GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study.

PURPOSE: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. METHODS: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. RESULTS: Classification of 37 distinct variants using ACMG criteria resulted in the upgrade of six and the submission of four new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial MRIs demonstrated progressive brain atrophy, more pronounced in late infantile patients. MR spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile than juvenile onset disease. CONCLUSION: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

Hyperammonemia in the Pediatric Emergency Department.

ABSTRACT: Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.

Increased diagnostic yield from negative whole genome-slice panels using automated reanalysis.

We evaluated the diagnostic yield using genome-slice panel reanalysis in the clinical setting using an automated phenotype/gene ranking system. We analyzed whole genome sequencing (WGS) data produced from clinically ordered panels built as bioinformatic slices for 16 clinically diverse, undiagnosed cases referred to the Pediatric Mendelian Genomics Research Center, an NHGRI-funded GREGoR Consortium site. Genome-wide reanalysis was performed using Moon™, a machine-learning-based tool for variant prioritization. In five out of 16 cases, we discovered a potentially clinically significant variant. In four of these cases, the variant was found in a gene not included in the original panel due to phenotypic expansion of a disorder or incomplete initial phenotyping of the patient. In the fifth case, the gene containing the variant was included in the original panel, but being a complex structural rearrangement with intronic breakpoints outside the clinically analyzed regions, it was not initially identified. Automated genome-wide reanalysis of clinical WGS data generated during targeted panels testing yielded a 25% increase in diagnostic findings and a possibly clinically relevant finding in one additional case, underscoring the added value of analyses versus those routinely performed in the clinical setting.

Cation leak through the ATP1A3 pump causes spasticity and intellectual disability.

ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.

The past, present, and future of child growth monitoring: A review and primer for clinical genetics.

Child growth measurements are critical vital signs to track, with every individual child growth curve potentially revealing a story about a child's health and well-being. Simply put, every baby born requires basic building blocks to grow and thrive: proper nutrition, love and care, and medical health. To ensure that every child who is missing one of these vital aspects is identified, growth is traditionally measured at birth and each well-child visit. While the blue and pink growth curves appear omnipresent in pediatric clinics, it is surprising to realize that their use only became standard of care in 1977 when the National Center for Health Statistics (NCHS) adopted the growth curve as a clinical tool for health. Behind this practice lies a socioeconomically, culturally, and politically complex interplay of individuals and institutions around the world. In this review, we highlight the often forgotten past, current state of practice, and future potential of this powerful clinical tool: the growth reference chart, with a particular focus on clinical genetics practice. The goal of this article is to understand ongoing work in the field of anthropometry (the scientific study of human measurements) and its direct impact on modern pediatric and genetic patient care.

Optimization of the biochemical genetics laboratory rotation using a multidesign approach to curriculum.

PURPOSE: A biochemical genetics laboratory rotation is required for multiple genetics training programs. Traditionally, this rotation has been observational with experience being dependent upon cases released and availability of laboratory director(s), resulting in inconsistent learning opportunities. This curriculum was created to standardize the learning experience. METHODS: The revised rotation provides multiple teaching modalities including small group didactic sessions (flipped classroom model), case-based sessions, and hands-on laboratory experience. Trainees prepare a presentation (learning by teaching) and discuss the differential diagnosis, metabolic pathway, newborn screening, treatment, and molecular characteristics of the gene(s) implicated. Learner assessment is performed using pre- and post-tests, learner evaluations, and instructor feedback. RESULTS: Pre- and post-test scores were significantly different (P < .001) for learners from all programs. Participants found the course to be effective, increased their learning, and allowed them to interact with metabolic testing results in helpful ways. Faculty appreciated the use of prerecorded lectures and additional time for in-depth teaching on interesting cases. CONCLUSION: The revised rotation has been well received by trainees and faculty. Interaction of learners with the laboratory staff was optimized by ensuring all parties were prepared to teach and learn. Future directions include expanding the program to include remote learners from other centers.

Case report: Early molecular confirmation and sodium polystyrene sulfonate management of systemic pseudohypoaldosteronism type I.

