A Lithuanian Case of Tyrosinemia Type 1 with a Literature Review: A Rare Cause of Acute Liver Failure in Childhood.

Hereditary type 1 tyrosinemia (HT1) is a rare inherited autosomal recessive disorder of tyrosine metabolism, characterized by progressive liver damage, dysfunction of kidney tubules, and neurological crises. In the course of this disease, due to the deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), toxic intermediate metabolites of tyrosine breakdown, such as fumarylacetoacetate (FAA), succinylacetoacetate (SAA), and succinylacetone (SA), accumulate in liver and kidney cells, causing cellular damage. Because of this, an increased SA concentration in the blood or urine is pathognomonic of HT1. In the year 2000, HT1 was diagnosed in Lithuania for the first time, and this was the first time when a specific treatment for HT1 was administered in the country. Over two decades, four cases of this disease have been diagnosed in Lithuania. In the first of these patients, the disease was diagnosed in infancy, manifesting as liver damage with liver failure. Treatment with nitisinone was initiated, which continues to be administered, maintaining normal liver function. Liver transplantation was performed on two subsequent patients due to complications of HT1. It is crucial to diagnose HT1 as early as possible in order to reduce or completely eliminate complications related to the disease, including progressive liver failure and kidney dysfunction, among others. This can only be achieved by conducting a universal newborn screening for tyrosinemia and by starting treatment with nitisinone (NTBC) before the age of 1 month in all cases of HT1. However, in those countries where this screening is not being carried out, physicians must be aware of and consider this highly rare disorder. They should be vigilant, paying attention to even minimal changes in a few specific laboratory test results-such as unexplained anemia alongside neutropenia and thrombocytopenia-and should conduct more detailed examinations to determine the causes of these changes. In this article, we present the latest clinical case of HT1 in Lithuania, diagnosed at the Children's Diseases' Clinic of the Lithuanian University of Health Sciences (LUHS) Hospital Kaunas Clinics. The case manifested as life-threatening acute liver failure in early childhood. This article explores and discusses the peculiarities of diagnosing this condition in the absence of universal newborn screening for tyrosinemia in the country, as well as the course, treatment, and ongoing monitoring of patients with this disorder.

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1.

Dried blood spot succinylacetone (SA) is often used as a biomarker for newborn screening (NBS) for tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D. We reevaluated/measured uOA (GC-MS) and/or Q-uMA (LC-MS/MS) in available urine samples of nine referred newborns (2 TT1, 7 false-positive), eight genetically confirmed MAAI-D children, and 66 controls. Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three available samples of confirmed MAAI-D children, but not in TT1 patients. Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n = 66) and from 0.95 to 192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n = 10). MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the two newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA. Our study shows that MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1.

[Clinical features and genetic analysis of a child with acute form of Tyrosinemia type I due to a novel variant of FAH gene].

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a child with acute form of tyrosinemia type I (TYRSN1). METHODS: A child with TYRSN1 who presented at the Gansu Provincial Maternal and Child Health Care Hospital in October 2020 was selected as the subject. The child was subjected to tandem mass spectrometry (MS-MS) and urine gas chromatography-mass spectrometry (GC-MS) for the detection of inherited metabolic disorders, in addition with whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: The child's clinical features included abdominal distension, hepatomegaly, anemia and tendency of bleeding. By mass spectrometry analysis, her serum and urine tyrosine and succinylacetone levels have both exceeded the normal ranges. WES and Sanger sequencing revealed that she has harbored c.1062+5G>A and c.943T>C (p.Cys315Arg) compound heterozygous variants of the FAH gene, which were inherited from her father and mother, respectively. Among these, the c.943T>C was unreported previously. CONCLUSION: Considering her clinical phenotype and result of genetic testing, the child was diagnosed with TYRSN1 (acute type). The compound heterozygous variants of the FAH gene probably underlay the disease in this child. Above finding has further expanded the spectrum of FAH gene variants, and provided a basis for accurate treatment, genetic counseling and prenatal diagnosis for her family.

Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias.

Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.

Evaluation of dynamic thiol/disulfide homeostasis in hereditary tyrosinemia type 1 patients.

