Pre-analytic decrease of phenylalanine in plasma of patients with phenylketonuria treated with pegvaliase.

Treatment of phenylketonuria (PKU) has evolved since the initial introduction of a phenylalanine (Phe) restricted diet. The most recent option for adults affected with PKU is treatment with an alternate enzyme, phenylalanine ammonia lyase (PAL), that metabolizes excess Phe. Proper management of all patients with PKU relies on accurate measurement of Phe levels in blood, to comply with guidance intended to minimize the neurological symptoms.

Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder.

Purpose: CTR9 is a subunit of the PAF1 complex (PAF1C) that plays a crucial role in transcription regulation by binding CTR9 to RNA polymerase II. It is involved in transcription-coupled histone modification through promoting H3K4 and H3K36 methylation. We describe the clinical and molecular studies in 13 probands, harboring likely pathogenic CTR9 missense variants, collected through GeneMatcher.

Reduction in Newborn Screening False Positive Results Following a New Collection Protocol: a Quality Improvement Project.

Objective: Premature infants are known to have a higher rate of false positive newborn screening (NBS) results, with TPN as a contributing factor. The purpose of this quality improvement (QI) project is to reduce false positive NBS results via a TPN interruption protocol.

Methods: A multidisciplinary team reviewed the literature and developed a new NBS collection protocol, which was implemented in 2 periods.

Mutations in PDLIM5 are rare in dilated cardiomyopathy but are emerging as potential disease modifiers.

Background: A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM.

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive.

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α-subunit of the voltage-gated Ca2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission.

Adoptees' Pursuit of Genomic Testing to Fill Gaps in Family Health History and Reduce Healthcare Disparity.

In the symposium of stories by adoptees who have faced health issues without family health history information, genomic testing is considered as a potentially life-saving means for adoptees to obtain family medical information. The authors share feelings of loss, frustration in healthcare settings, fear of unknown genetic susceptibility to disease, desire for knowledge and self-empowerment in medical decision making, and uncertainty about the utility of genomic testing. Adoptees may pursue ancestry testing, genetic genealogy to find biological relatives, and medical genomic testing.

Can untreated PKU patients escape from intellectual disability? A systematic review.

Background: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability.

The first patient with tandem duplication of 6q14q16: Molecular and phenotypic characterization.

Duplications of the long arm of chromosome 6 have been previously reported in a limited number of patients; however, most reported duplications encompass regions of chromosome 6 distal to band q21. Duplications restricted to the proximal portion of 6q are rare. We report an 8-year-old male with a 16.

De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome.

Mutations in POLG are a major contributor to pediatric and adult mitochondrial diseases. However, the consequences of many POLG mutations are not well understood. We investigated the molecular cause of Alpers syndome in a patient harboring the POLG mutations A467T in trans with c.

De novo three-way chromosome translocation 46,XY,t(4;6;21)(p16;p21.1;q21) in a male with cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal dysplasia associated with cranial, clavicular, and dental anomalies. It is caused by mutations in the RUNX2 gene, which encodes an osteoblast-specific transcription factor and maps to chromosome 6p21. We report clinical and molecular cytogenetic studies in a patient with clinical features of CCD including wormian bones, delayed fontanel closure, hypoplastic clavicles and pubic rami, and supernumerary dentition.

Chromosome 2q37 deletion: clinical and molecular aspects.

Terminal deletions of chromosome 2 with breakpoints at or within band 2q37, ranging from visible abnormalities to cryptic, subtelomeric deletions, have been recognized with increasing frequency among children with mild-moderate mental retardation, characteristic facial appearance, and behavioral manifestations which often place them on the autism spectrum. The stereotypic facial characteristics include prominent forehead, thin, highly arched eyebrows, depressed nasal bridge, full cheeks, deficient nasal alae and prominent columella, thin upper lip, and various minor anomalies of the pinnae. Abnormal nipples, including inverted nipples, have been reported in a number of cases.

Mitochondrial myopathy, sideroblastic anemia, and lactic acidosis: an autosomal recessive syndrome in Persian Jews caused by a mutation in the PUS1 gene.

We report the seventh case of autosomal recessive inherited mitochondrial myopathy, lactic acidosis, and sideroblastic anemia The patient, a product of consanguineous Persian Jews, had the association of mental retardation, dysmorphic features, lactic acidosis, myopathy, and sideroblastic anemia. Muscle biopsy demonstrated low activity of complexes 1 and 4 of the respiratory chain. Electron microscopy revealed paracrystalline inclusions in most mitochondria.

Chromosome 2q terminal deletion: report of 6 new patients and review of phenotype-breakpoint correlations in 66 individuals.

We report a new patient with terminal deletion of chromosome 2 with breakpoint at 2q36 and five additional new patients with 2q terminal deletion with breakpoint at 2q37. Hemidiaphragmatic hernia is a novel finding in one patient with a breakpoint at 2q37.1.

Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).

Mitochondrial myopathy and sideroblastic anemia (MLASA) is a rare, autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow. Linkage analysis and homozygosity testing of two families with MLASA localized the candidate region to 1.2 Mb on 12q24.

Gene responsible for mitochondrial myopathy and sideroblastic anemia (MSA) maps to chromosome 12q24.33.

Mitochondrial myopathy and sideroblastic anemia (MSA) is a rare autosomal recessive disorder of oxidative phosphorylation and iron metabolism. Individuals with MSA present with weakness and anemia in late childhood and may become dependent on blood transfusions. Recently, we reported affected sibling pairs from a Jewish-Iranian kindred living in the US [Casas and Fischel-Ghodsian, 2003].

Mitochondrial myopathy and sideroblastic anemia.

We report four new cases of mitochondrial myopathy and sideroblastic anemia (MSA). Hallmark features of MSA include progressive exercise intolerance during childhood, onset of sideroblastic anemia around adolescence, basal lactic acidemia, and mitochondrial myopathy. Autosomal recessive inheritance of MSA in the family we describe is assumed due to the presence of two affected sibling pairs, unaffected parents, an unaffected sibling, and parental consanguinity.