MPDZ, a gene with diverse functions mediating cell-cell junction interactions, receptor signaling, and binding multivalent scaffold proteins, is associated with a spectrum of clinically heterogeneous phenotypes with biallelic perturbation. Despite its clinical relevance, the mechanistic underpinnings of these variants remain elusive, underscoring the need for extensive case series and functional investigations. In this study, we conducted a systematic review of cases in the literature through two electronic databases following the PRISMA guidelines. We selected nine studies, including 18 patients, with homozygous or compound heterozygous variants in MPDZ and added five patients from four unrelated families with novel MPDZ variants. To evaluate the role of Mpdz on hearing, we analyzed available auditory electrophysiology data from a knockout murine model (Mpdzem1(IMPC)J/em1(IMPC)J) generated by the International Mouse Phenotyping Consortium. Using exome and genome sequencing, we identified three families with compound heterozygous variants, and one family with a homozygous frameshift variant. MPDZ-related disease is clinically heterogenous with hydrocephaly, vision impairment, hearing impairment and cardiovascular disease occurring most frequently. Additionally, we describe two unrelated patients with spasticity, expanding the phenotypic spectrum. Our murine analysis of the Mpdzem1(IMPC)J/em1(IMPC)J allele showed severe hearing impairment. Overall, we expand understanding of MPDZ-related phenotypes and highlight hearing impairment and spasticity among the heterogeneous phenotypes.

The trafficking protein particle (TRAPP) complex is a multisubunit protein complex that functions as a tethering factor involved in intracellular trafficking. TRAPPC11, a crucial subunit of this complex, is associated with pathogenic variants that cause a spectrum of disease, which can range from a limb girdle muscular dystrophy (LGMD) to developmental disability with muscle disease, movement disorder and global developmental delay (GDD)/intellectual disability (ID), or even a congenital muscular dystrophy (CMD). We reviewed the phenotype of all reported individuals with TRAPPC11-opathies, including an additional Mexican patient with novel compound heterozygous missense variants in TRAPPC11 (c.751 T > C and c.1058C > G), restricted to the Latino population. In these 54 patients muscular dystrophy signs are common (early onset muscle weakness, increased serum creatine kinase levels, and dystrophic changes in muscle biopsy). They present two main phenotypes, one with a slowly progressive LGMD with or without GDD/ID (n = 12), and another with systemic involvement characterized by short stature, GDD/ID, microcephaly, hypotonia, poor speech, seizures, cerebral atrophy, cerebellar abnormalities, movement disorder, scoliosis, liver disease, and cataracts (n = 42). In 6 of them CMD was identified. Obstructive hydrocephaly, retrocerebellar cyst, and talipes equinovarus found in the individual reported here has not been described in TRAPPC11 deficiency. As in previous patients, membrane trafficking assays in our patient showed defective abnormal endoplasmic reticulum-Golgi transport as well as decreased expression of LAMP2, and ICAM-1 glycoproteins. This supports previous statements that TRAPPC11-opathies are in fact a congenital disorder of glycosylation (CDG) with muscular dystrophy.

Macrocephaly is defined as an abnormal increase in head circumference greater than two standard deviations above the mean for a given age and sex. We present the case of a 16-month-old boy with congenital progressive macrocephaly, who was referred to our hospital for a ventriculoperitoneal shunt placement for external hydrocephalus diagnosed at 13 months of age. The patient had a febrile seizure 12 hours after the shunt was placed and the emergency CT exam revealed collapsed ventricles and a right frontal subdural collection, suggestive of an over-drainage and intracranial hypotension. A subsequent electroencephalogram (EEG) revealed some anomalies, but the patient was discharged two days later due to having no neurological symptoms after being placed on anticonvulsants. The patient returned to the hospital one week later due to recurrent seizures. Further clinical examination revealed prominent and tortuous veins of the skull, palpated in the left occipital region. A thrill and a left carotid murmur were heard during auscultation. A subsequent brain MRI with MR arteriography and venography was performed in search of an explanation for hydrocephaly. The sequences were suggestive of a dural arteriovenous fistula, which was confirmed and then treated using coils during an interventional angiography. A second procedure was performed two months later to complete the embolization, with subsequent imaging follow-ups showing the procedure to have been successful. The measurement of the cranial circumference, its regular evaluation, and its evolution allow a hierarchical diagnosis strategy by distinguishing primary and secondary macrocephaly, progressive or not. Dural arteriovenous fistulas (DAVF) are an under-appreciated cause of macrocephaly, with which they are associated in 35% of cases. Intracranial DAVFs are pathologic shunts between dural arteries and dural venous sinuses, meningeal veins, or cortical veins. Patients with DAVFs may be completely asymptomatic. Symptoms, when present, may range from neurological deficits, seizures, and hydrocephaly to fatal hemorrhage. The symptoms depend on the location and venous and drainage patterns of the DAVF. They can be difficult to identify on routine MRIs unless specifically searched for, especially in cases of technically suboptimal examinations. We aim to give a practical approach to identify the clinical clues that warrant further investigation. Several specific protocols exist regarding the management of macrocephaly and should be followed carefully once a diagnosis has been reached, but further studies are needed to integrate more clinical and neuroimaging findings to permit an early diagnosis.