BACKGROUND: Despite successful treatment with nitisinone, the pathophysiology of long-term complications, including hepatocellular carcinoma and mental decline in tyrosinemia type 1 patients, is still obscure. Oxidative stress may play a role in these complications. While increased fumarylacetoacetate and maleylacetoacetate cause oxidative stress in the liver, increased tyrosine causes oxidative stress in the brain. The aim of this study is to evaluate dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed tyrosinemia type 1 patients. METHODS: Twenty-four late-diagnosed (age of diagnosis; 14.43 ± 26.35 months) tyrosinemia type 1 patients (19 under nitisinone treatment and 5 with liver transplantation) and 25 healthy subjects were enrolled in the study. Serum native thiol, total thiol, and disulfide levels were measured, and disulfide/native, disulfide/total, and native thiol/total thiol ratios were calculated from these values. RESULTS: No significant difference was observed in native, total, and disulfide thiol levels between the groups and no increase in disulfide/native, disulfide/total, and native/total thiol ratios was detected, despite significantly higher plasma tyrosine levels in the nitisinone-treated group. CONCLUSIONS: We suggest that providing sufficient metabolic control with good compliance to nitisinone treatment can help to prevent oxidative stress in late-diagnosed tyrosinemia type 1 patients. IMPACT: Despite successful nitisinone (NTBC) treatment, the underlying mechanisms of long-term complications in hereditary tyrosinemia type 1 (HT1), including hepatocellular carcinoma and mental decline, are still obscure. Oxidative stress may play a role in these complications. Thiol/disulfide homeostasis, which is an indicator of oxidative stress, is not disturbed in hereditary tyrosinemia patients under NTBC treatment, despite higher plasma tyrosine levels and patients who had liver transplantation. This is the first study evaluating dynamic thiol/disulfide homeostasis as an indicator of oxidative stress in late-diagnosed HT1 patients.

Hepatocellular carcinoma requiring liver transplantation in hereditary tyrosinemia type 1 despite nitisinone therapy and α1-fetoprotein normalization.

BACKGROUND: Hereditary tyrosinemia type 1 is a rare metabolic condition associated with an increased risk of hepatocellular carcinoma. Nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione, NTBC) treatment has reduced but not eliminated the risk. The delayed initiation of nitisinone treatment, and persistently abnormal α1-fetoprotein (AFP) levels are recognized to be risk factors for late-onset hepatocellular carcinoma. We report three children diagnosed and treated with nitisinone since infancy who developed hepatocellular carcinoma despite long-term normalization of AFP. METHODS: A retrospective review of all patients with tyrosinemia on nitisinone managed at our center was undertaken. Patient demographics, age at diagnosis, duration of therapy, timing of AFP normalization, and radiographic imaging findings were noted. RESULTS: Three patients at our center with tyrosinemia type 1 developed hepatocellular carcinoma 9-13 years after diagnosis despite long-term nitisinone therapy and normalization of AFP. Two patients developed new nodules on imaging with an elevation of AFP leading to the diagnosis and subsequent liver transplant. The third patient proceeded with liver transplant because of a very nodular liver and increasing splenomegaly despite normal AFP and no change in surveillance gadoxetate magnetic resonance imaging. Early hepatocellular carcinoma was found in her liver explant. All three patients were cirrhotic at diagnosis. CONCLUSIONS: Patients with hereditary tyrosinemia type 1, especially those already cirrhotic at diagnosis, remain at high risk of developing hepatocellular carcinoma despite long-term nitisinone therapy and AFP normalization, and warrant close monitoring and surveillance.

Hereditary tyrosinemia type â : newborn screening, diagnosis and treatment.

Hereditary tyrosinemia type Ⅰ (HT-1) is a severe autosomal recessive inherited metabolic disease. Due to the deficiency of fumarylacetoacetase hydrolase (FAH), the toxic metabolites are accumulated in the body, resulting in severe liver dysfunction, renal tubular dysfunctions, neurological crises, and the increased risk of hepatocellular carcinoma. Clinical symptoms typically begin at after the birth; the prognosis of patients is poor if they are not treated timely. Succinylacetone is a specific and sensitive marker for HT-1, and the screening in newborns can make early diagnosis of HT-1 at the asymptomatic stage. The diagnosis of HT-1 can be confirmed based on the characteristic biochemical findings and molecular testing of mutations in both alleles of gene. Combined treatment with nitisinone and a low tyrosine diet may significantly improve outcomes for patients. Liver transplantation is an effective treatment in cases where nitisinone is not available. Some novel HT-1 treatments are in clinical trials, including enzyme replacement therapy, hepatocyte transplantation and gene-targeted therapy.

