Congenital Cerebellar Hypoplasia Research Articles

Novel genes bearing mutations in rare cases of early-onset ataxia with cerebellar hypoplasia.

We propose an approach for the identification of mutant genes for rare diseases in single cases of unknown etiology. All genes with rare biologically significant variants sorted from individual exome data are tested further for profiling of their spatial-temporal and cell/tissue specific expression compared to that of their paralogs. We developed a simple bioinformatics tool ("Essential Paralogue by Expression" (EPbE)) for such analysis. Here, we present rare clinical forms of early ataxia with cerebellar hypoplasia. Using whole-exome sequencing and the EPbE tool, we identified two novel mutant genes previously not associated with congenital human diseases. In Family I, the unique missense mutation (p.Lys258Glu) was found in the LRCH2 gene inherited in an X-linked manner. p.Lys258Glu occurs in the evolutionarily invariant site of the leucine-rich repeat domain of LRCH2. In Family II and Family III, the identical genetic variant was found in the CSMD1 gene inherited as an autosomal-recessive trait. The variant leads to amino acid substitution p.Gly2979Ser in a highly conserved region of the complement-interacting domain of CSMD1. The LRCH2 gene for Family I patients (in which congenital cerebellar hypoplasia was associated with demyelinating polyneuropathy) is expressed in Schwann and precursor Schwann cells and predominantly over its paralogous genes in the developing cerebellar cortex. The CSMD1 gene is predominantly expressed over its paralogous genes in the cerebellum, specifically in the period of late childhood. Thus, the comparative spatial-temporal expression of the selected genes corresponds to the neurological manifestations of the disease.

CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.

Joubert syndrome (JS) is a recessive ciliopathy in which all affected individuals have congenital cerebellar vermis hypoplasia. Here, we report that CEP120, a JS-associated protein involved in centriole biogenesis and cilia assembly, regulates timely neuronal differentiation and the departure of granule neuron progenitors (GNPs) from their germinal zone during cerebellar development. Our results show that depletion of Cep120 perturbs GNP cell cycle progression, resulting in a delay of cell cycle exit in vivo. To dissect the potential mechanism, we investigated the association between CEP120 interactome and the JS database and identified KIAA0753 (a JS-associated protein) as a CEP120-interacting protein. Surprisingly, we found that CEP120 recruits KIAA0753 to centrioles, and that loss of this interaction induces accumulation of GNPs in the germinal zone and impairs neuronal differentiation. Importantly, the replenishment of wild-type CEP120 rescues the above defects, whereas expression of JS-associated CEP120 mutants, which hinder KIAA0753 recruitment, does not. Together, our data reveal a close interplay between CEP120 and KIAA0753 for the germinal zone exit and timely neuronal differentiation of GNPs during cerebellar development, and mutations in CEP120 and KIAA0753 may participate in the heterotopia and cerebellar hypoplasia observed in JS patients.

A Proposed Clinical Classification and a Diagnostic Approach for Congenital Ataxias

This review proposes a clinical classification for congenital ataxias based on clinical features, neuroimaging, and course of the disease. Congenital ataxias are an unusual group of neurologic disorders, with heterogeneous clinical and genetic presentation. Typical clinical features of congenital ataxias include variable degrees of motor developmental delay, very early onset cerebellar ataxia, cognitive impairment, and hypotonia, frequently mistakenly diagnosed as cerebral palsy. Congenital ataxias are usually nonprogressive. Neuroimaging plays an important role in the characterization of congenital ataxias. Despite the development of genetics with exome sequencing, several congenital ataxias remain undetermined, and medical literature on this topic is scarce. A didactic classification based on the clinical and neuroimaging features for congenital ataxias include the following 4 main groups: cerebellar malformation, syndromic congenital ataxias, congenital cerebellar hypoplasia, and pontocerebellar hypoplasia. A diagnostic approach for congenital ataxias is proposed, and its differential diagnosis is also discussed.

SYNE1-related autosomal recessive cerebellar ataxia, congenital cerebellar hypoplasia, and cognitive impairment.

The spectrin repeat-containing nuclear envelope protein 1 (SYNE1) gene encodes a family of spectrin structural proteins that are associated with anchoring the plasma membrane to the actin cytoskeleton. SYNE1-related disease is most commonly reported in autosomal recessive spinocerebellar ataxia 8, which demonstrates variable age of onset with a median of 30 years of age. However pathogenic mutations in SYNE1 are also causative of arthrogryposis multiplex congenital, a severe congenital neuromuscular condition. Here in we report monozygous twins with childhood onset ataxia, cerebellar hypoplasia, dysarthria, and cognitive impairment sharing two novel heterozygous mutations in the SYNE1 gene. Our family may expand the clinical phenotype associated with SYNE1-related disease and offers possible genotype-phenotype correlations of a rare continuum of clinical disease phenotypes from neonatal to adult onset.

