Morning specimen is not representative of metabolic control in Tunisian children with phenylketonuria: a repeated cross-sectional study.

Objective and methods To evaluate variation of capillary phenylalanine concentrations over the day in patients treated for phenylketonuria and the reliability of the morning sample to assess metabolic control, we conducted a repeated cross-sectional study in 25 Tunisian patients on phenylalanine-low diet. For each patient, we collected nine capillary samples over the day. Phenylalanine was dosed by fluorimetry. Results There was a wide variability of phenylalanine concentrations over the day (p<0.001). Compared to morning sample, phenylalanine concentration was significantly lower before lunch (p=0.038), after lunch (p=0.025), before dinner (p<0.001), after dinner (p=0.035) and at 4:00 a.m. (p=0.011). Compared to the 24 h sampling, the morning sample had a 68% to identify unbalanced patients. 60% of patients, had peak phenylalanine concentration after the morning. Half of the patients with normal morning phenylalanine concentration had low phenylalanine values over 8-20 h. Percentages of high phenylalanine concentrations over the last semester were higher in patients with poor metabolic control over the 24 h (21% ± 43 vs. 0% ± 9%); p=0.043. Conclusion A single morning sample gives an incomplete information on metabolic control in phenylketonuric patients. Using four pre-prandial samples on the day should be considered as alternative in patients with good metabolic control.

Quality of life and associated factors in parents of children with late diagnosed phenylketonuria. A cross sectional study in a developing country (Tunisia).

Objectives We investigated the quality of life (QOL) in parents of children with late treated phenylketonuria (PKU) and its associated factors. Methods We conducted a cross sectional study in the reference center of inherited metabolic disease in Tunisia. We used the Tunisian version of the 36-item short-form health survey questionnaire (SF-36). We compared variables in the groups with and without impaired QOL and the SF-36 scores between subgroups of parents and children and between our sample and the Tunisian general population based on published data. We looked for associations between SF-36 scores and quantitative variables. Linear regression and logistic binary regression were used for multivariate analysis. Results Sixty-five parents from 42 families participated. QOL was impaired in 61% of them. The mean SF-36 score was 55.3 ± 25.07. The physical component sub-score was higher than that reported in the Tunisian general population (63.66 ± 27.77 vs. 50.11 ± 8.53; p<0.001). The mental component sub-score was comparable to that reported in the Tunisian general population (46.99 ± 25.94 vs. 47.96 ± 9.82; p=0.830). Gender (mothers) (p=0.008), low monthly income (p = 0.027), low education (p=0.011), and autism in PKU children (p = 0.001) were associated with impaired QOL. Conclusions We identified at risk parents for altered quality of life among parents of PKU children. Our findings were used to develop a psychological and social support strategy for at-risk parents and to promote the implementation of newborn screening of this treatable disease in our low-income country.

Role play for genetic counseling learning: Value and students perceptions.

BACKGROUND: Performing genetic counseling is one of the tasks of every paediatrician. This assumes prior training during the residency. AIM: To assess the impact of role-play (RP) for training of paediatric residents in genetic counseling and participants' perception. METHODS: Repetitive cross-sectional evaluation study. During two RP sessions, two residents played the role of the parents of a patient with cystic fibrosis, and another the role of the doctor. Residents had an evaluation by standardized patient exercises immediately before and after the session. Test scores were compared by the Wilcoxon rank test for associated samples. A satisfaction questionnaire was completed by the participants anonymously. RESULTS: Post-test scores were better than pre-test scores overall (p = 0.002) and for items in the cognitive domain (p = 0.002). Of the 12 participants, only one had had previous training in genetic counseling. All participants were satisfied with the learning and felt that it would change the way they practice. All participants thought they could do genetic counseling autonomously, but nine of them wanted to have other RP sessions on the same theme. Only one participant found the session stressful and all wanted to multiply this type of sessions for other learning. CONCLUSION: RP is an effective and well-accepted means for genetic counseling training. It should be integrated with paediatric resident training.

Neuromuscular Involvement in Glycogen Storage Disease Type III in Fifty Tunisian Patients: Phenotype and Natural History in Young Patients.

