Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Biallelic hypomorphic variants in CAD cause uridine-responsive macrocytic anaemia with elevated haemoglobin-A2.

Biallelic pathogenic variants in CAD, that encode the multienzymatic protein required for de-novo pyrimidine biosynthesis, cause early infantile epileptic encephalopathy-50. This rare disease, characterized by developmental delay, intractable seizures and anaemia, is amenable to treatment with uridine. We present a patient with macrocytic anaemia, elevated haemoglobin-A2 levels, anisocytosis, poikilocytosis and target cells in the blood smear, and mild developmental delay. A next-generation sequencing panel revealed biallelic variants in CAD. Functional studies did not support complete abrogation of protein function; however, the patient responded to uridine supplement. We conclude that biallelic hypomorphic CAD variants may cause a primarily haematological phenotype.

A novel SLC25A13 gene splice site variant causes Citrin deficiency in an infant.

Citrin deficiency is an autosomal recessive disorder associated with SLC25A13 gene pathogenic variants, with more than a hundred known at present. It manifests in neonates as failure to thrive and acute liver insufficiency. We herein describe a case of a 4-week-old infant who presented with insufficient weight gain and liver failure accompanied by hyperammonemia. She was diagnosed with Citrin deficiency after a thorough biochemical and molecular analysis including amino acid profile, DNA sequencing of genes of interest and RNA splice site evaluation, to reveal a yet unknown damaging variant of the SLC25A13 gene.

Clinical score for early diagnosis and treatment of stroke-like episodes in MELAS syndrome.

BACKGROUND AND OBJECTIVES: Stroke-like episodes (SLEs) in patients with MELAS syndrome are often initially misdiagnosed as acute ischemic stroke (AIS), resulting in treatment delay. We aimed to determine clinical features that may distinguish SLEs from AISs and explore the benefit of early L-arginine treatment on patient outcomes. METHODS: We looked retrospectively for MELAS patients admitted between January 2005 and January 2022 and compared them to an AIS cohort with similar lesion topography. MELAS patients who received L-arginine within 40 days of their first SLE were defined as the early treatment group and the remaining as late or no treatment group. RESULTS: Twenty-three SLEs in 10 MELAS patients and 21 AISs were included. SLE patients had significantly different features: they were younger, more commonly reported hearing loss, lower body mass index, had more commonly a combination of headache and/or seizures at presentation, serum lactate was higher, and hemiparesis was less common. An SLE Early Clinical Score (SLEECS) was constructed by designating one point to each above features. SLEECS ≥ 4 had 80% sensitivity and 100% specificity for SLE diagnosis. Compared to late or no treatment, early treatment group patients (n = 5) had less recurrent SLEs (total 2 vs. 11), less seizures (14% vs. 25%, p = 0.048), lower degree of disability at first and last follow-up (modified ranking scale, mRS 2 ± 0.7 vs. 4.2 ± 1, p = 0.005; 2 ± 0.7 vs. 5.8 ± 0.5, p < 0.001, respectively), and a lower mortality (0% vs. 80% p = 0.048). CONCLUSIONS: The SLEECS model may aid in the early diagnosis and treatment of SLEs and lead to improved clinical outcomes.

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Long COVID-19 Liver Manifestation in Children.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. METHODS: This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. RESULTS: We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative. CONCLUSIONS: We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

The effects of the COVID-19 pandemic on patients with lysosomal storage disorders in Israel.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is the causative agent of the current COVID-19 pandemic. Lysosomal storage disorders (LSD) comprise of 70 inherited inborn errors of metabolism. Affected individuals suffer from multi-systemic involvement with variable severity and rate of disease progression between different diseases. Some of the LSDs have established treatments, whether parenteral or oral therapies. The full impact of the COVID-19 pandemic together with the lockdown on the wellbeing and medical management of patients with rare diseases, such as LSDs, is widely unknown. Herein, we describe the effects of the COVID-19 pandemic and its associated mandatory home lockdown on patients with LSDs in Israel. RESULTS: We present a prospective multi-center questionnaire study including 48 LSD patients from four medical centers in Israel. The study objective was to assess the impact of the COVID-19 pandemic restrictions on individuals with LSDs in Israel, as reported by their caregivers. Secondary objectives were to assess the morbidity from SARS CoV-2 in LSD patients and the impact of changes in mood and behavior on compliance to treatment and to assess the relationship between changes in mood to changes in cognition and behavior. Thirty one of 38 patients (82%) who received any kind of regular treatment did not miss treatments. Among patients receiving enzyme replacement therapy (ERT) in the in-hospital setting, 5 patients (20%) experienced treatment disruptions. Four patients had tested positive for SARS-Cov-2 virus infection by PCR. Seven out of the 48 patients (14%) described mood changes with cognitive and motor deterioration during the home quarantine. CONCLUSIONS: We observed high rates of treatment adherence and low morbidity through the COVID-19 pandemic in patients with LSDs in Israel. LSDs patients can be a model for patients with complex chronic diseases requiring routine treatments and surveillance during a pandemic or other disruption of daily routine.

DLG4-related synaptopathy: a new rare brain disorder.

