Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge.

Organic Aciduria Disorders in Pregnancy: An Overview of Metabolic Considerations.

Organic acidurias are a heterogeneous group of rare inherited metabolic disorders (IMDs) caused by a deficiency of an enzyme or a transport protein involved in the intermediary metabolic pathways. These enzymatic defects lead to an accumulation of organic acids in different tissues and their subsequent excretion in urine. Organic acidurias include maple syrup urine disease, propionic aciduria, methylmalonic aciduria, isovaleric aciduria, and glutaric aciduria type 1.

The hypergonadotropic hypogonadism conundrum of classic galactosemia.

Background: Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur.

Determination of the lactose and galactose content of common foods: Relevance to galactosemia.

Classical galactosemia (CG) is a disorder of galactose metabolism which results from deficiency of the enzyme galactose-1-phosphate uridylyl transferase (GALT). Treatment consists of immediately eliminating galactose from the diet in the new-born and lifelong restriction of dietary galactose. The inclusion of a wider variety of foods for people with CG may provide many benefits, including improved nutritional adequacy and quality of life.

Glutaric aciduria type 1: Diagnosis, clinical features and long-term outcome in a large cohort of 34 Irish patients.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder that can lead to encephalopathic crises and severe dystonic movement disorders. Adherence to strict dietary restriction, in particular a diet low in lysine, carnitine supplementation and emergency treatment in pre-symptomatic patients diagnosed by high-risk screen (HRS) or newborn screen (NBS) leads to a favourable outcome. We present biochemical and clinical characteristics and long-term outcome data of 34 Irish patients with GA1 aged 1-40 years.

Management of pregnancy in a patient with long-chain 3-hydroxyacyl CoA dehydrogenase deficiency.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare mitochondrial defect of β-oxidation of long-chain fatty acids. Patients may present with muscle pain, hypotonia, peripheral neuropathy, cardiomyopathy, recurrent rhabdomyolysis and sudden death. Dietary management of LCHADD aims at preventing prolonged fasting and decreasing energy production from long-chain fatty acids compensated by an increase in medium-chain triglyceride fat.

Late-onset ornithine transcarbamylase deficiency mimicking a focal opercular syndrome.

A previously healthy 27-year-old man was brought to hospital after been found late at night confused, agitated and talking incoherently. He represented 12 days later with focal seizures, progressing to anarthria and encephalopathy. MR scan of brain showed diffuse cerebral oedema and his plasma ammonia was >2000 µmol/L (12-55 µmol/L).

Impact of trimethylaminuria on daily psychosocial functioning.

Background: Trimethylaminuria (TMAU) (OMIM #602079) is a rare inherited metabolic condition. TMAU is associated with decreased hepatic trimethylamine N-oxidation, which leads to an excess of the volatile trimethylamine (TMA) instead of substrate conversion to trimethylamine N-oxide (TMAO). TMA is a tertiary amine derived from the enterobacterial metabolism of precursors such as choline and phosphatidylcholine present in the diet, and is also a bacterial metabolite of TMAO, a normal constituent of saltwater fish.

Rare Disease Research Partnership (RAinDRoP): a collaborative approach to identify research priorities for rare diseases in Ireland.

Rare diseases are individually rare, but collectively these conditions are common. Research on rare diseases are currently focused on disease-specific needs rather than a life-course perspective. The Rare Disease Research Partnership (RAinDRoP) was established in 2018 to bring together a wide variety of diverse voices in the rare disease community in Ireland and form a research partnership.

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland.

Since 1972, 18 patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal-onset maple syrup urine disease (MSUD) in Ireland. Patients were stratified into three clusters according to clinical outcome at the time of data collection, including developmental, clinical, and IQ data. A fourth cluster comprised of two early childhood deaths; a third patient died as an adult.

A retrospective review of the contribution of rare diseases to paediatric mortality in Ireland.

