Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If ...left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care. Professionals from 10 different European countries developed the guidelines according to the AGREE (Appraisal of Guidelines for Research and Evaluation) method. Literature search, critical appraisal and evidence grading were conducted according to the SIGN (Scottish Intercollegiate Guidelines Network) method. The Delphi-method was used when there was no or little evidence available. External consultants reviewed the guidelines. Using these methods 70 statements were formulated based on the highest quality evidence available. The level of evidence of most recommendations is C or D. Although study designs and patient numbers are sub-optimal, many statements are convincing, important and relevant. In addition, knowledge gaps are identified which require further research in order to direct better care for the future.
Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine.
In ...2017 the first European PKU Guidelines were published. These guidelines contained evidence based and/or expert opinion recommendations regarding diagnosis, treatment and care for patients with PKU of all ages. This manuscript is a supplement containing the practical application of the dietary treatment.
This handbook can support dietitians, nutritionists and physicians in starting, adjusting and maintaining dietary treatment.
•PNES subgroup presented higher cognitive and psychiatric vulnerabilities.•A higher frequency of cognitive impairment was reported in PNES patients than in FMDs.•Dissociative traits were equally ...reported both in PNES and FMDs.
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. Moreover, a comparison of neuropsychological and psychopathological profiles of PNES and FMD patients was carried out to identify specific vulnerabilities and therapeutic targets linked with these different clinical manifestations.
A total of 43 FNDs patients (age range 7–17 years old) were retrospectively included in our study, enrolled in two subgroups: 20 with FMDs and 23 with PNES diagnosis. They were inpatients and outpatients referred over a period of 5 years and a standardized neurological, neuropsychological (WISC-IV/WAIS-IV), and psychiatric (CDI-2, MASC-2, ADES, DIS-Q, PID-5) evaluation was assessed.
In PNES patients the most common clinical phenotypes were functional tonic-clonic (52%) and atonic (32%) manifestations while in the FMDs group were gait alterations (60%), functional myoclonus (35%), and tremor (35%). A higher frequency of cognitive impairment was reported in PNES patients with higher anxiety-depressive symptom rates than FMDs patients.
Notably, specific neurocognitive and psychopathological profiles were described in PNES and FMDs, highlighting higher cognitive and psychiatric vulnerabilities in PNES, suggesting as well different strategy for therapeutic approaches.
Introduction
Literature on childhood Functional Neurological Disorders (FNDs) is spare. Clinical presentations are vaguely characterized and often misdiagnosed in younger ages. Their main ...neurological features enrol: Psychogenic non-epileptic seizures (PNES), Functional movement disorders (FMDs), sensory alterations, cephalgia and feeding problems.
Objectives
The study was aimed to better characterize the childhood population of FND, because of they represent an emerging challenge for clinicians, giving its higher presentation in the younger age and the difficulties of an early and differential diagnosis as well as an effective management.
Methods
Our study retrospectively examined the characteristics of 82 FNDs children and adolescents (8 to 16 y.o.; 13 males; 29 females) referred as neurological inpatients of an urban academic neuropsychiatric department, from 2014 to 2019. Three main clinical aspects were analysed: type and pattern of symptoms manifestations (DSM-5 criteria); Life Events; family functioning.
Results
FND accounted for 2% of 5-years consultations of neurological inpatients (M: F=1:2). The clinical presentation was characterized in 70% by pattern of co-expressed neurological symptoms: FMDs (9.5%); PNES (12%); dizziness/lipothymia (12%); paraesthesia/anaesthesia (16%). Generalized pain was associated in 38% of the reported patterns while cephalgia in 44%. Sleep disorders were reported in 40%. Previous psychiatric diagnoses were uncommon (2 out 82). Antecedent stressors were identified in 97% of patients for personal illness history and in the 93% for chronic illness in the family anamnesis. Family problems were in 25% of cases.
