B.02 Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy

Background:ATP8A2 mutations have only recently been associated with human disease. We present the clinical features from the largest cohort of patients with this disorder reported to date. Methods: An observational study of 9 unreported and 2 previously reported patients with biallelic ATP8A2 mutations was carried out at multiple centres. Results: The mean age of the cohort was 9.4 years old (range: 2.5-28 yrs). All patients demonstrated developmental delay, severe hypotonia and movement disorders: chorea/choreoathetosis (100%), dystonia (27%) or facial dyskinesia (18%). Hypotonia was apparent at birth (70%) or before 6 months old (100%). Optic atrophy was observed in 75% of patients who had a funduscopic examination. MRI of the brain was normal for most patients with a small proportion showing mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Epilepsy was seen in two older patients. Conclusions:ATP8A2 gene mutations have emerged as a cause of a novel phenotype characterized by developmental delay, severe hypotonia and hyperkinetic movement disorders. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation. Early recognition of the cardinal features of this condition will facilitate diagnosis of this disorder.

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Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-018-0825-3 ◽

2018 ◽

Vol 13 (1) ◽

Cited By ~ 7

Author(s):

Hugh J. McMillan ◽

Aida Telegrafi ◽

Amanda Singleton ◽

Megan T. Cho ◽

Daniel Lelli ◽

...

Keyword(s):

Cognitive Impairment ◽

Movement Disorders ◽

Optic Atrophy ◽

Recessive Mutations ◽

Severe Hypotonia

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New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy

Neurogenetics ◽

10.1007/s10048-016-0496-y ◽

2016 ◽

Vol 17 (4) ◽

pp. 259-263 ◽

Cited By ~ 20

Author(s):

Elena Martín-Hernández ◽

María Elena Rodríguez-García ◽

Ana Camacho ◽

Antoni Matilla-Dueñas ◽

María Teresa García-Silva ◽

...

Keyword(s):

Intellectual Disability ◽

Optic Atrophy ◽

Gene Mutations ◽

Severe Hypotonia

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New syndrome associated with ATP8A2 gene mutations: Encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy Whole-exome sequencing role in the diagnosis of new diseases

European Journal of Paediatric Neurology ◽

10.1016/j.ejpn.2017.04.935 ◽

2017 ◽

Vol 21 ◽

pp. e65 ◽

Cited By ~ 2

Author(s):

Sofia Quintas ◽

Oana Moldovan ◽

Tiago Proença dos Santos ◽

António Levy

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Optic Atrophy ◽

Gene Mutations ◽

Whole Exome ◽

Severe Hypotonia

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Cerebrovascular diseases in two patients with entire NSD1 deletion

Human Genome Variation ◽

10.1038/s41439-021-00151-z ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Toshiyuki Itai ◽

Satoko Miyatake ◽

Taku Hatano ◽

Nobutaka Hattori ◽

Atsuko Ohno ◽

...

Keyword(s):

Intellectual Disability ◽

Brain Imaging ◽

Developmental Delay ◽

Movement Disorders ◽

Subdural Hematoma ◽

Early Onset ◽

Cerebrovascular Diseases ◽

Brain Contusion ◽

Abnormal Gait

AbstractWe describe two patients with NSD1 deletion, who presented with early-onset, or recurrent cerebrovascular diseases (CVDs). A 39-year-old female showed developmental delay and abnormal gait in infancy, and developed slowly-progressive intellectual disability and movement disorders. Brain imaging suggested recurrent parenchymal hemorrhages. A 6-year-old male had tremor as a neonate and brain imaging revealed subdural hematoma and brain contusion. This report suggests possible involvement of CVDs associated with NSD1 deletion.

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Phenotypes in Children With SYNGAP1 Encephalopathy in China

Frontiers in Neuroscience ◽

10.3389/fnins.2021.761473 ◽

2021 ◽

Vol 15 ◽

Author(s):

Huiting Zhang ◽

Liu Yang ◽

Jing Duan ◽

Qi Zeng ◽

Li Chen ◽

...