Case report: Maternal tyrosinemia type 1a under NTBC treatment with tyrosine- and phenylalanine restricted diet in Chile.

We report the case of a 17-year-old girl with Tyrosinemia type 1a who carried a planned pregnancy to term while being under 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone) treatment and a tyrosine- and phenylalanine-restricted diet. She was on treatment since 2 months of age with poor metabolic control prior to her pregnancy (tyrosine 838 ± 106 umol/L). NTBC and a low tyrosine and phenylalanine diet were continued during her pregnancy. She unfortunately suffered from urinary tract infection and anemia during her pregnancy, with median plasma tyrosine and phenylalanine levels of 613 ± 106 umol/L (200-400 umol/L) and 40.2 ± 8 umol/L (35-90 umol/L), respectively. After 40 weeks of gestation, the patient gave birth to a healthy boy, with no adverse effects related to the use of NTBC. The newborn presented with a transitory elevation of plasma tyrosine levels and normal phenylalanine, methionine, and succinylacetone levels. By 12 months of age, the child was determined to have normal psychomotor development. At 20 months old, he was diagnosed with a mild developmental delay; however, global cognitive evaluation with the Wechsler Intelligence Scale for Children (WISC) test at 5 years old showed normal performance. Here, we discuss one of the few reported cases of nitisinone treatment during pregnancy and demonstrate a lack of teratogenicity and long-term cognitive disabilities.

Laboratory monitoring of patients with hereditary tyrosinemia type I.

BACKGROUND: The prognosis of patients with Hereditary Tyrosinemia Type 1 (HT-1) has greatly improved with early detection through newborn screening and the introduction of nitisinone (NTBC) therapy. A recent guideline calls for periodic monitoring of biochemical markers and NTBC levels to tailor treatment; however, this is currently only achieved through a combination of clinical laboratory tests. We developed a multiplexed assay measuring relevant amino acids, succinylacetone (SUAC), and NTBC in dried blood spots (DBS) to facilitate treatment monitoring. METHODS: Tyrosine, phenylalanine, methionine, NTBC and SUAC were eluted from DBS with methanol containing internal standards for each analyte and analyzed by liquid chromatography tandem mass spectrometry over 6.5 min in the multiple reaction monitoring positive mode. RESULTS: Pre-analytical and analytical factors were studied and demonstrated a reliable assay. Chromatography resolved an unknown substance that falsely elevates SUAC concentrations and was present in all samples. To establish control and disease ranges, the method was applied to DBS collected from controls (n = 284) and affected patients before (n = 2) and after initiation of treatment (n = 29). In the treated patients SUAC concentrations were within the normal range over a wide range of NTBC levels. CONCLUSIONS: This assay enables combined, accurate measurement of revelevant metabolites and NTBC in order to simplify treatment monitoring of patients with HT-1. In addition, the use of DBS allows for specimen collection at home to facilitate more standardization in relation to drug and dietary treatment.

[Screening for hereditary tyrosinemia and genotype analysis in newborns].