Aims: To ascertain the number of paediatric deaths (0-14 years) with an underlying rare disease in the Republic of Ireland between the years 2006-2016, and to analyse bed usage by a paediatric cohort of rare disease inpatients prior to in-hospital death.

Background: Rare diseases are often chronically debilitating and sometimes life-threatening diseases, with the majority (69.9%) of rare diseases being of paediatric onset.

Galactokinase deficiency: lessons from the GalNet registry.

Purpose: Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype.

The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes.

Background: The high variability in clinical outcome of patients with Classical Galactosemia (CG) is poorly understood and underlines the importance of prognostic biomarkers, which are currently lacking. The aim of this study was to investigate if residual galactose metabolism capacity is associated with clinical and biochemical outcomes in CG patients with varying geno- and phenotypes.

Methods: Galactose Metabolite Profiling (GMP) was used to determine residual galactose metabolism in fibroblasts of CG patients.

The role of primary care in management of rare diseases in Ireland.

Background: 'Slaintecare' aims to address complex patient care needs in an integrated fashion with an emphasis on patient-centred, patient-empowered community care.Currently there is a lack of knowledge of the impact of rare disease management in primary care and of the information tools required by general practitioners to deliver integrated care for rare disease patients.

Aims: To complete a pilot survey to estimate the general practice clinical workload attributable to selected rare diseases and assess the use of relevant information sources.

Insights into the Pathophysiology of Infertility in Females with Classical Galactosaemia.

Classical galactosaemia (CG) (OMIM 230400) is a rare inborn error of galactose metabolism caused by the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT, EC 2.7.7.

The genetic and biochemical basis of trimethylaminuria in an Irish cohort.

Background: Inherited trimethylaminuria (TMAU), a rare genetic disorder of hepatic metabolism of trimethylamine (TMA) causing excessive accumulation of malodorous trimethylamine (TMA), is a socially distressing disorder. Diagnosis is made by biochemical analysis of urine, with the calculation of flavin monooxygenase trimethylamine conversion capacity. Genetic testing, sequencing the entire coding region of the gene has been recommended for affected individuals who convert less than 90% of the total TMA load to TMAO.

Ten-year retrospective review (2003-2013) of 56 inpatient admissions to stabilize elevated phenylalanine levels.

Phenylketonuria (PKU) is an inherited metabolic disorder affecting phenylalanine metabolism. The Irish incidence is 1:4500. Currently, there are 500 patients under the care of the National Centre for Inherited Metabolic Disorders in Temple Street Children's University Hospital.

Long-term outcomes in a 25-year-old female affected with lipin-1 deficiency.

Lipin-1 is a phosphatidic acid phosphohydrolase (EC 3.1.3.

Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency.

The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans.

Challenges in diagnosing and managing adult patients with urea cycle disorders.

Urea cycle disorders (UCD) are a group of rare inherited metabolic conditions of amino acid catabolism caused by an enzyme deficiency within the hepatic ammonia detoxification pathway. The presentation of these disorders ranges from life-threatening intoxication in the neonate to asymptomatic status in adults. Late-onset UCDs can present for the first time in adulthood and may mimic other causes of acute confusion or psychiatric diseases, and are often associated with neurological symptoms.

Fertility in classical galactosaemia, a study of N-glycan, hormonal and inflammatory gene interactions.

Background: Classical Galactosaemia (CG) (OMIM #230400) is a rare inborn error of galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). Long-term complications persist in treated patients despite dietary galactose restriction with significant variations in outcomes suggesting epigenetic glycosylation influences. Primary Ovarian Insufficiency (POI) is a very significant complication affecting females with follicular depletion noted in early life.

Profiling of intracellular metabolites produced from galactose and its potential for galactosemia research.

Background: Clinical outcome of patients with a classical presentation of galactosemia (classical patients) varies substantially, even between patients with the same genotype. With current biomarkers, it is not possible to predict clinical outcome early in life. The aim of this study was to develop a method to provide more insight into galactose metabolism, which allows quantitative assessment of residual galactose metabolism in galactosemia patients.