Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

A Methionine-Portioning-Based Medical Nutrition Therapy with Relaxed Fruit and Vegetable Consumption in Patients with Pyridoxine-Nonresponsive Cystathionine-ß-Synthase Deficiency.

The main treatment for pyridoxine-nonresponsive cystathionine-ß-synthase deficiency is a strict diet. Most centers prescribe low-protein diets based on gram-protein exchanges, and all protein sources are weighed. The purpose of this study is to investigate the effects of a more liberal methionine (Met)-based diet with relaxed consumption of fruits and vegetables on metabolic outcomes and dietary adherence. Ten patients previously on a low-protein diet based on a gram-protein exchange list were enrolled. The natural protein exchange lists were switched to a "Met portion exchange list". Foods containing less than 0.005 g methionine per 100 g of the food were accepted as exchange-free foods. The switch to Met portioning had no adverse effects on the control of plasma homocysteine levels in terms of metabolic outcomes. It resulted in a significant reduction in patients' daily betaine dose. All patients preferred to continue with this modality. In conclusion, methionine-portion-based medical nutrition therapy with relaxed consumption of fruits and vegetables seems to be a good and safe option to achieve good metabolic outcomes and high treatment adherence.

Ocular manifestations in classic homocystinuria.

BACKGROUND: Classic homocystinuria (HCU), or cystathionine beta-synthase (CBS) deficiency, is a rare inborn error of methionine metabolism. Main clinical features may include skeletal and vascular manifestations, developmental delay, intellectual disability and eye disorders. MATERIAL AND METHODS: This is an observational and retrospective study aiming at describing eye abnormalities presented by a cohort of late-diagnosed HCU patients. Data regarding ophthalmological evaluation included visual acuity, refraction, biomicroscopy, Perkins tonometry, fundus examination, retinography, biometry, ocular ultrasound, optical coherence tomography, anterior segment photography and topography. RESULTS: Ten patients with HCU (20 eyes) were included. The most frequent findings were ectopia lentis(n = 20) and myopia (n = 9). Biometry, ultrasound, OCT and topography findings were available for four patients. One patient had keratoconus; one had abnormal retinal pigmentation; and two had lens surgery scars with irregular astigmatism. CONCLUSIONS: Eye abnormalities are very frequent in late-diagnosed HCU patients. The presence of ectopia lentis should always raise the diagnostic hypothesis of HCU.

Proteomic exploration of cystathionine ß-synthase deficiency: implications for the clinic.

Introduction: Homocystinuria due to cystathionine ß-synthase (CBS) deficiency, the most frequent inborn error of sulfur amino acid metabolism, is characterized biochemically by severely elevated homocysteine (Hcy) and related metabolites, such as Hcy-thiolactone and N-Hcy-protein. CBS deficiency reduces life span and causes pathological abnormalities affecting most organ systems in the human body, including the cardiovascular (thrombosis, stroke), skeletal/connective tissue (osteoporosis, thin/non-elastic skin, thin hair), and central nervous systems (mental retardation, seizures), as well as the liver (fatty changes), and the eye (ectopia lentis, myopia). Molecular basis of these abnormalities were largely unknown and available treatments remain ineffective. Areas covered: Proteomic and transcriptomic studies over the past decade or so, have significantly contributed to our understanding of mechanisms by which the CBS enzyme deficiency leads to clinical manifestations associated with it. Expert opinion: Recent findings, discussed in this review, highlight the involvement of dysregulated proteostasis in pathologies associated with CBS deficiency, including thromboembolism, stroke, neurologic impairment, connective tissue/collagen abnormalities, hair defects, and hepatic toxicity. To ameliorate these pathologies, pharmacological, enzyme replacement, and gene transfer therapies are being developed.

Cystathionine beta synthase deficiency and brain edema associated with methionine excess under betaine supplementation: Four new cases and a review of the evidence.

CBS deficient individuals undergoing betaine supplementation without sufficient dietary methionine restriction can develop severe hypermethioninemia and brain edema. Brain edema has also been observed in individuals with severe hypermethioninemia without concomitant betaine supplementation. We systematically evaluated reports from 11 published and 4 unpublished patients with CBS deficiency and from additional four cases of encephalopathy in association with elevated methionine. We conclude that, while betaine supplementation does greatly exacerbate methionine accumulation, the primary agent causing brain edema is methionine rather than betaine. Clinical signs of increased intracranial pressure have not been seen in patients with plasma methionine levels below 559 µmol/L but occurred in one patient whose levels did not knowingly exceed 972 µmol/L at the time of manifestation. While levels below 500 µmol/L can be deemed safe it appears that brain edema can develop with plasma methionine levels close to 1000 µmol/L. Patients with CBS deficiency on betaine supplementation need to be regularly monitored for concordance with their dietary plan and for plasma methionine concentrations. Recurrent methionine levels above 500 µmol/L should alert clinicians to check for clinical signs and symptoms of brain edema and review dietary methionine intake. Levels approaching 1000 µmol/L do increase the risk of complications and levels exceeding 1000 µmol/L, despite best dietetic efforts, should be acutely addressed by reducing the prescribed betaine dose.