BACKGROUND: Our aim was to describe the natural history of neuromuscular involvement (NMI) in glycogen storage disease type III (GSDIII). METHODS: We conducted a longitudinal study of 50 Tunisian patients, 9.87 years old in average. RESULTS: NMI was diagnosed at an average age of 2.66 years and was clinically overt in 85% of patients. Patients with clinical features were older (p = 0.001). Complaints were dominated by exercise intolerance (80%), noticed at 5.33 years in average. Physical signs, observed at 6.75 years in average, were dominated by muscle weakness (62%). Functional impairment was observed in 64% of patients, without any link with age (p = 0.255). Among 33 patients, 7 improved. Creatine kinase (CK) and aspartate aminotransferase (AST) levels were higher with age.Electrophysiological abnormalities, diagnosed in average at 6.5 years, were more frequent after the first decade (p = 0.0005). Myogenic pattern was predominant (42%). Nerve conduction velocities were slow in two patients. Lower caloric intake was associated with more frequent clinical and electrophysiological features. Higher protein intake was related to fewer complaints and physical anomalies. CONCLUSION: Neuromuscular investigation is warranted even in asymptomatic patients, as early as the diagnosis of GSDIII is suspected. Muscle involvement can be disabling even in children. Favorable evolution is possible in case of optimal diet.

High Frequency of Cardiovascular Complications in Tunisian Kawasaki Disease Patients: Need for a Further Awareness.

BACKGROUND: The outcome of Kawasaki disease (KD) depends on cardiovascular complications (CVCs). OBJECTIVES: This study aimed to explore diagnostic features and CVCs in Tunisian patients with KD. METHODS: In total, 33 Tunisian patients (age, 2.9 ± 2.2 years) fulfilling the diagnosis criteria of KD, were retrospectively reviewed. Nonparametric tests were used to compare the two groups with regards to coronary complications (CCs). RESULTS: Diagnosis of KD was established at day 11 ± 5.1 from the beginning of the fever. Apyrexia was obtained in an average of 29 h after completion of intravenous immunoglobulin. CVCs were identified in 52% of cases: CC in 15 patients (giant aneurysm >8 mm in five patients) and non-CCs in 6 patients (severe in three patients). CCs were more frequently associated with the male sex (p = 0.037), fever lasting >8 days (p = 0.028) and longer time to apyrexia (p = 0.031). CONCLUSION: In Tunisia, better knowledge and monitoring of KD are warranted.

Patient-management Problem (PMP) for paediatrics learning: Value and students perceptions.

BACKGROUND: The use of the pedagogic tool Patient-Management Problem (PMP) for medical teaching and evaluation remains limited in Tunisia. AIM: to evaluate the value of PMP learning sessions in pediatrics and students' perception of the use of PMP for learning and evaluation. METHODS: We conducted a cross-sectional evaluative study in four pediatric departments in Tunis. Students had a learning session with an electronic PMP. Their knowledge was assessed using a pre-test and a post-test. Their perception of the learning was assessed using a questionnaire. RESULTS: Forty-four students participated. The post-test scores were statistically higher than those of the pre-test (p <0.001). More than 90% of the students, found that the PMP was a useful learning tool, which would change their way of thinking and agreed to its regular use for teaching. 86% of students declared that the PMP were better than other means of learning and 79% that PMP was a reliable assessment tool, but 75% believed it was more stressful than other means of assessment. The degree of satisfaction with previous PMP experience was negatively correlated with perception of reliability (p = 0.043), impact on clinical reasoning (p = 0.044), and PMP being better than the other learning means (p = 0.044). CONCLUSION: The PMP is an effective learning tool and is well accepted by students. Its use should be generalized to all disciplines for teaching and evaluation. Further trainings are necessary for medical teachers to guarantee quality PMPs.

Correction to: Full title: peripheral venous catheter complications in children: predisposing factors in a multicenter prospective cohort study.

Following publication of the original article [1], one of the authors flagged that the title of the article was submitted (incorrectly) with "Full title:" at the beginning.

A lower energetic, protein and uncooked cornstarch intake is associated with a more severe outcome in glycogen storage disease type III: an observational study of 50 patients.

