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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Congenital cerebellar hypoplasia/aplasia can occur as a component of a heterogeneous group of brain malformations.9 A typical molar tooth sign is not usually seen, and these disorders are usually sporadic.
Fetal Structural Malformations and Recurrent Pregnancy Loss
Published in Howard J.A. Carp, Recurrent Pregnancy Loss, 2020
Howard J.A. Carp, Thomas Philipp, Micha Baum, Michal Berkenstadt
As the vast majority of anomalies occur in the first trimester, it would be desirable to have an anomaly scan prior to the stage of previous miscarriages. Such a diagnosis requires a thorough knowledge of embryology in order to know when different organs develop and at which stage pathological effects can be seen. In addition, equipment needs to be of a higher resolution than currently available. However, there are some hints, as described by Arslan et al. [26], who reported some anomalies can be relatively easily detected in the first trimester, such as anencephaly. Anencephaly has been diagnosed as early as 9 weeks. There are anomalies that reveal signs later in gestation and have no possibility of early detection, such as cerebellar hypoplasia. There is also a third group of anomalies that can be detected in the first trimester with meticulous examination using high-tech devices. This group of anomalies includes spina bifida occulta, skeletal dysplasia, and some kinds of cardiac defects. However, ultrasound is still not able to compete with embryoscopy in detecting the very early anomalies that may lead to miscarriage.
Mitochondrial Dysfunction and Epilepsies
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Bindu Parayil Sankaran, Arun B. Taly
RARS2 encode arginyl-tRNA synthetase synthetase and has been implicated in an early onset mitochondrial encephalopathy. Mutations in this gene have been classically described to be associated with ponto-cerebellar hypoplasia 6. The manifestations are neonatal or infantile onset epileptic encephalopathy, neonatal hypoglycemia, feeding difficulties, abnormal visual behaviour, hypotonia acquired microcephaly and early raised serum and/CSF lacate (Ngoh et al. 2016). In addition to the common seizure types of myoclonic seizures, generalized tonic-clonic seizures and focal clonic seizures, infantile spasms also have been described (Ngoh et al. 2016).
Maternal Germline Mosaicism of a de Novo TUBB2B Mutation Leads to Complex Cortical Dysplasia in Two Siblings
Published in Fetal and Pediatric Pathology, 2022
Complex cortical dysplasia with other brain malformations-7 (a.k.a. polymicrogyria) is a clinically heterogeneous condition that begins before birth with abnormal development of the brain. In these patients, the brain folds are much smaller than usual. Part or all of the brain can be involved and clinical severity is directly proportional to the affected part of the brain [1]. Some prominent findings include microcephaly, limited extraocular movements, sialorrhea, oromotor dyspraxia, cortical malformations of the brain, contralateral hemiparesis, congenital seizures, delayed motor development, cognitive delay, learning difficulties, abnormalities of the corpus callosum, cerebellar hypoplasia, movement abnormalities, and brainstem abnormalities. Complex cortical dysplasia is an autosomal dominant or recessive polyphenotypic disorder and can be caused by mutations TUBA1A, TUBA8, TUBB2B, TUBB3, or TUBB5 [2]. These genes encode tubulin proteins, and several missense and nonsense mutations generally result in tubulinopathies [3]. The beta subunit of tubulin, encoded by the TUBB2B gene, plays a role in microtubular development [4]. Microtubules are important to bind and hydrolyze GTP which provides migration and differentiation of the neurons [5]. TUBB2B gene is highly expressed in the brain [6]. We present a Turkish family with complex cortical dysplasia with other brain malformations-7 (Phenotype MIM number: 610031) caused by a de novo TUBB2B mutation. While parents are healthy, the detection of the same mutation in the TUBB2B gene in both siblings suggest germline mosaicism in one of the parents.
A Novel Variant in CWF19L1 Gene in a Family with Late-Onset Autosomal Recessive Cerebellar Ataxia 17
Published in Neurological Research, 2021
Hussein Algahtani, Bader Shirah, Samah Almatrafi, Mohammad H. Al-Qahtani, Angham Abdulrahman Abdulkareem, Muhammad Imran Naseer
While performing a literature review, three previous publications have reported the clinical features and genetic analysis of four patients with novel variants in CWF19L1 (Table 1). In 2014, Burns et al [5]. reported two siblings born of consanguineous Turkish parents with non-progressive congenital cerebellar ataxia. They presented with motor delay, unsteady gait, and frequent falls. In their adolescent age, their physical examination showed florid cerebellar signs with hyperreflexia in the lower extremities. The IQ of one of their patients was low indicating cognitive impairment. Brain MRI of both siblings showed cerebellar hypoplasia predominantly affecting the vermis. Another study by Nguyen et al [6]. described a 10-year-old girl from a Dutch non-consanguineous family, who had dystonic movements in upper extremities, hypotonia, and cerebellar atrophy on MRI. Also, this patient had oculomotor apraxia and intellectual disability as additional features. Evers et al [7]. reported a 9-year-old boy from consanguineous Turkish parents who presented with motor developmental delay and unsteady gait with subsequent development of florid cerebellar symptoms and signs. Other interesting clinical features in this report were microcephaly and mildly impaired intellectual development. Sequential neuroimaging showed progressive cerebellar atrophy.
An update on the biology and management of dyskeratosis congenita and related telomere biology disorders
Published in Expert Review of Hematology, 2019
Marena R. Niewisch, Sharon A. Savage
The original description of two brothers with cerebellar hypoplasia and pancytopenia was published by Hoyeraal in 1970, followed by a case description of a boy with progressive pancytopenia, microcephaly, cerebellar hypoplasia, and growth retardation by Hreidarsson in 1988 [108,109]. The name Hoyeraal-Hreidarsson syndrome (HH) was subsequently proposed by the following fourth case report in 1995 [110] and the identification of DKC1 mutations [111] as well as short telomeres in HH patients connected it to the TBD spectrum. To date germline pathogenic variants causing HH have been identified in DKC1 [112], TERT [64], TERC [65], TINF2 [85,113], WRAP53 [71], RTEL1 [83], PARN [114], and ACD [73]. Most HH is due to XLR or AR inheritance, except for all patients with heterozygous TINF2 and one reported patient with heterozygous TERC [65]. HH typically presents in infancy with numerous complications including cerebellar hypoplasia, microcephaly, developmental delay, immunodeficiency, intrauterine growth retardation (IUGR), as well as progressive bone marrow failure. HH-related immunodeficiency may be non-specific and challenging to diagnose [80,112,115]. Due to the young age at onset, the DC-associated mucocutaneous triad might not be present at diagnosis of HH but often develops over time [69,116]. Other HH-associated clinical features may include nonspecific enteropathy and intracranial calcifications [117]. Cerebellar hypoplasia is considered a requirement to establish the diagnosis of HH in the setting of DC-related features.