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Background Gyrate atrophy of the choroid and retina is a rare autosomal recessive metabolic disorder caused by biallelic variants in the OAT gene, encoding the enzyme ornithine δ-aminotransferase. Impaired enzymatic activity leads to systemic hyperornithinaemia, which in turn underlies progressive chorioretinal degeneration. In this study, we describe the clinical and molecular findings in a cohort of individuals with gyrate atrophy. Methods Study participants were recruited through a tertiary UK clinical ophthalmic genetic service. All cases had a biochemical and molecular diagnosis of gyrate atrophy. Retrospective phenotypic and biochemical data were collected using electronic healthcare records. Results 18 affected individuals from 12 families (8 male, 10 female) met the study inclusion criteria. The median age at diagnosis was 8 years (range 10 months – 33 years) and all cases had hyperornithinaemia (median: 800 micromoles/L; range: 458–1244 micromoles/L). Common features at presentation included high myopia (10/18) and nyctalopia (5/18). Ophthalmic findings were present in all study participants who were above the age of 6 years. One third of patients had co-existing macular oedema and two thirds developed pre-senile cataracts. Compliance with dietary modifications was suboptimal in most cases. A subset of participants had extraocular features including a trend towards reduced fat-free mass and developmental delay. Conclusions Our findings highlight the importance of multidisciplinary care in families with gyrate atrophy. Secondary ophthalmic complications such as macular oedema and cataract formation are common. Management of affected individuals remains challenging due to the highly restrictive nature of the recommended diet and the limited evidence-base for current strategies.

Glycogen storage disease 1b (GSD1b) typically presents in early infancy with poor fasting tolerance, hepatomegaly, and neutropenia. We report two siblings who were diagnosed with GSD1b in adulthood. Both had a normal fasting tolerance throughout childhood and, as adults, were able to fast for at least 16 h without developing hypoglycaemia. The older sibling developed nodular cirrhosis during adolescence. The younger sibling exhibited a more pronounced metabolic phenotype, including hyperuricaemia leading to recurrent gout and nephrolithiasis. He experienced occasional episodes of mild neutropenia that were corrected with empagliflozin treatment. To our knowledge, these represent the first reported patients with GSD1b presenting in adulthood with non‐hypoglycaemic complications of the disease and without overt neutropenia or neutrophil dysfunction. Highlights GSD1b usually presents in early childhood with hypoglycaemia, lactic acidosis, hepatomegaly and neutropenia. GSD1b patients can rarely withstand prolonged fasting periods without hypoglycaemic symptoms. The absence of these symptoms contributed to the late diagnosis in these two patients. Differing phenotypes and severity can be present even in the same underlying GSD1b genotype.

Ornithine transcarbamylase deficiency (OTCD) is the most common inherited disorder of the urea cycle and, in general, is transmitted as an X-linked recessive trait. Defects in the OTC gene cause an impairment in ureagenesis, resulting in hyperammonemia, which is a direct cause of brain damage and death. Patients with late-onset OTCD can develop symptoms from infancy to later childhood, adolescence or adulthood. Clinical manifestations of adults with OTCD vary in acuity. Clinical symptoms can be aggravated by metabolic stressors or the presence of a catabolic state, or due to increased demands upon the urea. A prompt diagnosis and relevant biochemical and genetic investigations allow the rapid introduction of the right treatment and prevent long-term complications and mortality. This narrative review outlines challenges in diagnosing and managing patients with late-onset OTCD.

Background The clinical presentation of ARG1‐D is characterised by elevated arginine levels leading to neurological and mobility impairments. Information about long‐term outcomes in adults is lacking, which prompted us to undertake a retrospective observational study. Methods We extracted ARG1‐D patient data spanning a 5‐year period from electronic health records. Ethical approval was not required for the study. Informed consent was obtained. Results We identified nine ARG1‐D patients from consanguineous backgrounds. Age of symptom onset ranged from infancy to age 7 years, age of diagnosis from infancy to 20 years. Patients had paraparesis or altered gait of varying degree and had experienced early ARG1‐D onset. Over 5 years, mobility declined in six (6/9, 67%) patients. Three patients (3/9, 33%) were fully dependent and hoisted. Two (2/9, 22%) reached adulthood before experiencing hyperammonaemia, another one (1/9, 11%) first experienced hyperammonaemia at age 15 years. One patient (1/9, 11%) started on ammonia scavenger therapy in adulthood, one (1/9, 11%) required a second scavenger to be added to their treatment regimen. Two patients (2/9, 22%) had gastrostomy tubes inserted for nutrition and supplements at age 9 years and 15 years. Six patients (6/9, 67%) had raised levels of ALT; of these, four (4/9, 44%) also had elevated AFP. Heterogeneity of ARG1‐D symptoms was evident, suggesting complex genetic and environmental interactions. Conclusion ARG1‐D presents significant lifelong challenges with deteriorating mobility and more frequent metabolic crises. Current management strategies are insufficient for preventing progression, highlighting the need for innovative treatments like enzyme replacement and gene therapy.

