The neurological and psychological phenotype of adult patients with early-treated phenylketonuria: A systematic review.

Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long-term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine-restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early-treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early-treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU-specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

The long-term treatment of a patient with type 1 diabetes mellitus and glutaric aciduria type 1: the effect of insulin.

UNLABELLED: The coexistence of two diseases associated with different metabolic disorders is a very rare event. Some associations, although sporadic, can be particularly challenging both in terms of diagnostic and therapeutic management and in terms of theoretical perspective. Here, we report a child affected by type 1 diabetes mellitus (T1DM) and glutaric aciduria type 1 (GA1). The child was diagnosed with classical T1DM at 15 months of age, with a tendency toward hypoglycemia. A few months later, during an acute intercurrent infective episode, the child displayed acute hypotonia of the lower limbs and limbs dystonia. A brain MRI showed bilateral striatal necrosis, suggesting GA1 diagnosis. Treatment with a low-lysine dietary regimen and carnitine supplementation was started and resulted in an improvement in metabolic control and a reduction of hypoglycemic episodes along with an increasing in insulin daily dose. After 2 years, the neurological outcome consisted of a reduction in dystonic movements and a metabolic stability of both diseases. CONCLUSION: This case provides some insight into the reciprocal interconnections between the two metabolic disorders. Similar pathogenic mechanisms responsible for the neuronal injury might have impacted each other, and a strict relationship between a specific aspect of GA1-impaired metabolism and glucose homeostasis might explain how the tailored management of GA1 was not only effective in controlling the disease, but it also resulted in an improvement in the control of the glycemic profile. What in known: • Glutaric aciduria type 1 (GA1) usually presents in childhood with severe and possibly irreversible neuronal damage, triggered by a catabolic stress • The association of GA1 with other diseases, including type 1 diabetes mellitus (T1DM), is a rare event, complicating the treatment management What is new: • Insulin treatment has a role in preventing GA1 metabolic decompensation, even in the catabolic condition of hypoglycemia • Promoting GA1 metabolic equilibrium by tailoring drug and dietary treatment in our patient affect by T1DM has a positive impact also in improving glycemic balance.

Quality of Life (QoL) assessment in a cohort of patients with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is a chronic inborn error of amino acid metabolism that requires lifelong follow-up and intervention, which may represent strains on Quality of Life (QoL). This observational study evaluated QoL in a cohort of PKU patients, using updated and detailed instruments. METHODS: 22 patients with mild PKU respondent to BH4 and 21 patients with classical PKU treated with diet were recruited in this study. Adult patients completed WHOQOL questionnaire-100 (WHOQOL-100) and pediatric patients the Pediatric QoL inventory (PedsQL(TM)). Psychiatric and mood disorders were also evaluated using TAD or BDI and STAI-Y inventories. A multivariable linear regression model was fitted to investigate the predictors of QoL, including age, sex, treatment type, length of current treatment, educational level and employment status (only for adults) as covariates. Results were presented as regression coefficients with 95% confidence interval. RESULTS: Global QoL scores were within normal range both in patients with mild and classical disease but global QoL scores were significantly higher in patients with mild PKU under BH4 treatment as compared to those affected by classical disease who were under diet regimen. Furthermore, QoL significantly increased in long treated PKU patients. Among adult patients, QoL scores were significantly lower in males, in patients with lower education and in those employed or unemployed as compared to students (baseline). CONCLUSIONS: Both diet and medical treatment based upon BH4 seem to be associated with higher QoL in the long run. However, patients with mild PKU can rely on BH4 to achieve a higher Phe tolerance and a better compliance to therapy due to diet relaxation/avoidance. Some specific categories of patients with a lower QoL should be investigated more in depth, engaging with those at risk of lower treatment compliance. The questionnaires employed in the present study seemed to be able to effectively detect criticalities in QoL assessment and represent an advance from previous inventories employed in the past.

Current insights into familial spastic paraparesis: new advances in an old disease.

