Browsing by Author "McLean, Melissa"

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    ItemOpen Access
    Alternating Hemiplegia of Childhood: gastrointestinal manifestations and correlation with neurological impairments.
    (Orphanet journal of rare diseases, 2020-09-03) Pratt, Milton; Uchitel, Julie; McGreal, Nancy; Gordon, Kelly; Prange, Lyndsey; McLean, Melissa; Noel, Richard J; Rikard, Blaire; Rogers Boruta, Mary K; Mikati, Mohamad A

    Background

    Alternating Hemiplegia of Childhood (AHC) is caused by mutations of the ATP1A3 gene which is expressed in brain areas that include structures controling autonomic, gastrointestinal, gut motility and GABAergic functions. We aimed to investigate, in a cohort of 44 consecutive AHC patients, two hypotheses: 1) AHC patients frequently manifest gastrointestinal, particularly motility, problems. 2) These problems are often severe and their severity correlates with neurological impairments.

    Results

    41/44 (93%) exhibited gastrointestinal symptoms requiring medical attention. For these 41 patients, symptoms included constipation (66%), swallowing problems (63%), vomiting (63%), anorexia (46%), diarrhea (44%), nausea (37%), and abdominal pain (22%). Symptoms indicative of dysmotility occurred in 33 (80%). The most common diagnoses were oropharyngeal dysphagia (63%) and gastroesophageal reflux (63%). 16 (39%) required gastrostomy and two fundoplication. Severity of gastrointestinal symptoms correlated with non-paroxysmal neurological disability index, Gross Motor Function Classification System scores, and with the presence/absence of non-gastrointestinal autonomic dysfunction (p = 0.031, 0.043, Spearman correlations and 0.0166 Cramer's V, respectively) but not with the paroxysmal disability index (p = 0.408).

    Conclusions

    Most AHC patients have gastrointestinal problems. These are usually severe, most commonly are indicative of dysmotility, often require surgical therapies, and their severity correlates with that of non-paroxysmal CNS manifestations. Our findings should help in management-anticipatory guidance of AHC patients. Furthermore, they are consistent with current understandings of the pathophysiology of AHC and of gastrointestinal dysmotility, both of which involve autonomic and GABAergic dysfunction.
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    Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.
    (Neurology, 2020-11) Balestrini, Simona; Mikati, Mohamad A; Álvarez-García-Rovés, Reyes; Carboni, Michael; Hunanyan, Arsen S; Kherallah, Bassil; McLean, Melissa; Prange, Lyndsey; De Grandis, Elisa; Gagliardi, Alessandra; Pisciotta, Livia; Stagnaro, Michela; Veneselli, Edvige; Campistol, Jaume; Fons, Carmen; Pias-Peleteiro, Leticia; Brashear, Allison; Miller, Charlotte; Samões, Raquel; Brankovic, Vesna; Padiath, Quasar S; Potic, Ana; Pilch, Jacek; Vezyroglou, Aikaterini; Bye, Ann ME; Davis, Andrew M; Ryan, Monique M; Semsarian, Christopher; Hollingsworth, Georgina; Scheffer, Ingrid E; Granata, Tiziana; Nardocci, Nardo; Ragona, Francesca; Arzimanoglou, Alexis; Panagiotakaki, Eleni; Carrilho, Inês; Zucca, Claudio; Novy, Jan; Dzieżyc, Karolina; Parowicz, Marek; Mazurkiewicz-Bełdzińska, Maria; Weckhuysen, Sarah; Pons, Roser; Groppa, Sergiu; Sinden, Daniel S; Pitt, Geoffrey S; Tinker, Andrew; Ashworth, Michael; Michalak, Zuzanna; Thom, Maria; Cross, J Helen; Vavassori, Rosaria; Kaski, Juan P; Sisodiya, Sanjay M

    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.
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    D-DEMØ, a distinct phenotype caused by ATP1A3 mutations.
    (Neurology. Genetics, 2020-10) Prange, Lyndsey; Pratt, Milton; Herman, Kristin; Schiffmann, Raphael; Mueller, David M; McLean, Melissa; Mendez, Mary Moya; Walley, Nicole; Heinzen, Erin L; Goldstein, David; Shashi, Vandana; Hunanyan, Arsen; Pagadala, Vijay; Mikati, Mohamad A
    Objective:To describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset. Methods:Review and analysis of clinical and genetic data. Results:Patients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia. Conclusions:D-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.