OBJECTIVE: To analyze the results of screening for hereditary tyrosinemia (HT) in newborns and its clinical features and genotype. METHODS: The HT screening was conducted among 2 188 784 newborns from November 2013 to November 2018. The tyrosine (TYR)/ succinylacetone (SA) levels were detected by tandem mass spectrometry (MS-MS). The clinical characteristics, genetic results and following up data of identified patients were analyzed. RESULTS: The normal ranges (0.5%-95.5%) of TYR and SA were 34.5-280.0 µmol/L and 0.16-2.58 µmol/L, respectively. Three HT cases were confirmed with a detection rate of 1∶729 595. There was 1 case of tyrosinemia type Ⅰ (HTⅠ) (homozygous variations of c.455G>A in FAH gene), 1 case of tyrosinemia type Ⅱ(HTⅡ) (heterozygous variations of c.890G>T and c.408+1G>A in TAT gene), and 1 case of tyrosinemia type Ⅲ (HT Ⅲ) (homozygous variations of c.257T>C in HPD gene). The variations of c.890G>T, c.4081G>A of TAT and c.257T>C of HPD were novel. The positive predictive value of the screening was 3.4%. Case 1 (HTⅠ) with TYR and SA values of 666.9 µmol/L and 3.87 µmol/L respectively, presented cholestasis, mild elevated of liver enzyme and lactic acid, who were although fed with TYR and phenylalanine free milk, but died at 2 months of age. Case 2 (HTⅡ) with higher TYR (625.6 µmol/L) and normal SA at screening, received medical milk treatment; during the 7 months of follow-up the baby showed normal score of Bayley assessment and normal TYR without eye and skin symptoms. Case 3 (HT Ⅲ) with TYR of 1035.3 µmol/L and normal SA at screening; during the 29 months of follow-up the value of TYR fluctuated from 532.1 µmol/L to 1060.3 µmol/L due to irregular medical milk treatment, while the score of Bayley assessment was normal. CONCLUSIONS: HT is rare in the southern Chinese population, and the gene spectrum is scattered. Early treatment with nitisinone is recommended in children with HTⅠ, otherwise the prognosis is poor; the prognosis of children with HTⅡ is good when early treated with special diet; the prognosis of children with HTⅢ needs to be determined with more data.

The somatic FAH C.1061C>A change counteracts the frequent FAH c.1062+5G>A mutation and permits U1snRNA-based splicing correction.

In tyrosinaemia type 1(HT1), a mosaic pattern of fumarylacetoacetase (FAH) immunopositive or immunonegative nodules in liver tissue has been reported in many patients. This aspect is generally explained by a spontaneous reversion of the mutation into a normal genotype. In one HT1 patient carrying the frequent FAH c.1062+5G>A mutation, a second somatic change (c.1061C>A) has been reported in the same allele, and found in immunopositive nodules. Here, we demonstrated that the c.1062+5G>A prevents usage of the exon 12 5' splice site (ss), even when forced by an engineered U1snRNA specifically designed on the FAH 5'ss to strengthen its recognition. Noticeably the new somatic c.1061C>A change, in linkage with the c.1062+5G>A mutation, partially rescues the defective 5'ss and is associated to trace level (~5%) of correct transcripts. Interestingly, this combined genetic condition strongly favored the rescue by the engineered U1snRNA, with correct transcripts reaching up to 60%. Altogether, these findings elucidate the molecular basis of HT1 caused by the frequent FAH c.1062+5G>A mutation, and demonstrate the compensatory effect of the c.1061C>A change in promoting exon definition, thus unraveling a rare mechanism leading to FAH immune-reactive mosaicism.

Markers of cognitive function in individuals with metabolic disease: Morquio syndrome and tyrosinemia type III.

We characterized cognitive function in two metabolic diseases. MPS-IVa (mucopolysaccharidosis IVa, Morquio) and tyrosinemia type III individuals were assessed using tasks of attention, language and oculomotor function. MPS-IVa individuals were slower in visual search, but the display size effects were normal, and slowing was not due to long reaction times (ruling out slow item processing or distraction). Maintaining gaze in an oculomotor task was difficult. Results implicated sustained attention and task initiation or response processing. Shifting attention, accumulating evidence and selecting targets were unaffected. Visual search was also slowed in tyrosinemia type III, and patterns in visual search and fixation tasks pointed to sustained attention impairments, although there were differences from MPS-IVa. Language was impaired in tyrosinemia type III but not MPS-IVa. Metabolic diseases produced selective cognitive effects. Our results, incorporating new methods for developmental data and model selection, illustrate how cognitive data can contribute to understanding function in biochemical brain systems.

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

INTRODUCTION: In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. METHODS: All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. RESULTS: NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 µmol/l. DISCUSSION: NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.