Is the gut microbiota dysbiotic in patients with classical homocystinuria?

Classical homocystinuria (HCU) is characterized by increased plasma levels of total homocysteine (tHcy) and methionine (Met). Treatment may involve supplementation of B vitamins and essential amino acids, as well as restricted Met intake. Dysbiosis has been described in some inborn errors of metabolism, but has not been investigated in HCU. The aim of this study was to investigate the gut microbiota of HCU patients on treatment. Six unrelated HCU patients (males = 5, median age = 25.5 years) and six age-and-sex-matched healthy controls (males = 5, median age = 24.5 years) had their fecal microbiota characterized through partial 16S rRNA gene sequencing. Fecal pH, a 3-day dietary record, medical history, and current medications were recorded for both groups. All patients were nonresponsive to pyridoxine and were on a Met-restricted diet and presented with high tHcy. Oral supplementation of folate (n = 6) and pyridoxine (n = 5), oral intake of betaine (n = 4), and IM vitamin B12 supplementation (n = 4), were reported only in the HCU group. Patients had decreased daily intake of fat, cholesterol, vitamin D, and selenium compared to controls (p < 0.05). There was no difference in alpha and beta diversity between the groups. HCU patients had overrepresentation of the Eubacterium coprostanoligenes group and underrepresentation of the Alistipes, Family XIII UCG-001, and Parabacteroidetes genera. HCU patients and controls had similar gut microbiota diversity, despite differential abundance of some bacterial genera. Diet, betaine, vitamin B supplementation, and host genetics may contribute to these differences in microbial ecology.

The psychopharmacology of Wilson disease and other metabolic disorders.

Wilson disease (WD) is a hereditary metabolic disorder (HMD) caused by a mutation in the copper-transporting gene ATP7B affecting the liver and central nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and management can be difficult. More generally, HMDs are a rare but important cause of psychiatric disorders in adolescents and adults. Main signs of HMDs may remain isolated for years before the appearance of hepatic or neurologic signs. The incidence of HMDs has been estimated at approximately 40 cases per 100,000 live births. Some of them are treatable and new diagnostic methods and therapies have become available. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists and neurologists. However, it is important to identify HMDs in order to provide disease-specific treatment and possible prevention of irreversible physical and neurologic complications. Genetic counseling can also be provided. Psychotropic medications should be prescribed carefully in that indication. This chapter focuses on three HMD categories: chronic, treatable HMDs (e.g., WD); acute, treatable HMDs; and chronic HMDs that are difficult to treat. In this review we focus on the psychopharmacology of WD and other chronic and difficult-to-treat HMDs. We provide some keys to take into account the main side effects associated with common psychotropic medications.

Hypermethioninemia in Campania: Results from 10 years of newborn screening.

In the last years tandem mass spectrometry (MS/MS) has become a leading technology used for neonatal screening purposes. Newborn screening by MS/MS on dried blood spot samples (DBS) has one of its items in methionine levels: the knowledge of this parameter allows the identification of infant affected by homocystinuria (cystathionine ß-synthase, CBS, deficiency) but can also lead, as side effect, to identify cases of methionine adenosyltransferase (MAT) type I/III deficiency. We started an expanded newborn screening for inborn errors of metabolism in Campania region in 2007. Here we report our ten years experience on expanded newborn screening in identifying patients affected by hypermethioninemia. During this period we screened approximately 77,000 infants and identified two cases: one case of classical homocystinuria and one patient affected by defect of MAT I/III. In this paper we describe these patients and their biochemical follow-up and review the literature concerning worldwide newborn screening reports on incidence of CBS and MAT deficiency.

Feasibility of domino liver transplantation from hyperhomocsyteinemia.

Hyperhomocysteinemia, resulting from a cystathionine beta synthase (CBS) deficiency, is an autosomal recessive disease associated with high levels of homocysteine. Such patients can present with severe mental retardation, ectopia lentis and osteoporosis and thromboembolic disease. To the best of our knowledge, only two cases of liver transplantation for CBS deficiency have been published. Here, we report a case of an 8-year-old male with a CBS deficiency that underwent living donor liver transplantation. The postoperative course was uneventful and homocysteine levels remained normal. The liver of this CBS deficiency patient was then successfully used in domino transplantation. The domino liver transplantation recipient was a 41-year-old male diagnosed with acute liver failure following hemi-liver resection due to cholangiocarcinoma. The domino recipient developed acquired hyperhomocysteinemia, which was controlled with a special regimen of medications. No complications relative to CBS deficiency were observed up to 11 months post-transplant. At this time, the patient expired as a result of cholangiocarcinoma recurrence. In conclusion, our data suggest that liver transplantation for CBS deficiency can be effective, safe and beneficial. It is possible to be both safe and beneficial to use a CBS deficiency patient as a domino donor for salvage liver transplantation in a selective category of recipients.

Diagnosis and Management of Classica Homocystinuria in Brazil: A Summary of 72 Late-Diagnosed Patients

Abstract This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 mmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis.