Publications by authors named "Gregory M Rice"

21 Publications

  • Page 1 of 1

Acute Strokelike Presentation and Long-term Evolution of Diffusion Restriction Pattern in Ethylmalonic Encephalopathy.

J Child Neurol 2021 Apr 26:8830738211006507. Epub 2021 Apr 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Ethylmalonic encephalopathy is a rare autosomal recessive mitochondrial disorder caused by pathogenic biallelic variants in the gene. The phenotype of this disease has been attributed to deficiency in the mitochondrial sulfur dioxygenase leading to many downstream effects. Ethylmalonic encephalopathy classically presents with developmental regression, petechiae, acrocyanosis, and chronic diarrhea. The neurologic phenotype includes hypotonia, spastic diplegia, ataxia, and developmental delay. As more patients with this condition are described, the neurologic phenotype continues to expand. Although strokelike episodes or metabolic strokes have been studied in other mitochondrial disorders, they have not been thoroughly reported in this disorder. Herein, we describe 3 patients with ethylmalonic encephalopathy who presented clinically with strokelike episodes and strokelike abnormalities on brain magnetic resonance imaging in the setting of acute illness, and the long-term sequelae with evolution into cystic changes in one of these subjects.
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http://dx.doi.org/10.1177/08830738211006507DOI Listing
April 2021

Reversal of Vision Loss in a 49-Year-Old Man With Progressive Optic Atrophy Due to Profound Biotinidase Deficiency.

J Neuroophthalmol 2021 03;41(1):e27-e30

Medical Genetics (ERK), Waisman Center, University of Wisconsin, Madison, Wisconsin; Department of Ophthalmology and Visual Sciences (ERK, KES), University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; Genetics, Birth Defects & Metabolism (BW), Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern Feinberg School of Medicine, Chicago, Illinois; and Department of Pediatrics (GMR), University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

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http://dx.doi.org/10.1097/WNO.0000000000000933DOI Listing
March 2021

Newborn Screening for Inherited Metabolic Disorders: Early Identification and Long-Term Care for Patients in the Plain Community, Wisconsin, 2011-2017.

Public Health Rep 2019 Nov/Dec;134(2_suppl):58S-63S

Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

The Plain community is the fastest-growing religious minority in Wisconsin. This community has a high incidence of genetic disorders, many of which are identifiable through newborn screening. We describe efforts by the Wisconsin Newborn Screening Program (WNSP) to improve health care in the Plain community by targeting early identification of, and intervention for, patients with inherited metabolic disorders. WNSP formed partnerships with families and health care providers to increase awareness of screening procedures and the intended benefits of screening, modify testing algorithms to enhance detection, and establish medical homes for patients with confirmed disorders. The estimated number of Plain newborns screened increased by 25.5% during the study period, from 547 in 2011 to 736 in 2017; 122 persons underwent carrier testing, and 143 newborns received second-tier testing. From 2014 to 2017, affected patients received 71 metabolic evaluations in their community medical home without travel to major health centers. This article demonstrates how a comprehensive public health program can help increase screening rates, enhance detection, and establish follow-up care in a hard-to-reach religious community. A key lesson learned was the importance of communication among all stakeholders to develop an effective public health program.
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http://dx.doi.org/10.1177/0033354919878425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832032PMC
February 2020

Familial segregation of a 5q15-q21.2 deletion associated with facial dysmorphism and speech delay.

Clin Case Rep 2019 Jun 4;7(6):1154-1160. Epub 2019 May 4.

Division of Laboratory Genetics and Genomics, Departments of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota.

We report a two-generation family with four females harboring an 8.5Mb heterozygous deletion of 5q15-q21.2 who present with dysmorphic craniofacial features and speech delay. We hypothesize haploinsufficiency of to be contributing to the clinical features observed in this family.
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http://dx.doi.org/10.1002/ccr3.2186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552940PMC
June 2019

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy.