IntroductionGlycogen storage disease type III (GSD 3) is an inborn error of glycogen degradation caused by a deficiency of the glycogen debrancher enzyme. With improvements in medical care, patients are surviving longer into adulthood providing a better understanding of the condition’s long-term hepatic complications. Previous studies have demonstrated that individuals with GSD 3 are at risk of developing hepatocellular carcinoma (HCC). Our study is the first to assess HCC incidence in person-years at risk within the GSD 3 population.MethodsA retrospective analysis of clinical records was undertaken of all adult patients (alive and deceased) with GSD 3 at the Mark Holland Metabolic Unit, Salford Royal Hospital. Person-years at risk were calculated by measuring the time from age 18 years to one of the following outcomes: diagnosis of HCC, death, or end of follow-up (December 2024).ResultsA total of 19 patients with GSD 3 (58% male) were identified, with a median age of 33 years. The cohort had a median body mass index (BMI) of 31.9kg/m2 [IQR 25.6 – 40.8 kg/m2] and 47% had cirrhosis. 2 patients (11%) developed HCC. Both patients were male and aged 29 and 49 years at the time of diagnosis. Both had Child-Pugh A cirrhosis and were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stage A (early stage) HCC managed with curative intent. Patient A (29 years) was initially treated with bridging trans-arterial chemoembolisation (TACE) with the intention to proceed to liver transplantation. However, he was later de-listed due to a rise in alpha-fetoprotein and instead, underwent surgical resection. Patient B (49 years) was managed directly with surgical resection. Both patients died due to complications of HCC recurrence and survived 49 and 48 months from diagnosis. A total of 330 person-years at risk were accumulated during the follow-up period providing an HCC incidence of 6.06 per 1,000 person-years at risk. Among GSD 3 patients with cirrhosis, the HCC incidence was 9.57 per 1,000 person-years at risk.ConclusionsOur study was drawn from the cohort at one of the largest adult metabolic centres in Europe. The findings demonstrate that patients with GSD are at risk of developing HCC. The cohort exhibits high levels of obesity providing a metabolic risk factor for cirrhosis. Existing literature also implicates abnormal glycogen in the pathogenesis of cirrhosis in GSD 3. However, despite the potential combined effects of these factors, the observed HCC incidence in cirrhotic patients with GSD is similar to the rates reported in metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis (10–15 per 1,000 patient-years). Given the rarity of GSD 3, larger multi-centre studies are essential to better understand and address the hepatic complications in this cohort.

There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.

Background: Special low-protein foods are essential in the dietary treatment of phenylketonuria (PKU). In the UK, these are available on prescription through the General Practitioners (GPs) and distributed via nutritional home delivery companies or pharmacies. Methods: A 58-item online non-validated semi-structured questionnaire was emailed to British Inherited Metabolic Disease Group (BIMDG) dietitians and dietetic support workers (DSW)/administrators working in PKU to ascertain the main system issues and errors with the supply of low-protein prescription foods (LPPF). Results: 73% (n = 53/73) of dietitians and 72% (n = 18/25) of DSW/administrators responded. A total of 80 questionnaires (representing 44 paediatric and 36 adult PKU centres) were completed. A total of 50% (n = 40/80) of respondents reported patient/caregiver problems accessing LPPF at least weekly. The most common problems were unavailable products (82%), missing LPPF in deliveries (79%), and delayed deliveries (66%). For 64% of respondents, >25% of their patients had recurring problems accessing LPPF, and 69% of respondents spent ≥1 h/week and 11% >5 h/week correcting LPPF patient supply issues. The most common foods patients experienced supply issues with were bread (96%), pasta/rice (41%) and milk replacements (35%). This was associated with GP prescription errors (65%), LPPF prescriptions sent to incorrect dispensers/suppliers (60%), and manufacturer supply issues (54%). Problems with patients/caregivers included not ordering LPPF in a timely way (81%), not responding to messages from home delivery companies (73%) and poor understanding of the ordering process (70%). The majority (93%) of respondents reported that prescription issues impacted their patients’ blood Phe control. Suggestions for improving access to LPPF included centralisation of the system to one supplier (76%) and apps for ordering LPPF (69%). Conclusions: The supply of LPPF for PKU in the UK is problematic; it may adversely affect the ability of patients to adhere to dietary management, and a review investigating patient access to LPPF is urgently required.

Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England (n = 142) were examined. Their costs in comparison to regular protein-containing (n = 182) and ‘free-from’ products (n = 135) were also analysed. Similar foods were grouped into subgroups (n = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups (n = 39/40) were more expensive than regular and ‘free-from’ food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control.

Background/Objectives: In phenylketonuria (PKU), high blood phenylalanine (Phe) levels during pregnancy negatively influence foetal organogenesis and growth, leading to maternal PKU syndrome. Pregnancies must be carefully planned in order to maintain blood Phe levels ≤ 360 µmol/L pre-conception and throughout pregnancy. Our aim was to study metabolic control in PKU pregnancies across Europe. Methods: Eleven centres managing PKU participated. Data on blood Phe levels (µmol/L), natural protein intake (g/day), protein substitute intake (g/day) and maternal weight (kg) during pregnancy were collected retrospectively from dietetic records between 2012 and 2018. Results: In total, 84 female patients with PKU, accounting for 102 pregnancies (mean age: 30.4 ± 4.8 years), participated. Of these, 7 had hyperphenylalaninemia (HPA), 26 had mild PKU, 55 had classical PKU and 14 were unclassified. Sapropterin was prescribed in two pregnancies. Only 27% (28/102) of pregnancies successfully achieved consistent blood Phe levels ≤ 360 µmol/L for at least 2 weeks pre-conception. During pregnancy, 88% of blood Phe levels were ≤360 µmol/L, with a mean Phe of 229 ± 65 µmol/L. The mean number of blood Phe samples was 60 (1.5 per week) per pregnancy. In pre-pregnancy, over a mean of 2.9 years, only 35% of blood Phe levels were ≤360 µmol/L and 61% were <600 µmol/L. Post-pregnancy, over a mean of 2.8 years, 43% of Phe levels were <600 µmol/L with mean Phe 462 ± 226 µmol/L and 724 ± 230 µmol/L, respectively. 25% (25/102) had no levels performed post-pregnancy (mean of 2.8 ± 1.6 years) compared to 7% (7/102) pre-pregnancy (mean of 2.9 ± 1.5 years). Mean prescribed Phe intake pre-/during/post-pregnancy was 810 ± 721 vs. 787 ± 552 vs. 1110 ± 722 mg/day. Natural protein intake was 17 ± 15 vs. 17 ± 11 vs. 23 ± 15 g/day. Protein equivalent from protein substitute intake was 57 ± 21 vs. 66 ± 16 vs. 50 ± 23 g/day and total protein remained stable, 73 ± 14 vs. 83 ± 14 vs. 71 ± 19 g/day (1.1 ± 0.3 vs. 1.1 ± 0.4 vs. 1.0 ± 0.4 g/kg/day). Conclusions: Although a high level of metabolic control was maintained during pregnancy, fewer than 30% of pregnancies achieved constant Phe levels ≤ 360 µmol/L prior to conception, with minimal monitoring post-pregnancy. The long-term impact on the offspring remains unknown and requires further investigation.

Background: Metabolic control in phenylketonuria (PKU) is known to deteriorate with age, but national-level data describing blood phenylalanine (Phe) control across the United Kingdom (UK) are limited. Objective: To characterise blood Phe control in individuals with PKU attending UK metabolic centres. Methods: Sixteen UK centres (nine paediatric, six adult, one mixed) retrospectively extracted blood Phe results collected between 2012 and 2018. Demographic, phenotypic and monitoring-related variables were analysed. Written consent for data collection was obtained from all patients or their caregivers. Results: Data were available for 871 individuals (55% female), of whom 744 (85%) were classified as follows: classical PKU, 75%, mild PKU, 22% and hyperphenylalaninaemia, 3%. Mean blood Phe concentrations were significantly higher in adults than children (491 ± 308 vs. 303 ± 199 µmol/L; p < 0.001), and the proportion of samples within target range declined steadily with age, from 78% in children < 2 years to 36% in adults ≥ 41 years. Individuals with classical PKU had higher mean Phe concentrations and lower target attainment than those with HPA (386 vs. 300 µmol/L; 61% vs. 78%; p < 0.001), while mild PKU and HPA showed comparable control. Females generally demonstrated better metabolic control than males. More frequent dried blood spot sampling for blood Phe was strongly associated with improved metabolic control: weekly (254 ± 175 µmol/L; 82% within target), fortnightly (319 ± 207 µmol/L; 70%), monthly (397 ± 231 µmol/L; 61%), and less than monthly (624 ± 349 µmol/L; 44%). Nearly half of the blood Phe samples (47%) with recorded timing were taken in a non-fasting state. Conclusions: Achieving lifelong metabolic stability on a Phe-restricted diet alone remains challenging. These national data highlight the need for broader therapeutic options to support individuals with PKU across the lifespan.