Introduction: Type 1 pseudohypoaldosteronism (PHA) consists of resistance to aldosterone. Neonatal presentation is characterized by salt wasting, hyperkalemia, and metabolic acidosis with high risk of mortality. Type 1 PHA can be autosomal dominant (renal type 1) or autosomal recessive (systemic type 1). Renal PHA type 1 can be feasibly managed with salt supplementation; however, systemic PHA type 1 tends to have more severe electrolyte imbalance and can be more refractory to treatment. Case Presentation: We present a case of a 3-year-old girl with systemic PHA type 1, diagnosed and confirmed molecularly in infancy, who has been successfully managed with sodium polystyrene sulfonate decanted into feeds along with sodium supplementation. On day 5 of life, a full-term female infant presented to the ED for 2 days of non-bloody, non-bilious emesis, along with hypothermia to 94°F. Laboratory results were notable for hyponatremia (Na) of 127, hyperkalemia (K) of 7.9, and acidosis with bicarbonate level of 11.2. Genetic testing ordered within a week of life confirmed PHA type 1 with a homozygous pathogenic frameshift variant in SCNN1A c.575delA (p.Arg192GlyfsX57). Sodium polystyrene sulfonate and feeds were decanted until the age of 16 months, and she was also continued on NaCl supplementation. She was gradually transitioned to directly administered sodium polystyrene sulfonate without any electrolyte issues. She has overall done well after gastrostomy-tube (G-tube) placement without severe hyperkalemia even with several hospitalizations for gastrointestinal or respiratory illnesses. Discussion/Conclusion: A treatment approach to systemic PHA and sodium polystyrene sulfonate administration in neonates and infants is described.

Starting the conversation on gene therapy for phenylketonuria: Current perspectives of patients, caregivers, and advocates.

Phenylketonuria (PKU) is a rare genetic condition caused by inborn error(s) in the gene for the enzyme phenylalanine hydroxylase. Resulting loss of phenylalanine (Phe) metabolism requires strict dietary therapy and/or medication to prevent toxic accumulation of Phe. Novel investigational therapies, including gene therapies that aim to address underlying causes of PKU, are now entering clinical trials. However, perceptions of this technology in the PKU community have not been assessed. We conducted a qualitative survey recruiting adult patients, caregivers, and patient advocates from the US and 3 EU countries to assess the impact of living with PKU and the perceptions of gene therapy. Telephone interviews were conducted for up to 60 min following a standardized discussion guide. Interviewers classified each participant by their level of knowledge regarding gene therapy as either: low (little or no prior awareness); moderate (awareness of gene therapy as a concept in PKU); or high (working knowledge of gene therapy, e.g., vectors). In total, 33 participants were recruited (patients, n = 24; caregivers, n = 5; advocates, n = 4). The patient sample was well balanced among age groups, sex, and US/EU geographies. The participants' experiences and burden of living with PKU were largely negative, characterized by frustrations with current management consistent with prior reports. Most participants (n = 18/33) were identified as displaying moderate gene-therapy knowledge, 10/33 as displaying high knowledge, and 5/33 as displaying low knowledge. Both positive and negative perceptions were observed; positive perceptions were often linked to "hope" that gene therapy may represent a cure, whereas negative perceptions were linked to the "uncertainty" of outcomes. High knowledge of gene therapy appeared to trend with negative perceptions; 7/10 participants from this group reported high levels of concern over gene therapy. In contrast, participants who displayed low knowledge reported low (n = 3/5) or moderate (n = 2/5) concern, with predominantly positive perceptions. These data highlight the need for education around the theoretical risk:benefit profile of gene therapy. Despite current unknowns around gene therapy, our study demonstrates the important role of healthcare providers as educators who can use available data to provide balanced information to patients and caregivers.

Maple syrup urine disease decompensation misdiagnosed as a psychotic event.

Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disease resulting in impaired or absent breakdown of branched-chain amino acids (BCAA) valine, isoleucine, and leucine. Classic MSUD often presents in post-natal periods, at times before newborn screening results, and is treated with a protein restricted diet supplemented with medical food and close follow up to prevent toxic buildup of blood leucine. Acute episodes of decompensation are prevented by early recognition and treatment. Acute episodes of metabolic decompensation in patients with MSUD are medical emergencies that require immediate treatments as cerebral edema may lead to brain-stem compression resulting in death. As the early outcomes improve for MSUD patients, the long-term sequelae of chronic hyperleucemia are being elucidated and include cognitive impairment, mental health disorders, and movement disorders. In this report we present an adult patient with MSUD with attention deficit, hyperactivity type (ADHD) and depression due to prolonged exposure to elevated leucine managed with community support services who presented to the emergency department with new onset of acute hallucinations. He was held in the emergency department awaiting involuntary commitment to a psychiatric facility and underwent psychiatric treatments for suspected new onset hallucinations without improvement. Upon notification of metabolic specialists and initiation of appropriate therapy of MSUD, his leucine level normalized rapidly with resolution of his acute psychosis. This case describes the acute presentation of psychosis in the setting of long-term toxicity of leucine. This case also highlights the importance of transition of care, education and planning in patients with inborn errors of metabolism.

The Rare Disease Research Scholars Program: A training curriculum for clinical researchers with mixed methods evaluation study.

Rare disease clinician investigators are essential to ensure appropriate diagnosis, care, and treatment for the rapidly growing rare disease population. As these researchers are spread across many specialties, learning the unique skill set for rare disease research (RDR) can be a hurdle and may hinder progress in the field. The need for an RDR focused training program for investigators in many specialties and backgrounds was identified in a needs assessment of trainees in the NIH funded Rare Diseases Clinical Research Network. Based on this information, the Rare Disease Research Scholars Program (RDRSP) was developed. We describe the needs assessment, curriculum creation, scholar recruitment, and outcome evaluation based on four years of programmatic data (2015-2019). This one year-long RDRSP uses a blended approach that includes in-person, web-based, synchronous and asynchronous learning. We evaluated the RDRSP using quantitative and qualitative approaches. Quantitative measures included pre and post questionnaires about knowledge, self-efficacy, and intent to remain in RDR. Data were analyzed using descriptive statistics and a paired t-test. Qualitative semi-structured interviews explored the RDR scholars' perceptions of the RDRSP; thematic analysis examined the textual data. Quantitative pre- and post-measures were statistically significant in the following areas: 1) improved knowledge content in RDR, 2) enhanced self-efficacy in clinical research, and 3) intent to remain in the field of RDR. Qualitative data analysis found the program supported the development of the scholar's research skills as well as 'soft-skills'. By combining training of skills unique to RDR with the more general topics of leadership, mentorship and collaboration among participants in diverse specialties, we created a program that supports the development of the next generation of rare disease clinician investigators and serves as a model for training in other niche research areas.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations.

Individuals with LPIN1 deficiency have early recurrent, life-threatening rhabdomyolysis but the full phenotypic spectrum and optimal treatment of the disorder remains unknown. Here we report the clinical details and treatment outcomes of 6 patients from our health system. The average age of presentation in our cohort was 23.8 months ±11.6 months (range 15-46 months). The average number of days for each hospitalization for this cohort is 11.7±13.2 days. Creatinine kinase (CK) levels peak during our care averaged 607,725 units/L (range 157,000-1,100,000 units/L). We observed that aspartate aminotransferase levels paralleled the CK levels in its elevation and resolution (Pearson's correlation R = 0.995); while alanine aminotransferase paralleled the elevation but lagged in the resolution of CK levels (R = 0.728). Unlike historical accounts, in our patient population, rhabdomyolysis was sometimes seen without inciting viral or traumatic events. We also cared for multiple individuals that had received treatment at other centers. This allowed us to compare multiple practice approaches and led to a standardized Care Recommendations.

A Case Series of Familial ARID1B Variants Illustrating Variable Expression and Suggestions to Update the ACMG Criteria.

ARID1B is one of the most frequently mutated genes in intellectual disability (~1%). Most variants are readily classified, since they are de novo and are predicted to lead to loss of function, and therefore classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines for the interpretation of sequence variants. However, familial loss-of-function variants can also occur and can be challenging to interpret. Such variants may be pathogenic with variable expression, causing only a mild phenotype in a parent. Alternatively, since some regions of the ARID1B gene seem to be lacking pathogenic variants, loss-of-function variants in those regions may not lead to ARID1B haploinsufficiency and may therefore be benign. We describe 12 families with potential loss-of-function variants, which were either familial or with unknown inheritance and were in regions where pathogenic variants have not been described or are otherwise challenging to interpret. We performed detailed clinical and DNA methylation studies, which allowed us to confidently classify most variants. In five families we observed transmission of pathogenic variants, confirming their highly variable expression. Our findings provide further evidence for an alternative translational start site and we suggest updates for the ACMG guidelines for the interpretation of sequence variants to incorporate DNA methylation studies and facial analyses.

