Ataxia/metabolism , Foot Deformities, Congenital/metabolism , Hearing Loss, Sensorineural/metabolism , Membrane Potentials , Mutation, Missense , Optic Atrophy/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Adenosine Triphosphate/genetics , Amino Acid Substitution , Animals , Cerebellar Ataxia/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/genetics , Humans , Optic Atrophy/genetics , Protein Domains , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics , Vanadates/pharmacology , Xenopus laevis
16.
Brain Dev ; 40(7): 576-581, 2018 Aug.
Article in English | MEDLINE | ID: mdl-29625811

ABSTRACT

A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8 months, and 2, 4, and 37 years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452G > A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review.


Subject(s)
Cerebellar Ataxia/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/genetics , Mutation , Optic Atrophy/genetics , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Adult , Brain/diagnostic imaging , Brain/physiopathology , Cerebellar Ataxia/diagnostic imaging , Cerebellar Ataxia/drug therapy , Cerebellar Ataxia/physiopathology , Disease Progression , Female , Foot Deformities, Congenital/diagnostic imaging , Foot Deformities, Congenital/drug therapy , Foot Deformities, Congenital/physiopathology , Hearing Loss, Sensorineural/diagnostic imaging , Hearing Loss, Sensorineural/drug therapy , Hearing Loss, Sensorineural/physiopathology , Humans , Optic Atrophy/diagnostic imaging , Optic Atrophy/drug therapy , Optic Atrophy/physiopathology , Phenotype
17.
Hum Genet ; 137(2): 111-127, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29305691

ABSTRACT

Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS) is a rare clinically distinct syndrome caused by a single dominant missense mutation, c.2452G>A, p.Glu818Lys, in ATP1A3, encoding the neuron-specific alpha subunit of the Na+/K+-ATPase α3. Allelic mutations cause the neurological diseases rapid dystonia Parkinsonism and alternating hemiplegia of childhood, disorders which do not encompass hearing or visual impairment. We present detailed clinical phenotypic information in 18 genetically confirmed patients from 11 families (10 previously unreported) from Denmark, Sweden, UK and Germany indicating a specific type of hearing impairment-auditory neuropathy (AN). All patients were clinically suspected of CAPOS and had hearing problems. In this retrospective analysis of audiological data, we show for the first time that cochlear outer hair cell activity was preserved as shown by the presence of otoacoustic emissions and cochlear microphonic potentials, but the auditory brainstem responses were grossly abnormal, likely reflecting neural dyssynchrony. Poor speech perception was observed, especially in noise, which was beyond the hearing level obtained in the pure tone audiograms in several of the patients presented here. Molecular modelling and in vitro electrophysiological studies of the specific CAPOS mutation were performed. Heterologous expression studies of α3 with the p.Glu818Lys mutation affects sodium binding to, and release from, the sodium-specific site in the pump, the third ion-binding site. Molecular dynamics simulations confirm that the structure of the C-terminal region is affected. In conclusion, we demonstrate for the first time evidence for auditory neuropathy in CAPOS syndrome, which may reflect impaired propagation of electrical impulses along the spiral ganglion neurons. This has implications for diagnosis and patient management. Auditory neuropathy is difficult to treat with conventional hearing aids, but preliminary improvement in speech perception in some patients suggests that cochlear implantation may be effective in CAPOS patients.


Subject(s)
Cerebellar Ataxia/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Central/genetics , Hearing Loss, Sensorineural/genetics , Optic Atrophy/genetics , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Adolescent , Adult , Cerebellar Ataxia/epidemiology , Cerebellar Ataxia/physiopathology , Child , Child, Preschool , Denmark/epidemiology , Female , Foot Deformities, Congenital/epidemiology , Foot Deformities, Congenital/physiopathology , Germany/epidemiology , Hearing Loss, Central/epidemiology , Hearing Loss, Central/physiopathology , Hearing Loss, Sensorineural/epidemiology , Hearing Loss, Sensorineural/physiopathology , Humans , Male , Molecular Dynamics Simulation , Mutation, Missense/genetics , Optic Atrophy/epidemiology , Optic Atrophy/physiopathology , Phenotype , Retrospective Studies , Sodium-Potassium-Exchanging ATPase/chemistry , Sweden/epidemiology , Young Adult
18.
Eur J Paediatr Neurol ; 22(2): 257-263, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29291920