BACKGROUND: Congenital hydrocephaly, an abnormal accumulation of fluid within the ventricular spaces at birth, can cause disability or death if untreated. Limited information is available about survival of infants born with hydrocephaly in Texas. Therefore, the purpose of the study was to calculate survival estimates among infants born with hydrocephaly without spina bifida in Texas.
METHODS: A cohort of live-born infants delivered during 1999-2017 with congenital hydrocephaly without spina bifida was identified from the Texas Birth Defects Registry. Deaths within 1 year of delivery were identified using vital and medical records. One-year infant survival estimates were generated for multiple descriptive characteristics using the Kaplan-Meier method. Crude hazard ratios (HRs) for one-year survival among infants with congenital hydrocephaly by maternal and infant characteristics and adjusted HRs for maternal race and ethnicity were estimated using Cox proportional hazard models.
RESULTS: Among 5709 infants born with congenital hydrocephaly without spina bifida, 4681 (82%) survived the first year. The following characteristics were associated with infant survival: maternal race and ethnicity, clinical classification (e.g., chromosomal or syndromic), preterm birth, birth weight, birth year, and maternal education. In the multivariable Cox proportional hazards model, differences in survival were observed by maternal race and ethnicity after adjustment for other maternal and infant characteristics. Infants of non-Hispanic Black (HR: 1.28, 95% CI: 1.04-1.58) and Hispanic (HR: 1.31, 95% CI: 1.12-1.54) women had increased risk for mortality, compared with infants of non-Hispanic White women.
CONCLUSIONS: This study showed infant survival among a Texas cohort differed by maternal race and ethnicity, clinical classification, gestational age, birth weight, birth year, and maternal education in infants with congenital hydrocephaly without spina bifida. Findings confirm that mortality continues to be common among infants with hydrocephaly without spina bifida. Additional research is needed to identify other risk factors of mortality risk.

Amino-terminal acetylation is catalyzed by a set of N-terminal acetyltransferases (NATs). The NatA complex (including X-linked Naa10 and Naa15) is the major acetyltransferase, with 40-50% of all mammalian proteins being potential substrates. However, the overall role of amino-terminal acetylation on a whole-organism level is poorly understood, particularly in mammals. Male mice lacking Naa10 show no globally apparent in vivo amino-terminal acetylation impairment and do not exhibit complete embryonic lethality. Rather Naa10 nulls display increased neonatal lethality, and the majority of surviving undersized mutants exhibit a combination of hydrocephaly, cardiac defects, homeotic anterior transformation, piebaldism, and urogenital anomalies. Naa12 is a previously unannotated Naa10-like paralog with NAT activity that genetically compensates for Naa10. Mice deficient for Naa12 have no apparent phenotype, whereas mice deficient for Naa10 and Naa12 display embryonic lethality. The discovery of Naa12 adds to the currently known machinery involved in amino-terminal acetylation in mice.