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.

Four patients with D-bifunctional protein (DBP) deficiency: Expanding the phenotypic spectrum of a highly variable disease.

INTRODUCTION: Peroxisomal D-bifunctional protein (DBP) deficiency is an autosomal recessive disorder historically described as a Zellweger-like syndrome comprising neonatal seizures, retinopathy, hearing loss, dysmorphic features, and other complications. The HSD17B4 gene encodes DBP which is essential for oxidation of peroxisomal substrates. We describe 4 patients - 2 unrelated female girls and 2 monozygotic twin sisters - with DBP deficiency and phenotypic diversity. PATIENT REPORTS: Patient 1 presented neonatally with hypotonia and seizures, and later on developed global developmental delay and regression, sensorineural hearing loss, nystagmus and cortical blindness. The brain MRI demonstrated bilateral peri-sylvian polymicrogyria. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.752G>A, p.(Arg251Gln); c.868 + 1delG).Patient 2 presented with hypotonia, motor delay, and sensorineural hearing loss in infancy, considerable developmental regression during her fourth year, nystagmus, and peripheral neuropathy. Brain MRI demonstrated cerebellar atrophy and abnormal basal ganglia and white matter signal, which appeared after the age of two years. Whole exome sequencing revealed 2 mutations in the HSD17B4 gene (c.14 T>G, p.(Leu5Arg); c.752G>A, p.(Arg251Gln)).Patients 3 and 4, two female monozygotic twins, presented with hypotonia, developmental delay, and macrocephaly from birth, and later on also sensorineural hearing loss, infantile spasms and hypsarrhythmia, and adrenal insufficiency. Brain MRI demonstrated delayed myelination, and an assay of peroxisomal beta oxidation suggested DBP deficiency. Sequencing of the HSD17B4 gene revealed the same 2 mutations as in patient 1. DISCUSSION: We describe 4 patients with variable and diverse clinical picture of DBP deficiency and particularly emphasize the clinical, biochemical, and neuroimaging characteristics. Interestingly, the clinical phenotype varied even between patients with the exact two mutations in the HSD17B4 gene. In addition, in two of the three patients in whom levels of VLCFA including phytanic acid were measured, the levels were within normal limits. This is expanding further the clinical spectrum of this disorder, which should be considered in the differential diagnosis of every patient with hypotonia and developmental delay especially if accompanied by polymicrogyria, seizures, sensorineural hearing loss, or adrenal insufficiency regardless of their VLCFA profile.

Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases.

BACKGROUND: Rhabdomyolysis is a clinical emergency that may cause acute kidney injury (AKI). It can be acquired or due to monogenic mutations. Around 60 different rare monogenic forms of rhabdomyolysis have been reported to date. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to nonspecific presentation, the high number of causative genes, and current lack of data on the prevalence of monogenic forms. METHODS: We employed whole exome sequencing (WES) to reveal the percentage of rhabdomyolysis cases explained by single-gene (monogenic) mutations in one of 58 candidate genes. We investigated a cohort of 21 unrelated families with rhabdomyolysis, in whom no underlying etiology had been previously established. RESULTS: Using WES, we identified causative mutations in candidate genes in nine of the 21 families (43%). We detected disease-causing mutations in eight of 58 candidate genes, grouped into the following categories: (1) disorders of fatty acid metabolism (CPT2), (2) disorders of glycogen metabolism (PFKM and PGAM2), (3) disorders of abnormal skeletal muscle relaxation and contraction (CACNA1S, MYH3, RYR1 and SCN4A), and (4) disorders of purine metabolism (AHCY). CONCLUSIONS: Our findings demonstrate a very high detection rate for monogenic etiologies using WES and reveal broad genetic heterogeneity for rhabdomyolysis. These results highlight the importance of molecular genetic diagnostics for establishing an etiologic diagnosis. Because these patients are at risk for recurrent episodes of rhabdomyolysis and subsequent risk for AKI, WES allows adequate prophylaxis and treatment for these patients and their family members and enables a personalized medicine approach.

Long-term outcome of expanded newborn screening at Boston children's hospital: benefits and challenges in defining true disease.

INTRODUCTION: There is no universal consensus of the disorders included in newborn screening programs. Few studies so far, mostly short-term, have compared the outcome of disorders detected by expanded newborn screening (ENBS) to the outcome of the same disorders detected clinically. METHODS: We compared the clinical and neurodevelopmental outcomes in patients with metabolic disorders detected by ENBS, including biotinidase testing, with those detected clinically and followed at the Metabolism Clinic at Boston Children's Hospital. RESULTS: One hundred eighty-nine patients came to attention from ENBS and 142 were clinically diagnosed. 3-methylcrotonyl-CoA carboxylase, biotinidase, and carnitine deficiencies were exclusively identified by ENBS and medium chain acyl-CoA dehydrogenase (MCADD) and very long chain acyl-CoA dehydrogenase deficiencies (VLCADD) were predominantly identified by ENBS whereas the organic acid disorders more often came to attention clinically. Only 2% of the ENBS-detected cases had clinically severe outcomes compared to 42% of those clinically detected. The mean IQ score was 103 + 17 for the ENBS-detected cases and 77 + 24 for those clinically detected. Those newly included disorders that seem to derive the greatest benefit from ENBS include the fatty acid oxidation disorders, profound biotinidase deficiency, tyrosinemia type 1, and perhaps carnitine deficiency. CONCLUSION: Although the NBS-identified and clinically-identified cohorts were not completely comparable, this long-term study shows likely substantial improvement overall in the outcome of these metabolic disorders in the NBS infants. Infants with mild disorders and benign variants may represent a significant number of infants identified by ENBS. The future challenge will be to unequivocally differentiate the disorders most benefitting from ENBS and adjust programs accordingly.

