Inherited muscle disorders are caused by pathogenic changes in numerous genes. Herein, we aimed to investigate the etiology of muscle disease in 24 consecutive Greek patients with myopathy suspected to be genetic in origin, based on clinical presentation and laboratory and electrophysiological findings and absence of known acquired causes of myopathy. Of these, 16 patients (8 females, median 24 years-old, range 7 to 67 years-old) were diagnosed by Whole Exome Sequencing as suffering from a specific type of inherited muscle disorder. Specifically, we have identified causative variants in 6 limb-girdle muscular dystrophy genes (6 patients; ANO5, CAPN3, DYSF, ISPD, LAMA2, SGCA), 3 metabolic myopathy genes (4 patients; CPT2, ETFDH, GAA), 1 congenital myotonia gene (1 patient; CLCN1), 1 mitochondrial myopathy gene (1 patient; MT-TE) and 3 other myopathy-associated genes (4 patients; CAV3, LMNA, MYOT). In 6 additional family members affected by myopathy, we reached genetic diagnosis following identification of a causative variant in an index patient. In our patients, genetic diagnosis ended a lengthy diagnostic process and, in the case of Multiple acyl-CoA dehydrogenase deficiency and Pompe's disease, it enabled specific treatment to be initiated. These results further expand the genotypic and phenotypic spectrum of inherited myopathies.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.

Objectives: Phenylalanine hydroxylase deficiency is an autosomal recessive inborn error of phenylalanine metabolism.

What is new?: Εven in cases with negative newborn screening for inborn errors of metabolism, the possibility of a metabolic disorder including PKU should be considered in any child presenting symptoms of developmental disorders. Late diagnosed PKU patients require a more specialized and individualized management than if they were early treatment cases.

Case presentation: We discuss a case of a child with typical autistic symptomatology, in whom years later a diagnosis of phenylketonuria was set, even neonatal screening was negative. Τhe patient was placed on a phenylalanine-restricted diet. After a period of clinical improvement, severe behavioral problems with aggressiveness and anxiety were presented. Less restrictive diet ameliorated the symptomatology.

Conclusion: This case highlights the major medical importance of adequate newborn screening policy, in order to avoid missed diagnosed cases. PKU may be presented as autism spectrum disorder. Dietary management needs individualized attentive monitoring.

Alzheimer disease (AD) is a global health concern with the majority of pharmacotherapy choices consisting of symptomatic treatment. Recently, ketogenic therapies have been tested in randomized controlled trials (RCTs), focusing on delaying disease progression and ameliorating cognitive function. The present systematic review aimed to aggregate the results of trials examining the effects of ketogenic therapy on patients with AD/mild cognitive impairment (MCI). A systematic search was conducted on PubMed, CENTRAL, clinicaltrials.gov, and gray literature for RCTs performed on adults, published in English until 1 April, 2019, assessing the effects of ketogenic therapy on MCI and/or AD compared against placebo, usual diet, or meals lacking ketogenic agents. Two researchers independently extracted data and assessed risk of bias with the Cochrane tool. A total of 10 RCTs were identified, fulfilling the inclusion criteria. Interventions were heterogeneous, acute or long term (45-180 d), including adherence to a ketogenic diet, intake of ready-to-consume drinks, medium-chain triglyceride (MCT) powder for drinks preparation, yoghurt enriched with MCTs, MCT capsules, and ketogenic formulas/meals. The use of ketoneurotherapeutics proved effective in improving general cognition using the Alzheimer's Disease Assessment Scale-Cognitive, in interventions of either duration. In addition, long-term ketogenic therapy improved episodic and secondary memory. Psychological health, executive ability, and attention were not improved. Increases in blood ketone concentrations were unanimous and correlated to the neurocognitive battery based on various tests. Cerebral ketone uptake and utilization were improved, as indicated by the global brain cerebral metabolic rate for ketones and [11C] acetoacetate. Ketone concentrations and cognitive performance differed between APOE ε4(+) and APOE ε4(-) participants, indicating a delayed response among the former and an improved response among the latter. Although research on the subject is still in the early stages and highly heterogeneous in terms of study design, interventions, and outcome measures, ketogenic therapy appears promising in improving both acute and long-term cognition among patients with AD/MCI. This systematic review was registered at www.crd.york.ac.uk/prospero as CRD42019128311.

Background: Promising genetic treatments targeting the molecular defect of severe early-onset genetic conditions are expected to dramatically improve patients' quality of life and disease epidemiology. Spinal Muscular Atrophy (SMA), is one of these conditions and approved therapeutic approaches have recently become available to patients.