ABSTRACT

Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) are three distinct, yet partially overlapping clinical syndromes that have long been thought to be allelic disorders. From 2004 to 2012, both autosomal dominant and de novo mutations in ATP1A3 have been detected in patients affected by these three conditions. Growing evidence suggests that AHC, RDP and CAPOS syndrome are part of a large and continuously expanding clinical spectrum and share some recurrent clinical features, such as abrupt-onset, asymmetric anatomical distribution and the presence of triggering factors, which are highly suggestive of ATP1A3 mutations. In this review, we will highlight the main clinical and genetic features of ATP1A3-related disorders focussing on shared and distinct features that can be helpful in clinical practice to individuate mutation carriers.


Subject(s)
Cerebellar Ataxia/genetics , Dystonic Disorders/genetics , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/genetics , Hemiplegia/genetics , Optic Atrophy/genetics , Reflex, Abnormal/genetics , Sodium-Potassium-Exchanging ATPase/genetics , Child, Preschool , Female , Genetic Association Studies , Humans , Mutation
19.
Am J Med Genet A ; 176(1): 235-240, 2018 01.
Article in English | MEDLINE | ID: mdl-29090527

ABSTRACT

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.


Subject(s)
Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/genetics , Foot Deformities, Congenital/diagnosis , Foot Deformities, Congenital/genetics , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/genetics , Optic Atrophy/diagnosis , Optic Atrophy/genetics , Phenotype , Pregnancy Complications , Reflex, Abnormal/genetics , Alleles , Child, Preschool , Female , Genetic Association Studies , Genotype , Humans , Infant , Male , Pedigree , Pregnancy , Sodium-Potassium-Exchanging ATPase/genetics
20.
Am J Physiol Heart Circ Physiol ; 313(4): H700-H707, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28778914

ABSTRACT

The last two decades have seen the emergence of Cre-Lox recombination as one of the most powerful and versatile technologies for cell-specific genetic engineering of mammalian cells. Understandably, the primary concerns in the practice of Cre-Lox recombination are whether the predicted genome has been correctly modified and the targeted phenotypes expressed. Rarely are the physiological conditions of the animals routinely examined because the general assumption is that they are normal. Based on corroborative results from radiotelemetric recording, power spectral analysis, and magnetic resonance imaging/diffusion tensor imaging in brain-derived neurotrophic factor-floxed mice, the present study revealed that this assumption requires amendment. We found that despite comparable blood pressure and heart rate with C57BL/6 or Cre mice under the conscious state, floxed and Cre-Lox mice exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex. We further found that the capacity and plasticity of baroreflex of these two strains of mice under isoflurane anesthesia were retarded, as reflected by reduced connectivity between the nucleus tractus solitarii and rostral ventrolateral medulla or nucleus ambiguus. The identification of anomalous baroreflex functionality inherent in floxed and Cre-Lox mice points to the importance of incorporating physiological phenotypes into studies that engage gene manipulations such as Cre-Lox recombination.NEW & NOTEWORTHY We established that anomalous baroreflex functionality is inherent in floxed and Cre-Lox mice. These two mouse strains exhibited diminished baroreflex-mediated sympathetic vasomotor tone and cardiac vagal baroreflex under the conscious state, retarded capacity and plasticity of baroreflex under isoflurane anesthesia, and reduced connectivity between key nuclei in the baroreflex neural circuits.


Subject(s)
Baroreflex/genetics , Blood Pressure/genetics , Heart Rate/genetics , Reflex, Abnormal/genetics , Anesthetics, Inhalation/pharmacology , Animals , Animals, Genetically Modified , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/physiology , Brain-Derived Neurotrophic Factor/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics , Consciousness , Diffusion Tensor Imaging , Heart Rate/physiology , Integrases , Isoflurane/pharmacology , Magnetic Resonance Imaging , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neural Pathways , Phenotype , Reflex, Abnormal/drug effects , Reflex, Abnormal/physiology , Solitary Nucleus/physiopathology , Vagus Nerve/physiopathology , Vasomotor System
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