Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic–pituitary–axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association

SLC35A2â CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals

Pathogenic de novo variants in the Xâ linked gene SLC35A2 encoding the major Golgiâ localized UDPâ galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2â congenital disorders of glycosylation (CDG; formerly CDGâ IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin Nâ glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2â CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2â dependent UDPâ galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wildâ type to mutant alleles in fibroblasts from affected individuals.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/1/humu23731_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/2/humu23731-sup-0001-Supp_Mat__2019.2.10_.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150498/3/humu23731.pd

Tyrosinemia type I: an unusual case presentation

Background: Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive inherited metabolic disorder caused by the fumerylacetoacetate hydrolase enzyme deficiency. It is characterized by liver dysfunction and/ or failure, renal tubular dysfunction. If left untreated it may lead to Fanconi syndrome and neurological crisis (porphyria-like crisis). Nitisinone is the recommended therapy for HT1 in combination with tyrosine and phenylalanine restricted diet. Case Presentation: In this report, we present 3 years and 8-months-old boy who was referred to the Metabolic Clinic after his cousin was diagnosed with HT1. His history was significant for pleural effusion at 8 months of age which contributed to pulmonary tuberculosis. His alpha-fetoprotein was checked (for no apparent reason) at one and a half years of age and was elevated. Upon evaluation at 3 years and 8 months at our facility, his succinylacetone was significantly elevated. Liver function tests and coagulation results were also mildly elevated. Liver ultrasound was routine apart from gallstones. Targeted mutation testing revealed a fumarylacetoacetate hydrolase gene's homozygous pathogenic variant (c.982C>T; p. Gln328*). Conclusion: In conclusion, we presented a patient with an unusual, late presentation of HT1, to highlight the clinical variability in this rare, treatable metabolic disease. [JBCGenetics 2022; 5(1.000): 17-19

Tyrosinemia type I: an unusual case presentation

Background: Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive inherited metabolic disorder caused by the fumerylacetoacetate hydrolase enzyme deficiency. It is characterized by liver dysfunction and/ or failure, renal tubular dysfunction. If left untreated it may lead to Fanconi syndrome and neurological crisis (porphyria-like crisis). Nitisinone is the recommended therapy for HT1 in combination with tyrosine and phenylalanine restricted diet. Case Presentation: In this report, we present 3 years and 8-months-old boy who was referred to the Metabolic Clinic after his cousin was diagnosed with HT1. His history was significant for pleural effusion at 8 months of age which contributed to pulmonary tuberculosis. His alpha-fetoprotein was checked (for no apparent reason) at one and a half years of age and was elevated. Upon evaluation at 3 years and 8 months at our facility, his succinylacetone was significantly elevated. Liver function tests and coagulation results were also mildly elevated. Liver ultrasound was routine apart from gallstones. Targeted mutation testing revealed a fumarylacetoacetate hydrolase gene&amp;apos;s homozygous pathogenic variant (c.982C&amp;gt;T; p. Gln328*). Conclusion: In conclusion, we presented a patient with an unusual, late presentation of HT1, to highlight the clinical variability in this rare, treatable metabolic disease.</jats:p

Opsismodysplasia and Dilated Cardiomyopathy: a case report

Background: Opsismodysplasia (OPSMD) is an extremely rare and severe autosomal recessive skeletal dysplasia that is under the category of severe spondylodysplastic dysplasia. It is characterized by delayed bone maturation, and affected patients are identified by a peculiar craniofacioskeletal dysmorphism in the form of wide anterior fontanelle, depressed nasal bridge, anteverted nares, and short limbs and feet. Radiologically, they are characterized by severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. Case Presentation: We present the clinical and radiological features of a 14-month-old boy with a homozygous, likely pathogenic variant in INPPL1 gene c.2627dup (p.Pro977Thrfs*7) consistent with the diagnosis of OPSMD. He also has dilated cardiomyopathy. Conclusion: OPSMD is an uncommon form of skeletal dysplasia that should be suspected in the context of short stature with characteristic radiological features. Up to now, no definitive therapeutic measures are available, and hence preventive measures are essential in the management of families with affected members. [JBCGenetics 2020; 3(2.000): 100-103

Method to Operate Water Wells at Optimum Rates Utilizing Orifice Performance Curves

Abstract Wells, e.g., water wells (injectors, disposal and supply) operate at designated rates set by reservoir engineers. The objective of producing/injecting these wells at optimum rates is to prolong the well's and reservoir's life. To effectively apply the mentioned objective, each well is assigned a target by the reservoir engineer to either produce or inject. Wells meeting this assigned target are called "compliant" wells while wells that do not meet the set target, whether above or below the target with a specified margin, are classified as "noncompliant" wells. This paper discusses a unique method that will significantly help in maintaining assigned target rates for water wells. The method is applicable to wells that are equipped with intelligent field equipment (DAS—data acquisition system) to monitor the wells in real time. All these wells are equipped with a specific size of orifice plate that maintains a differential pressure (dP), subsequently enabling the flowmeter to read a rate at that point of restriction in the orifice. Each orifice plate, depending on its dimensions, can have its very own orifice performance curve (OPC), which is generated based on multiple parameters. The OPC reflects dP (differential pressure) on its x-axis and flow rate on its y-axis, these curves are beneficial to be used while maintaining the well's target rate. Once a target rate is assigned by the reservoir engineer, a production engineer reviews the OPC and defines the required dP to be communicated for direct field implementation. By this exercise, targeted rates can be obtained without any back and forth communication or field visits for the ultimate goal of achieving compliance in water wells.</jats:p

Nitric Oxide Deficiency in Mitochondrial Disorders: The Utility of Arginine and Citrulline

Mitochondrial diseases represent a growing list of clinically heterogeneous disorders that are associated with dysfunctional mitochondria and multisystemic manifestations. In spite of a better understanding of the underlying pathophysiological basis of mitochondrial disorders, treatment options remain limited. Over the past two decades, there is growing evidence that patients with mitochondrial disorders have nitric oxide (NO) deficiency due to the limited availability of NO substrates, arginine and citrulline; decreased activity of nitric oxide synthase (NOS); and NO sequestration. Studies evaluating the use of arginine in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) presenting with stroke-like episodes showed symptomatic improvement after acute administration as well as a reduction in the frequency and severity of stroke-like episodes following chronic use. Citrulline, another NO precursor, was shown through stable isotope studies to result in a greater increase in NO synthesis. Recent studies showed a positive response of arginine and citrulline in other mitochondrial disorders besides MELAS. Randomized-controlled studies with a larger number of patients are warranted to better understand the role of NO deficiency in mitochondrial disorders and the efficacy of NO precursors as treatment modalities in these disorders.</jats:p