Objective: Analysis of genetic and clinical data from SMA patients referred to the single public-sector provider of genetic services for the disease throughout Greece followed by a retrospective assessment in the context of epidemiology and genotype-phenotype associations.

Methods: Molecular genetic analysis and retrospective evaluation of findings for 361 patients tested positive for SMA- and 862 apparently healthy subjects from the general population. Spearman rank test and generalized linear models were applied to evaluate secondary modifying factors with respect to their impact on clinical severity and age of onset.

Results: Causative variations- including 5 novel variants- were detected indicating a minimal incidence of about 1/12,000, and a prevalence of at least 1.5/100,000. For prognosis a minimal model pertaining disease onset before 18 months was proposed to include copy numbers of NAIP (OR = 9.9;95% CI, 4.7 to 21) and SMN2 (OR = 6.2;95% CI, 2.5-15.2) genes as well as gender (OR = 2.2;95% CI, 1.04 to 4.6).

Conclusions: This long-term survey shares valuable information on the current status and practices for SMA diagnosis on a population basis and provides an important reference point for the future assessment of strategic advances towards disease prevention and health care planning.

Rationale & objective: Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD.

Study design: Prospective observational study.

Setting & participants: 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied.

Predictors: Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants.

Outcomes: Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate.

Analytical approach: Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis.

Results: 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m². The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants.

Limitations: The presence of cardiovascular disease was mainly based on medical history.

Conclusions: The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.

Background: While there are guidelines for the use of intravenous immunoglobulins in children with Guillain-Barre syndrome and myasthenia gravis based on high-level evidence studies, data are scarce for the majority of neurologic disorders in this age group. Neuronal antibodies are detected in children with seizures of autoimmune etiology. Intravenous immunoglobulins with their broad immunomodulatory mechanism of action could be ideally effective in different forms of immunedysregulated intractable epilepsies such as autoimmune epilepsy and autoimmune Rasmussen encephalitis. We conducted a systematic review of the literature for evidence of the use of intravenous immunoglobulins in a variety of neurologic diseases in childhood.

Method: A comprehensive literature search was conducted using Pubmed as the medical database source without date range. Prospective studies in pediatric groups including objective measures of clinical outcomes were systematically selected.

Results: A total of 11 prospective studies were identified in the literature demonstrating a favorable effect of this therapeutic option in children with drug-resistant epilepsy and in cases of encephalitis. No serious adverse effects were reported. No prospective studies about the use of intravenous immunoglobulins in children with demyelinating disorders or neurologic paraneoplasmatic syndromes were found.

Conclusion: In this review, we summarize the recent advances in the field of intravenous immunoglobulins used in pediatric neurological diseases. Literature data supports a beneficial effect in this age group. Whilst awaiting the results of large scale studies, administration of intravenous immunoglobulins could be justified in refractory child epilepsy. Otherwise, its use should be guided by the individual needs of each child, depending on the underlying neurological disease.

Need and purpose: Cardiac involvement is a part of many inborn errors of metabolism, but has not been systematically studied. This review focuses on studies describing cardiac manifestations of inborn errors of metabolism in childhood.

Methods: Two independent reviewers searched the topic using PubMed database. Studies published within 20 years were considered, without applying any restrictions related to study design. Despite the small number of existing systematic studies on the topic, several case series/reports were identified.

Conclusions: Cardiomyopathy is the most frequent heart disorder in most metabolic defects. Heart rhythm disorders are mainly encountered in mitochondrial disorders and acidemias, whereas valvular dysfunction is a prominent finding in storage disorders. Cardiac involvement in mitochondrial disorders, congenital disorders of glycosylation and acidemias usually constitute an early symptom. On the contrary, in storage disorders, heart problems are revealed in later stages during routine multisystemic evaluation, with the exception of Pompe disease. As a variety of cardiac manifestations can be found in inborn errors of metabolism, these children should be systematically screened for heart problems during their follow-up.

The authors present a case of carnitine transporter deficiency, which was unmasked after an episode of respiratory distress resistant to treatment with bronchodilators. Chest radiograph showed cardiomegaly; electrocardiogram showed left ventricular hypertrophy and echocardiography revealed dilated cardiomyopathy. Heart failure therapy was initiated and metabolic screening was requested, as family history was indicative of inborn errors of metabolism. Very low levels of free carnitine and carnitine esters in blood were found and genetic testing confirmed the diagnosis of carnitine transporter deficiency. After oral supplementation with L-carnitine, symptoms gradually ameliorated and heart function had fully recovered. Sequence analysis in the SLC22A5 gene revealed the missense mutation c.1319C > T (p.Th440Met) in homozygous state. Homozygous c.1319C > T (p.Th440Met) mutation has not been associated with a pure cardiac phenotype before.

