Branched-chain amino acids as adjunctive-alternative treatment in patients with autism: a pilot study.

The branched-chain amino acid (BCAA) is a group of essential amino acids that are involved in maintaining the energy balance of a human being as well as the homoeostasis of GABAergic, glutamatergic, serotonergic and dopaminergic systems. Disruption of these systems has been associated with the pathophysiology of autism while low levels of these amino acids have been discovered in patients with autism. A pilot open-label, prospective, follow-up study of the use of BCAA in children with autistic behaviour was carried out. Fifty-five children between the ages of 6 and 18 participated in the study from May 2015 to May 2018. We used a carbohydrate-free BCAA-powdered mixture containing 45·5 g of leucine, 30 g of isoleucine and 24·5 g of valine in a daily dose of 0·4 g/kg of body weight which was administered every morning. Following the initiation of BCAA administration, children were submitted to a monthly psychological examination. Beyond the 4-week mark, BCAA were given to thirty-two people (58·18 %). Six of them (10·9 %) discontinued after 4-10 weeks owing to lack of improvement. The remaining twenty-six children (47·27 %) who took BCAA for longer than 10 weeks displayed improved social behaviour and interactions, as well as improvements in their speech, cooperation, stereotypy and, principally, their hyperactivity. There were no adverse reactions reported during the course of the treatment. Although these data are preliminary, there is some evidence that BCAA could be used as adjunctive treatment to conventional therapeutic methods for the management of autism.

Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303.

Blood pressure in children with sickle cell disease is higher than in the general pediatric population.

BACKGROUND: Sickle cell disease (SCD) is associated with an increased risk of cardiovascular disease that may be due to a variety of possible risk factors, including abnormal blood pressure. Blood pressure (BP) of children and adolescents with SCD has been reported to be lower compared to the BP of the general pediatric population. METHODS: To confirm this prior observation, we compared reference BP values for children with SCD with reference BP values of the general pediatric population. We hypothesized that children with SCD do not have lower BPs than children without SCD. RESULTS: Systolic BP differed for both males and females, over the different age groups between pediatric subjects with and without SCD. Systolic BP was higher in children with SCD, in both obese and non-obese populations. Diastolic BP did not differ between the groups. CONCLUSIONS: Our analysis demonstrated that systolic BP values are indeed higher in children with SCD than in the general pediatric population. This finding is consistent with the most recent literature showing abnormal BP patterns in the SCD pediatric population utilizing 24-hour BP monitoring devices. This is an important step for recognizing abnormal BP as a risk factor for cardio- and neurovascular events in SCD.

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Hypertension and childhood stroke.

Cerebrovascular disease (stroke) is one of the ten leading causes of death in children and adolescents. Multiple etiologies, from arteriopathies to prothrombic states, can cause stroke in youth. In adult stroke, hypertension has been shown to be the single most important modifiable risk factor. Although hypertension has not been strongly identified as a risk factor in childhood stroke to date, there is preliminary evidence that suggests that hypertension may also be associated with stroke in children. In this review, we summarize the literature that may link hypertension to stroke in the young. We have identified a series of barriers and limitations in the fields of pediatric hypertension and pediatric neurology that might explain why hypertension has been overlooked in childhood stroke. We suggest that hypertension may be a relevant risk factor that, alone or in combination with other multiple factors, contributes to the development of stroke in children. Currently, there are no consensus guidelines for the management of post-stroke hypertension in children. Thus, we recommend that blood pressure be assessed carefully in every child presenting with acute stroke in order to better understand the effects of hypertension in the development and the outcome of childhood stroke. We suggest a treatment algorithm to help practitioners manage hypertension after a stroke.

Severe clinical presentation in monozygotic twins with 10p15.3 microdeletion syndrome.

