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Background Neuronal ceroid lipofuscinoses (NCLs) form a clinically and genetically heterogeneous group of inherited neurodegenerative disorders that share common neuropathological features. Although they are the first cause of neurodegenerative disorders in children, their congenital forms are rarely documented. They are classically due to mutations in the CTSD gene (the CLN10 disease). Affected newborns usually present severe microcephaly, seizures and respiratory failure leading to death within the first postnatal days or weeks. Cases We report on two siblings, in which exome sequencing identified a novel homozygous CTSD variant. The first sib presented at birth with seizures, rapidly progressive postnatal microcephaly and visual deficiency related to retinal dysfunction. Progressive neurological deterioration leads to death at the age of 24 months. Cathepsin D activity was reduced in the cultured fibroblasts of this patient. The second sib, a fetus of 36 weeks of gestation, was delivered after pregnancy termination for brain abnormalities (in accordance with French Legislation) suggesting a recurrence of the disease. Fetal postmortem examination disclosed neuropathological features consistent with NCL. Conclusions Congenital NCL related to CTSD mutations is a neuronal storage disorder that produces in the developing brain diffuse neurodegeneration and white matter atrophy resulting in a progressive and rapidly lethal microcephaly.

BackgroundGenes implicated in the Golgi and endosomal trafficking machinery are crucial for brain development, and mutations in them are particularly associated with postnatal microcephaly (POM).MethodsExome sequencing was performed in three affected individuals from two unrelated consanguineous families presenting with delayed neurodevelopment, intellectual disability of variable degree, POM and failure to thrive. Patient-derived fibroblasts were tested for functional effects of the variants.ResultsWe detected homozygous truncating variants in ATP9A. While the variant in family A is predicted to result in an early premature termination codon, the variant in family B affects a canonical splice site. Both variants lead to a substantial reduction of ATP9A mRNA expression. It has been shown previously that ATP9A localises to early and recycling endosomes, whereas its depletion leads to altered gene expression of components from this compartment. Consistent with previous findings, we also observed overexpression of ARPC3 and SNX3, genes strongly interacting with ATP9A.ConclusionIn aggregate, our findings show that pathogenic variants in ATP9A cause a novel autosomal recessive neurodevelopmental disorder with POM. While the physiological function of endogenous ATP9A is still largely elusive, our results underline a crucial role of this gene in endosomal transport in brain tissue.

Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52 and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the trans-Golgi network is mediated by GARP and endocytic recycling by EARP. Here we report two unrelated individuals with homozygous variants in VPS50, a splice variant (c.1978-1G>T) and an in-frame deletion (p.Thr608del). Both patients had severe developmental delay, postnatal microcephaly, corpus callosum hypoplasia, seizures and irritability, transient neonatal cholestasis and failure to thrive. Light and transmission electron microscopy of liver from one revealed the absence of gamma-glutamyltransferase at bile canaliculi, with mislocalization to basolateral membranes and abnormal tight junctions. Using patient-derived fibroblasts, we identified reduced VPS50 protein accompanied by reduced levels of VPS52 and VPS53. While the transferrin receptor internalization rate was normal in cells of both patients, recycling of the receptor to the plasma membrane was significantly delayed. These data underscore the importance of VPS50 and/or the EARP complex in endocytic recycling and suggest an additional function in establishing cell polarity and trafficking between basolateral and apical membranes in hepatocytes. Individuals with biallelic hypomorphic variants in VPS50, VPS51 or VPS53 show an overarching neurodegenerative disorder with severe developmental delay, intellectual disability, microcephaly, early-onset epilepsy and variable atrophy of the cerebellum, cerebrum and/or brainstem. The term ‘GARP/EARP deficiency’ designates disorders in such individuals.

Early infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

BackgroundNext-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.MethodsHere, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).ResultsWe identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from −4 SD to −8 SD), profound psychomotor delay, hypertonic–dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (−2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.ConclusionOur findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.

Muscular dystrophy-dystroglycanopathies are autosomal recessive neurologic disorders, caused by homozygous or compound heterozygous mutations in the POMGNT1 gene-encoding protein O-mannose beta-1,2-N-acetylglucosaminyl transferase. This type of muscular dystrophy is characterized by early-onset muscle weakness, gait ataxia, microcephaly, and developmental delay.We performed whole-exome sequencing to detect the disease-causing variants in a 4 year-old boy. Afterwards, Sanger sequencing was performed to confirm the detected variant in the patient and his family. We evaluated a 4 year-old Iranian boy presented with delayed speech and language development, gait ataxia, global developmental delay, motor delay, neurodevelopmental delay, postnatal microcephaly and strabismus. His parents were first cousins, and the mother had a history of spontaneous abortion. In this study, we report a novel missense c.386G > A; p.(Arg129Gln) variant in the POMGNT1 gene which was confirmed by Sanger sequencing in the patient and segregated with the disease in the family.

PurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.ConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.

Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF.

Christianson syndrome (CS), an X-linked neurological disorder characterized by postnatal attenuation of brain growth (postnatal microcephaly), is caused by mutations in SLC9A6 (also termed NHE6), the gene encoding endosomal Na(+)/H(+) exchanger 6 (NHE6). To hasten treatment development, we established CS patient-derived induced pluripotent stem cell (iPSC) lines representing a mutational spectrum, as well as biologically related and isogenic control lines. We demonstrated that pathogenic mutations lead to loss of protein function by a variety of mechanisms: the majority of mutations caused loss of mRNA due to nonsense-mediated mRNA decay; however, a recurrent, missense mutation (the G383D mutation) had both loss-of-function and dominant-negative activities. Regardless of mutation, all patient-derived neurons demonstrated reduced neurite growth and arborization, likely underlying diminished postnatal brain growth in patients. Phenotype rescue strategies showed mutation-specific responses: a gene transfer strategy was effective in nonsense mutations, but not in the G383D mutation, wherein residual protein appeared to interfere with rescue. In contrast, application of exogenous trophic factors (BDNF or IGF-1) rescued arborization phenotypes across all mutations. These results may guide treatment development in CS, including gene therapy strategies wherein our data suggest that response to treatment may be dictated by the class of mutation.

Forkhead box (Fox) family transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental delay associated with ade novomissense variant (M280L) in theFOXR1gene. At the protein level, M280L impaired FOXR1 expression and induced a nuclear aggregate phenotype due to protein misfolding and proteolysis. RNAseq and pathway analysis showed that FOXR1 acts as both a transcriptional activator and repressor with central roles in heat shock response, chaperone cofactor-dependent protein refolding and cellular response to stress. Indeed, FOXR1 expression is increased in response to cellular stress, a process in which it directly controlsHSPA6, HSPA1AandDHRS2transcripts. Meanwhile, the ability of the M280L mutant to respond to stress is compromised, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Combined, these results suggest FOXR1 plays a role in cellular stress and is necessary for normal brain development.

There is no clearly established association between the gene NUP188 and human pathology. Only a few reports of patients with different clinical presentation and different heterozygous or compound heterozygous missense or splice region variants have been identified in several sequencing projects; however, a causative association between the clinical features and the identified variants has not been established. For the first time, we report 2 unrelated patients with 2 different homozygous nonsense gene variants of NUP188, p.Tyr96* and p.Gln113*, respectively. Although having different supposedly truncating mutations, the patients presented with strikingly comparable phenotypes including pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes (such as loss of periventricular white matter), thin corpus callosum, and delayed myelinization. Both patients showed very similar facial features such as laterally extended arched eyebrows, wide convex nose with a wide prominent nasal bridge, and prominent angulated antihelix. They were both born small for gestational age and died shortly after birth at the age of 67 and 140 days, respectively, as a result of central respiratory failure. Our findings strongly suggest a correlation between the homozygous nonsense gene variants of NUP188 and a severe phenotype of a new developmental syndrome with poor prognosis resulting from nucleoporin 188 homolog protein insufficiency.

ObjectiveDe novo missense mutations in the RHOBTB2 gene have been described as causative for developmental and epileptic encephalopathy.MethodsThe clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three RHOBTB2 patients have been described with acute encephalopathy and febrile epileptic status. All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.ResultsWe describe the episode of acute encephalopathy after head trauma in a 5-year-old RHOBTB2 patient. At admission, Glasgow coma scale score was E4M4V1. EEG was severely abnormal showing a noncontinuous pattern with slow activity without epileptic activity indicating severe encephalopathy. A second EEG on day 8 was still severely slowed and showed focal delta activity frontotemporal in both hemispheres. Gradually, he recovered, and on day 11, he had regained his normal reactivity, behavior, and mood. Two months after discharge, EEG showed further decrease in slow activity and increase in normal electroencephalographic activity. After discharge, parents noted that he showed more hyperkinetic movements compared to before this period of encephalopathy. Follow-up MRI showed an increment of hippocampal atrophy. In addition, we summarize the clinical characteristics of a second RHOBTB2 patient with increase of focal periventricular atrophy and development of hemiparesis after epileptic status.ConclusionsAcute encephalopathy in RHOBTB2 patients can also be triggered by head trauma.

Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a family of enzymes that play critical roles in protein biosynthesis. Mutations in mt-aaRSs are associated with various diseases. As a member of the mt-aaRS family, PARS2 encoding prolyl-tRNA synthetase 2 was recently shown to be associated with Alpers syndrome and certain infantile-onset neurodegenerative disorders in four patients. Here, we present two patients in a pedigree with early developmental delay, epileptic spasms, delayed myelination combined with cerebellar white matter abnormalities, and progressive cortical atrophy. Whole-exome sequencing revealed pathogenic compound heterozygous variants [c.283 G > A (p.95 V > I)] and [c.604 G > C (p.202 R > G)] in PARS2. Nearly all patients had epileptic spasms with early response to treatment, early developmental delay and/or regression followed by generalized hypotonia, postnatal microcephaly, elevated lactate levels, and progressive cerebral atrophy. Our study provides further evidence for validating the role of PARS2 in the pathology of related infantile-onset encephalopathy, contributing to the phenotypic features of this condition, and providing clinical and molecular insight for the diagnosis of this disease entity.