Experience of carrier couples identified through a population-based carrier screening pilot program for four founder autosomal recessive diseases in Saguenay-Lac-Saint-Jean.

A pilot population-based carrier screening program started in 2010 in the Saguenay-Lac-Saint-Jean region of Quebec, Canada, for four recessive diseases with local founder effects (tyrosinemia type I, autosomal recessive spastic ataxia of Charlevoix-Saguenay, congenital lactic acidosis, and Andermann syndrome). OBJECTIVES: The objective of this study was to describe the experience of carrier couples identified through this program. METHODS: Semi-structured interviews were performed with carrier couples. Thematic analysis of interview transcripts was performed to identify emerging themes. RESULTS: Interviews were performed with 15 carrier couples (56% response rate). Carrier couples had little knowledge about the target diseases before being identified as carriers, despite pre-test education sessions. The main motivation for screening was a recommendation by a peer who had been screened, even for those with a positive family history of one of the target conditions. Couples perceived themselves at low risk of being a carrier couple, whatever their family history. Being found to be a carrier couple was initially a shock, illustrating how ill prepared they were for such a result, but carrier couples appreciated knowing their status. CONCLUSION: Our results emphasize the informational needs of couples to make informed decisions and the importance of post-test counseling for those with positive results. Our findings can inform counseling procedures in expanded carrier screening. © 2017 John Wiley & Sons, Ltd.

Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.

Tyrosinemia type I (hepatorenal tyrosinemia, HT-1) is an autosomal recessive condition resulting in hepatic failure with comorbidities involving the renal and neurologic systems and long term risks for hepatocellular carcinoma. An effective medical treatment with 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC) exists but requires early identification of affected children for optimal long-term results. Newborn screening (NBS) utilizing blood succinylacetone as the NBS marker is superior to observing tyrosine levels as a way of identifying neonates with HT-1. If identified early and treated appropriately, the majority of affected infants can remain asymptomatic. A clinical management scheme is needed for infants with HT-1 identified by NBS or clinical symptoms. To this end, a group of 11 clinical practitioners, including eight biochemical genetics physicians, two metabolic dietitian nutritionists, and a clinical psychologist, from the United States and Canada, with experience in providing care for patients with HT-1, initiated an evidence- and consensus-based process to establish uniform recommendations for identification and treatment of HT-1. Recommendations were developed from a literature review, practitioner management survey, and nominal group process involving two face-to-face meetings. There was strong consensus in favor of NBS for HT-1, using blood succinylacetone as a marker, followed by diagnostic confirmation and early treatment with NTBC and diet. Consensus recommendations for both immediate and long-term clinical follow-up of positive diagnoses via both newborn screening and clinical symptomatic presentation are provided.

Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation.

BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.

Herpetiform keratitis and palmoplantar hyperkeratosis: warning signs for Richner-Hanhart syndrome.

Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.

High-protein goat's milk diet identified through newborn screening: clinical warning of a potentially dangerous dietetic practice.

OBJECTIVE: Breast-feeding is an unequalled way of providing optimal food for infants' healthy growth and development and the WHO recommends that infants should be exclusively breast-fed for the first 6 months of life. For mothers who are unable to breast-feed or who decide not to, infant formulas are the safest alternative. Despite recommendations, it is possible that parents make potentially harmful nutritional choices for their children because of cultural beliefs or misinformation on infant nutrition. We describe a possible health risk of not breast-feeding, highlighting a potentially dangerous dietetic practice. Design/Setting/Subjects We report the case of a newborn who was fed with undiluted goat's milk because her mother could not breast-feed and was not aware of infant formulas. RESULTS: The dietary mistake was detected because of a positive expanded newborn screening result, characterized by severe hypertyrosinaemia with high methionine and phenylalanine levels, a pattern suggestive of severe liver impairment. The pattern of plasma amino acids was related to a goat's milk diet, because of its very different composition compared with human milk and infant formula. CONCLUSIONS: Our experience demonstrates that, when breast-feeding is not possible or is not exclusive, infants may be at risk of dangerous nutritional practices, including diets with very high protein content, such as a goat's milk diet. Families of not breast-fed infants may need appropriate advice on safe alternatives for infant nutrition to avoid the risks of inappropriate diets.