Submicroscopic deletion of 10p15.3 is a rare genetic disorder, currently reported in 21 unrelated patients. It is mainly associated with cognitive deficits, speech disorders, motor delay and hypotonia. The size of the deleted region ranges between 0.15 and 4 Mb and does not generally correlate with phenotype. A monozygotic female twin pair with a de novo 2.7 Mb deletion of 10p15.3 is herein reported. The girls presented at the age of 8 months with severe developmental delay and failure to thrive since the first month of life. Their perinatal and family history was unremarkable. On admission they both exhibited generalized dystonia, microcephaly, complete absence of voluntary movements and visual/auditory unresponsiveness. Their brain MRIs demonstrated dilatation of ventricles, subarachnoid spaces and anterior interhemispheric fissure and sylvian fissures bilaterally. Cranial radiography revealed partial fusion of both coronal sutures. Visual and brainstem auditory evoked potentials were markedly abnormal, indicating severe visual and sensorineural hearing impairment. The electroencephalogram, as well as a screening for inborn errors of metabolism, were unremarkable. Both patients required gastrostomy and tracheostomy before the age of 1 year. They were, additionally, managed with physical therapy, as well as baclofen and low-dose haloperidol. Their current state at the age of 2 years is relatively stable. The index patients' phenotype includes features, such as dystonic cerebral palsy, visual and sensorineural hearing impairment or craniosynostosis, which have not been previously reported in individuals with 10p15.3 deletion. It is necessary to consider these novel clinical features and investigate their possible relationship with the recently recognized syndrome.

Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy.

OBJECTIVE: Sepiapterin reductase deficiency (SRD) is an under-recognized levodopa-responsive disorder. We describe clinical, biochemical, and molecular findings in a cohort of patients with this treatable condition. We aim to improve awareness of the phenotype and available diagnostic and therapeutic strategies to reduce delayed diagnosis or misdiagnosis, optimize management, and improve understanding of pathophysiologic mechanisms. METHODS: Forty-three individuals with SRD were identified from 23 international medical centers. The phenotype and treatment response were assessed by chart review using a detailed standardized instrument and by literature review for cases for which records were unavailable. RESULTS: In most cases, motor and language delays, axial hypotonia, dystonia, weakness, oculogyric crises, and diurnal fluctuation of symptoms with sleep benefit become evident in infancy or childhood. Average age of onset is 7 months, with delay to diagnosis of 9.1 years. Misdiagnoses of cerebral palsy (CP) are common. Most patients benefit dramatically from levodopa/carbidopa, often with further improvement with the addition of 5-hydroxytryptophan. Cerebrospinal fluid findings are distinctive. Diagnosis is confirmed by mutation analysis and/or enzyme activity measurement in cultured fibroblasts. INTERPRETATION: Common, clinical findings of SRD, aside from oculogyric crises and diurnal fluctuation, are nonspecific and mimic CP with hypotonia or dystonia. Patients usually improve dramatically with treatment. Consequently, we recommend consideration of SRD not only in patients with levodopa-responsive motor disorders, but also in patients with developmental delays with axial hypotonia, and patients with unexplained or atypical presumed CP. Biochemical investigation of cerebrospinal fluid is the preferred method of initial investigation. Early diagnosis and treatment are recommended to prevent ongoing brain dysfunction.

Clinical course and seizure outcome of idiopathic childhood epilepsy: determinants of early and long-term prognosis.

BACKGROUND: Idiopathic epilepsies and epileptic syndromes predominate childhood and adolescence epilepsy. The aim of the present study was to investigate the clinical course and outcome of idiopathic childhood epilepsy and identify variables determining both early and long-term prognosis. METHODS: We followed 303 children with newly diagnosed idiopathic epilepsy aged 1-14 years old, both prospectively and retrospectively. Outcome was defined at one, 2 and 4 years of follow-up, as well as at the end of the study period for all patients. Based on the data collected, patients were classified in four patterns of clinical course: "excellent", "improving", "relapsing" and "poor". Variables defined at intake and after the initial year of treatment were analyzed for their prognostic relevance towards the clinical course and outcome of the patients. RESULTS: The mean age at seizure onset was 6.7 years and the mean duration of follow-up was 8.3 years (range 2,0-22,0,SD 4,24). During the initial year of treatment, 70,3% of patients were seizure-free. The course of epilepsy was "excellent" in 53,1% of the subjects, "improving" in 22,8%, "relapsing" in 22,1% whereas only 6 children with idiopathic epilepsy (2%) had a "poor" clinical course exhibiting drug-resistance. After multivariate analysis, variables predictive of a poor initial response to therapy were early seizure onset, multiple seizure types and history of status epilepticus. At the end of follow-up, early response to treatment was of significant positive predictive value, while the presence of multiple seizure types and the history of migraine had a negative impact on prognosis. CONCLUSIONS: In the vast majority of children, the long-term prognosis of idiopathic epilepsy is favorable. More than half of the patients attain seizure freedom immediately and their clinical course is considered "excellent". About one fifth exhibit either an improving or a fluctuating course. Early seizure onset, multiple seizure types and status epilepticus are predictive of an initial poor response to treatment in children with idiopathic epilepsy. Initial non-response to treatment, multiple seizure types and history of migraine are determinants of a less favorable final outcome after long-term follow-up.