Am J Med Genet A 2019 06 12;179(6):1015-1019. Epub 2019 Mar 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Ethylmalonic encephalopathy (EE) is a rapidly progressive autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the ETHE1 gene that encodes the mitochondrial sulfur dioxygenase. It is characterized by neurodevelopmental delay and regression, pyramidal and extrapyramidal signs, recurrent petechiae, chronic diarrhea, and orthostatic acrocyanosis. Laboratory findings include elevated serum levels of lactate and C4-C5 acylcarnitines, and elevated urinary excretion of ethylmalonic acid and C4-C6 acylglycines, notably isobutyrylglycine and 2-methylbutyrylglycine. These findings are attributed to deficiency of the mitochondrial sulfur dioxygenase resulting in toxic accumulation of hydrogen sulfide metabolites in vascular endothelium and mucosal cells of the large intestine. Medical management has thus far been directed toward decreasing the accumulation of hydrogen sulfide metabolites using a combination of metronidazole and N-acetylcysteine. More recently, orthotopic liver transplant (OLT) has been reported as a new therapeutic option for EE. Here, we report two additional cases of EE who achieved psychomotor developmental improvement after 7- and 22-months following OLT. The second case serves as the longest developmental outcome follow-up reported, thus far, following OLT for EE. This report provides additional evidence to validate OLT as a promising therapeutic approach for what was considered to be a fatal disease.
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http://dx.doi.org/10.1002/ajmg.a.61104DOI Listing
June 2019

Volatile anesthesia for a pediatric patient with very long-chain acyl-coenzyme A dehydrogenase deficiency: A case report.

Paediatr Anaesth 2018 03 9;28(3):296-297. Epub 2018 Jan 9.

Department of Anesthesiology, University of Wisconsin Hospital and Clinics, Madison, WI, USA.

We report the case of a 3-year-old boy with very long-chain acyl-coenzyme A dehydrogenase deficiency presenting for adenotonsillectomy who was successfully and safely managed with a balanced anesthetic including sevoflurane. The anesthetic management is described, and the controversy surrounding volatile anesthetics in these patients is discussed.
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http://dx.doi.org/10.1111/pan.13314DOI Listing
March 2018

Prenatal presentation of Mabry syndrome with congenital diaphragmatic hernia and phenotypic overlap with Fryns syndrome.

Am J Med Genet A 2017 Oct 17;173(10):2776-2781. Epub 2017 Aug 17.

Drexel University College of Medicine, Philadelphia, Pennsylvania.

We report on a family in which initial features were compatible with Fryns syndrome. The first sibling was a stillborn female with a left diaphragmatic hernia (DH). Her clinical features overlapped with Fryns syndrome. The second pregnancy, a male fetus, was followed for polyhydramnios, hypoplastic mandible, mild enlargement of the fetal bladder, hydronephrosis, and rocker bottom foot deformities. He had facial features similar to his sibling and a large cleft of the secondary palate, small jaw, and secundum atrial septal defect. He underwent surgical repair of imperforate anus, intestinal malrotation, and placement of mucous fistula for biopsy positive Hirschsprung disease. An elevated alkaline phosphatase level of 1569 U/L was reported. Whole exome sequencing performed on the second child demonstrated compound heterozygosity for the PIGV gene with the p.A341E and p.A418D variants in trans. Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by mutations in PIGV and includes hyperphosphatasia as a diagnostic hallmark. Our patient exhibited hyperphosphatasia but without any storage material in his skin cells. His features remain similar to his sister's, but includes seizures and lacks diaphragmatic hernia. Until now, HPMRS and Fryns syndrome, despite overlapping features, were considered mutually exclusive as HPMRS involves hyperphosphatasia and Fryns typically exhibits DH. Recent identification of PIGN mutations associated with several cases of Fryns syndrome point to a common pathogenetic etiology involving inborn errors of the glycosylphosphatidylinositiol anchor biosynthetic pathway. A diagnosis of HPMRS should be considered when DH is encountered on prenatal ultrasound.
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http://dx.doi.org/10.1002/ajmg.a.38379DOI Listing
October 2017

Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree.

Hum Mutat 2017 11 1;38(11):1485-1490. Epub 2017 Aug 1.

Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.