Background Glycogen storage disease type III (GSDIII), due to a deficiency of glycogen debrancher enzyme (GDE), is particularly frequent in Tunisia. Phenotypic particularities of Tunisian patients remain unknown. Our aim was to study complications of GSDIII in a Tunisian population and to explore factors interfering with its course. Methods A retrospective longitudinal study was conducted over 30 years (1986-2016) in the referral metabolic center in Tunisia. Results Fifty GSDIII patients (26 boys), followed for an average 6.75 years, were enrolled. At the last evaluation, the median age was 9.87 years and 24% of patients reached adulthood. Short stature persisted in eight patients and obesity in 19 patients. Lower frequency of hypertriglyceridemia (HTG) was associated with older patients (p<0.0001), higher protein diet (p=0.068) and lower caloric intake (p=0.025). Hepatic complications were rare. Cardiac involvement (CI) was frequent (91%) and occurred early at a median age of 2.6 years. Severe cardiomyopathy (50%) was related to lower doses of uncooked cornstarch (p=0.02). Neuromuscular involvement (NMI) was constant, leading to a functional discomfort in 64% of cases and was disabling in 34% of cases. Severe forms were related to lower caloric (p=0.005) and protein intake (p<0.015). Conclusions A low caloric, protein and uncooked cornstarch intake is associated with a more severe outcome in GSDIII Tunisian patients. Neuromuscular and CIs were particularly precocious and severe, even in childhood. Genetic and epigenetic factors deserve to be explored.

Peripheral venous catheter complications in children: predisposing factors in a multicenter prospective cohort study.

BACKGROUND: Peripheral venous catheterization (PVC) is frequently used in children. This procedure is not free from potential complications. Our purpose was to identify the types and incidences of PVC complications in children and their predisposing factors in a developing country. METHODS: We conducted a prospective observational multicenter study in five pediatric and pediatric surgery departments over a period of 2 months. Two hundred fifteen PVC procedures were conducted in 98 children. The times of insertion and removal and the reasons for termination were noted, and the lifespan was calculated. Descriptive data were expressed as percentages, means, standard deviations, medians and interquartile ranges. The Chi2 test or the Fisher test, with hazard ratios and 95% confidence intervals (CI95%), as well as Student's t test or the Mann-Whitney U test were used to compare categorical and quantitative variables, respectively, in groups with and without complications. The Spearman test was used to determine correlations between the lifespan and the quantitative variables. The Kruskal Wallis test was used to test for differences in the median lifespan within 3 or more subgroups of a variable. Linear regression and logistic binary regression were used for multivariate analysis. A p-value <0.05 was considered significant. RESULTS: The mean lifespan was 68.82 ± 35.71 h. A local complication occurred in 111 PIVC (51.9%) cases. The risk factors identified were a small catheter gauge (24-gauge) (p = 0.023), the use of a volume-controlled burette (p = 0.036), a longer duration of intravenous therapy (p < 0.001), a medical diagnosis of respiratory or infectious disease (p = 0.047), the use of antibiotics (p = 0.005), including cefotaxime (p = 0.024) and vancomycin (p = 0.031), and the use of proton pump inhibitors (p = 0.004).The lifespan of the catheters was reduced with the occurrence of a complication (p < 0.001), including the use of 24-gauge catheters (p = 0.001), the use of an electronic pump or syringe(p = 0.036) and a higher rank of the intravenous device in each patient (p = 0.010). CONCLUSIONS: PVC complications were frequent in our pediatric departments and are often associated with misuse of the device. These results could engender awareness among both doctors and nurses regarding the need for rationalization of the use of PVC and better adherence to the recommendations for the use of each drug and each administration method.

Clinical and Genetic Characterization of 26 Tunisian Patients with Allgrove Syndrome.