Congenital cerebellar hypoplasia in Holstein-Friesian calf-A case report

A 5 days old female Holstein-Friesian calf weighing 21 kg with the history of not being able to stand on its own since the birth was presented. The calf had held its head backwards and was very weak despite having normal sucking reflex. On clinical examination the calf was seen having exaggerated movements of the limbs with hyperaesthesia. As there was no response to medicinal treatment. The case was diagnosed as a case of cerebellar hypoplasia on the basis of history, clinical signs and clinical examination. Therefore euthanasia was recommended.

A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia

Background and aimWe identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar...

牛ウイルス性下痢ウイルス感染に関連するミエリン形成不全により先天性小脳症状を呈したホルスタイン種子牛の５症例

牛ウイルス性下痢ウイルス感染に関連するミエリン形成不全により先天性小脳症状を呈したホルスタイン種子牛の５症例

Verbal short-term memory and cerebellum: Evidence from a patient with congenital cerebellar vermis hypoplasia

The impairment of phonological short-term memory has been reported in adults with cerebellar lesions. At the same time, a role of the cerebellum in speech production has been hypothesized. Cerebellar malformations have been related to developmental problems and language acquisition in children. We describe a 5-year-old male child with cerebellar vermis hypoplasia who presented a severe linguistic deficit. On language testing, verbal production was almost absent, while comprehension was partially spared. Digit span was markedly reduced. An extensive examination of phonological short-term memory confirmed a deficit at this level. Positron Emission Tomography revealed hypometabolism both in the cerebellum and the supratentorial areas involved in language function. This finding supports the hypothesis that the cerebellum is included in a cerebro-cerebellar network, that underlies the phonological short-term memory, whose integrity is necessary for language acquisition.

PHACE Syndrome Associated With Congenital Oculomotor Nerve Palsy

PHACE syndrome is a multisystem disorder presenting with facial hemangiomas, arterial anomalies, cardiac anomalies, posterior fossa malformations and eye abnormalities. The eye abnormalities include microphthalmos, cataracts, optic atrophy and iris hypoplasia. Amongst the neurological anomalies, posterior fossa malformations are common. Fourth nerve palsy has been reported with PHACE syndrome. We report a child presenting with a triad of congenital third nerve palsy, cerebellar hypoplasia and facial capillary hemangioma.

DMP04 Congenital left cerebellar hypoplasia in two siblings

DMP04 Congenital left cerebellar hypoplasia in two siblings

¿Desempeña el cerebelo un papel en los procesos cognitivos?

OBJECTIVE AND DEVELOPMENT: We review the different cognitive and behaviour disorders in whose genesis the cerebellum has been thought to play a part. These disorders include infantile autism, Williams' syndrome, attention-deficit hyperactivity disorder and congenital cerebellar hypoplasia. We also consider the consequences of an acquired cerebellar lesion in the light of the following neuropsychological sequelas. It would seem that the cerebellum is involved in the functioning of the executive system due to its relationship with the prefrontal operative system and in the function of the working memory, and may share some of the characteristics of the acquired frontal syndrome.

Studies of the candidate genes in X-linked congenital cerebellar hypoplasia.

A gene for X-linked congenital cerebellar hypoplasia was recently localized to chromosome Xp11.21-q24. This region comprises several brain-specific genes responsible for various neurological disorders, including the proteolipid protein (PLP), doublecortin, and PAK3 genes. We screened these genes for mutations in patients with X-linked congenital cerebellar hypoplasia and found no pathogenic nucleotide changes or gene dose alterations. These findings allow the ruling out of PLP, doublecortin, and PAK3 as the disease-causing genes in this hereditary neurological syndrome.

Autosomal recessive congenital cerebellar hypoplasia and short stature in a large inbred family

American Journal of Medical GeneticsVolume 87, Issue 1 p. 88-90 Letter to the Editor Autosomal recessive congenital cerebellar hypoplasia and short stature in a large inbred family André Mégarbané, Corresponding Author André Mégarbané megarban@dm.net.lb Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonUnité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, 42, rue de Grenelle. 75007 Paris, FranceSearch for more papers by this authorValérie Delague, Valérie Delague Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonSearch for more papers by this authorNabiha Salem, Nabiha Salem Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonSearch for more papers by this authorJacques Loiselet, Jacques Loiselet Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonSearch for more papers by this author André Mégarbané, Corresponding Author André Mégarbané megarban@dm.net.lb Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonUnité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, 42, rue de Grenelle. 75007 Paris, FranceSearch for more papers by this authorValérie Delague, Valérie Delague Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonSearch for more papers by this authorNabiha Salem, Nabiha Salem Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonSearch for more papers by this authorJacques Loiselet, Jacques Loiselet Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, LebanonSearch for more papers by this author First published: 19 October 1999 https://doi.org/10.1002/(SICI)1096-8628(19991105)87:1<88::AID-AJMG20>3.0.CO;2-2Citations: 10AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume87, Issue15 November 1999Pages 88-90 RelatedInformation