Keyword(s):

Developmental Delay ◽

Behavioral Problems ◽

Disease Onset ◽

Gene Mutations ◽

Global Developmental Delay ◽

Clinical Trial Registry ◽

Neurodevelopmental Delay ◽

Epileptic Spasms ◽

Registration Number ◽

Drug Resistant Epilepsy

Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G > A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).

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Paraneoplastic movement disorders

Reviews in the Neurosciences ◽

10.1515/revneuro-2017-0081 ◽

2018 ◽

Vol 29 (7) ◽

pp. 745-755 ◽

Cited By ~ 7

Author(s):

Karolina Popławska-Domaszewicz ◽

Jolanta Florczak-Wyspiańska ◽

Wojciech Kozubski ◽

Sławomir Michalak

Keyword(s):

T Cell ◽

Cell Surface ◽

Movement Disorders ◽

Clinical Symptoms ◽

Early Recognition ◽

Neuronal Loss ◽

Synaptic Proteins ◽

Malignant Neoplasms ◽

Cell Surface Antigens ◽

Opsoclonus Myoclonus Syndrome

Abstract Paraneoplastic movement disorders are rare, autoimmune-mediated, nonmetastatic complications of malignant neoplasms. Common paraneoplastic movement disorders include paraneoplastic chorea, dystonia, cerebellar degeneration, different types of encephalitis, opsoclonus-myoclonus syndrome, stiff person syndrome, and neuromyotonia. Syndromes usually develop before tumor diagnosis, have subacute onset, and are associated with serum or cerebrospinal fluid antibodies. Two types of antibodies can be distinguished: antibodies against nuclear and cytoplasmic neuronal antigens (anti-Hu, anti-Ri, anti-Yo, anti-Ma, anti-CV2/CRMP5, anti-Gephrin, and anti-GABATRAP) and antibodies recently identified against cell surface and synaptic proteins (anti-NMDAR, anti-LGI1, and anti-Caspr2). These two types differ from each other in a few important aspects. Antibodies against cell surface and synaptic protein disrupt cell-surface antigens. Clinical symptoms are related to the disruption of antigens and potentially can be reversed by immunotherapy. The association between these antibodies and malignancy is much less consistent. On the other hand, antibodies against nuclear and cytoplasmic neuronal antigens seem to be not pathogenic; however, they most likely indicate a T-cell-mediated immune response against neurons. Due to T-cell-mediated neuronal loss, response to immunotherapy is generally disappointing. Early recognition of all these diseases is crucial because it may lead to the disclosure of occult cancer. This review is focused on paraneoplastic movement disorders with emphasis on clinical presentations, investigational findings, and therapeutic results.

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Harding’s disease: an important MS mimic

BMJ Case Reports ◽

10.1136/bcr-2018-228337 ◽

2019 ◽

Vol 12 (3) ◽

pp. e228337

Author(s):

Stuti Joshi ◽

Allan G Kermode

Keyword(s):

Multiple Sclerosis ◽

Mitochondrial Dna ◽

Optic Neuropathy ◽

Movement Disorders ◽

Optic Atrophy ◽

Cardiac Arrhythmias ◽

Visual Loss ◽

Mtdna Mutation ◽

Individual Family ◽

Hereditary Optic Neuropathy

Leber’s hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised by bilateral, painless visual loss which leads to severe optic atrophy. It can be associated with other conditions including multiple sclerosis (MS), movement disorders, epilepsy and cardiac arrhythmias. The association of LHON with an MS-like illness is often referred to as Harding’s disease (or Harding’s syndrome). We report two siblings, who both harbour the 11 778 mitochondrial DNA (mtDNA) mutation, but who manifest markedly different clinical phenotypes; a male with classical LHON and a female with an MS-like illness. LHON affects males four to five times more often than females. By contrast, Harding’s disease is seen predominantly in females, in a pattern comparable to that seen in MS. The pathogenic basis behind the variation in penetrance and phenotype between genders and individual family members remains unclear.

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