Posts Categorized: Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT



A2ML1 mutations are associated with a Noonan-like syndrome

Posted by & filed under Exome sequencing, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Vissers L et al. Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. European Journal of Human Genetics (2015) 23, 317-324.   For a quarter of patients clinically diagnosed with Noonan syndrome, the molecular cause cannot be identified. Through exome sequencing in a case-parent trio, followed by targeted resequencing […]



Natural history of Leigh disease

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Leigh syndrome is a neurodegenerative disease associated with primary or secondary mitochondrial dysfunction at the level of oxidative phosphorylation. Sofou et al. published a retrospective study describing patients with Leigh syndrome (n=130; 77 with pathogenic mutations) from eight European centers specializing in mitochondrial diseases. They described the natural history of Leigh syndrome and identified novel […]



Liver transplantation in CDG

Posted by & filed under Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT, Treatment.

Janssen et al. recently reported the first successful liver transplantation in a Congenital Disorders of Glycosylation (CDG), and specifically in  phosphomannose isomerase deficiency (MPI-CDG). MPI-CDG has been considered a treatable disorder usually presenting with hepato-intestinal pathology. Treatment with mannose can improve the life-threatening protein-losing enteropathy and coagulation disorder but patients ultimately develop progressive liver insufficiency. […]



Exome sequencing redefining phenotypes

Posted by & filed under Exome sequencing, Part 06: DIAGNOSTIC APPROACHES, Part 28: NEUROGENETICS, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

One would intuitively expect that Whole-exome sequencing (WES) will help broaden the phenotypic spectrum of known syndromes since in the past only patients closely matching the described phenotype of a documented genetic syndrome would be tested for the respective diagnosis. Some recent examples illustrating the direction the field is moving include the publications of Dr. […]



MECP2 expression influences aggressive behavior

Posted by & filed under Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

The X-chromosomal MECP2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. MECP2 is mutated in Rett syndrome. This paper found that that mice with ~50% transgenic overexpression of Mecp2 have enhanced aggressive behavior. When the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This […]



Cholesterol metabolism is altered in Rett syndrome

Posted by & filed under Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Monica Justice and colleagues identified a mutation in Sqle encoding squalene epoxidase, a rate-limiting enzyme in cholesterol biosynthesis, that suppresses the phenotype of Mecp2-null mice, a model of Rett syndrome. They also showed that lipid metabolism is perturbed in the brains and livers of Mecp2-null male mice. Importantly, statin drugs improve systemic perturbations of lipid metabolism, […]



Yunis-Varón syndrome gene identification links this skeletal dysplasia with neurological involvement to phosphoinositide metabolism

Posted by & filed under Part 16: LYSOSOMAL DISORDERS, Part 22: CONNECTIVE TISSUE, Part 28: NEUROGENETICS, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Yunis-Varón syndrome is a skeletal dyplasia with features of cleidocranial dysplasia, with digital hypoplasia and severe neurological involvement (http://omim.org/entry/216340). Through exome sequencing, we identified three families with mutations of FIG4, encoding a phosphoinositide phosphatase. This enzyme had previously been implicated in Charcot-Marie-Tooth type 4J (CMT-4J). While CMT-4J is usually caused by a combination of a […]



Targeting nuclear RNA for in vivo correction of myotonic dystrophy.

Posted by & filed under Part 25: MUSCLE, Part 28: NEUROGENETICS, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT, Treatment.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder characterized by myotonia, weakness, cardiac arrhythmias, diabetes and cognitive deficits. Patients carry an expansion of the CTG DNA repeat sequence in the DMPK gene. As a result, when the mutant gene is expressed, it yields a toxic messenger RNA molecule (a gain-of-function effect). In addition […]



Intranasal ERT in LSDs may bypass BBB

Posted by & filed under Part 16: LYSOSOMAL DISORDERS, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT, Treatment.

According to the study by Wolf et al. intranasal administration of α-l-iduronidase (IDUA) enzyme may be able to bypass the blood-brain barrier. This appears to be the case in IDUA-deficient mice after a single intranasal treatment with concentrated Aldurazyme®. Promising results in mice were also noted after intranasal treatment with an adeno-associated virus (AAV) vector expressing […]



Mutations in histone acetyltransferase KAT6B cause Genitopatellar syndrome.

Posted by & filed under Exome sequencing, Part 22: CONNECTIVE TISSUE, Part 28: NEUROGENETICS, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

Sorry to blow my own horn but I’m quite passionate about the findings described below. Late last year, the group of Clayton-Smith et al. identified mutations in KAT6B in Ohdo syndrome, a condition characterized by blepharophimosis and developmental delay. Shortly after, our group and the group of Simpson et al. identified mutations in the same […]