Biallelic Variants of MRPS36 Cause a New Form of Leigh Syndrome.

BACKGROUND: The MRPS36 gene encodes a recently identified component of the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the Krebs cycle catalyzing the oxidative decarboxylation of 2-oxoglutarate to succinyl-CoA. Defective OGDHC activity causes a clinically variable metabolic disorder characterized by global developmental delay, severe neurological impairment, liver failure, and early-onset lactic acidosis. METHODS: We investigated the molecular cause underlying Leigh syndrome with bilateral striatal necrosis in two siblings through exome sequencing. Functional studies included measurement of the OGDHC enzymatic activity and MRPS36 mRNA levels in fibroblasts, assessment of protein stability in transfected cells, and structural analysis. A literature review was performed to define the etiological and phenotypic spectrum of OGDHC deficiency. RESULTS: In the two affected brothers, exome sequencing identified a homozygous nonsense variant (c.283G>T, p.Glu95*) of MRPS36. The variant did not affect transcript processing and stability, nor protein levels, but resulted in a shorter protein lacking nine residues that contribute to the structural and functional organization of the OGDHC complex. OGDHC enzymatic activity was significantly reduced. The review of previously reported cases of OGDHC deficiency supports the association of this enzymatic defect with Leigh phenotypic spectrum and early-onset movement disorder. Slightly elevated plasma levels of glutamate and glutamine were observed in our and literature patients with OGDHC defect. CONCLUSIONS: Our findings point to MRPS36 as a new disease gene implicated in Leigh syndrome. The slight elevation of plasma levels of glutamate and glutamine observed in patients with OGDHC deficiency represents a candidate metabolic signature of this neurometabolic disorder. © 2024 International Parkinson and Movement Disorder Society.

Myelin basic protein recovery during PKU mice lifespan and the potential role of microRNAs on its regulation.

Untreated phenylketonuria (PKU) patients and PKU animal models show hypomyelination in the central nervous system and white matter damages, which are accompanied by myelin basic protein (MBP) impairment. Despite many assumptions, the primary explanation of the mentioned cerebral outcomes remains elusive. In this study, MBP protein and mRNA expression on brains of wild type (WT) and phenylketonuric (ENU2) mice were analyzed throughout mice lifespan (14-60-180-270-360-540 post-natal days, PND). The results confirmed the low MBP expression at first PND times, while revealed an unprecedented progressive MBP protein expression recovery in aged ENU2 mice. Unexpectedly, unaltered MBP mRNA expression between WT and ENU2 was always observed. Additionally, for the same time intervals, a significant decrease of the phenylalanine concentration in the peripheral blood and brain of ENU2 mice was detected, to date, for the first time. In this scenario, a translational hindrance of MBP during initial and late cerebral development in ENU2 mice was hypothesized, leading to the execution of a microRNA microarray analysis on 60 PND brains, which was followed by a proteomic assay on 60 and 360 PND brains in order to validate in silico miRNA-target predictions. Taken together, miR-218-1-3p, miR-1231-3p and miR-217-5p were considered as the most impactful microRNAs, since a downregulation of their potential targets (MAG, CNTNAP2 and ANLN, respectively) can indirectly lead to a low MBP protein expression. These miRNAs, in addition, follow an opposite expression trend compared to MBP during adulthood, and their target proteins revealed a complete normalization in aged ENU2 mice. In conclusion, these results provide a new perspective on the PKU pathophysiology understanding and on a possible treatment, emphasizing the potential modulating role of differentially expressed microRNAs in MBP expression on PKU brains during PKU mouse lifespan.

Towards precision medicine for phenylketonuria: The effect of restoring a strict metabolic control in adult patients with early-treated phenylketonuria.

BACKGROUND AND OBJECTIVE: Neonatal screening and early treatment have changed the natural history of PKU, preventing severe neurological and intellectual disability. Nevertheless, the outcome of the disease in early-treated adult patients (ETPKU) is less than optimal, the predictive value of metabolic biomarkers is feeble, and the recommended levels of blood phenylalanine (Phe) for adulthood are controversial. A crucial question whose answer will improve our understanding and treatment of PKU is whether cognitive outcomes can be modulated by levels of Phe even in early-treated adults. To address this question, we carried out an interventional study in seven ETPKU women planning a pregnancy. METHODS: They underwent an extensive neurocognitive assessment at baseline, and 3 and 6 months after having attained the blood Phe concentration recommended to prevent PKU fetopathy, but before pregnancy. RESULTS: After 3 and 6 months with a stable blood Phe level of about 240 µmol/L, all participants experienced significant improvements in almost all neurocognitive domains and tasks. IQ also increased of 11 to 21 points from the last assessment before enrolment. This pattern remained strong and consistent after correction for multiple comparisons. CONCLUSION: Our results indicate that a) strong cognitive improvement is possible even in adulthood and may be demonstrated by lowering Phe near normal levels; b) testing cognition under different metabolic conditions may unveil an individual vulnerability to Phe. These results pave the way for personalised treatment of the disease in adults with ETPKU.

The diagnostic challenge of mild citrulline elevation at newborn screening.

Citrulline is a target analyte measured at expanded newborn screening (NBS) and its elevation represents a biomarker for distal urea cycle disorders and citrin deficiency. Altered ratios of citrulline with other urea cycle-related amino acids are helpful for the differential diagnosis. However, the use of cut-off values in screening programmes has raised the issue about the interpretation of mild elevation of citrulline levels detected at NBS, below the usual range observed in the "classical/severe" forms of distal urea cycle disorders and in citrin deficiency. Herein, we report ten subjects with positive NBS for a mild elevation of citrulline (<100 µmol/L), in whom molecular investigations revealed carriers status for argininosuccinate synthase deficiency, a milder form of argininosuccinate lyase deficiency and two other diseases, lysinuric protein intolerance and dihydrolipoamide dehydrogenase deficiency, not primarily affecting the urea cycle. To guide the diagnostic process, we have designed an algorithm for mild citrulline elevation (<100 µmol/L) at NBS, which expands the list of disorders to be included in the differential diagnosis.

3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature.

3-Methylglutaconic aciduria type I (MGCA1) is an inborn error of the leucine degradation pathway caused by pathogenic variants in the AUH gene, which encodes 3-methylglutaconyl-coenzyme A hydratase (MGH). To date, MGCA1 has been diagnosed in 19 subjects and has been associated with a variable clinical picture, ranging from no symptoms to severe encephalopathy with basal ganglia involvement. We report the case of a 31-month-old female child referred to our center after the detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening, which were associated with increased urinary excretion of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid. A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria failed to establish a definitive diagnosis. To further investigate the strong biochemical indication, we measured MGH activity, which was markedly decreased. Finally, single nucleotide polymorphism array analysis disclosed the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis. The patient was then supplemented with levocarnitine and protein intake was slowly decreased. At the last examination, the patient showed mild clumsiness and an expressive language disorder. This case exemplifies the importance of the biochemical phenotype in the differential diagnosis of metabolic diseases and the importance of collaboration between clinicians, biochemists, and geneticists for an accurate diagnosis.

Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients.

INTRODUCTION: 6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia. We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it. METHODS: At total of 28 PTPSd patients (aged 19.9 ±â€¯10.9 years) underwent clinical (neurological and psychiatric) and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form (MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd. RESULTS: Approximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment, although delayed, is effective in improving the neurological status. CONCLUSIONS: Neurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement in the neurological condition has been observed in patients receiving treatment, even when delayed. The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes.

Clinical characterization of tremor in patients with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is due to the deficit of the enzyme phenylalanine hydroxylase, the first step of dopamine synthesis. If not early treated the disease results in severe neurological impairment. Minor neurological signs have been reported in early treated PKU (ETPKU) subjects. Prolactin level is affected by (and reflects) brain dopamine availability. Object of the study was to assess the occurrence, age at onset, distribution, associated neurological signs, and possible pathogenetic biomarkers of tremor in ETPKU. METHODS: Fifty-nine ETPKU and 43 control subjects (age range 7-54) underwent individual and familiar tremor history, clinical assessment of tremor by means of the Fahn-Tolosa-Marin Tremor Rating Scale, and IQ evaluation. Historical and concomitant biochemical data (blood levels of Phe) and serum prolactin were included in the analysis. RESULTS: Thirty-two percent of ETPKU patients were affected by postural and kinetic tremor. We found a significant correlation between severity of tremor and: prolactin level at the day of examination (part A: rs = 0.320; p = .014; part C: rs = 0.319; p = .014), Phe fluctuations from 12 years onwards (part B: rs = 0.300; p = .036). We also found a significant correlation between prolactin (18.2 ±â€¯9.6 ng/ml) and Phe levels (852 ±â€¯472 µmol/l) on the day of assessment (rs = 0.470; p < .001). CONCLUSIONS: The main clinical features of tremor in ETPKU evoke those of essential tremor, although with a higher prevalence and an earlier onset than in general population. The severity of tremor was related to concomitant prolactin rather than Phe levels. This pattern suggests that metabolic alterations associated with PKU may result in an anticipation of the tremor onset in subjects who are possibly prone to this disorder.

Newborn screening for homocystinurias: Recent recommendations versus current practice.

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

A new therapy prevents intellectual disability in mouse with phenylketonuria.

Untreated phenylketonuria (PKU) results in severe neurodevelopmental disorders, which can be partially prevented by an early and rigorous limitation of phenylalanine (Phe) intake. Enzyme substitution therapy with recombinant Anabaena variabilis Phe Ammonia Lyase (rAvPAL) proved to be effective in reducing blood Phe levels in preclinical and clinical studies of adults with PKU. Aims of present study were: a) to gather proofs of clinical efficacy of rAvPAL treatment in preventing neurological impairment in an early treated murine model of PKU; b) to test the advantages of an alternative delivering system for rAvPAL such as autologous erythrocytes. BTBR-Pahenu2-/- mice were treated from 15 to 64 post-natal days with weekly infusions of erythrocytes loaded with rAvPAL. Behavioral, neurochemical, and brain histological markers denoting untreated PKU were examined in early treated adult mice in comparison with untreated and wild type animals. rAvPAL therapy normalized blood and brain Phe; prevented cognitive developmental failure, brain depletion of serotonin, dendritic spine abnormalities, and myelin basic protein reduction. No adverse events or inactivating immune reaction were observed. In conclusion present study testifies the clinical efficacy of rAvPAL treatment in a preclinical model of PKU and the advantages of erythrocytes as carrier of the enzyme in term of frequency of the administrations and prevention of immunological reactions.

Predictability and inconsistencies in the cognitive outcome of early treated PKU patients.

Long-term cognitive outcome and treatment of adult early treated (ET)PKU patients is a main issue in PKU research. We questioned whether the intellectual development of ETPKU patients is stable and to what extent its variation may be predicted by the quality of metabolic control. The aims of the present longitudinal retrospective study were to assess in young adult ETPKU patients: i) the relationship between IQ and metabolic control during the first two decades of life; and ii) the intra- and interindividual variability in the developmental trajectory which cannot be predicted by the disease's biomarkers. We collected biochemical data from 65 ETPKU patients (diagnostic blood Phe > 360 µmol/l) who were assessed twice for IQ (Wechsler Intelligence Scale) during their lifetime (mean age: 10.2 and 19.6 years, respectively). Results show that in ETPKU patients IQ over the second decade of life remained stable in about half of the patients (51%); while the rest experienced a gain (7 to 15 points) or loss (7 to 28 points) in IQ scores (23 and 26% respectively) whatever the quality of metabolic control was. The main factor affecting the second IQ was the value of the first IQ (p < 0.000) whose effect overruled that of the markers of metabolic control. Looking at the developmental trajectory of our ETPKU patients, the present study disclosed a remarkable interindividual variability in their cognitive outcome and also an inconsistent linkage between cognitive performances and biochemical control, thus supporting the hypothesis of an individual resilience or vulnerability to Phe in young adult ETPKU.

Altered tetrahydrobiopterin metabolism in patients with phenylalanine hydroxylase deficiency.

The tetrahydrobiopterin (BH4) cofactor is essential for the activity of various enzymes, including phenylalanine (Phe) hydroxylase. In phenylketonuria (PKU) patients, who are chronically exposed to high Phe levels, high urinary excretion of BH4 metabolites neopterin and biopterin is observed. The aim of this longitudinal study was to investigate consistence and variability of the urinary excretion of pterins (neopterin and biopterin) in PKU patients in relation to age and concomitant blood Phe and tyrosine levels. The study was based on the result of 274 pterin examinations (3-13 exams per subject) performed in 47 PKU patients (aged 6 days to 37 years). Multivariate analysis showed that urinary biopterin and neopterin excretion was affected by age and concomitant blood Phe concentration. The influence of blood Phe on both biopterin and neopterin levels was greater in patients younger than 4 months. Later on, interindividual variability was higher than intraindividual variability for both biopterin and neopterin. CONCLUSION: Common metabolic (blood Phe levels) and individual (age) factors implicated in the assessment of PKU outcome account only marginally and transiently for the variability of neopterin and biopterin excretion in PKU patients. Other unknown homeostatic factors may probably affect the individual response to chronically elevated Phe levels. What is Known: • In PKU patients, a high urinary excretion of biopterin and neopterin is found. • Biopterin and neopterin excretion is influenced by age and phenylalanine levels. W hat is New: • Blood phenylalanine concentration is the major determinant on pterin excretion in PKU patients in the first months of life. • In older PKU patients, the influence of phenylalanine on pterin excretion is less prominent.

Psychiatric disorders in adolescent and young adult patients with phenylketonuria.

BACKGROUND AND OBJECTIVES: Psychiatric symptoms are a challenging aspect in adolescent and adult early treated phenylketonuric (ETPKU) patients. To assess the occurrence of psychiatric disorders we explored the presence of symptoms requiring intervention and further investigated the link between psychiatric disorders, the quality of biochemical control and cognitive functioning. PATIENTS AND METHODS: Forty-six ETPKU patients (aged 12 to 44) and 30 age-matched healthy controls were subjected to cognitive and psychiatric assessment by means of self-report questionnaires and psychiatric interview. Psychiatric diagnoses, if detected, were made according to DSM-5 criteria. Concomitant IQ, historical and concurrent biochemical metabolic controls were included in the statistical analysis. RESULTS: Twenty-five out of 46 ETPKUs showed clinical scores on at least one scale of the psychiatric assessment (7/30 in controls); anxiety and withdrawal were the most frequent self-reported symptoms. Seventeen patients (and no controls) met criteria for a psychiatric diagnosis, most of them belonging to the Anxiety Disorders category. The occurrence of psychiatric symptoms was not associated with the life-long and concurrent quality of metabolic control but patients with good metabolic control (≤ 500 µM) in the first 11 years of life showed higher frequency of psychiatric diagnosis (Fisher's exact p=.0300). DISCUSSION/CONCLUSION: ETPKUs show a higher than normal vulnerability to psychiatric disorders, which cannot be explained by the usual biochemical alterations influencing intellectual outcome. Our data support the hypothesis that the burden of the disease acts as psychological stress for children and their families. Possible involvement of neuromediators in the pathogenesis of these complex symptoms requires further investigation.

Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: A longitudinal study.

The aim of the study was to explore the outcome of neurocognitive deficits and neuroimaging correlates in young adult early treated phenylketonuric (PKU) patients. We conducted a longitudinal study of 14 PKU patients that were assessed for IQ and neuropsychological functioning including executive functions (EF) over 14 years of follow-up (age range at 1st and 2nd assessments were 7.8-13.5 and 22.2-27.7 years, respectively). The IQ of all 14 PKU patients was within the normal range. With respect to the 1st assessment, mean IQ at follow-up did not decrease significantly. Compared to control subjects (n = 14), mean IQ of patients was significantly lower (p = .0005). Throughout adolescence and early adulthood there was an improvement of neuropsychological functioning of PKU patients in spite of the relaxation of diet, however some deficits were still detectable when compared to controls. All patients that underwent a second MRI scan showed white matter alterations ranging from mild to severe which was correlated neither with IQ nor with EF scoring. Cognitive, neuropsychological and neuroimaging outcome was influenced from life-long and/or second decade of life metabolic control. Nevertheless patients' developmental trajectories were in some cases independent from metabolic control. Our results support the hypothesis of an individual vulnerability to phenylalanine. However, as long as individual factors that account for the vulnerability to Phe are not recognized, strict dietary control is recommended for all the patients also in the second decade of life.

Urine sepiapterin excretion as a new diagnostic marker for sepiapterin reductase deficiency.

Sepiapterin reductase deficiency (SRD) causes depletion of biogenic amines in the brain, early onset motor disorder, and intellectual disability. The diagnostic marker for this rare disease is increased sepiapterin and biopterin in CSF. Through a new analytic methodology we demonstrated accumulation of sepiapterin in urine of four SRD patients several times greater than that found in healthy controls and carriers, regardless of age or treatment. Our findings suggest a new interpretation of current theories of peripheral pterin metabolism and provide a new noninvasive diagnostic tool for children with early onset cryptogenetic developmental delay and/or movement disorder.

The outcome of white matter abnormalities in early treated phenylketonuric patients: A retrospective longitudinal long-term study.

BACKGROUND: Pathogenesis and clinical consequences of white matter abnormalities on magnetic resonance imaging (MRI) in phenylketonuric (PKU) patients are incompletely known. OBJECTIVE: To study white matter alterations progression and outcome and its relationships with phenylalanine levels and intelligence quotient (IQ) in early treated PKU subjects who underwent serial MRIs during a prolonged follow-up. METHODS: 47 early treated PKU patients (mean age 25.1 ± 5.6 years; range 12-37 years) have been enrolled when two or more consecutive brain MRIs, a complete biochemical history, and MRI-concurrent blood phenylalanine levels were available. The severity and extension of white matter abnormalities were expressed in a computed score. Consecutive IQ assessments were available in 24 patients. We analyzed intra- and interindividual white matter alterations variations and their relationship with quality of biochemical control and cognitive outcome. RESULTS: Early treated PKU patients showed a high rate of white matter alterations with a relevant increase in frequency/severity from the second decade of life onwards. Age and quality of dietary control before or between subsequent examinations showed an independent cumulative effect on white matter alterations outcome. No significant association was found between white matter alterations and cognitive outcome. A remarkable interindividual variability was found and several patients disclosed incongruity between the trajectory of white matter alterations and biochemical control. About 30% of white matter alterations variability remains unexplained by the disease-associated determinants. CONCLUSIONS: The evolution of white matter alterations is not significantly affected by intellectual outcome and is affected by aging, chronic exposure to phenylalanine, and unknown individual factors.

Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood.

Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine 'transportopathy' to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5-34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having 'juvenile parkinsonism'. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more severely impacted in dopamine transporter mutants causing infantile-onset rather than juvenile-onset disease. Dopamine transporter mutants also showed diminished dopamine binding affinity, reduced cell surface transporter, loss of post-translational dopamine transporter glycosylation and failure of amphetamine-mediated dopamine efflux. Our data series expands the clinical phenotypic continuum of dopamine transporter deficiency syndrome and indicates that there is a phenotypic spectrum from infancy (early onset, rapidly progressive disease) to childhood/adolescence and adulthood (later onset, slower disease progression). Genotype-phenotype analysis in this cohort suggests that higher residual dopamine transporter activity is likely to contribute to postponing disease presentation in these later-onset adult cases. Dopamine transporter deficiency syndrome remains under-recognized and our data highlights that dopamine transporter deficiency syndrome should be considered as a differential diagnosis for both infantile- and juvenile-onset movement disorders, including cerebral palsy and juvenile parkinsonism.

A Systematic Review on Autism and Hyperserotonemia: State-of-the-Art, Limitations, and Future Directions.

Hyperserotonemia is one of the most studied endophenotypes in autism spectrum disorder (ASD), but there are still no unequivocal results about its causes or biological and behavioral outcomes. This systematic review summarizes the studies investigating the relationship between blood serotonin (5-HT) levels and ASD, comparing diagnostic tools, analytical methods, and clinical outcomes. A literature search on peripheral 5-HT levels and ASD was conducted. In total, 1104 publications were screened, of which 113 entered the present systematic review. Of these, 59 articles reported hyperserotonemia in subjects with ASD, and 26 presented correlations between 5-HT levels and ASD-core clinical outcomes. The 5-HT levels are increased in about half, and correlations between hyperserotonemia and clinical outcomes are detected in a quarter of the studies. The present research highlights a large amount of heterogeneity in this field, ranging from the characterization of ASD and control groups to diagnostic and clinical assessments, from blood sampling procedures to analytical methods, allowing us to delineate critical topics for future studies.

Case report: Childhood epilepsy and borderline intellectual functioning hiding an AADC deficiency disorder associated with compound heterozygous DDC gene pathogenic variants.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder leading to severe combined serotonin, dopamine, norepinephrine, and epinephrine deficiency. We report on a female patient with borderline functioning and sporadic clear-cut focal to bilateral seizures from age 10 years. A neuropsychological assessment highlighted a mild impairment in executive functions, affecting attention span and visual-spatial abilities. Following the diagnosis of epilepsy with a presumed genetic etiology, we applied a diagnostic approach inclusive of a next-generation sequencing (NGS) gene panel, which uncovered two variants in trans in the DOPA decarboxylase (DDC) gene underlying an AADC deficiency. This compound heterozygous genotype was associated with a mild reduction of homovanillic acid, a low level of the norepinephrine catabolite, and a significant reduction of 5-hydroxyindoleacetic acid in cerebrospinal fluid. Remarkably, 3-O-methyldopa (3-OMD) and 5-hydroxytryptophan were instead increased. During the genetically guided re-evaluation process, some mild signs of dysautonomic dysfunction (nasal congestion, abnormal sweating, hypotension and fainting, excessive sleepiness, small hands and feet, and increased levels of prolactin, tiredness, and fatigue), more typical of AADC deficiency, were evaluated with new insight. Of the two AADC variants, the R347Q has already been characterized as a loss-of-function with severe catalytic impairments, while the novel L391P variant has been predicted to have a less severe impact. Bioinformatic analyses suggest that the amino acid substitution may affect affinity for the PLP coenzyme. Thus, the genotype corresponds to a phenotype with mild and late-onset symptoms, of which seizures were the clinical sign, leading to medical attention. This case report expands the spectrum of AADC deficiency phenotypes to encompass a less-disabling clinical condition including borderline cognitive functioning, drug-responsive epilepsy, and mild autonomic dysfunction.

Phenotypes and Genotypes of Inherited Disorders of Biogenic Amine Neurotransmitter Metabolism.

Inherited disorders of biogenic amine metabolism are genetically determined conditions resulting in dysfunctions or lack of enzymes involved in the synthesis, degradation, or transport of dopamine, serotonin, adrenaline/noradrenaline, and their metabolites or defects of their cofactor or chaperone biosynthesis. They represent a group of treatable diseases presenting with complex patterns of movement disorders (dystonia, oculogyric crises, severe/hypokinetic syndrome, myoclonic jerks, and tremors) associated with a delay in the emergence of postural reactions, global development delay, and autonomic dysregulation. The earlier the disease manifests, the more severe and widespread the impaired motor functions. Diagnosis mainly depends on measuring neurotransmitter metabolites in cerebrospinal fluid that may address the genetic confirmation. Correlations between the severity of phenotypes and genotypes may vary remarkably among the different diseases. Traditional pharmacological strategies are not disease-modifying in most cases. Gene therapy has provided promising results in patients with DYT-DDC and in vitro models of DYT/PARK-SLC6A3. The rarity of these diseases, combined with limited knowledge of their clinical, biochemical, and molecular genetic features, frequently leads to misdiagnosis or significant diagnostic delays. This review provides updates on these aspects with a final outlook on future perspectives.