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De novo variants in QRICH1 (Glutamine‐rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs. [ABSTRACT FROM AUTHOR]

We performed haplotype analysis using nine single nucleotide polymorphisms in the ornithine transcarbamylase gene to explore the ancestral origins of three mutations associated with late-onset phenotype in male patients: p.R40H, p.R277W and p.Y55D. Overall, 8 haplotypes were defined among 14 families carrying p.R40H, 5 families carrying p.R277W and 2 families with p.Y55D mutations. Of nine Japanese families carrying p.R40H, eight exhibited haplotype (HT)1, whereas the other family harbored HT2. Among three Caucasian families, one Spanish and one Australian family bore HT3; one Austrian family had HT4. Two US patients harbored HT2 and HT4. Among families carrying p.R277W, HT5 was found in one Japanese, one Korean and one US family. Two other US families had HT2 and HT6. Two families carrying p.Y55D, both Japanese, shared HT1. These results indicate that the p.R40H mutation has arisen recurrently in all populations studied, although there is evidence for a founder effect in Japan, with most cases probably sharing a common origin, and to a lesser extent in subjects of European ancestry (HT3). It is evident that p.R277W mutation has recurred in discrete populations. The p.Y55D mutation appears to have arisen from a common ancestor, because this transversion (c.163T>G) occurs rarely. [ABSTRACT FROM AUTHOR]

For most inherited metabolic disorders on newborn screening (NBS) panels, prompt, expert confirmation and treatment are critical to optimize clinical outcomes for children with inherited metabolic diseases (IMD). In the Washington Metropolitan Area (WMA), 3 different short-term follow-up (STFU) systems exist for linking infants with positive newborn screens for IMD to appropriate specialty care. We diagrammed the STFU systems for the District of Columbia, Maryland and Virginia and calculated clinically relevant intervals of time between NBS collection and diagnosis/treatment initiation. We also surveyed representatives from 48 other state NBS programs to classify the STFU systems in the rest of the country. We found that in the WMA the STFU system that did not include the IMD specialist at the same time as the primary care provider (PCP) was associated with a longer median collection-to-specialist contact interval for true positive NBS for critical diagnoses (p=0.013). Nationally, 25% of state NBS programs report having a STFU system that does not include the IMD specialist at the same time as the PCP. In conclusion, there is variability among the STFU systems employed by NBS programs in the US which may lead to delays in diagnosis confirmation and treatment. National standards for STFU systems that include early involvement of an IMD specialist for all presumed positive NBS results may decrease the collection-to-specialist contact interval which could improve clinical outcomes in children with IMD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30, 2011 in Washington, D.C., Children's National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge., (Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Propionic acidemia is a relatively rare inborn error of metabolism. Individuals with propionic acidemia often have life-threatening episodes of hyperammonemia and metabolic acidosis, as well as intellectual disability. There are many reports of additional problems, including poor growth, stroke-like episodes of the basal ganglia, seizures, cardiomyopathy, long QTc syndrome, immune defects, pancreatitis and optic neuropathy; however, there is little information about the incidence of these problems in this rare disease. Additionally, there are no clear guidelines for medical or surgical management of individuals with propionic acidemia. Through a comprehensive and systematic review of the current medical literature and survey of expert opinion, we have developed practice guidelines for the chronic management of individuals with propionic acidemia, including dietary therapy, use of medications, laboratory monitoring, chronic health supervision, use of gastrostomy tubes and liver transplantation., (Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Propionic acidemia (PA) is an organic acidemia which has a broad range of neurological complications, including developmental delay, intellectual disability, structural abnormalities, metabolic stroke-like episodes, seizures, optic neuropathy, and cranial nerve abnormalities. As the PA consensus conference hosted by Children's National Medical Center progressed from January 28 to 30, 2011, it became evident that neurological complications were common and a major component of morbidity, but the role of imaging and the basis for brain pathophysiology were unclear. This paper reviews the hypothesized pathophysiology, presentation and uses the best available evidence to suggest programs for treatment, imaging, and monitoring the neurological complications of PA., (Copyright © 2011. Published by Elsevier Inc. All rights reserved.)