Hereditary spastic paraparesis (HSP) comprises a clinically and genetically heterogeneous group of disorders characterized by progressive spasticity and hyperreflexia of the lower limbs. The past few years have witnessed an exponential increase in knowledge of this disease and we can now list 19 loci mapped on the human genome and eight genes cloned. However, this wider knowledge of the molecular basis of HSP has had limited impact on clinical practice: the use of antispastic drugs and regular physiotherapy still remain crucial in the therapeutic management of patients. Nonetheless, the identification of new genes mutated in HSP furthers comprehension of the pathomechanisms involved and helps in genetic counseling, especially of asymptomatic individuals who request molecular analyses.

A new case of malonic aciduria with a presymptomatic diagnosis and an early treatment.

Malonyl-CoA decarboxylase deficiency (MLYCD) is a rare autosomal recessive inborn error of metabolism presenting a variable clinical phenotype. We report an affected Italian male receiving an early diagnosis (8days after birth) and a timely dietary therapy (high carbohydrate, low long chain fatty acid and medium chain triglyceride supplemented diet with l-carnitine supplementation). The boy was born at term and presented normal function of the heart (except for a tricuspid Ebstein-like dysplasia) and neurodevelopmental status. Genomic sequencing of MLYCD gene revealed two point mutations (c.672G>A, c.869C>T) not listed in the Human MLYCD Allelic Variant Database nor in Human Gene Mutation Database, responsible for a deleterious effect on protein structure and function according to a computational analysis (MuPro, SIFT, ConSEQ v1.1). At the age of 2years he only showed a mild language and psychomotor delay, while heart functioning became normal. Brain MRI examination was normal. Thirty-five cases, including our patient, have been described to date. This is the first report concerning a malonic aciduria patient diagnosed on newborn screening and treated in a presymptomatic stage of the disease.

Diagnostic work-up and therapeutic options in management of pediatric status epilepticus.

BACKGROUND: Status epilepticus (SE) is a life-threatening neurologic disorder comprising prolonged and unremitting crisis, and two or more series of seizures without complete intercritical recovery. DATA SOURCES: We reviewed the literature through a Pubmed/Medline research using key words including status epilepticus, antiepileptic drugs and children, in order to revise and compare international/national protocols and to examine pediatric guidelines in SE management. RESULTS: Neurologic impairment and SE etiology seem to be the most independent risks for mortality. A deep semiologic evaluation is essential to addressing diagnostic work-up. Ematochemical parameters, plasma levels of antiepileptic drugs and clinically oriented toxic/metabolic screening should be mandatory for investigating both causes and effects of SE. Electroencephalography is clearly helpful to characterize focal from generalized SE and to distinguish epileptic events from pseudoseizures, and it is deal to find nonconvulsive SE. Neuroimaging techniques could detect epileptogenic lesions (such as cortical malformations, tumors, demyelinating disorders or strokes) but are common in practice to find negative or controversial results. Pharmacologic management can be essentially arranged in three stages: benzodiazepines for early SE (lasting less than 30 minutes), phenytoin/fosphenytoin, phenobarbital, valproate, levetiracetam or lacosamide for established SE (30-90 minutes), and anesthetics for refractory SE (more than 90 minutes). CONCLUSIONS: Status epilepticus is the most common neurologic emergency in childhood. A systematic diagnostic work-up and a three steps based therapeutic approach is required at this age.

A diagnostic algorithm for the evaluation of early onset genetic-metabolic epileptic encephalopathies.

Early onset epileptic encephalopathies represent a struggling challenge in neurological clinical practice, mostly in infants and very young children, partly due to an unclear and still debated cathegorization. In this scenario genetic and metabolic epileptic encephalopathies play a central role, with new entries still needing an arrangement. In this Paper we present a brief overview on genes, metabolic disorders and syndromes picturing the pathogenesis of genetic and metabolic epileptic encephalopathies with onset under one year of age. These forms will be classified, according to a combined clinical and genetic-metabolic criterion, into two main groups including seizures as prominent/unique symptom and seizures associated with a syndromic phenotype. Starting from this classification we suggest a possible simplified diagnostic algorithm, discussing main decision making nodes in practical patients management. The aim of the proposed algorithm is to guide through metabolic and molecular-genetic work up and to clarify "where" and "what" to search in biochemical, electroencephalographic and neuroimaging investigations.