BACKGROUND AND AIMS: Allgrove syndrome is characterized by achalasia, alacrima, and adrenal insufficiency as well as being associated with progressive neurological signs. This is an autosomal recessive disorder due to mutations in the AAAS gene located on chromosome 12q13. The AAAS gene encodes a protein of 546 amino acids, ALADIN. Mutations in this genwere reported in families from North Africa and Europe. Our objective is to conduct a clinical, molecular and genetic study of 26 Tunisian patients with Allgrove syndrome. METHODS: We report 26 Tunisian patients with between two and four clinical features associated with Allgrove syndrome. Blood samples were collected and isolated DNA derived from subjects was amplified. The entire sequence of the AAAS gene was analyzed by PCR and sequencing. PCR-RFLP method was performed to identify the frequent mutations found. RESULTS: Sequencing of the AAAS gene revealed a major homozygous mutation (c.1331+1G>A) in 25 patients and R286X mutation in one patient. The presence of a major mutation in several unrelated affected individuals suggests the presence of a founder effect in Tunisia and allows for a fast and targeted molecular diagnosis. CONCLUSIONS: We created an easy and rapid molecular enzymatic protocol based on PCR-RFLP using MvaI restriction enzyme that directly targets this major mutation and can be used for prenatal diagnosis and genetic counseling for Tunisian families at risk. To the best of our knowledge, this is the first major series report of Allgrove syndrome in Tunisia.

Severe respiratory complex III defect prevents liver adaptation to prolonged fasting.

BACKGROUND & AIMS: Next generation sequencing approaches have tremendously improved the diagnosis of rare genetic diseases. It may however be faced with difficult clinical interpretation of variants. Inherited enzymatic diseases provide an invaluable possibility to evaluate the function of the defective enzyme in human cell biology. This is the case for respiratory complex III, which has 11 structural subunits and requires several assembly factors. An important role of complex III in liver function is suggested by its frequent impairment in human cases of genetic complex III defects. METHODS: We report the case of a child with complex III defect and acute liver dysfunction with lactic acidosis, hypoglycemia, and hyperammonemia. Mitochondrial activities were assessed in liver and fibroblasts using spectrophotometric assays. Genetic analysis was done by exome followed by Sanger sequencing. Functional complementation of defective fibroblasts was performed using lentiviral transduction followed by enzymatic analyses and expression assays. RESULTS: Homozygous, truncating, mutations in LYRM7 and MTO1, two genes encoding essential mitochondrial proteins were found. Functional complementation of the complex III defect in fibroblasts demonstrated the causal role of LYRM7 mutations. Comparison of the patient's clinical history to previously reported patients with complex III defect due to nuclear DNA mutations, some actually followed by us, showed striking similarities allowing us to propose common pathophysiology. CONCLUSIONS: Profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting leading to severe lactic acidosis, hypoglycemia, and hyperammonemia, potentially leading to irreversible brain damage. LAY SUMMARY: The diagnosis of rare genetic disease has been tremendously accelerated by the development of high throughput sequencing technology. In this paper we report the investigations that have led to identify LYRM7 mutations causing severe hepatic defect of respiratory complex III. Based on the comparison of the patient's phenotype with other cases of complex III defect, we propose that profound complex III defect in liver does not induce actual liver failure but impedes liver adaptation to prolonged fasting.

Autism in Phenylketonuria Patients: From Clinical Presentation to Molecular Defects.

Autism has been reported in untreated patients with phenylketonuria. The authors aimed to explore autism in 15 Tunisian and 4 Algerian phenylketonuria patients, and report their clinical, biochemical and molecular peculiarities. The Childhood Autism Rating Scale and the Autism Diagnostic Interview-Revised were used for the diagnosis of autism. Five exons of phenylalanine hydroxylase gene (7, 6, 10, 11, and 5) were amplified by polymerase chain reaction and directly sequenced. Among these patients, 15 were suffering from autism at the time of evaluation. Six mutations were identified: p.E280K, p.G352Vfs, IVS10nt11, p.I224T, p.R261Q, and p.R252W. There was no correlation between autism and mutations affecting the phenylalanine hydroxylase gene, but the age of diet onset was the determining factor in autistic symptoms' evolution.

A novel homozygous missense mutation in the insulin receptor gene results in an atypical presentation of Rabson-Mendenhall syndrome.

Leprechaunism (Donohue syndrome) and Rabson-Mendenhall syndrome are caused by mutations in the insulin receptor gene and are associated with extreme insulin resistance. Clinically these syndromes appear to represent points on a continuum of severity of receptor dysfunction, rather than completely distinct syndromes. We investigated a Libyan infant with growth retardation, facial dysmorphism (elfin-like features), acanthosis nigricans and hirsutism. Fasting hypoglycaemia and postprandial hyperglycaemia with persistent hyperinsulinemia were found. A novel homozygous missense mutation was found in exon 2, resulting in a substitution of a glycine-132 for a serine in the INSR α-subunit (c.394G > A; p.Gly132Ser). At age ten, he developed diabetes mellitus. At age eleven, patient is still alive with mental retardation and severe growth retardation.