Recurrent unexplained hyperammonemia in an adolescent with arginase deficiency.

OBJECTIVES: This report investigates the etiology of recurrent episodic elevations in plasma ammonia in an adolescent male with arginase deficiency as there were concerns regarding pre-analytical and analytical perturbations of ammonia measurements. There were repeated discrepancies between the magnitude of his ammonia levels and the severity of his clinical signs of hyperammonemia. PATIENT AND METHODS: The patient is a fourteen-year-old arginase-deficient male diagnosed at three years of age. Since 2008 (when he reached 10 years of age), there appeared to be an increase in the frequency of hospitalizations with elevated ammonia. A typical emergency visit with initial ammonia of 105 µmol/L (reference interval: 16-47 µmol/L) is illustrated. Pre-analytical and analytical procedures for the patient's sample handling were retrospectively examined. His ammonia levels were compiled since diagnosis. The frequency of his initial or peak ammonia levels greater than two times (94 µmol/L) or four times (188 µmol/L) the upper limit of normal was computed. Student t-test was used to calculate the significance of the differences before 2008 and since 2008. RESULTS: One out of eleven and ten out of 19 hospitalizations had initial ammonia greater than two times normal before and after 2008, respectively. Both the patient's overall ammonia and peak ammonia levels are significantly higher since 2008 (p value <0.001 for both) than those before 2008. CONCLUSIONS: To our knowledge, few adolescent males with arginase deficiency experience recurrent episodes of hyperammonemia requiring intravenous nitrogen scavenging agents. We hope that this study provides new insights into the natural history of arginase deficiency and the management of such patients.

Pediatric Neurologic Complications Associated With Influenza A H1N1.

Influenza is associated with a variety of neurologic complications. Although the epidemiologic and clinical characteristics of influenza A H1N1 were reviewed in depth, only brief descriptions of neurologic complications exist. We describe the neurologic complications of children hospitalized with influenza A H1N1 infection. We undertook a retrospective study of all hospitalized children with laboratory-confirmed influenza A H1N1 infection accompanied by neurologic complications during a 4-month winter period. Their demographics and clinical characteristics of neurologic presentations were reviewed. Fourteen of 74 children (19%) with laboratory-confirmed influenza A H1N1 infection presented with neurologic complications. Eleven (11/14, 79%) were previously healthy, and three exhibited chronic conditions. Ten (10/14, 71%) presented with seizures: six were febrile, and four were nonfebrile. Other complications included transverse myelitis, myositis, expressive aphasia, and syncope. Only the child with transverse myelitis required a course of rehabilitation. Neurologic complications associated with influenza A H1N1 in our patients were relatively mild. Seizures (febrile or nonfebrile) were the most common. However, the possibility of influenza A H1N1 infection should be borne in mind when diagnosing children with neurologic signs during the influenza A H1N1 season.

Management of children with nonfebrile seizures in the emergency department.

BACKGROUND: Children with seizures are often referred to the emergency department where they are typically evaluated by a physician with limited knowledge of pediatric epileptology and undergo a costly and extensive work-up that contributes little to the final decision. AIM: The aim of this study was to examine the medical management of children with nonfebrile seizures in the emergency department and to define the potential role of the neurology clinic in this context. MATERIALS AND METHODS: The files of 85 children who made 104 visits to the emergency department of a pediatric tertiary hospital for nonfebrile seizures were retrospectively reviewed. RESULTS: Average age was 7.5 years. Blood tests were performed in almost all visits; a minority also involved the use of brain scans and electroencephalography. A neurologist was consulted in about half the visits. Only electroencephalography and neurologic consultation contributed significantly to the final decision. Hospitalization was recommended in 71% of cases, but it was usually short term and not accompanied by significant changes in the management. CONCLUSION: In children with nonfebrile seizures, a problem-oriented approach including only the necessary work-up (e.g. electroencephalography) with neurologist consultation can potentially decrease the inpatient load and lower health care costs, while sparing patients unnecessary tests.

Acute motor axonal neuropathy--an atypical presentation.

Guillain-Barré syndrome, an autoimmune disorder of the peripheral nervous system, is divided into several subtypes according to clinico-pathologic findings and epidemiologic characteristics. A pure motor variant without involvement of the sensory nerves has been reported in rare cases. This report details the clinical, immunologic, and serial electrophysiologic findings of two patients with an acute, exclusively motor, axonal neuropathy.