Autosomal recessive congenital cerebellar hypoplasia and short stature in a large inbred family

Autosomal recessive congenital cerebellar hypoplasia and short stature in a large inbred family

X‐linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq

We examined a large family in which an X-linked recessive congenital ataxia manifested in 7 males from three generations. The affected boys first exhibited a marked delay of early developmental motor milestones. A neurological syndrome became evident by 5 to 7 years of age and included cerebellar ataxia, dysarthria, and external ophthalmoplegia; there were no symptoms of mental retardation, spastic paraparesis, or sensory loss. Neuroimaging studies revealed hypoplasia of cerebellar hemispheres and vermis. The disease showed no progression beyond early childhood. The unique heredity and clinical features clearly distinguish this new entity from a variety of previously described familial ataxias. Pairwise linkage analysis and haplotype reconstruction allowed us to map the gene responsible for this disorder to a 38-cM interval on chromosome Xp11.21-q24 flanked by the loci DXS991 and DXS1001. Upon multipoint linkage analysis, the disease gene was determined to be located most likely in the proximal part of chromosome Xq, with the maximal lod score of 4.66 at the locus DXS1059 (Xq23). This is the first example of the genetic mapping of a pure congenital cerebellar hypoplasia syndrome.

Non-progressive familial congenital cerebellar hypoplasia

A syndrome is reported of congenital non-progressive, gradually slightly improving, ataxia in 3 out of 5 male sibs, issues of a first-order consanguineous mating. Additional characteristic features included: moderate microcephaly, generalised muscle weakness and hypotonia, nystagmus, and moderate mental retardation. A pyramidal syndrome of hyperreflexia and Babinski signs, without any spasticity, became manifest in the 2nd or 3rd year of life. In all three, the caudal part of the vermis was absent, the enlarged IVth ventricle opening up via Magendie's foramen into the cisterna magna. The middle and rostral vermian parts as well as the sagittal paravermian parts of the cerebellar hemispheres were hypoplastic. The differential diagnosis of this syndrome is analysed and the developmental pathogenetic mechanisms likely to produce the typifying distribution of aplasia are indicated.

Congenital cerebellar hypoplasia with granular cell atrophy

Congenital cerebellar hypoplasia with granular cell atrophy

Autosomal recessive cerebellar hypoplasia and endosteal sclerosis: A newly recognized syndrome

We describe a brother and sister and an unrelated boy with congenital cerebellar hypoplasia and endosteal sclerosis. All 3 children presented with ataxia and developmental delay, and were found to have microcephaly, short stature, oligodontia, strabismus, nystagmus, and congenital hip dislocation. A previously published case is reviewed. The disorder appears to represent a newly recognized autosomal recessive syndrome.

An outbreak of congenital hydranencephaly and cerebellar hypoplasia among calves in South Kyushu, Japan: a pathological study

An outbreak of congenital hydranencephaly and cerebellar hypoplasia occurred between November 1985 and May 1986 in Miyazaki, South Kyushu, Japan. Seventy-three calves had nervous signs of varying severity such as inability to stand, locomotor difficulties, defective vision and difficulty in sucking. At necropsy, 62 calves had macroscopic lesions in the central nervous system: hydranencephaly accompanied by cerebellar hypoplasia in 47; hydranencephaly alone in eight; and dilatation of the lateral ventricle in seven; none had arthrogryposis. Microscopically, all 62 cases involved various degrees of hypoplasia of neural components, such as total or partial thinning of the cerebral or cerebellar laminae. Heterotopia, such as abnormal islands of granule cells or Purkinje cells was also observed. Fourteen of these animals had other lesions such as non-purulent encephalitis, focal gliosis, neuronal degeneration, calcification or pseudocalcification, and cholesterol deposits, activation of vascular endothelial cells and haemorrhage. From the findings, these cases were considered to represent mainly hypoplasia of nerve tissue due to infection with a virus different from Akabane virus.

CONGENITAL CEREBELLAR HYPOPLASIA IN JERSEY CALVES

Congenital cerebellar hypoplasia and hydrocephalus is reported in 8 Jersey calves. The possible relationship between this entity and BVDMD virus is discussed.