D-mannose as a new therapy for fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG).

INTRODUCTION: Fucokinase deficiency-related congenital disorder of glycosylation (FCSK-CDG) is a rare autosomal recessive inborn error of metabolism characterized by a decreased flux through the salvage pathway of GDP-fucose biosynthesis due to a block in the recycling of L-fucose that exits the lysosome. FCSK-CDG has been described in 5 individuals to date in the medical literature, with a phenotype comprising global developmental delays/intellectual disability, hypotonia, abnormal myelination, posterior ocular disease, growth and feeding failure, immune deficiency, and chronic diarrhea, without clear therapeutic recommendations. PATIENT AND METHODS: In a so far unreported FCSK-CDG patient, we studied proteomics and glycoproteomics in vitro in patient-derived fibroblasts and also performed in vivo glycomics, before and after treatment with either D-Mannose or L-Fucose. RESULTS: We observed a marked increase in fucosylation after D-mannose supplementation in fibroblasts compared to treatment with L-Fucose. The patient was then treated with D-mannose at 850 mg/kg/d, with resolution of the chronic diarrhea, resolution of oral aversion, improved weight gain, and observed developmental gains. Serum N-glycan profiles showed an improvement in the abundance of fucosylated glycans after treatment. No treatment-attributed adverse effects were observed. CONCLUSION: D-mannose is a promising new treatment for FCSK-CDG.

S-adenosylmethionine and nicotinamide riboside therapy in Arts syndrome: A case report and literature review.

Phospho-ribosyl-pyrophosphate synthetase 1 (PRPS1) deficiency is secondary to loss of function variants in PRPS1. This enzyme generates phospho-ribosyl-pyrophosphate (PRPP), which is utilized in the synthesis of purines, nicotinamide adenine dinucleotide (NAD), and NAD phosphate (NADP), among other metabolic pathways. Arts syndrome, or severe PRPS1 deficiency, is an X-linked condition characterized by congenital sensorineural hearing loss, optic atrophy, developmental delays, ataxia, hypotonia, and recurrent infections that can cause progressive clinical decline, often resulting in death before 5 years of age. Supplementation of the purine and NAD pathways outside of PRPP-dependent reactions is a logical approach and has been reported in a handful of patients, two with S-adenosylmethionine (SAMe) and one with SAMe and nicotinamide riboside (NR). We present the clinical course of a fourth Arts syndrome patient who was started on therapy and review previously reported patients. All patients had stability or improvement of symptoms, suggesting that SAMe and NR can be a treatment option in Arts syndrome, though further studies are warranted.

Treatment and outcomes of symptomatic hyperammonemia following asparaginase therapy in children with acute lymphoblastic leukemia.

Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.

Infantile-onset Pompe disease complicated by sickle cell anemia: Case report and management considerations.

Infantile-onset Pompe disease (IOPD) is a rare, severe disorder of lysosomal storage of glycogen that leads to progressive cardiac and skeletal myopathy. IOPD is a fatal disease in childhood unless treated with enzyme replacement therapy (ERT) from an early age. Sickle cell anemia (SCA) is a relatively common hemoglobinopathy caused by a specific variant in the hemoglobin beta-chain. Here we report a case of a male newborn of African ancestry diagnosed and treated for IOPD and SCA. Molecular testing confirmed two GAA variants, NM_000152.5: c.842G>C, p.(Arg281Pro) and NM_000152.5: c.2560C>T, p.(Arg854*) in trans, and homozygosity for the HBB variant causative of SCA, consistent with his diagnosis. An acute neonatal presentation of hypotonia and cardiomyopathy required ERT with alglucosidase alfa infusions preceded by immune tolerance induction (ITI), as well as chronic red blood cell transfusions and penicillin V potassium prophylaxis for treatment of IOPD and SCA. Clinical course was further complicated by multiple respiratory infections. We review the current guidelines and interventions taken to optimize his care and the pitfalls of those guidelines when treating patients with concomitant conditions. To the best of our knowledge, no other case reports of the concomitance of these two disorders was found. This report emphasizes the importance of newborn screening, early intervention, and treatment considerations for this complex patient presentation of IOPD and SCA.

Outpatient Primary Care Genetic Testing Primer: What to Order and Testing Considerations.

The field of genetics has evolved rapidly over the last few decades, from testing methods to genetic diagnoses, bringing new genetic testing guidelines and considerations for health care providers. Overall geneticists are limited in number and availability, particularly in non-academic settings, and many patients first present to a primary care provider. Here, we aim to review various modalities of genetic testing, their indications, limitations, and other pretest considerations for the primary care provider. In addition, we comment on the limitations of direct-to-consumer (DTC) genetic testing, which has seen a rise in popularity among the general population.

Case Report: A Novel EIF2B3 Pathogenic Variant in Central Nervous System Hypomyelination/Vanishing White Matter.

Leukodystrophies are a group of heterogeneous disorders affecting brain myelin. Among those, childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM) is one of the more common inherited leukodystrophies. Pathogenic variants in one of the genes encoding five subunits of EIF2B are associated with CACH/VWM. Herein, we presented a case of CACH/VWM who developed ataxia following a minor head injury. Brain magnetic resonance imaging showed extensive white matter signal abnormality. Diagnosis of CACH/VWM was confirmed by the presence of compound heterozygous variants in EIF2B3: the previously known pathogenic variant c c.260C>T (p.Ala87Val) and the novel variant c.673C>T (p.Arg225Trp). Based on the American College of Medical Genetics (ACMG) recommendations, we classified p.Arg225Trp as likely pathogenic. We report a novel variant in a patient with CACH/VWM and highlight the importance of genetic testing in patients with leukodystrophies.

Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.