Gain-of-function variants in the ion channel gene underlie a spectrum of neurodevelopmental disorders.

TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function .

Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies.

Cerebral folate deficiency syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appears to be largely determined by the presence or absence of intrauterine folate deficiency as well as postnatal age at which cerebral folate deficiency occurs. The primary cause of CFDS is identified as the presence of serum folate receptor-alpha (FRα) autoantibodies impairing folate transport across the choroid plexus to the brain whereas, in a minority of cases, mitochondrial disorders, inborn errors of metabolism and loss of function mutations of the FRα () gene are identified.

Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention.

Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) pregnancies but is unlikely to prevent pregnancy-related complications in the presence of folate receptor autoantibodies (FRAb). In pregnancy, these autoantibodies can block folate transport to the fetus and in young children, folate transport to the brain.

Oxidative Stress, Folate Receptor Autoimmunity, and CSF Findings in Severe Infantile Autism.

Background: Biomarkers such as oxidative stress, folate receptor alpha (FR) autoimmunity, and abnormal brain serotonin turnover are common in autism.

Methods: Oxidative stress biomarkers with pro- and antioxidants were measured in the severe form of infantile autism ( = 38) and controls ( = 24). Children and parents had repeated testing for serum FR autoantibodies, spinal fluid dopamine and serotonin metabolites, pterins, and N-methyltetrahydrofolate (MTHF).

loss of function variants contribute to cerebral folate deficiency by downregulating expression.

Cerebral folate deficiency (CFD) syndrome is characterised by a low concentration of 5-methyltetrahydrofolate in cerebrospinal fluid, while folate levels in plasma and red blood cells are in the low normal range. Mutations in several folate pathway genes, including , , and ) have been previously identified in patients with CFD. In an effort to identify causal mutations for CFD, we performed whole exome sequencing analysis on eight CFD trios and identified eight de novo mutations in seven trios.

Improving Outcome in Infantile Autism with Folate Receptor Autoimmunity and Nutritional Derangements: A Self-Controlled Trial.

Background: In contrast to multiple rare monogenetic abnormalities, a common biomarker among children with infantile autism and their parents is the discovery of serum autoantibodies directed to the folate receptor alpha (FR) localized at blood-brain and placental barriers, impairing physiologic folate transfer to the brain and fetus. Since outcome after behavioral intervention remains poor, a trial was designed to treat folate receptor alpha (FR) autoimmunity combined with correction of deficient nutrients due to abnormal feeding habits.

Methods: All participants with nonsyndromic infantile autism underwent a routine protocol measuring CBC, iron, vitamins, coenzyme Q10, metals, and trace elements.

A novel missense variant in causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets.

Background: Brain monoamine vesicular transport disease is an infantile onset neurodevelopmental disorder caused by variants in , which codes for the vesicular monoamine transporter 2 (VMAT2) protein, involved in the transport of monoamines into synaptic vesicles and of serotonin into platelet dense granules.

Case Presentation: The presented case is of a child, born of healthy consanguineous parents, who exhibited hypotonia, mental disability, epilepsy, uncontrolled movements, and gastrointestinal problems. A trial treatment with L-DOPA proved unsuccessful and the exact neurological involvement could not be discerned due to normal metabolic and brain magnetic resonance imaging results.

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

Purpose: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome.

Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.

Paraspinal Arterio-Venous Fistula in Children: Two More Cases of an Exceptional Malformation.

We report on the case of two toddlers who presented in the last 2 years with heart and vascular murmur, respectively, and in whom the diagnosis of paraspinal arterio-venous fistula was made. Paraspinal arterio-venous fistulae in children are extremely rare congenital or post-traumatic vascular malformations. In the rare case of connection with the spinal venous system, they might affect spinal vascularization due to potential venous congestion.

Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene.

Background: Patients with autism spectrum disorder (ASD) may have low brain serotonin concentrations as reflected by the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in cerebrospinal fluid (CSF).

Methods: We sequenced the candidate genes SLC6A4 (SERT), SLC29A4 (PMAT), and GCHFR (GFRP), followed by whole exome analysis.

Results: The known heterozygous p.

The diagnostic utility of folate receptor autoantibodies in blood.

Folate supplementation reduces the risk of neural tube defect (NTD) pregnancy, and folinic acid has been used to correct cerebral folate deficiency (CFD) in children with developmental disorders. In the absence of systemic folate deficiency, the discovery of autoantibodies (AuAbs) to folate receptor α (FRα) that block the uptake of folate offers one mechanism to explain the response to folate in these disorders. The association of FRα AuAbs with pregnancy-related complications, CFD syndrome, and autism spectrum disorders and response to folate therapy is highly suggestive of the involvement of these AuAbs in the disruption of brain development and function via folate pathways.