Developmental glaucoma can occur as an isolated or syndromic condition and is genetically heterogeneous. We describe a three-generation family affected with developmental glaucoma, myopia, and/or retinal defects associated with variable craniofacial/dental, auditory, brain, renal, and limb anomalies. Whole-exome sequencing identified a heterozygous c.124T> C, p.(Trp42Arg) allele in ADAMTSL1; cosegregation analysis confirmed the presence of this allele in four affected family members. The mutation affects a highly conserved residue and is strongly predicted to have a deleterious effect on protein function. Trp42 is normally modified by protein C-mannosylation, an unusual post-translational modification. Comparison of ADAMTSL1-WT (also known as punctin-1) and ADAMTSL1-p.Trp42Arg in vitro demonstrated that the latter was not secreted from transfected cells but retained intracellularly. Moreover, ADAMTSL1-p.Trp42Arg reduced secretion of cotransfected wild-type ADAMTSL1, suggesting a dominant negative effect for this mutation. These data imply a multisystem role for ADAMTSL1 and present the first disease-associated variant affecting a C-mannosylation motif.
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http://dx.doi.org/10.1002/humu.23299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638704PMC
November 2017

Successful pregnancy and delivery in a woman with propionic acidemia from the Amish community.

Mol Genet Metab Rep 2016 Sep 2;8:4-7. Epub 2016 Jun 2.

LaFarge Medical Clinic, LaFarge, WI, USA.

Propionic acidemia (PA) is an inborn error of protein metabolism with a variable clinical presentation ranging from neonatal encephalopathy to seemingly asymptomatic individuals who present with cardiomyopathy or sudden death. PA is recognized in the Amish population, often with an early asymptomatic course and eventual cardiac complications. Thus, Amish women with PA may reach reproductive age without clinical sequelae, but are at increased risk for metabolic decompensation during pregnancy, delivery and postpartum period. We describe the care of an Amish woman with PA during her first pregnancy and delivery.
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http://dx.doi.org/10.1016/j.ymgmr.2016.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471548PMC
September 2016

Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness.

Am J Hum Genet 2016 Dec 23;99(6):1388-1394. Epub 2016 Nov 23.

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD 20892, USA; Children's National Medical Center, Washington, DC 20010, USA. Electronic address:

Human MITF is, by convention, called the "microphthalmia-associated transcription factor" because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142105PMC
December 2016

Glycomacropeptide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial.

Am J Clin Nutr 2016 Aug 13;104(2):334-45. Epub 2016 Jul 13.

Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA.

Background: To prevent cognitive impairment, phenylketonuria requires lifelong management of blood phenylalanine (Phe) concentration with a low-Phe diet. The diet restricts intake of Phe from natural proteins in combination with traditional amino acid medical foods (AA-MFs) or glycomacropeptide medical foods (GMP-MFs) that contain primarily intact protein and a small amount of Phe.

Objective: We investigated the efficacy and safety of a low-Phe diet combined with GMP-MFs or AA-MFs providing the same quantity of protein equivalents in free-living subjects with phenylketonuria.

Design: This 2-stage, randomized crossover trial included 30 early-treated phenylketonuria subjects (aged 15-49 y), 20 with classical and 10 with variant phenylketonuria. Subjects consumed, in random order for 3 wk each, their usual low-Phe diet combined with AA-MFs or GMP-MFs. The treatments were separated by a 3-wk washout with AA-MFs. Fasting plasma amino acid profiles, blood Phe concentrations, food records, and neuropsychological tests were obtained.

Results: The frequency of medical food intake was higher with GMP-MFs than with AA-MFs. Subjects rated GMP-MFs as more acceptable than AA-MFs and noted improved gastrointestinal symptoms and less hunger with GMP-MFs. ANCOVA indicated no significant mean ± SE increase in plasma Phe (62 ± 40 μmol/L, P = 0.136), despite a significant increase in Phe intake from GMP-MFs (88 ± 6 mg Phe/d, P = 0.026). AA-MFs decreased plasma Phe (-85 ± 40 μmol/L, P = 0.044) with stable Phe intake. Blood concentrations of Phe across time were not significantly different (AA-MFs = 444 ± 34 μmol/L, GMP-MFs = 497 ± 34 μmol/L), suggesting similar Phe control. Results of the Behavior Rating Inventory of Executive Function were not significantly different.

Conclusions: GMP-MFs provide a safe and acceptable option for the nutritional management of phenylketonuria. The greater acceptability and fewer side effects noted with GMP-MFs than with AA-MFs may enhance dietary adherence for individuals with phenylketonuria. This trial was registered at www.clinicaltrials.gov as NCT01428258.
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http://dx.doi.org/10.3945/ajcn.116.135293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962165PMC
August 2016

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

Neurology 2016 07 8;87(1):77-85. Epub 2016 Jun 8.

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24.

Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).

Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.

Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
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http://dx.doi.org/10.1212/WNL.0000000000002807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932231PMC
July 2016

Clinical relevance of the discrepancy in phenylalanine concentrations analyzed using tandem mass spectrometry compared with ion-exchange chromatography in phenylketonuria.

Mol Genet Metab Rep 2016 Mar 16;6:21-6. Epub 2016 Jan 16.

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, United States.

Introduction: Metabolic control of phenylketonuria (PKU) and compliance with the low-phenylalanine (phe) diet are frequently assessed by measuring blood phe concentrations in dried blood spots (DBS) collected by patients instead of plasma phe concentrations.

Objective: Our objective was to investigate the difference in blood phe concentrations in DBS collected by subjects and analyzed using either a validated newborn screening tandem mass spectrometry (MS/MS) protocol or ion-exchange chromatography (IEC) compared to plasma phe concentrations obtained simultaneously and analyzed using IEC.

Design: Three to four fasting blood samples were obtained from 29 subjects with PKU, ages 15-49 years. Capillary blood was spotted on filter paper by each subject and the DBS analyzed using both MS/MS and IEC. Plasma was isolated from venous blood and analyzed using IEC.

Results: Blood phe concentrations in DBS analyzed using MS/MS are 28% ± 1% (n = 110, p < 0.0001) lower than plasma phe concentrations analyzed using IEC resulting in a blood phe concentration of 514 ± 23 μmol/L and a plasma phe concentration of 731 ± 32 μmol/L (mean ± SEM). This discrepancy is larger when plasma phe is > 600 μmol/L. Due to the large variability across subjects of 13.2%, a calibration factor to adjust blood phe concentrations is not recommended. Analysis of DBS using IEC reduced the discrepancy to 15 ± 2% lower phe concentrations compared to plasma analyzed using IEC (n = 38, p = 0.0001). This suggests that a major contributor to the discrepancy in phe concentrations is the analytical method.

Conclusion: Use of DBS analyzed using MS/MS to monitor blood phe concentrations in individuals with PKU yields significantly lower phe levels compared to plasma phe levels analyzed using IEC. Optimization of current testing methodologies for measuring phe in DBS, along with patient education regarding the appropriate technique for spotting blood on filter paper is needed to improve the accuracy of using DBS to measure phe concentrations in PKU management.
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http://dx.doi.org/10.1016/j.ymgmr.2016.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789345PMC
March 2016

Inborn Errors of Metabolism (Metabolic Disorders).

Pediatr Rev 2016 Jan;37(1):3-15; quiz 16-7, 47

Department of Pediatrics and the Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, WI. Marshfield Clinic Research Foundation, Marshfield, WI.

By their very nature, rare inborn errors of metabolism challenge the generation and application of evidence-based medicine. • On the basis of limited research evidence as well as consensus, newborn screening for select metabolic disorders, including phenylketonuria, medium-chain acyl CoA dehydrogenase deficiency, and glutaric acidemia type I, may improve long-term outcomes for affected children. • On the basis of primarily consensus, due to lack of relevant clinical studies, inborn errors due to defects in the metabolism of energy sources (protein, fatty acids, and carbohydrates) may present in infancy with overwhelming metabolic decompensation, and initial laboratory evaluations may reveal hyperammonemia, nonketotic hypoglycemia, or a metabolic acidosis with an elevated anion gap, depending on the disorder. • On the basis of primarily consensus, due to lack of relevant clinical studies, specific laboratory testing for inborn errors of metabolism should include plasma amino acids, urine organic acids, plasma carnitine, and plasma acylcarnitine profile. • On the basis of primarily consensus, due to lack of relevant clinical studies, disorders of cellular organelles, such as lysosomal and peroxisomal disorders, may present with progressive organomegaly, developmental regression, dysmorphic facial characteristics. or sensory loss.
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http://dx.doi.org/10.1542/pir.2014-0122DOI Listing
January 2016

Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.

Lancet 2014 Jul 14;384(9937):37-44. Epub 2014 Apr 14.

BioMarin Pharmaceutical, Novato, CA, USA.

Background: Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria.

Methods: In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054.

Findings: 25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89-106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54·2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection.

Interpretation: Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing.

Funding: BioMarin Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(13)61841-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447208PMC
July 2014

Phenotype of FOXP2 haploinsufficiency in a mother and son.

