Filippo Manti

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype.

Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be common; however, very little is known about causative genes and genotype–phenotype correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic nature make it difficult to pool multiple pedigrees with the same underlying genetic defect to achieve consistent nosology. Nearly all autosomal genes responsible for recessive cognitive disorders have been identified in large consanguineous families from the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total of 5. Although several recurrent phenotypic abnormalities are described in some of these patients, the associated phenotype is usually referred to as nonsyndromic. By means of single-nucleotide polymorphism-array first and then by exome sequencing, we identified a new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and apparently nonconsanguineous parents. It consists of a homozygous splice site mutation causing exon skipping with frameshift and premature termination, as confirmed by mRNA sequencing. By detailed phenotypic analysis of our patients, and by critical literature review, we found that homozygous TRAPPC9 loss-of-function mutations cause a distinctive phenotype, characterized by peculiar facial appearance, obesity, hypotonia (all signs resembling a Prader–Willi-like phenotype), moderate-to-severe ID, and consistent brain abnormalities.

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 (Fishers 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.

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.

Age-Related Psychophysiological Vulnerability to Phenylalanine in Phenylketonuria

Background: Phenylketonuria (PKU) is caused by the inherited defect of the phenylalanine hydroxylase enzyme, which converts phenylalanine (Phe) into tyrosine (Tyr). Neonatal screening programs and early treatment have radically changed the natural history of PKU. Nevertheless, an increased risk of neurocognitive and psychiatric problems in adulthood remains a challenging aspect of the disease. In order to assess the vulnerability of complex skills to Phe, we explored: (a) the effect of a rapid increase in blood Phe levels on event-related potentials (ERP) in PKU subjects during their second decade of life; (b) the association (if existing) between psychophysiological and neurocognitive features. Methods: Seventeen early-treated PKU subjects, aged 10–20, underwent ERP [mismatch negativity, auditory P300, contingent negative variation (CNV), and Intensity Dependence of Auditory Evoked Potentials] recording before and 2 h after an oral loading of Phe. Neurocognitive functioning, historical and concurrent biochemical values of blood Phe, Tyr, and Phe/Tyr ratio, were all included in the statistical analysis. Results: Event-related potential components were normally detected in all the subjects. In subjects younger than 13 CNV amplitude, W2-CNV area, P3b latency, and reaction times in motor responses were negatively influenced by Phe-loading. Independently from the psychophysiological vulnerability, some neurocognitive skills were more impaired in younger patients. No correlation was found between biochemical alterations and neurocognitive and psychophysiological findings. Conclusion: The vulnerability of the emerging neurocognitive functions to Phe suggests a strict metabolic control in adolescents affected by PKU and a neurodevelopmental approach in the study of neurocognitive outcome in PKU.

Running apraxia as a presenting symptom of neuronal ceroid lipofuscinosis 6

condition by changing the stimulation parameters and by implanting a pump for intrathecal infusion of Baclofen were unsuccessful in modifying the symptomatic progress. Six years after GPi DBS, his clinical deterioration was evident on both the motor (70/120) and disability sections (20/30) of the BFMDRS (Fig. 1; Video Segment 3). Ours is the first case report of a genetically confirmed atypical form of PKAN, treated with GPi DBS with a follow-up of 6 years. Similarly to the patients in the Castelnau et al cohort, our patient maintained a global motor improvement up to 24 months after surgery. Differently, Krause et al. found that GPi DBS significantly improved motor function in a typical case of PKAN up to 5 years after surgery. This discrepancy was probably due to the different age of onset and clinical presentation of the two cases (classic vs atypical form). Moreover, spasticity progression accounted for most of the deterioration in our patient, and DBS of course does not relieve pyramidal symptoms. In conclusion, in our patient GPi DBS was effective in the short and mid-term, and less so in the long term. However, a multicenter, prospective study is necessary to collect both typical and atypical PKAN treated with GPi DBS in order to better predict both short and long-term outcomes from surgery.

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. 123I-Ioflupane SPECT was normal. Blood phenylalanine was slightly increased and PAH sequencing revealed compound heterozygosity for two variants, p.[Asp151Glu]:[Thr380Met]. CSF examination unexpectedly detected a remarkable reduction of homovanillic, 5-hydroxyindolacetic, and 5-methylthetrahydrofolic acids, which could not be ascribed to any alteration of tetrahydrobiopterin and related biogenic amine pathways. METHODS Trio-based exome sequencing was performed. RESULT A de novo missense variant (c.2669C > T/p.Pro890Leu) was detected in CLTC. Treatment with biogenic amine precursors was ineffective, while the inhibitor of MAO-A selegiline resulted in persistent clinical improvement. CONCLUSIONS We suggest CLTC defect as a new disorder of biogenic amine trafficking, resulting in neurodevelopmental derangement and movement disorder. Neurotransmitter depletion in CSF may be a biomarker of this disease, and selegiline a possible treatment option.