Pediatric medical genetics house call: Telemedicine for the next generation of patients and providers.

In an era of increasing technology and interaction with the patient bedside, we explore the role of relocating the bedside from the hospital to the home using telemedicine. The COVID-19 pandemic pushed telemedicine from small and pilot programs to widespread practice at an unprecedented rate. With the rapid implementation of telemedicine, it is important to consider how to create a telehealth system that provides both good care for patients and families while maintaining an excellent education environment for trainees of all levels. To this end, we developed telemedicine educational milestones to describe novel skills required to provide high quality telemedicine care, and allow trainees and clinical educators a metric by which to assess trainee progress. We also created methods and tools to help trainees learn and families feel comfortable in their new role as virtual collaborators. We envision a time when safety does not set the venue; instead the needs of the patient will dictate whether a virtual or in-person visit is the right choice for a family. We expect that pediatric medical genetics and metabolism groups across the country will continue to set a standard of a hybrid care system to meet the unique needs of each individual patient, using telemedicine technology.

Rapid deployment of a telemedicine care model for genetics and metabolism during COVID-19.

The national importance of telemedicine for safe and effective patient care has been highlighted by the current COVID-19 pandemic. Prior to the 2020 pandemic the Division of Genetics and Metabolism piloted a telemedicine program focused on initial and follow-up visits in the patients' home. The goals were to increase access to care, decrease missed work, improve scheduling, and avoid the transport and exposure of medically fragile patients. Visits were conducted by physician medical geneticists, genetic counselors, and biochemical dietitians, together and separately. This allowed the program to develop detailed standard operating procedures. At the onset of the COVID-19 pandemic, this pilot-program was deployed by the full team of 22 providers in one business day. Two physicians remained on-site for patients requiring in-person evaluations. This model optimized patient safety and workforce preservation while providing full access to patients during a pandemic. We provide initial data on visit numbers, types of diagnoses, and no-show rates. Experience in this implementation before and during the pandemic has confirmed the effectiveness and value of telemedicine for a highly complex medical population. This program is a model that can and will be continued well-beyond the current crisis.

Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations.

Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late-onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC-based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally.

Use of dexamethasone in idiopathic, acute pediatric rhabdomyolysis.

Current rhabdomyolysis treatment guidelines vary based on the etiology and diagnosis, yet many cases evade conclusive diagnosis. In these cases, treatment options remain largely limited to fluids and supportive therapy. We present two cases of acute rhabdomyolysis diagnosed in the emergency department: a 5-year-old boy with sudden onset bilateral flank pain, and a 13-year-old boy with 2-3 days of worsening pectoral and shoulder pain. Each patient had a prior similar episode requiring hospitalization in the past. The 5-year-old had no inciting trauma or trigger, medication use, or illness. The 13-year-old previously had an upper respiratory infection during the week prior and had been strenuously exercising at the time of onset. Genetic testing results were unknown for both patients during their hospitalizations, and insurance and other barriers led to delay. Later results for the first patient revealed a heterozygous deletion in intron 19 on the LPIN1 gene interpreted as a variant of unknown significance. During their hospitalizations, both children were started on intravenous (i.v.) fluids, and creatine kinase (CK) initially trended downward, but then began to rise or plateau. After reviewing the cases, prior literature, and anecdotal evidence of benefit from corticosteroid therapy in rhabdomyolysis with our consultant metabolic physicians, dexamethasone was initiated. In both patients, dexamethasone use correlated with relief of patient symptoms, significantly decreased CK value, and our ability to discharge these patients home quickly. Our cases, discussion, and literature review all lead to the consideration of the use of dexamethasone in conjunction with standard therapy for acute rhabdomyolysis.