A Case of Lysosomal Acid Lipase Deficiency Confirmed by Response to Sebelipase Alfa Therapy.

Lysosomal acid lipase (LAL) deficiency, or cholesterol ester storage disease, is a disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. Clinical findings include hepatomegaly, hepatic dysfunction, and dyslipidemia with a wide range of phenotypic variability and age of onset. The available clinical and molecular information of the patient presented herein was consistent with a diagnosis of LAL deficiency, but her LAL activity assay repeatedly showed normal or borderline low results. Her response to enzyme replacement therapy and demonstrable deficiency on a newer specific enzymatic assay ultimately confirmed her diagnosis of LAL deficiency.

BRAT1-related disease--identification of a patient without early lethality.

We present a patient with neonatal onset of hypertonia and seizures identified through whole exome sequencing to have compound heterozygous variants, c.294dupA (p.Leu99fs) and c.1925C>A (p.Ala642Glu), in the BRCA1-associated protein required for ATM activation-1 (BRAT1) gene. Variants in BRAT1 have been identified to cause lethal neonatal rigidity and multifocal seizure syndrome (OMIM# 614498), which consistently manifests a severe neurological phenotype that includes neonatal presentation of rigidity and hypertonia, microcephaly and arrested head growth, intractable seizures, absence of developmental progress, apneic episodes, and death usually by 6 months of age. Our patient initially had a similarly severe neurological picture but remains alive at 6 years of age, expanding the phenotype to include longer term survival and providing further insights into genotype-phenotype correlations and the natural history of this disease.

Activin signaling: effects on body composition and mitochondrial energy metabolism.

Activin-betaA and activin-betaB (encoded by Inhba and Inhbb genes, respectively) are closely related TGF-beta superfamily members that participate in a variety of biological processes. We previously generated mice with an insertion allele at the Inhba locus, Inhba(BK). In this allele, the sequence encoding the Inhba mature domain is replaced with that of Inhbb, rendering the gene product functionally hypomorphic. Homozygous (Inhba(BK/BK)) and hemizygous (Inhba(BK/-)) mice are smaller and leaner than their wild-type littermates, and many tissues are disproportionately small relative to total body weight. To determine the mechanisms that contribute to these phenomena, we investigated the metabolic consequences of the mutation. Although the growth of Inhba(BK) mice is improved by providing a calorie-rich diet, diet-induced obesity, fatty liver, and insulin resistance (hallmarks of chronic caloric excess) do not develop, despite greater caloric intake than wild-type controls. Physiological, molecular, and biochemical analyses all revealed characteristics that are commonly associated with increased mitochondrial energy metabolism, with a corresponding up-regulation of several genes that reflect enhanced mitochondrial biogenesis and function. Oxygen consumption, an indirect measure of the metabolic rate, was markedly increased in Inhba(BK/BK) mice, and polarographic analysis of liver mitochondria revealed an increase in ADP-independent oxygen consumption, consistent with constitutive uncoupling of the inner mitochondrial membrane. These findings establish a functional relationship between activin signaling and mitochondrial energy metabolism and further support the rationale to target this signaling pathway for the medical treatment of cachexia, obesity, and diabetes.

Low factor XII level in an individual with Sotos syndrome.

Sotos syndrome is an overgrowth disorder that manifests characteristic dysmorphic features, neurological problems, and an increased risk for cancers and heart defects. Alterations of NSD1 are responsible for this disease. A subset of cases arise from deletions, which is of interest as the factor XII locus lies in close proximity to NSD1. This case report describes an individual with Sotos syndrome and factor XII deficiency, providing a potential link between these two genes and, consequently, expanding the clinical phenotype of Sotos syndrome.

Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy-Walker malformation.

Two patients with partial deletions of the long arm of chromosome 13, del(13)(13q21-q34) and del(13)(13q22-q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy-Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage-sensitive gene in 13q22-q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22-q33 may cause this anomaly. These findings suggest that microdeletions in 13q22-q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high-resolution cytogenetic analysis (550 band level or greater) of 13q22-q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM.

Partial deletions of the long arm of chromosome 13 associated with holoprosencephaly and the Dandy-Walker malformation.

Two patients with partial deletions of the long arm of chromosome 13, del(13)(13q21-q34) and del(13)(13q22-q33), respectively, multiple congenital anomalies including holoprosencephaly (HPE) and the Dandy-Walker malformation (DWM) are described. The occurrence of HPE and the DWM in both of these patients suggests that, in addition to ZIC2, which is important for normal development of the forebrain, there is at least one other dosage-sensitive gene in 13q22-q33 that plays an important role in brain development. The DWM is anatomically and developmentally distinct from HPE. The presence of a DWM in each of these two patients with partial deletions of the long arm of chromosome 13 suggests that haploinsufficiency at a locus in 13q22-q33 may cause this anomaly. These findings suggest that microdeletions in 13q22-q33 may be found in a proportion of patients with an apparently isolated DWM. Therefore, careful high-resolution cytogenetic analysis (550 band level or greater) of 13q22-q33 may be considered in these patients. Furthermore, future molecular studies of this region may reveal candidate gene loci for the DWM.