A novel GNAS variant presents with disorders of GNAS inactivation and cardiomyopathy.

The GNAS gene (OMIM#139320), located on chromosome 20q13.2, encodes for the alpha-subunit of the stimulatory signaling protein, Gsα protein. GNAS variants with inactivating properties are associated with Albright's hereditary osteodystrophy (AHO) and when maternally inherited, pseudohypoparathyroidism 1a (OMIM#103580), which includes multiple hormone resistance. In this clinical report we describe a novel GNAS variant, c.159A>G, p.K53N, in an individual with features consistent with AHO and pseudohypoparathyroidism 1a and its segregation through multiple maternal relatives, including two genotype positive maternal first cousins who also display features classic for AHO. The proband developed unique features including cardiomyopathy which required a heart transplant at 5 years old and immune dysregulation resulting in multisystem organ failure and ultimately, death at the age of 18 years. Additional investigations exploring alternative explanations for the proband's presentation were pursued including whole genome sequencing which was negative. We postulate that the atypical features seen in the proband may have resulted from dysregulated Gsα signaling in cardiac tissue. Future studies are needed to explore the properties of the K53N GNAS variant and this proposed mechanism.

Neuropsychiatric features of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well as developmental delays, a spectrum of behavioral and psychiatric concerns, endocrinopathies, orthopedic issues, and less commonly, seizures, sleep apnea, and narcolepsy with or without cataplexy. This study used data in the Global PWS Registry (N = 893) to explore the onset and severity over time of the neuropsychiatric features reported in individuals with PWS and explored its associations with sleep disorders, seizures, and psychiatric symptoms. Results demonstrate that seizures are more common in the deletion subtype and that narcolepsy and cataplexy are more common in individuals who have sleep-related seizures. Finally, this work shows that anxiety and compulsive behaviors are persistent features of PWS that may arise early in childhood, and that anxiety is associated with higher frequency of other comorbid psychiatric diagnoses. In conclusion, this study is one of the largest to date characterizing sleep disorders and neuropsychiatric characteristics of individuals with PWS and reports on the novel association between sleep disorders and seizures. This study is also one of the first to offer details on the nature of the progression of these features in individuals with PWS.

IRF2BPL gene mutation: Expanding on neurologic phenotypes.

Heterozygous loss of function variants in the IRF2BPL are a newly described cause of neurodevelopmental disabilities and epilepsy. As of 2019, fewer than 20 patients have been described in the published literature. This article reports an additional case of a patient with a pathogenic IRF2BPL variant and offers a comprehensive review of the published cases of individuals with IRF2BPL variants, in order to help expand the phenotype. The patient has a history of infantile spasms evolving into drug-resistant epilepsy with underlying epileptic encephalopathy consistent with Lennox-Gastaut syndrome. While at the extreme end of the spectrum, his phenotype is consistent with those previously described. Our literature review highlights the wide range of phenotypes exhibited by those with diseases related to IRF2BPL gene variants. This article also briefly discusses other comorbidities seen in the patient and those previously reported. While the molecular underpinnings of the role of IRF2BPL gene in the central nervous system are newly established, the specifics of its effects elsewhere have yet to be delineated. Furthermore, its pathogenesis in other organ systems is not yet understood and could be of importance from a management perspective.

Counseling for personal care options at neonatal end of life: a quantitative and qualitative parent survey.

BACKGROUND: The death of a newborn is a traumatic life changing event in the lives of parents. We hypothesized that bereaved parents of newborn infants want to have choices in the personal care of their infant at the end of life. METHODS: Parents who had suffered a perinatal or neonatal loss between 1 and 6 years before the survey in a regional level IV neonatal intensive care unit (NICU) and associated labor and delivery room were invited to participate. Parents chose between an online survey, paper survey or telephone interview. The survey included multiple choice and open ended questions. RESULTS: Parents prefer multiple options for the personal care of their infant at the end of life. Emergent themes were need for guidance by the medical team, memory making, feeling cared for and respected by staff, and regrets related to missed opportunities. CONCLUSION: While parents differ in their preferences in utilizing specific personal care options for their infant's end of life, they share a common preference for being presented with multiple options to choose from and in being guided and supported by healthcare providers, while being afforded the opportunity to make memories with their infant by bonding with and parenting them.

Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia.

BACKGROUND: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. METHODS: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. RESULTS: Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. CONCLUSIONS: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

Serial Magnetic Resonance Imaging (MRI) in Pyruvate Dehydrogenase Complex Deficiency.

OBJECTIVES: To report 2 additional cases of pyruvate dehydrogenase complex deficiency with reversible deep gray matter lesions following initiation of ketogenic diet and to perform a literature review of serial imaging in patients with pyruvate dehydrogenase complex. METHODS: Clinical data on 3 previously unpublished cases of patients with pyruvate dehydrogenase complex deficiency and with serial magnetic resonance imagings (MRIs) before and after institution of ketogenic diet were reported. A systematic literature review was performed to search for published cases of patients with confirmed pyruvate dehydrogenase complex deficiency who underwent serial MRIs. RESULTS: The 3 subjects in this series demonstrated clinical improvement on ketogenic diet. Two subjects showed reversal of some brain lesions on repeat MRI following initiation of ketogenic diet. Of the 21 published cases with serial MRIs, 13 patients underwent some form of treatment, and of this smaller subset 4 patients had repeat MRIs that showed definitive improvement. In both our described cases and those published in the literature, improvement occurred in lesions in the basal ganglia. CONCLUSIONS: In patients with pyruvate dehydrogenase complex deficiency, basal ganglia lesions on MRI are reversible with treatment in some cases and could serve as a biomarker for measuring response to treatment.

The mitochondrial DNA variant m.9032T > C in MT-ATP6 encoding p.(Leu169Pro) causes a complex mitochondrial neurological syndrome.

Diagnosing complex V deficiencies caused by new variants in mitochondrial DNA is challenging due to the rarity, phenotypic diversity, and limited functional assessments. We describe a child with the m.9032T > C variant in MT-ATP6 encoding p.(Leu169Pro), with primary presentation of microcephaly, ataxia, hearing loss, and lactic acidosis. Functional studies reveal abnormal fragment F1 of complex V on blue native gel electrophoresis. Respirometry showed excessively tight coupling through complex V depressing oxygen consumption upon ADP stimulation and an excessive increase following uncoupling, in the presence of upregulation of mitochondrial biogenesis. These data add evidence about pathogenicity and functional impact of this variant.