Autism spectrum disorders: the quest for genetic syndromes.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD.

Developing treatment options for metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) represents a devastating lysosomal storage disease characterized by intralysosomal accumulation of the sphingolipid sulfatide in various tissues. Three types of the disease are currently distinguished: the late-infantile, which is the most commonly observed, the juvenile and the adult type. Demyelination represents the main histopathological feature of the disorder, leading to neurological impairment with no curative treatment currently available. Nevertheless, the increased scientific interest on the disease has led to the experimental use of innovative therapeutic approaches in animal models, aiming to provide an effective therapeutic regimen for human patients, as well. This paper provides an overview of developing treatment options among patients with MLD. Apart from hematopoietic stem cell transplantation, already in use for decades, other recent data discussed includes umbilical cord blood and stem cell transplantation, enzyme replacement therapy, gene therapy and autologous hematopoietic transplantation of genetically modified stem cells. Gene therapy with oligodedroglial, neural progenitor, embryonic and microencapsulated recombinant cells represents add-on treatment options still on experimental level.

MYH9-related disorders: report on a patient of Greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation.

Myosin heavy chain-9 (MYH9)-related disorders represent a heterogenous group of hereditary diseases caused by mutations in the gene encoding the heavy chain of nonmuscle myosin IIA. May-Hegglin anomaly and Fechtner, Sebastian, and Epstein syndromes are the four phenotypes of the disease, characterized by congenital macrothrombocytopenia and distinguished by different combinations of clinical signs that may include glomerulonephritis, sensorineural hearing loss, and presenile cataract. The spectrum of mutations responsible for the disease is wide and the existence of genotype-phenotype correlation remains a critical issue. We report the first case of an MYH9-RD in a patient of Greek origin presenting with macroscopic hematuria and presenile cataract caused by a p.R1165C mutation. The same mutation was present in the patient's father, who exhibited no extrahematological features of the disease. The p.R1165C mutation is one of the MYH9 alterations whose prognostic significance is still poorly defined. Thus, the patients described add to the limited existing data on the MYH9 mutations and their resultant phenotypes.

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis.

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

Hemimegalencephaly and tuberous sclerosis complex: A rare yet challenging association.

Hemimegalencephaly is a rare malformation of cortical development characterised by enlargement of one cerebral hemisphere. The association between hemimegalencephaly and tuberous sclerosis complex, an autosomal dominant genetic disorder, is uncommon and has so far been reported only in a few cases. Intractable epilepsy and severe developmental delay are typical clinical manifestations. Aberrant activation of the mTOR signalling pathway is considered to be the hallmark of the pathogenesis of these two disorders. Thus, mTOR inhibitors such as everolimus represent a promising therapeutic approach to mTOR-associated manifestations. We present a thorough literature review of the association between hemimegaloencephaly and tuberous sclerosis complex.

The Complex Interplay of Cortex, Cerebellum, and Age in a Cohort of Pediatric Patients With Tuberous Sclerosis Complex.

BACKGROUND: The neurodevelopmental impairment in tuberous sclerosis complex (TSC) has a multifactorial origin. Various factors have been proposed as predictors of neurological outcome such as tuber load, seizure onset, and TSC2 mutation. Cerebellar lesions have been associated with worse neuroradiological phenotype, but their contribution is not well understood. METHODS: A partly retrospective and partly prospective pediatric cohort study was conducted at three hospitals in Greece between 2015 and 2020. Patients aged ≤ 18 years with a confirmed TSC daignosis were included and underwent brain imaging, a semistructured interview (authorized Greek version of the tuberous sclerosis-associated neuropsychiatric disorders, or TAND, checklist), and intellectual ability assessment. RESULTS: The study populations consisted of 45 patients with TSC (22 females, 23 males; mean age 9.53 years). Twenty patients (44.4%) had cerebellar lesions. Cerebellar involvement was the most powerful predictor of tuber load (P = 0.03). Cerebellar lesions were associated with giant cell astrocytomas (SEGAs) (P = 0.01) and severe neurological outcome (P = 0.01). Even though in the univariate analysis early seizure onset, tuber load, and cerebellar involvement were associated with intellectual impairment and neurological severity, none of them was an independent predictor of cognitive outcome and neurological severity. CONCLUSIONS: Cerebellar lesions are common among individuals with TSC. Cerebellar involvement correlates with supratentorial derangement and the development of SEGAs, which is suggestive of a more severe clinical and neuroradiological phenotype. Cerebellar involvement and early seizure onset were not independent predictors of either neurological severity or intellectual disability or neurobehavioral outcome; their role in TSC clinical phenotype should be further investigated.