History of settlement of villages from Central Tunisia by studying families sharing a common founder Glycogenosis type III mutation.

Glycogen storage disease type III (GSD III; Cori disease; Forbes disease) is an autosomal recessive inherited metabolic disorder resulting from deficient glycogen debrancher enzyme activity in liver and muscle. In this study, we focused on a single AGL gene mutation p.W1327X in 16 Tunisian patients from rural area surrounding the region of Mahdia in Central Tunisia. This constitutes the largest pool of patients with this mutation ever described. This study was performed to trace the history of the patients' ancestries in a single region. After extraction of genomic DNA, exon 31 of AGL gene was sequenced. The patients were investigated for the hypervariable segment 1 of mitochondrial DNA and 17 Y-STR markers. We found that the p.W1327X mutation was a founder mutation in Tunisia Analysis of maternal lineages shows an admixture of autochthonous North African, sub-Saharan and a predominance of Eurasian haplogroups. Heterogeneity of maternal haplogroups indicates an ancient settlement. However, paternal gene flow was highly homogeneous and originates from the Near East. We hypothesize that the p.W1327X mutation was introduced into the Tunisian population probably by a recent migration event; then the mutation was fixed in a small region due to the high rate of consanguineous marriages and genetic drift. The screening for this mutation should be performed in priority for GSD III molecular diagnosis, for patients from the region of Mahdia and those from regions sharing the same settlement history.

Clinical and Biochemical Profile of Tyrosinemia Type 1 in Tunisia.

BACKGROUND: Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease caused by a defect of fumarylacetoacetate hydrolase. This study aimed to estimate the prevalence of HT1 in Tunisia and report its clinical, biochemical and genetic features. METHODS: During the last 25 years, 69 patients were diagnosed with HT1 based on clinical features and increased succinylacetone (SA) in blood and urine. SA was detected by GC-MS after oximation and quantified by a spectrophotometric method. Nine prenatal diagnoses for HT1 have been done and nine unrelated patients were screened for the hotspot IVS6-1(G-T) mutation using PCR. RESULTS: Using the Hardy-Weinberg formula, the incidence of HT1 was estimated at 1/14804 births in Tunisia. According to clinical form, 21 patients (30%) had the acute form and 48 patients (70%) had the chronic form. Mean plasma and urine SA were higher in the acute form (24 and 193 µmol/L vs. 9 and 90 µmol/L, respectively). Diagnosis of HT1 was done for 4 fetuses. The hotspot IVS6-1(G-T) mutation was found in six of nine explored patients. CONCLUSIONS: The incidence of HT1 is relatively high in Tunisia with a predominance of the chronic form. It is important to diagnose the disease as early as possible to prevent unfavorable issues. Prenatal diagnosis should be recommended to minimize the recurrence of the disease.

[Renal involvement in glycogen storage disease type 1: Practical issues]. / Complications rénales dans la glycogénose de type 1 : quelles implications pratiques ?

AIM: To investigate risk factors of renal complications in glycogen storage disease type I, in order to identify practical implications for renal preservation. METHODS: A retrospective study of 38 patients with glycogen storage disease type I. RESULTS: The patients studied were 8.6 years old in average (1.5 to 22 years) and were followed during 7.4 ± 4.5 years. Hypercalciuria was detected in 23 patients and was related to acidosis (P=0.028), higher lactate levels (5.9 ± 3.5 versus 3.7 ± 1.7 mmol/L; P=0.013) and smaller height (-2.1 ± 1.5 SD versus -0.8 ± 1.5 SD; P=0.026). Urolithiasis was diagnosed in 7 cases. Glomerular disease (19/38) was more frequent in cases with severe hypertriglyceridemia (P=0.042) and occurred at an older age (P=0.007). Microalbuminuria occurred in 15/31 cases; ACE inhibitors were prescribed in only 8 cases. The frequency of renal complications did not differ according to the diet group (continuous enteral feeding or uncooked starch). Logistic regression concluded as risk factors: lactic acidosis for tubular disease and age>10 years for glomerular disease. CONCLUSIONS: Renal involvement is common in glycogen storage disease type I patients. Tubular abnormalities are precocious, related to lactic acidosis and may be detected by monitoring of urinary calcium. Glomerular hyperfiltration is the first stage of a progressive glomerular disease and is related to age. Practical implications for renal preservation are discussed based on our results and literature.