Introduction: Although ketogenic diet has been proven useful in the management of intractable seizures, interactions with other medicines have been reported. This study reports two patients on co-administration with ketogenic diet and valproate appearing undesirable side effects after increase or decrease of valproate pharmaceutical levels.

Methods: Totally 75 patients suffering from drug-resistant epilepsy were treated with ketogenic diet in our departments. Their age varied from 6 months to 9 years. All patients were followed for at least 12 months and up to five years. Clinical and laboratory variables have been regularly assessed.

Results: In 75 patients treated with ketogenic diet and valproate at the same time treatment was well tolerated. Two patients presented mild to moderate undesirable effects. In these patients the removal of valproate treatment resulted in an increase of ketosis with respective clinical signs. The conversion of the diet from 4:1 to 1:1 and 2,5:1 respectively resulted in reduction of ketosis and clinical improvement.

Conclusion: In the majority of cases co-administration of valproate and ketogenic diet seems to be safe. In two cases, valproate appeared to have a negative effect on ketosis (and weaning it led to over-ketosis). This interaction is worthy of future study.

Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.

We screened for the presence of inborn errors of metabolism (IEM) in 187 children (105 males; 82 females, ages 4-14 years old) who presented with confirmed features of autism spectrum disorder (ASD). Twelve patients (7%) manifested increased 3-hydroxyisovaleric acid (3-OH-IVA) excretion in urine, and minor to significant improvement in autistic features was observed in seven patients following supplementation with biotin. Five diagnoses included: Lesch Nyhan syndrome (2), succinic semialdehyde dehydrogenase (SSADH) deficiency (2), and phenylketonuria (1) (2.7%). Additional metabolic disturbances suggestive of IEMs included two patients whose increased urine 3-OH-IVA was accompanied by elevated methylcitrate and lactate in sera, and 30 patients that showed abnormal glucose-loading tests. In the latter group, 16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD). Five patients showed decreased serum ketone body production with glucose loading. Twelve of 187 patients demonstrated non-specific MRI pathology, while 25/187 had abnormal electroencephalogram (EEG) findings. Finally, family history was positive for 22/187 patients (1st or 2nd degree relative with comparable symptomatology) and consanguinity was documented for 12/187 patients. Our data provide evidence for a new biomarker (3-OH-IVA) and novel treatment approaches in ASD patients. Concise 1 sentence take-home message: Detailed metabolic screening in a Greek cohort of ASD patients revealed biomarkers (urine 3-hydroxyisovaleric acid and serum b-OH-b) in 7% (13/187) of patients for whom biotin supplementation or institution of a KD resulted in mild to significant clinical improvement in autistic features.

Isovaleric acidemia is a rare branched-chain organic acidemia. The authors describe a 3.5-year-old girl with isovaleric acidemia and acute abdominal pain associated with bilious emesis. Elevated serum amylase and abdominal ultrasonography demonstrating an enlarged and edematous pancreas, along with the presence of peripancreatic exudates, confirmed the presence of acute pancreatitis. The patient recovered quickly with intravenous hydration, pancreatic rest, and administration of intravenous L-carnitine. Pancreatitis should be ruled out in the context of vomiting in any patient with isovaleric acidemia. Conversely, branched-chain organic acidemias should be included in the differential diagnosis of any child with pancreatitis of unknown origin.

Glucose metabolism of children with drug-resistant epilepsy, controlled by antiepileptic drugs epilepsy, and first-time nonfebrile seizures was studied through the performance of an oral glucose tolerance test and through insulin, C-peptide, and glycosylated hemoglobin measurements. In the refractory epilepsy group, there were more abnormal oral glucose tolerance test results (62.07%) in comparison to the controlled epilepsy group (25%) and the group of first-time seizures (21.21%). There was a significant difference between the group of refractory epilepsy and every other group concerning the abnormality of the oral glucose tolerance test (P < .05). The mean values of insulin, HbA_1c, and C-peptide levels were normal for all groups. The results of the present study suggest that there is a distinction of refractory epilepsies from the drug-controlled ones and the first-induced seizures relating to their metabolic profile, regardless of the type of seizures.