OBJECTIVE To assess yield of MECP2 gene sequence variations analysis and large deletions in suspected cases of Rett syndrome. DESIGN Descriptive study. SETTING Tertiary-care medical genetics center. PATIENTS Girls with neuroregression, postnatal microcephaly and signs and symptoms suggestive of classical and atypical Rett syndrome were classified into two groups. Group I consisted of girls with Classical and atypical Rett syndrome on basis on the Revised Rett Syndrome diagnostic criteria, 2010. Group II included girls with neuroregression and postnatal microcephaly and other Rett like features but not fulfilling the above criteria. PROCEDURE Sanger sequencing of coding regions and large deletional analysis of MECP2 gene. OUTCOME MEASURES Identification of mutation in MECP2 gene. RESULTS Mutation in MECP2 gene was identified in 74% (14/19) in group I and none (0/17) in group II. The mutation detection rate was 93% (13/14) in group I classical Rett syndrome girls (2 with large deletions identified with Multiplex ligation dependent probe amplification) and 20% (1/5) in group I atypical Rett syndrome girls. One novel MECP2 sequence variation was identified in group I classical Rett syndrome. CONCLUSIONS The yield of the mutation detection in MECP2 is higher in classical Rett syndrome. In girls with some Rett like features, but not fulfilling revised Rett syndrome diagnostic criteria, mutation testing for MECP2 gene has a low yield.

Cohen syndrome is a rare, genetic, connective-tissue disorder, which is caused by mutations in the gene COH1 (VPS13B, Vacuolar Protein Sorting 13 Homolog B) at the chromosome 8q22. The disease is rare reported, which major clinical features include postnatal microcephaly, obesity, short stature, intellectual disability, progressive retinal dystrophy, intermittent neutropenia and many other unusual facial feature. We report four patients in China who were diagnosed with Cohen syndrome by genetic testing and clinical manifestations. At the same time, we review the related literature, and further expound the molecular mechanism of the disease, a variety of clinical manifestations, treatment and prognosis.

TRAPPC9 gene mutations have been linked recently to autosomal recessive mental retardation 13 (MRT13; MIM#613192) with only eight families reported world-wide. We assessed patients from two consanguineous pedigrees of Pakistani descent with non-syndromic intellectual disability and postnatal microcephaly through whole exome sequencing (WES) and cosegregation analysis. Here we report six further patients from two pedigrees with homozygous TRAPPC9 gene mutations, the novel nonsense mutation c.2065G>T (p.E689*) and the previously identified nonsense mutation c.1423C>T (p.R475*). We provide an overview of previously reported clinical features and highlight common symptoms and variability of MRT13. Common findings are intellectual disability and absent speech, and frequently microcephaly, motor delay and pathological findings on MRI including diminished cerebral white matter volume are present. Mutations in TRAPPC9 should be considered in non-syndromic autosomal recessive intellectual disability with severe speech disorder.

Background Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3. Materials and Methods We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed. Results Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro-imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37). Conclusion This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3-related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro-imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.

BACKGROUND AND PURPOSE: Although microcephaly is the most prominent feature of congenital Zika syndrome, a spectrum with less severe cases is starting to be recognized. Our aim was to review neuroimaging of infants to detect cases without microcephaly and compare them with those with microcephaly. MATERIALS AND METHODS: We retrospectively evaluated all neuroimaging (MR imaging/CT) of infants 1 year of age or younger. Patients with congenital Zika syndrome were divided into those with microcephaly at birth, postnatal microcephaly, and without microcephaly. Neuroimaging was compared among groups. RESULTS: Among 77 infants, 24.6% had congenital Zika syndrome (11.7% microcephaly at birth, 9.1% postnatal microcephaly, 3.9% without microcephaly). The postnatal microcephaly and without microcephaly groups showed statistically similar imaging findings. The microcephaly at birth compared with the group without microcephaly showed statistically significant differences for the following: reduced brain volume, calcifications outside the cortico-subcortical junctions, corpus callosum abnormalities, moderate-to-severe ventriculomegaly, an enlarged extra-axial space, an enlarged cisterna magna (all absent in those without microcephaly), and polymicrogyria (the only malformation present without microcephaly). There was a trend toward pachygyria (absent in groups without microcephaly). The group with microcephaly at birth compared with the group with postnatal microcephaly showed significant differences for simplified gyral pattern, calcifications outside the cortico-subcortical junctions, corpus callosum abnormalities, moderate-to-severe ventriculomegaly, and an enlarged extra-axial space. CONCLUSIONS: In microcephaly at birth, except for polymicrogyria, all patients showed abnormalities described in the literature. In postnatal microcephaly, the only abnormalities not seen were a simplified gyral pattern and calcifications outside the cortico-subcortical junction. Infants with normocephaly presented with asymmetric frontal polymicrogyria, calcifications in the cortico-subcortical junction, mild ventriculomegaly, and delayed myelination.