1471 delTTCT a Common Mutation of Tunisian Patients with Lysinuric Protein Intolerance.

BACKGROUND: Lysinuric protein intolerance is an inherited aminoaciduria caused by defective cationic amino acid transport. It is an autosomal recessive disease caused by mutations in the SLC7A 7 gene. The objective of this study was to identify the mutations of Tunisians patients in order to offer the genetic counseling and the prenatal diagnosis to families. METHODS: Five affected Tunisian children (4 girls and 1 boy) belonging to four consanguineous families were considered. The diagnosis was made based on the plasma for amino acids quantification by Ion Exchange chromatography, the DNA for mutational analysis by DHPLC and sequencing, and the amniotic fluid for prenatal diagnosis. RESULTS: For the 5 patients, clinical features were dominated by failure to thrive, bone marrow abnormalities, hepatosplenomegaly, and mental retardation. The diagnosis for all patients was confirmed by biochemical analysis with hyperammonemia, hyperexcretion of urinary dibasic amino acids, and a high amount of orotic acid in the urine. The 1471 delTTCT mutation was identified in exon 9 in the homozygous state for all Tunisian patients. Genetic counseling was performed for three out of four families, four heterozygous and two homozygous healthy siblings were identified. The result of prenatal diagnosis showed the presence of the 1471 de1TTCT mutation in the homozygous state for the third pregnancy and heterozygous state for the fourth. CONCLUSIONS: The 1471 deITTCT mutation seems to be a common mutation of Tunisian population. The identification of this specific mutation provides a tool for confirmatory diagnosis, genetic counseling, and prenatal diagnosis.

Molecular investigation of distal renal tubular acidosis in Tunisia, evidence for founder mutations.

BACKGROUND: Distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H+ ions in the intercalated cells of the collecting duct. Both autosomal dominant and recessive forms have been described; the latter is also associated with sensorineural hearing loss. METHODS: Twenty-two Tunisian families were analyzed for mutations in the ATP6V1B1 and ATP6V0A4 genes by direct sequencing. Dating of the founder mutations was performed. RESULTS: Two founder mutations in the ATP6V1B1 gene were found in 16/27 dRTA cases. The p.Ile386Hisfs*56 founder mutation was estimated to be older than 2400 years and no correlations were found with deafness. For the remaining patients, two mutations in the ATP6V0A4 gene, one of them being novel, were found in three Tunisian cases. The presence of a heterozygous missense mutation p.T30I, of the ATP6V1B1 gene, was identified in six patients, while no mutations of the second gene were detected. No deleterious mutations of either ATP6V1B1 or ATP6V0A were found for the two probands. CONCLUSION: Our study gives evidence of phenotypic and genotypic heterogeneity of dRTA in the Tunisian population. Five different mutations were found, two of them were due to a founder effect, and screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA.

Novel and recurrent mutations in the TAT gene in Tunisian families affected with Richner-Hanhart syndrome.

Tyrosinemia type II, also designated as oculocutaneous tyrosinemia or Richner-Hanhart syndrome (RHS), is a very rare autosomal recessive disorder. In the present study, we report clinical features and molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in two young patients, both born to consanguineous unions between first-degree cousins. These two unrelated families originated from Northern and Southern Tunisia. The clinical diagnosis was based on the observation of several complications related to Richner-Hanhart syndrome: recurrent eye redness, tearing and burning pain, photophobia, bilateral pseudodendritic keratitis, an erythematous and painful focal palmo-plantar hyperkeratosis and a mild delay of mental development. The diagnosis was confirmed by biochemical analysis. Sequencing of the TAT gene revealed the presence of a previously reported missense mutation (c.452G>A, p.Cys151Tyr) in a Tunisian family, and a novel G duplication (c.869dupG, p.Trp291Leufs 6). Early diagnosis of RHS and protein-restricted diet are crucial to reduce the risk and the severity of long-term complications of hypertyrosinemia such as intellectual disability.