Clinical recognition and aspects of the cerebral folate deficiency syndromes.

We characterized cerebral folate deficiency (CFD) as any neuro-psychiatric condition associated with low spinal fluid (CSF) N5-methyltetrahydrofolate (MTHF) but normal folate status outside the central nervous system (CNS). The commonest cause underlying CFD syndromes is the presence of serum autoantibodies of the blocking type directed against folate receptor-α (FRα) attached to the plasma-side of choroid plexus epithelial cells. Blocking FR antibodies inhibit MTHF transport across the choroid plexus.

Autism associated with low 5-hydroxyindolacetic acid in CSF and the heterozygous SLC6A4 gene Gly56Ala plus 5-HTTLPR L/L promoter variants.

The known Gly56Ala mutation in the serotonin transporter SERT (or 5-HTT), encoded by the SLC6A4 gene, causes increased serotonin reuptake and has been associated with autism and rigid-compulsive behavior. We report a patient with macrocephaly from birth, followed by hypotonia, developmental delay, ataxia and a diagnosis of atypical autism (PDD-NOS) in retrospect at the age of 4½years. Low levels of the serotonin end-metabolite 5-hydroxyindolacetic acid (5HIAA) in CSF were detected, and SLC6A4 gene analysis revealed the heterozygous Gly56Ala alteration and the homozygous 5-HTTLPR L/L promoter variant.

Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport.

Metabolic breakdown of valproate (VPA), carbamazepine (CBZ) and phenytoin (PHT) by the cytochrome P450 pathway generates toxic drug intermediates and reactive oxygen species (ROS). This mechanism has been suspected to play a role in the pathogenesis of secondary cerebral folate deficiency (CFD). Using KB-cell cultures, highly expressing the folate receptor 1 (FOLR1), the effect of antiepileptic drugs (AEDs) and reactive oxygen species (ROS) on the FOLR1 dependent 5-methyltetrahydrofolate (MTHF) uptake was studied.

Cerebral folate deficiency and CNS inflammatory markers in Alpers disease.

We describe a 3.5-year-old female with Alpers disease with a POLG genotype of p.A467T/p.

Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.

We describe members of 4 kindreds with a previously unrecognized syndrome characterized by seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (hypokalemia, metabolic alkalosis, and hypomagnesemia). By analysis of linkage we localize the putative causative gene to a 2.5-Mb segment of chromosome 1q23.

Progressive encephalopathy in a child with cerebral folate deficiency syndrome.

Cerebral folate deficiency syndrome, a recently recognized cause of developmental delay, regression, and seizures, is associated with autoantibodies against folate receptors. A female child with developmental delay and a history of seizures who presented with seizures and unexplained coma is reported. Extensive testing to evaluate the patient's coma and subsequent developmental regression were unrevealing until the results of her cerebrospinal fluid neurotransmitter analysis returned.

A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome.

In cerebral folate deficiency syndrome, the presence of autoantibodies against the folate receptor (FR) explains decreased folate transport to the central nervous system and the clinical response to folinic acid. Autoantibody crossreactivity with milk FR from different species prompted us to test the effect of a milk-free diet. Intervention with a milkfree diet in 12 children (nine males, three females; mean age 6y [SD 4y 11mo], range 1-19y), decreased autoantibody titer significantly from 2.

Analysis of 5-methyltetrahydrofolate in serum of healthy children.

5-Methyltetrahydrofolate (5MTHF) is the active one-carbon donor and the principal circulating form of plasma folates. It is involved in a number of metabolic and neurodevelopmental processes and analysis of cerebrospinal fluid (CSF) 5MTHF is of great importance in the diagnosis of cerebral folate deficiency (CFD). Serum 5MTHF levels and the 5MTHF serum/CSF ratio may be important additional parameters for the understanding of CFD.

Autoantibodies to folate receptors in the cerebral folate deficiency syndrome.

In infantile-onset cerebral folate deficiency, 5-methyltetrahydrofolate (5MTHF) levels in the cerebrospinal fluid are low, but folate levels in the serum and erythrocytes are normal. We examined serum specimens from 28 children with cerebral folate deficiency, 5 of their mothers, 28 age-matched control subjects, and 41 patients with an unrelated neurologic disorder. Serum from 25 of the 28 patients and 0 of 28 control subjects contained high-affinity blocking autoantibodies against membrane-bound folate receptors that are present on the choroid plexus.

Cerebral folate deficiency.

Cerebral folate deficiency (CFD) can be defined as any neurological syndrome associated with low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), the active folate metabolite, in the presence of normal folate metabolism outside the nervous system. CFD could result from either disturbed folate transport or from increased folate turnover within the central nervous system (CNS). We report on a novel neurometabolic syndrome in 20 children, which we term 'idiopathic CFD'.