In 2015, there was an increase in the incidence of congenital microcephaly in newborns in Brazil. Months later, the causal relationship between Zika virus and these findings was discovered. In Argentina, during the first outbreak there were 5 cases of congenital Zika syndrome reported. In 2017, there was a new outbreak which involved Salta province. We describe 2 patients with autochthonous congenital Zika syndrome: one of the babies with severe congenital microcephaly with lissencephaly, calcifications and ventriculomegaly; and another baby with postnatal microcephaly with asymmetric polymicrogyria, calcifications and delayed myelination. The real impact of this disease is still uncertain, so it is necessary an adequate multidisciplinary monitoring of patients exposed to Zika virus to better understand the infection and its natural history.

Christianson syndrome (CS) is an X-linked intellectual disorder caused by mutations in the SLC9A6 gene. Clinical features of CS include an inability to speak, truncal ataxia, postnatal microcephaly, hyperkinesis, and epilepsy. Almost all patients with CS develop drug-resistant epilepsy—its most serious complication. We report two cases of CS with drug-resistant epilpesy associated with the Lennox–Gastaut syndrome (LGS). One patient experienced generalized tonic seizures since 9 months of age with cognitive regression, which evolved to include atonic seizures at the age of 7 years. Electroencephalography (EEG) showed generalized slow spike–wave complexes and generalized paroxysmal fast activity. Seizures remained drug-resistant despite multiple anti-seizure drugs. The second patient experienced generalized tonic seizures since the age of 17 months and arrested development. EEG showed generalized slow spike–wave complexes, with frequent atonic seizures since the age of 6 years. Electrical status epilepticus during slow-wave sleep (ESES) developed at the age of 7 years. Our cases illustrate that CS may cause LGS in addition to other developmental and epileptic encephalopathies of the neonatal and infantile period. We suggest that generalized tonic or tonic–clonic seizures and generalized slow spike–wave complexes in interictal EEG be included as potential electroclinical features of epilepsy in CS., Highlights • Christianson syndrome (CS) is rare and difficult to diagnose from clinical symptoms. • Epilepsy, the most serious complication of CS, is drug-resistant. • CS epilepsy involves generalized tonic or tonic–clonic seizures. • CS epilepsy is characterized by generalized slow spike–wave complexes in EEG.

International audience; Whole exome sequencing undertaken in two siblings with delayed psychomotor development, absent speech, severe intellectual disability and postnatal microcephaly, with brain malformations consisting of cerebellar atrophy in the eldest affected and hypoplastic corpus callosum in the younger sister; revealed a homozygous intragenic deletion in VPS51, which encodes the vacuolar protein sorting-associated protein, one the four subunits of the Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes that promotes the fusion of endosome-derived vesicles with the trans-Golgi network (GARP) and recycling endosomes (EARP). This observation supports a pathogenic effect of VPS51 variants, which has only been reported previously once, in a single child with microcephaly. It confirms the key role of membrane trafficking in normal brain development and homeostasis.

Pathogenic variants in the TRAPPC6B gene were recently found to be associated in three consanguineous families, with microcephaly, epilepsy, and brain malformations. Here, we report on a 3.5-year-old boy, born to consanguineous Lebanese parents, who presented with developmental delay, lactic acidosis, postnatal microcephaly, and abnormal brain magnetic resonance imaging. By whole exome sequencing, a novel homozygous likely pathogenic variant in exon 1 of the TRAPPC6B gene (c.23T > A; [p.Leu8*]) was identified. A review of the clinical description and literature is discussed, pointing out the phenotypic heterogeneity associated with mutations in this gene.

We report three brothers born to consanguineous parents of Syrian descent, with a homozygous novel c.324G>A (p.W108*) mutation in PTRH2 that encodes peptidyl-tRNA hydrolase 2, causing infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We describe the core clinical features of postnatal microcephaly, motor and language delay with regression, ataxia, and hearing loss. Additional features include epileptic seizures, pancreatic insufficiency, and peripheral neuropathy. Clinical phenotyping enabled a targeted approach to the investigation and identification of a novel homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). We compare our patients with those recently described and review the current literature for IMNEPD.