Successful Pregnancy in a Patient with L-Amino Acid Decarboxylase Deficiency: Therapeutic Management and Clinical Outcome: FIRST PREGNANCY IN AADC DEFICIENCY

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder of biogenic amine metabolism presenting with developmental delay, hypokinetic movement disorders, hypotonia, and autonomic dysfunctions. We report on the successful pregnancy in a previously reported 26-year-old AADC patient with a mild phenotype (Table 1). Since the diagnosis at the age of 22, treatment with rotigotine, pyridoxine, and escitalopram resulted in a remarkable improvement of fluctuating muscular weakness, oculogyric crises, palpebral ptosis, balance, and gait. After, as consequence of behavioral disinhibition and reduced control of sexual impulses, rotigotine was replaced by a prolonged release formulation of pramipexole (up to 0.78 mg/day once a day). Selegine was added to improve diurnal fluctuation of motor symptoms (up to 7.5 mg/day after a very slow dose increasing). While MAO-inhibitors and SSRIs association is contraindicated in common neuropsychiatric disorders due to the risk of serotonin intoxication syndrome, their synergic effect may be exploited to magnify the residual enzymatic activity in the defect of serotonin synthesis, such as AADC deficiency. The pregnancy of our patient occurred naturally at the age of 26. Escitalopram was suspended to prevent the risk of low birth weight. Doses of pramipexole and selegiline could be decreased (Table 1) without obvious neurological worsening. No oculogyric crises or myoclonic jerks were observed, and limb rigidity, fatigability, and muscular weakness were well controlled. UPDRS-part III score did not change with respect the prepregnancy status (Table 1). Blood pressure remained below the normal range for the age. At the 31 week of gestation preeclampsia occurred. At the 38 week of gestation, a cesarean delivery (cardiac deceleration at cardiotocography) resulted in the birth of a vital (Apgar score 9 and 10) low birth weight (2.440 grams) and small (for gestational age) male newborn. The infant presented with transient tachypnea and hypoglycemia in the first day after birth. His growth was regular after the early introduction of artificial nursing. No significant health problems were observed in the following months. Pregnancy was previously reported in inherited neurotransmitter disorders with a less severe phenotype than AADC deficiency (35 women with autosomal dominant guanosine triphosphate cyclohydrolase 1 deficiency, one with dihydropterine reductase deficiency, and one with 6-pyrovoyl-tetrahydrobiopterin synthase deficiency). The defect of monoaminergic neurotransmitters in AADC deficiency potentially impairs embryo-maternal interactions at preimplantation stages of early embryogenesis, which could be prevented by the treatment with drugs acting on dopaminergic axis. Efficacy and safety profile of pramipexole and selegiline during pregnancy and lactation are reported, in 24 and three women affected by Parkinson disease or restless legs syndrome, respectively. Pramipexole was associated with spontaneous abortion in 3 cases (co-exposition with isotretinoin in one case) while selegiline was associated with a ventral septal defect in a twin newborn (co-exposition with L-DOPA/carbidopa and entacapone). The present case shows that in AADC deficiency: (a) fertility may be not impaired, (b) the course of pregnancy can be successfully managed in patients with mild phenotypes, and (c) low dosages of pramipexole and selegiline may have a good efficacy and safety profile during pregnancy.

Living with phenylketonuria in adulthood: The PKU ATTITUDE study

Dietary treatment is the cornerstone of therapy for phenylketonuria (PKU), but adherence to low- phenylalanine diet progressively decreases after adolescence. We designed a survey to characterize the dietary habits of Italian adult PKU patients and to identify psychological factors influencing disease perception and adherence to diet. Participants to the survey (n = 111; response rate 94%) were asked to complete a structured questionnaire. Patients appeared to have an altered perception and awareness of the disease. About 40% of them did not consider PKU a disease and, despite declaring regular monitoring of phenylalanine levels (85%), nearly half of them reported a high plasma value over the last 6 months (>600 μmol/L, 48%) or were unable to specify it (31%). Adherence to PKU diet was unsatisfactory, with increased consumption of natural protein sources and reduced daily use of amino-acid supplements (<4–5 times/day in 82% patients). In addition to the intrinsic characteristics of AA formula (palatability, ease of use), the most important factor influencing their consumption was the increased social pressure associated with their use (55%). Plasma phenylalanine periodical measurements (61%) and examinations at metabolic centers (49%) were considered relevant for compliance to diet. In Italian adult PKU patients dietary management was found to be inadequate, likely due to inappropriate perception and knowledge of the disease, and lack of awareness of the negative impact of poor metabolic control in adult life. Clinicians should consider implementing more intense and tailored educational measures, as well as structured transitional care processes.

Screening for Developmental Disorders in 3- and 4-Year-Old Italian Children: A Preliminary Study

Background The “Osserviamo” project, coordinated by the Municipality of Rome and the Department of Pediatrics and Child Neuropsychiatry of Sapienza University, aimed to validate an Italian version of the Ages and Stages Questionnaire-3 and to collect, for the first time in Italy, data on developmental disorders in a sample of 4,000 children aged 3 and 4 years. The present paper presents the preliminary results of the “Osserviamo” project. Methods 600 parents of children between 39 and 50 months of age (divided in two age stages: 42 and 48 months) were contacted from 15 kindergarden schools. Results 23.35% of the whole sample scored in the risk range of at least one developmental area of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and 7.78% scored in the clinical range. Specifically, 23.97% of the children in the 42-month age stage scored in the risk range and 5.79% scored in the clinical range. Males scored lower than females in the fine motor skills and personal–social development domains. Moreover, 22.79% of the children in the 48-month age stage scored in the risk range, while 9.55% scored in the clinical range. Males scored lower than females in fine motor skills. Conclusion Italian validation of the ASQ-3 and recruitment of all 4,000 participants will allow these data on the distribution of developmental disorders to be extended to the general Italian pediatric population. One main limitation of the study is the lack of clinical confirmation of the data yielded by the screening programme, which the authors aim to obtain in later stages of the study.