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.

Neuroimaging in early-treated phenylketonuria patients and clinical outcome: A systematic review.

Lacking direct neuropathological data, neuroimaging exploration has become the most powerful tool to give insight into pathophysiological alterations of early-treated PKU (ETPKU) patients. We conducted a systematic review of neuroimaging studies in ETPKU patients to explore 1) the occurrence of consistent neuroimaging alterations; 2) the relationship between them and neurological and cognitive disorders; 3) the contribution of neuroimaging in the insight of neuropathological background of ETPKU subjects; 4) whether brain neuroimaging may provide additional information in the monitoring of the disease course. Thirty-eight studies met the inclusion criteria for the full-text review, including morphological T1/T2 sequences, diffusion brain imaging (DWI/DTI) studies, brain MRI volumetric, functional neuroimaging studies, neurotransmission and brain energetic imaging studies.

Psychogenic non-epileptic seizures and functional motor disorders in developmental age: A comparison of clinical and psychopathological features.

Background: Psychogenic Non-Epileptic Seizures (PNES) and Functional Motor Disorders (FMDs) commonly represent the main clinical manifestations of Functional Neurological Disorders (FNDs). Despite their high prevalence in pediatric neurological services, literature on this topic is still spare for this population. The present study aimed to deepen the clinical knowledge of a pediatric FNDs sample through a demographic and clinical characterization of the most recurrent clinical patterns during the pediatric age.

Long-term neurological and psychiatric outcomes in patients with aromatic l-amino acid decarboxylase deficiency.

Introduction: l-amino acid decarboxylase deficiency (AADCD) is an ultrarare autosomal recessive defect of biogenic amine synthesis that presents with early-onset encephalopathy progressing to severe neurological impairment and intellectual disability. We aimed to explore neurocognitive and behavioral profiles associated with AADCD and possible factors predicting outcome in more detail.

Methods: Nine AADCD patients (23.

Simultaneous determination of 5-hydroxytryptophan and 3-O-methyldopa in dried blood spot by UPLC-MS/MS: A useful tool for the diagnosis of L-amino acid decarboxylase deficiency.

5-hydroxytryptophan (5HTP) and 3-O-methyldopa (3OMD) are CSF diagnostic biomarkers of the defect of aromatic L-amino acid decarboxylase (AADC), a rare inherited disorder of neurotransmitter synthesis which, if untreated, results in severely disabling neurological impairment. In the last few years, different methods to detect 3OMD in dried blood spot (DBS) were published. We developed and validated a fast and specific diagnostic tool to detect 5HTP alongside 3OMD.

Parkinsonism in children: Clinical classification and etiological spectrum.

Infantile- and childhood-onset parkinsonism is mainly due to genetic alterations and is an exceedingly rare condition, unlike Parkinson's disease (PD), which is one of the most common neurologic disorders in adulthood. The clinical characterization of parkinsonism during early stages of neuromotor development is controversial due to the lack of consensus regarding the clinical criteria of PD or parkinsonism in the immature brain. The classification here proposed is based on a review of conditions that emerge during infancy and childhood, with key symptoms evocative of adult parkinsonism.

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.

Co-occurring WARS2 and CHRNA6 mutations in a child with a severe form of infantile parkinsonism.

Objective: To investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants.

Methods: A trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were performed to explore the impact of these variants on protein function and relevant cellular processes.

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.

PNKP deficiency mimicking a benign hereditary chorea: The misleading presentation of a neurodegenerative disorder.

PNKP gene encodes for a kinase/phosphatase involved in DNA damage response, controlled and stabilized by ATM phosphorylation. PNKP deficiency, thus far described in 40 subjects, has been associated with a complex neurological phenotype encompassing microcephaly, seizures, developmental delay, ataxia, oculomotor apraxia and polyneuropathy. We report a new case expanding the clinical phenotype of this rare disorder.

Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: The multifaceted phenotypic spectrum of KCTD7-related disorders.

Background: Mutations in the KCTD7 gene have been associated with progressive myoclonus epilepsy and, in a single patient, with the so-called "Neuronal Ceroid Lipofuscinosis 14" (characterised by myoclonic seizures, cognitive regression, optic atrophy leading to visual loss, and progressive cortical and cerebellar atrophy).

Clinical Reports: We describe two new patients carrying two novel pathogenic mutations in the KCTD7 gene. Patient 1 (NM_153033.

Neurotransmitter trafficking defect in a patient with clathrin (CLTC) variation presenting with intellectual disability and early-onset parkinsonism.

Introduction: Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide.

Case Report: This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood.

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.

Development of a new UPLC-ESI-MS/MS method for the determination of biopterin and neopterin in dried blood spot.

Background: (6R)-5,6,7,8-tetrahydrobiopterin (BH4) deficiencies are rare inherited defects of synthesis or regeneration of BH4. Due to the resulting hyperphenylalaninemia (HPA), some of them are detected by newborn screening and require the assessment of the pattern of neopterin (Neo) and biopterin (Bio) excretion in urine to be confirmed. Aim of present study was to develop a method for the measurement of these diagnostic biomarkers in dried blood spot (DBS).

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.

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.

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.

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.