Doublecortin (DCX) mutations cause abnormal development of the DCX protein that normally aids in neuronal migration during fetal development. These mutations lead to lissencephaly, or the appearance of a “smooth brain,” which is varying levels of pachygyria or agyria in severe cases. Many genetic variants of the mutation have been identified, and an even greater range of phenotypic presentations have been described in the literature. The X-linked lissencephaly (DCX) mutation leads to an X-linked gender-dependent condition that causes subcortical heterotopia in females and lissencephaly in males. The authors report the case of a 13-year-old male who presented to our clinic for new-onset seizure disorder. He had a past medical history of developmental delay and features of autism spectrum disorder which was diagnosed at age 5 years at an outside clinic. Magnetic resonance imaging (MRI) brain at age 5 years showed pachygyria of the frontal and temporal lobes. After extensive genetic testing over the course of over a decade, the patient was found to have a de novo mutation in the DCX gene diagnosed via whole-exome sequencing. Specifically, he was found to have a mosaic mutation of the DCX gene as a c.30-31 deletion. His previous MRI findings were consistent with a diagnosis of X-linked sporadic lissencephaly sequence and included mainly a diffuse bilateral pachygyria (isolated lissencephaly sequence X chromosome). Thickening of the cortex and pachygyria or agyria are classic findings of lissencephaly, but do not help specify any mutation in the gene, of which there are over 70 possibilities. Our patient is unique in that most individuals with DCX mutation have infantile seizures, severe intellectual disability, orthopedic complications, and postnatal microcephaly, which our patient does not have.

This article is to demystify what has been written on this subject to date, about microcephaly. Come show the realcauses of this event through a new survey on mater contractile cells that is characterized by a set of highly specialized cells,organized, rational and accounting for all vital commands in our body, contractions, nerve synapses, reflex movements , systole,diastole, gas exchange, afferent and efferent systems, connective tissue etc. They are able to make an optical reading over tengenerations of cells around them, identifying their DNA.The CCMs appear to be five pairs of cells but are actually six pairs of cells, which sometimes JokeR and Beta are unitedin one block as in the cardiac system.The CCMs, representing the set of all our heredity (24 generations of maternal grandparents, 24 generations ofgrandparents) always appear in pairs and alternately. They are responsible for all our heredity, our DNA.Microcephaly is therefore an event resulting from invasive procedures to atrial cube six command pairs of cells, calledContractile Cells Mater Reverse, which happens fast closing of the brain cell also called command deoxyribose. That is becausethe MCCs that are control cells have a remarkable ability to make an optical other cells around them, or at a distance of up to tengenerations, and identify a JokeR-Delta brain is being formed, ie one brain contemplated by eight brains or parents and maternalgrandparents and paternal in pairs and alternately, starting with maternal grandparents and then grandparents, namely: Aa (Alfha-)father and mother-Bb (Beta ) the maternos- grandparents Cc (Ceci) grandparents paternos- Dd (Delta) maternal bizavos; so wehave a brilliant child." O c c u r r e n c e s o f m a l f o r m a t i o n i n i n f a n t s h a s b e e n a s s o c i a t e d w i t h Z i k a v i r u s . . . "(exame.abril.com.br/brasil/ferramentas zika virus and microcephaly)The researchers say that in early pregnancy, the virus can cause brain damage and interfere with brain developmentstages. In fact, those who cause these injuries are the Reverse command cells. According to researchers on the subject, thegreater risk of microcephaly by Zika virus still happens in cerebral cortex development phase of the fetus that is in the first fourmonths of pregnancy.In chromosomal split, we have the first 24 pairs of cells (the pair of No. 25 is deleted every intersection) scienceinterprets as 23 pairs of chromosomes only, is that JokeR, formed by the father and mother are in one block together, and this tape,we have the main tape command in the body which will be explained in front, they are;Aa Bb-Cc-Dd-Ee-Ff-Gg-Hh-Ii-Jj. In this tape, are reversed from Ee called Reverse And so then we have two cell groups,to consider a group of good cells, versus a group of cells reverse. The reversas- cells (DC- Ee - Gg- II) to detect the formation of thisbrain, you want possession of it at any cost, the deoxyribose cells (Aa Bb-Dd-Ff-Hh-Jj) conflicts with the reverse cell and these twocell groups waging a battle with big rivalry going on a general sweep in all the cells around them to ten generations (so they seek,following the generations that brain q is being formed for this reason they They are moving in several places where there can be arelationship of the brain) by the pursuit of JokeR-Delta brain, with the rapid closing of this by deoxyribose, thus getting theunfinished brain.On a brain, we can say that its size does not necessarily measures your ability, it can be small, and with all functionswithin the normal range, but will not be free of postnatal microcephaly and that a brain can be born unfinished and escape thenormal range and may be born small and grow, since he was born perfect and may be born large decrease, everything will goaccording to the movement of MCCs.(Https: en Wikipedia.org/wik/microcefalia.)"It is a neurological condition where the head size and his occipito-frontal head circumference (OFC) is two or morestandard deviations below the mean""A new epidemic of zika, chicungunya and dengue causes concern in Pernambuco doctors who leads the highestnumber of cases of microcephaly in the country, (https:. Wikipedia.org/wik/microcefalia en)Therefore, we conclude this study saying; the microcephaly, is not the result of a mosquito bite, and we can not considera small brain, but an unfinished brain, and that the epidemic has location and specific time, because the cells look with a certainprecision the place where it is being formed a brain Alfha- Delta, and GPS these cells are heredity them so this epidemic occurredespecially in Brazil, in the Northeast, specifically in Pernambuco.So it can be said that was born a JokeR-Delta child in this state, we can even identify the approximate time that the childwas born; April, May or June, since the recognition of this genius will happen much later, through science. They are very fewchildren who reach a high score in the HR (Human clock). That is a brain consists of eight brains coupled into one. Thus the reversecells do a scan for possession of this brain.