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.

An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.

L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients.

PURPOSE: To describe the pattern of magnetic resonance (MR) imaging abnormalities in l-2-hydroxyglutaric aciduria (L2HGA) and to evaluate the correlation between imaging abnormalities and disease duration. MATERIALS AND METHODS: MR images in 56 patients (30 male, 26 female; mean age +/- standard deviation, 11.9 years +/- 8.5) with genetically confirmed L2HGA were retrospectively reviewed, with institutional review board approval and waiver of informed consent. At least one complete series of transverse T2-weighted images was available for all patients. The images were evaluated by using a previously established scoring list. The correlation between MR imaging abnormalities and disease duration was assessed (Mann-Whitney or Kruskal-Wallis test). RESULTS: The cerebral white matter (WM) abnormalities preferentially affected the frontal and subcortical regions. The abnormal subcortical WM often had a mildly swollen appearance (37 patients). Initially, the WM abnormalities were at least partially multifocal (32 patients). In patients with longer disease duration, the WM abnormalities became more confluent and spread centripetally, but the periventricular rim remained relatively spared (41 patients). The mean disease duration in patients with WM atrophy (14.8 years) was significantly longer (P = .001) than that in patients without atrophy (6.7 years). Bilateral involvement of the globus pallidus (55 patients), caudate nucleus (56 patients), and putamen (56 patients) was seen at all stages. The cerebellar WM was never affected. The dentate nucleus was involved bilaterally in 55 of 56 patients. CONCLUSION: L2HGA has a distinct highly characteristic pattern of MR imaging abnormalities: a combination of predominantly subcortical cerebral WM abnormalities and abnormalities of the dentate nucleus, globus pallidus, putamen, and caudate nucleus. With increasing disease duration, WM abnormalities and basal ganglia signal intensity abnormalities become more diffuse and cerebral WM atrophy ensues.

Neurological complications in childhood nephrotic syndrome: A systematic review.

BACKGROUND AND OBJECTIVE: Nephrotic syndrome (NS) in childhood can be accompanied by serious neurological complications increasing the morbidity of disease. The study aimed to assess the spectrum of neurological complications in children with in terms of clinical presentation, contributory risk factors, and outcome. METHODS: In this systematic review, we searched for articles in PubMed, providing individual patient-level data for any neurological complication in children and adolescents with primary NS, between January 1, 1990 and April 30, 2018. FINDINGS: The search yielded 63 articles, involving 103 patients. Events occurred more frequently during nephrotic state relapses; 71.6% of cerebral thromboembolic (TE) events and 81.2% of posterior reversible encephalopathy (PRES) cases. Median duration of disease before a cerebral TE event was 3 months (IQR 0-27), and 18 months (IQR 1-37.5) for PRES. Among cases with TE, 73.1% presented with cerebral sinovenous thrombosis (CSVT), and 16.9% parenchymal lesions. 70% of patients had a risk factor for neurological complication including NS-associated thrombophilia, hypertension, and treatment with immunosuppressive agents. Outcome was favorable in 93.8% of the patients with PRES. In patients with cerebral TE outcome was favorable in 95.8% of the cases with CSVT only, and in 64.7% of the cases with parenchymal lesions. CONCLUSIONS: Neurological complications may occur in children with primary NS and risk factors during nephrotic state relapses. The outcome for PRES has been reported favorable. Outcome in cerebral TE events may differ by the presence of venous or artery infarct. Recognition of additional protrombotic state risk factors may help to lower the incidence of neurological complications.

Two Greek siblings with sepiapterin reductase deficiency.

BACKGROUND: Sepiapterin reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far. METHODS: We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis. RESULTS: Both patients suffered from a progressive and complex L-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X). CONCLUSIONS: Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with L-dopa, is illustrated again in our cases.