Am J Med Genet A 2012 Jan 21;158A(1):174-81. Epub 2011 Nov 21.

University of Wisconsin-Madison, Wisconsin, USA.

Disruptions in FOXP2, a transcription factor, are the only known monogenic cause of speech and language impairment. We report on clinical findings for two new individuals with a submicroscopic deletion of FOXP2: a boy with severe apraxia of speech and his currently moderately affected mother. A 1.57 Mb deletion on chromosome 7q31 was detected by array comparative genomic hybridization (aCGH). In addition to FOXP2, the patients' deletion involves two other genes, MDFIC and PPP1R3A, neither of which has been associated with speech or language disorders. Thus, findings for these two family members provide informative phenotypic information on FOXP2 haploinsufficiency. Evaluation by a clinical geneticist indicated no major congenital anomalies or dysmorphic features. Evaluations by a clinical psychologist and occupational therapist indicated cognitive-linguistic processing and sensorimotor control deficits, but did not support a diagnosis of autism spectrum disorder. Evaluation by clinical and research speech pathologists confirmed that both patients' speech deficits met contemporary criteria for apraxia of speech. Notably, the patients were not able to laugh, cough, or sneeze spontaneously, replicating findings reported for two other FOXP2 cases and a potential diagnostic sign of nonsyndromic apraxia of speech. Speech severity findings for the boy were not consistent with the hypothesis that loss of maternal FOXP2 should be relatively benign. Better understanding of the behavioral phenotype of FOXP2 disruptions will aid identification of patients, toward an eventual understanding of the pathophysiology of syndromic and nonsyndromic apraxia of speech.
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http://dx.doi.org/10.1002/ajmg.a.34354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319495PMC
January 2012

Mild clinical presentation in a child with prenatally diagnosed 45,X/47,XX,+18 mosaicism.

Am J Med Genet A 2009 Nov;149A(11):2588-92

Department of Obstetrics and Gynecology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53715-1599, USA.

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http://dx.doi.org/10.1002/ajmg.a.33084DOI Listing
November 2009

A case of congenitally absent left internal carotid artery: vascular malformations in 22q11.2 deletion syndrome.

Cleft Palate Craniofac J 2010 May;47(3):314-7

Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Our report is on a Hispanic boy for whom, shortly after birth, clinical suspicion of 22q11.2 deletion syndrome (22q11.2DS) was raised as a result of his characteristic features, including facial dysmorphisms and hypotonia. The 22q11.2DS was confirmed by fluorescence in situ hybridization (FISH), noting a 22q11.2 deletion. Further evaluation revealed complete congenital absence of the left internal carotid artery and focal pachygyria of the left hemisphere. Multiple cardiac and vascular anomalies have been previously described in 22q11 deletion syndrome, but congenital absence of the internal carotid has not been previously reported in the literature. We present a clinical case report in detail of this unique 22q11.2 deletion syndrome associated finding.
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http://dx.doi.org/10.1597/09-061.1DOI Listing
May 2010

The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia.

Am J Med Genet A 2008 Nov;146A(22):2885-90

Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Expanded newborn screening detects patients with modest elevations in citrulline; however it is currently unclear how to treat these patients and how to counsel their parents. In order to begin to address these issues, we compared the clinical, biochemical, and molecular features of 10 patients with mildly elevated citrulline levels. Three patients presented with clinical illness whereas seven came to attention as a result of expanded newborn screening. One patient presented during pregnancy and responded promptly to IV sodium phenylacetate/sodium benzoate and arginine therapy with no long-term adverse effects on mother or fetus. Two children presented with neurocognitive dysfunction, one of these responded dramatically to dietary protein reduction. ASS enzyme activity was not deficient in all patients with biallelic mutations suggesting this test cannot exclude the ASS1 locus in patients with mildly elevated plasma citrulline. Conversely, all symptomatic patients who were tested had deficient activity. We describe four unreported mutations (p.Y291S, p.R272H, p.F72L, and p.L88I), as well as the common p.W179R mutation. In silico algorithms were inconsistent in predicting the pathogenicity of mutations. The cognitive benefit in one patient of protein restriction and the lack of adverse outcome in seven others restricted from birth, suggest a role for protein restriction and continued monitoring to prevent neurocognitive dysfunction.
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http://dx.doi.org/10.1002/ajmg.a.32527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597641PMC
November 2008