We describe four families with affected siblings showing unique clinical features: early-onset (before 1 year of age) progressive diffuse brain atrophy with regression, postnatal microcephaly, postnatal growth retardation, muscle weakness/atrophy, and respiratory failure. By whole-exome sequencing, we identified biallelic TBCD mutations in eight affected individuals from the four families. TBCD encodes TBCD (tubulin folding co-factor D), which is one of five tubulin-specific chaperones playing a pivotal role in microtubule assembly in all cells. A total of seven mutations were found: five missense mutations, one nonsense, and one splice site mutation resulting in a frameshift. In vitro cell experiments revealed the impaired binding between most mutant TBCD proteins and ARL2, TBCE, and β-tubulin. The in vivo experiments using olfactory projection neurons in Drosophila melanogaster indicated that the TBCD mutations caused loss of function. The wide range of clinical severity seen in this neurodegenerative encephalopathy may result from the residual function of mutant TBCD proteins. Furthermore, the autopsied brain from one deceased individual showed characteristic neurodegenerative findings: cactus and somatic sprout formations in the residual Purkinje cells in the cerebellum, which are also seen in some diseases associated with mitochondrial impairment. Defects of microtubule formation caused by TBCD mutations may underlie the pathomechanism of this neurodegenerative encephalopathy.

We describe two siblings who were affected with early onset focal seizures, severe progressive postnatal microcephaly, muscular hypertonia, feeding problems and bouts of apnea, only minimal psychomotor development, as well as death in infancy and childhood. We identified compound heterozygous mutations in BRAT1 exons 5 (c.638_639insA) and 8 (c.1134+1G>A) in one affected child via next-generation sequencing of the disease-associated genome followed by phenotype-driven bioinformatic analysis. Sanger sequencing confirmed the presence of these mutations in both patients and a heterozygote status of the parents. Whereas the frameshift mutation (c.638_639insA) has been described in one family, the splice-site mutation (c.1134+1G>A) is novel. In contrast to all cases published so far, one of our patients showed a considerably milder clinical course with survival into childhood. Investigation of a skeletal muscle biopsy showed a severely reduced COX enzyme histochemical staining, indicating mitochondrial dysfunction. Our data expand the clinical and mutational spectrum of the BRAT1-associated phenotype. © 2016 Wiley Periodicals, Inc.

Postnatal microcephaly comprises a heterogeneous group of neurodevelopmental disorders of varying severity, characterized by normal head size at birth, followed by a postnatal deceleration in head circumference of greater than 3 standard deviations (SD) below the mean. Many postnatal microcephaly syndromes are caused by mutations in genes known to be important for the regulation of gene expression in the developing forebrain. We studied a consanguineous Pakistani family with postnatal microcephaly, orofacial dyskinesia, spastic quadriplegia and, on MRI, cortical atrophy with myelination delay, suggestive of a FOXG1-like presentation. Using trio-based exome sequencing, we identified a homozygous missense mutation in the Transducin-like enhancer of split-1 (TLE1) gene, encoding for a non DNA-binding transcriptional corepressor, highly expressed in the postnatal brain. The regulation of the post-mitotic neural survival activity of TLE1 depends critically on an interaction with FOXG1, a gene shown to be involved in a postnatal microcephaly syndrome. Functional analysis on affected dermal fibroblasts showed a significant decrease in mitotic and proliferative index, indicating a lengthening of the cell cycle and a delay in mitosis, supporting that this gene could be a new candidate for postnatal microcephaly.

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

ITPA related epileptic encephalopathy (epileptic encephalopathy, early infantile, 35) is a rare inborn error of metabolism. All reported individuals with this condition, including the present case manifest global developmental delay, seizures, progressive postnatal microcephaly, hypotonia, thin corpus callosum, cerebral atrophy, delayed myelination and white matter changes in posterior limb of internal capsule. Cataract and dilated cardiomyopathy are other characteristic findings. Currently, a single publication describes this condition in four families. Three truncating and two missense variants in ITPA have been identified in these families. We hereby report another family with ITPA related disorder and review the genotype and phenotype of the reported subjects.