Conclusions
Our data contributes to better characterize the childhood population of FND, describing clinical patterns of presentation, highlighting putative antecedent stressors and risk factors
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. This 25 years old girl presented with chorea at the age of 2 years and remained stable up to the adult age when the emergence of fatigability and asthenia of lower limbs prompted a new examination disclosing a sensory-motor axonal demyelinating neuropathy. Clinical exome sequencing revealed two previously described variants in PNKP gene. This case highlights the phenotypic variability of PNKP associated disorders, showing that an early onset apparently non progressive chorea can be the presenting symptoms of this rare condition.
A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH4), although there is no consensus on the definition of BH4 responsiveness. The aim of this study ...therefore was to gain insight into the definitions of long-term BH4 responsiveness being used around the world.
We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other).
We analysed 166 responses. Long-term BH4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently.
The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH4 treatment.
PMM2-CDG (
PMM2
gene mutations) is the most common congenital disorder of
N
-glycosylation. We conducted a nationwide survey to characterize the frequency, clinical features, glycosylation and ...genetic correlates in Italian patients with PMM2-CDG. Clinical information was obtained through a questionnaire filled in by the referral physicians including demographics, neurological and systemic features, neuroimaging data and genotype. Glycosylation analyses of serum transferrin were complemented by MALDI-Mass Spectrometry (MALDI-MS). Between 1996 and 2012, data on 37 Italian patients with PMM2-CDG were collected. All the patients with a severe phenotype were unable to walk unaided, 84 % had severe intellectual disability and 81 % microcephaly. Conversely, among 17 mildly affected patients 82 % had independent ambulation, 64 % had borderline to mild intellectual disability and 35 % microcephaly. Epilepsy and stroke-like events did not occur among patients with the mild phenotype. The rate and extent of systemic involvement were more pronounced in severely affected patients. The L32R misfolding mutation of the PMM2 gene occurred in 70 % of the patients with the mild phenotype and was associated with a less severe underglycosylation of serum Tf at MALDI-MS analyses. Despite their different disease severity, all patients had progressive (olivo)ponto-cerebellar atrophy that was the hallmark clinical feature for the diagnosis. A mild neurological phenotype of PMM2-CDG marked by preserved ambulatory ability and autonomy and associated with L32R mutation is particularly frequent in Italy. PMM2-CDG should be considered in patients with even mild developmental disability and/or unexplained progressive cerebellar atrophy.
Leuzzi V, Carducci Ca, Carducci Cl, Pozzessere S, Burlina A, Cerone R, Concolino D, Donati MA, Fiori L, Meli C, Ponzone A, Porta F, Strisciuglio P, Antonozzi I, Blau N. Phenotypic variability, ...neurological outcome and genetics background of 6‐pyruvoyl‐tetrahydropterin synthase deficiency.
This study aimed to investigate the clinical variability and factors implied in the outcome of 6‐pyruvoyl‐tetrahydropterin synthase deficiency (PTPSd). Biochemical and clinical phenotype, treatment variables, and 6‐pyruvoyl‐tetrahydropterin synthase (PTS) genotype, were explored retrospectively in 19 Italian patients (12 males and 7 females, aged 4 months to 33 years).
According to the level of biogenic amines in cerebrospinal fluid (CSF) at the diagnosis, the patients were classified as mild (6) (normal level) or severe (13) (abnormal low level) form (MF and SF, respectively). Blood Phe ranged from 151 to 1053 µmol/l in MF (mean ± SD: 698 ± 403) and 342–2120 µmol/l in SF (mean ± SD: 1175 ± 517) (p = 0.063). Patients with MF showed a normal neurological development (a transient dystonia was detected in one), while all SF patients except one presented with severe neurological impairment and only four had a normal neurological development. The outcome of the SF was influenced by the precocity of the treatment. Serial CSF examinations revealed a decline of 5‐hydroxyindolacetic acid in MFs and an incomplete restoration of neurotransmitters in SFs: neither obviously affected the prognosis. PTS gene analysis detected 17 different mutations (seven so far unreported) (only one affected allele was identified in three subjects). A good correlation was found between genotype and clinical and biochemical phenotype.
The occurrence of brain neurotransmitter deficiency and its early correction (by the therapy) are the main prognostic factors in PTPSd.
PDF
