Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Clinical characteristics of a sample of patients with cat eye syndrome.

OBJECTIVE: Cat eye syndrome is considered a rare chromosome disease with a highly variable phenotype. The objective of this paper was to describe the clinical characteristics of a sample of patients with cat eye syndrome who were seen at our service. METHODS: This is a retrospective analysis of a sample of six patients with diagnoses of cat eye syndrome. All of these patients' karyotypes exhibited the presence of an additional marker chromosome, inv dup(22)(pter->q11.2::q11.2->pter). One patient also exhibited mosaicism with a lineage that had a normal chromosomal constitution. Clinical and follow-up data were collected from the patients' medical records. Fisher's exact test was used to compare the frequencies observed in our study with figures given in the literature (P<0.05). RESULTS: The main abnormalities observed were preauricular tags and/or pits and anal atresia (both observed in 83% of cases). Coloboma of the iris, an important finding with this syndrome, was observed in two cases (33%). Congenital heart disease was detected in four patients (67%) and the main defect found was interatrial communication (75%). Uncommon findings included hemifacial microsomia combined with unilateral microtia and biliary atresia. Just one of these patients died, from chylothorax and sepsis. CONCLUSION: The phenotype observed in cat eye syndrome is highly variable and may be superimposed on the phenotype of the oculo-auriculo-vertebral spectrum. Although these patients usually have good prognosis, including from a neurological point of view, we believe that all patients with the syndrome should be assessed very early on for the presence of cardiac, biliary and anorectal malformations, which may avoid possible complications in the future, including patient deaths.

Características clínicas de uma amostra de pacientes com a síndrome do olho do gato / Clinical characteristics of a sample of patients with cat eye syndrome

OBJETIVO: A síndrome do olho do gato é considerada uma doença cromossômica rara e fenotipicamente bastante variável. O objetivo deste trabalho foi descrever as características clínicas de uma amostra de pacientes com a síndrome avaliada em nosso serviço. MÉTODOS: Foram analisados, retrospectivamente, seis pacientes com diagnóstico de síndrome do olho do gato. Todos eles apresentavam cariótipo com a presença de um cromossomo marcador adicional, inv dup(22)(pter->q11.2::q11.2->pter). Um deles, ainda, possuía mosacismo com uma linhagem com constituição cromossômica normal. A partir dos prontuários médicos foram coletados dados clínicos e de evolução dos pacientes. Para comparação entre as frequências encontradas em nosso estudo e a literatura foi utilizado o teste exato de Fisher (P<0,05). RESULTADOS: As principais anormalidades encontradas foram os apêndices/fossetas pré-auriculares e a imperfuração anal (ambas observadas em 83 por cento dos casos). O coloboma de íris, um achado importante da síndrome, foi verificado em dois casos (33 por cento). Cardiopatia congênita, por sua vez, foi observada em quatro pacientes (67 por cento), sendo o principal defeito a comunicação interatrial (75 por cento). Achados incomuns incluíram a microssomia hemifacial associada à microtia, além da atresia de vias biliares. Quanto à evolução clínica, apenas um dos pacientes foi a óbito, sendo que este ocorreu secundário a um quadro de quilotórax e sepse. CONCLUSÃO: O fenótipo observado na síndrome do olho do gato é bastante variável e pode se sobrepor àquele do espectro óculo-aurículo-vertebral. Apesar dos indivíduos apresentarem usualmente um bom prognóstico, incluindo do ponto de vista neurológico, acreditamos que todo paciente com a síndrome deveria ser precocemente avaliado quanto à presença de malformações cardíacas, biliares e anorretais. Isto evitaria possíveis complicações, incluindo o óbito.

OBJECTIVE: The cat eye syndrome is considered a rare chromosomal disease and a phenotypically quite variable condition. The objective of this study was to describe the clinical characteristics of a sample of patients with the syndrome evaluated in our Service. METHODS: Six patients with diagnosis of cat eye syndrome were retrospectively evaluated. All presented a karyotype with presence of an additional chromosome marker, inv dup(22)(pter->q11.2::q11.2->pter). One of them still had a mosaicism with a lineage with a normal chromosomal constitution. Clinical and evolution data were collected from their medical records. Fisher exact test (P<0.05) was used for comparison between the frequencies found in our study and literature. RESULTS: The main abnormalities found were preauricular skin tags/pits and imperforate anus (both observed in 83 percent of cases). Iris coloboma, an important feature of the syndrome was verified in 2 cases (33 percent). Congenital heart defect observed in 4 patients (67 percent), with the atrial septal defect (75 percent) as the most observed. Uncommon features included the hemifacial microsomia associated to microtia, besides biliary atresia. In relation to the evolution, only one of the patients died and this occurred secondary to quilothorax and sepsis. CONCLUSION: The phenotype observed in the cat eye syndrome is very variable and may overlap with that of oculo-auriculo-vertebral spectrum. Despite the good prognosis usually presented by the individuals, also from the neurological point of view, we believe that all patients with the syndrome should be evaluated as early as possible for presence of heart, biliary and anorectal malformations. This should avoid possible complications, including death.

Inv dup del(4)(:p13-->p16.3::p16.3-->qter) in a girl without typical manifestations of Wolf-Hirschhorn syndrome.

We report on a 4-year-old girl who presented with microcephaly, multiple minor anomalies of face and limbs, congenital heart defect, hypotonia, neuropsychomotor delay, deafness and seizures. A GTG-banded karyotype identified an additional fragment of unknown origin on the terminal region of 4p. Parental karyotypes were normal. FISH analysis using a whole chromosome paint probe for chromosome 4 and subtelomere probes showed a signal on the entire add (4) chromosome and loss of the 4p subtelomere region, respectively. Additional analysis using microsatellite markers for chromosome 4 and whole-genome array comparative genomic hybridization (array-CGH) identified a duplication of the region 4p13 --> 4p16.3. Her karyotype was thus interpreted as an inverted duplication with terminal deletion of 4p: 46,XX,der(4)(:p13 --> p16.3::p16.3 --> qter). The clinical features of our patient differed from those typically observed in Wolf-Hirschhorn syndrome and were more compatible with duplication 4(p14 --> p16.3), with preservation of the WHS critical region.