Background The disease Zika is considered as emergent. The infection can be acquired through different routes: a bite from the Aedes mosquito, sexual contact, from mother to child during pregnancy and by blood transfusion. The possibility of Zika transmission through human lactation has been considered. Zika is a disease of great concern for public health because it has been associated with neonatal and postnatal microcephaly, among other birth defects. Objectives To review published evidence of the probable transmission of Zika through human lactation. Data sources Electronic databases: Cochrane Central Register of Controlled Trials, EBSCO, Gale, Science Direct, Scopus, US National Library of Medicine (PubMed) and Web of Science. World Health Organization and Centers for Disease Control and Prevention web pages. Study eligibility criteria To be eligible, studies of any design had to provide primary data of human breast milk as a potential fluid for the transmission of Zika, or primary or secondary follow-up data of infants with at least one previous published study that complied with the first criterion of eligibility. Participants Studies about women with suspected, probable or confirmed Zika during pregnancy, or the postnatal period and beyond. Studies about infants who breastfeed directly from the breast or where fed with the expressed breast milk of the suspected, probable or confirmed women with Zika. Results This study only chose data from research papers; no patients were taken directly by the authors. A total of 1,146 were screened and nine studies were included in the qualitative synthesis, from which a total of 10 cases were identified, with documented follow-up in three of these cases. Through the timing of maternal Zika infection, five cases were classified as prenatal (time before delivery), one as immediate postnatal (period from 0 to 4 days after birth); no cases were classified as medium postnatal (period from 5 days to 8 weeks after birth); two were classified as long postnatal (period from 8 weeks to 6 months after birth) and two as beyond six months after birth. Conclusion Human milk may be considered as a potentially infectious fluid, but we found no currently documented studies of the long-term complications in infants up to 32 months of age, with suspected, probable or confirmed Zika through human lactation, or evidence with respect to the human pathophysiology of the infection acquired through human lactation. In the light of the studies reviewed here, the World Health Organization recommendation of June 29th 2016, remains valid: “the benefits of breastfeeding for the infant and mother outweigh any potential risk of Zika virus transmission through breast milk.”

Introduction Mutations of the ATP1A3 gene are associated with a wide spectrum of neurological disorders including rapid onset dystonia-parkinsonism and alternating hemiplegia of childhood (AHC). The genotype-phenotype correlations in these cases remain unclear however. We here report a pediatric case of catastrophic early life epilepsy, respiratory failure, postnatal microcephaly, and severe developmental disability associated with a novel heterozygous ATP1A3 mutation. Subject A boy with a normal birth to nonconsanguineous parents was transferred to the NICU due to postnatal respiratory failure at 2 days. He showed extreme hypotonia, episodic oculomotor abnormality and tachycardia, and frequent epileptic seizures. Mechanical ventilation was required but his epileptic seizures were intractable to multiple antiepileptic drugs, including extremely high doses of phenobarbital. Methods and Results Whole exome sequencing analysis of the case and his parents identified a de novo heterozygous mutation in the ATP1A3 gene (c.2736_2738CTTdel, p.Phe913del). Discussion The Phe913 residue in the ATP1α3 protein that is deleted in our case is highly conserved among vertebrates. Notably, an amino acid deletion in the same transmembrane domain of this protein, p.Val919del, has been reported previously in typical AHC cases, suggesting that p.Phe913del is a pathogenic mutation. Several reported cases with severe symptoms and very early onset epilepsy harbor ATP1α3 mutations at structural positions in this protein that differ from that of Phe913. Further functional studies are required to clarify the relationship between the loss of Phe913 and the very distinct resulting phenotype.

Intellectual disability (ID) has an estimated prevalence of 1.5–2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

Çalışmada 47 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. Purpose: Congenital microcephaly (CM) is an important birth defect with long term neurological sequelae. We aimed to perform detailed phenotypic and genomic analysis of patients with Mendelian forms of CM. Methods: Clinical phenotyping, targeted or exome sequencing, and autozygome analysis. Results: We describe 150 patients (104 families) with 56 Mendelian forms of CM. Our data show little overlap with the genetic causes of postnatal microcephaly. We also show that a broad definition of primary microcephaly -as an autosomal recessive form of nonsyndromic CM with severe postnatal deceleration of occipitofrontal circumference-is highly sensitive but has a limited specificity. In addition, we expand the overlap between primary microcephaly and microcephalic primordial dwarfism both clinically (short stature in >52% of patients with primary microcephaly) and molecularly (e.g., we report the first instance of CEP135-related microcephalic primordial dwarfism). We expand the allelic and locus heterogeneity of CM by reporting 37 novel likely disease-causing variants in 27 disease genes, confirming the candidacy of ANKLE2, YARS, FRMD4A, and THG1L, and proposing the candidacy of BPTF, MAP1B, CCNH, and PPFIBP1. Conclusion: Our study refines the phenotype of CM, expands its genetics heterogeneity, and informs the workup of children born with this developmental brain defect. King Salman Center for Disability Research Saudi Human Genome Program Howard Hughes Medical Institute National Institute of Neurological Disorders and Stroke Manton Center for Orphan Disease Research, Boston Children's Hospital King Abdullah University of Science and Technology King Abdulaziz City for Science and Technology Deanship of Scientific Research, King Saud University

Two siblings born to non-consanguineous parents showed nystagmus and sudden opistotonic posturing from the early infancy, and subsequent developmental delay and marked choreiform movements with hypotonia in the childhood. The brother had a mild postnatal microcephaly. Brain MRI of the sister showed mild delay of myelination, dilated anterior horn and mild cerebellar atrophy. Whole exome sequencing (WES) revealed compound heterozygous mutations in MED17 gene in both siblings: c.1013-5A>G and c.1484T>G mutations transmitted from their father and mother, respectively. The c.1013-5A>G mutation caused insertion of 4 bases of intron 6 in the transcript, resulting in frameshift (p. Ser338Asnfs*15), and mutant transcript underwent nonsense-mediated mRNA decay in lymphoblastoid cells derived from two siblings. The c.1484T>G mutation substituted a leucine residue, which is highly conserved among the vertebrates, and was predicted to be damaging by in silico analysis programs. Both mutations were not registered in dbSNP data and in our 575 control exomes. These results suggest that the siblings' mutations are likely to be pathogenic. This is the second case report concerning MED17 mutations. Compared with the first reported cases of Caucasian Jewish origin, the clinical symptoms and courses are much milder and slower, respectively, in our cases. Genotype difference (a homozygous mutation versus compound heterozygous mutations) might explain these clinical differences between two cases, though early-onset nystagmus and later choreiform movements were unique in our cases. Clinical spectrum and phenotype-genotype correlations in this rare mutation should be further elucidated.

Rearrangement of the actin cytoskeleton is controlled by RhoGTPases which are activated by RhoGEFs. We identified homozygosity for Arg204Trp mutation in the Rho guanidine exchange factor (RhoGEF) PLEKHG2 gene in five patients with profound mental retardation, dystonia, postnatal microcephaly, and distinct neuroimaging pattern. The activity of the mutant PLEKHG2 was significantly decreased, both in basal state and when Gβγ- or lysophosphatidic acid (LPA)-stimulated. SDF1a-stimulated actin polymerization was significantly impaired in patient cells, and this abnormality was duplicated in control cells when PLEKHG2 expression was downregulated. These results underscore the role of PLEKHG2 in actin polymerization and delineate the clinical and radiological findings in PLEKHG2 deficiency.

Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.

NMDA receptor agonists have been used for many years to generate animal models of polymicrogyria, a malformation of cortical development. Fry et al. identify de novo GRIN1 mutations in eleven patients with severe bilateral polymicrogyria. Polymicrogyria-associated GRIN1 mutations cluster in specific protein domains and significantly alter NMDA receptor function., Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Here we report a Japanese patient with new compound heterozygous truncating variants in the PCDH12 gene. As compared to the previously reported families who had congenital microcephaly, intrauterine growth retardation, intracranial calcification, and neonatal seizure associated with dysplasia of the midbrain-hypothalamus-optic tract, the present patient showed no midbrain-hypothalamus dysplasia or congenital/postnatal microcephaly, but dyskinetic cerebral palsy and severe intellectual disability as well as multifocal epilepsy. To understand phenotypic spectrum associated with PCDH12 variants, more reports are needed.

Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the "figure 8" shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic "figure 8" shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.

The Golgi apparatus plays a central role in cell homeostasis, not only in processing and maturing newly synthesized proteins and lipids but also in orchestrating their sorting, packing, routing and recycling on the way to their final destination. These multiple secretory pathways require a complex ballet of vesicular and tubular carriers that continuously bud off from donor membranes and fuse to acceptor membranes. Membrane trafficking is particularly prominent in axons, where cargo molecules have a long way to travel before they reach the synapse, and in oligodendrocytes, which require an immense increase in membrane surface in order to sheathe axons in myelin. Interestingly, in recent years, genes encoding Golgi-associated proteins with a role in membrane trafficking have been found to be defective in an increasing number of inherited disorders whose clinical manifestations include postnatal-onset microcephaly (POM), white matter defects and intellectual disability. Several of these genes encode RAB GTPases, RAB-effectors or RAB-regulating proteins, linking POM and intellectual disability to RAB-dependent Golgi trafficking pathways and suggesting that their regulation is critical to postnatal brain maturation and function. Here, we review the key roles of the Golgi apparatus in post-mitotic neurons and the oligodendrocytes that myelinate them, and provide an overview of these Golgi-associated POM-causing genes, their function in Golgi organization and trafficking and the likely mechanisms that may link dysfunctions in RAB-dependent regulatory pathways with POM.

International audience; Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.