Apoptosis-Inducing Factor (AIF) is a protein involved in mitochondrial electron transport chain assembly/stability and programmed cell death. The relevant role of this protein is underlined because mutations altering mitochondrial AIF properties result in acute pediatric mitochondriopathies and tumor metastasis. By generating an original AIF-deficient mouse strain, this study attempted to analyze, in a single paradigm, the cellular and developmental metabolic consequences of AIF loss and the subsequent oxidative phosphorylation (OXPHOS) dysfunction.
We developed a novel AIF-deficient mouse strain and assessed, using molecular and cell biology approaches, the cellular, embryonic, and adult mice phenotypic alterations. Additionally, we conducted ex vivo assays with primary and immortalized AIF knockout mouse embryonic fibroblasts (MEFs) to establish the cell death characteristics and the metabolic adaptive responses provoked by the mitochondrial electron transport chain (ETC) breakdown.
AIF deficiency destabilized mitochondrial ETC and provoked supercomplex disorganization, mitochondrial transmembrane potential loss, and high generation of mitochondrial reactive oxygen species (ROS). AIF-/Y MEFs counterbalanced these OXPHOS alterations by mitochondrial network reorganization and a metabolic reprogramming toward anaerobic glycolysis illustrated by the AMPK phosphorylation at Thr172, the overexpression of the glucose transporter GLUT-4, the subsequent enhancement of glucose uptake, and the anaerobic lactate generation. A late phenotype was characterized by the activation of P53/P21-mediated senescence. Notably, approximately 2% of AIF-/Y MEFs diminished both mitochondrial mass and ROS levels and spontaneously proliferated. These cycling AIF-/Y MEFs were resistant to caspase-independent cell death inducers. The AIF-deficient mouse strain was embryonic lethal between E11.5 and E13.5 with energy loss, proliferation arrest, and increased apoptotic levels. Contrary to AIF-/Y MEFs, the AIF KO embryos were unable to reprogram their metabolism toward anaerobic glycolysis. Heterozygous AIF+/- females displayed progressive bone marrow, thymus, and spleen cellular loss. In addition, approximately 10% of AIF+/- females developed perinatal hydrocephaly characterized by brain development impairment, meningeal fibrosis, and medullar hemorrhages; those mice died 5 weeks after birth. AIF+/- with hydrocephaly exhibited loss of ciliated epithelium in the ependymal layer. This phenotype was triggered by the ROS excess. Accordingly, it was possible to diminish the occurrence of hydrocephalus AIF+/- females by supplying dams and newborns with an antioxidant in drinking water.
In a single knockout model and at 3 different levels (cell, embryo, and adult mice) we demonstrated that by controlling the mitochondrial OXPHOS/metabolism, AIF is a key factor regulating cell differentiation and fate. Additionally, by providing new insights into the pathological consequences of mitochondrial OXPHOS dysfunction, our new findings pave the way for novel pharmacological strategies.

Hydrocephalus is characterized by increased cerebrospinal fluid within the brain, a causally heterogeneous disorder estimated to affect 1 per 1,000 live births, with the most severe cases often leading to fetal demise. The large number of known genetic and environmental factors that contribute to hydrocephalus makes the differential diagnosis challenging.
Three consecutive pregnancies of an unrelated couple were found by ultrasound to carry fetuses with hydrocephaly. DNA from two affected fetuses and the parents were subjected to whole exome sequencing. Heterozygous alterations in the TRAPPC12 gene were identified in the parents and compound heterozygous alterations were present in the two affected fetuses. The variant from the father (c.954del) leads to a premature termination of the transcript; the variant from the mother (c.1677+5G>A) affects a splice site which leads to aberrant splicing of the TRAPPC12 transcript.
Compound heterozygous variants in TRAPPC12, which encodes a protein involved in Golgi trafficking and mitosis, may disrupt normal brain embryogenesis leading to hydrocephalus and recurrent pregnancy loss.

BACKGROUND: Diabetes mellitus is the most frequent chronic complication in pregnancy and continues to contribute to increased perinatal morbidity and mortality in newborns. Macrosomia, respiratory distress syndrome, metabolic and electrolytic disturbances, and increased rates of congenital structural defects are well-known neonatal complications associated with maternal diabetes, even if well-controlled.
METHODS: A macrosomic infant born from an insulin-dependent mother, with uncontrolled diabetes and lack of adequate prenatal care, prenatally diagnosed with hydrocephaly showed a complicated postnatal course. Initial respiratory distress syndrome and transient hypoglycemia, rapidly corrected under treatment, were followed by persistent hypocalcemia and hyperphosphatemia due to hypoparathyroidism and evolving hydrocephaly. Ventriculoperitoneal shunting was followed by resolution of hypocalcemia, but seizures associated with schizencephaly and recurrent respiratory tract infections, aggravated by spondylocostal dysplasia, concurred to infant\'s demise at the age of 5 months.
CONCLUSIONS: The reported case is rare due to multiple aspects: persistent hypoparathyroidism, uncommon association of schizencephaly, and even rarely association with spondylocostal dysplasia, all these conditions requiring a multidisciplinary therapeutic approach. Also, the reported case is evocative for challenges associated with infants born from diabetic mothers.

Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far.
We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment.
The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease\'s mechanism due to the stabilization of the occluded conformation or a protein misfolding.
Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.

Whole-exome and targeted sequencing of 13 individuals from 10 unrelated families with overlapping clinical manifestations identified loss-of-function and missense variants in KIAA1109 allowing delineation of an autosomal-recessive multi-system syndrome, which we suggest to name Alkuraya-Kučinskas syndrome (MIM 617822). Shared phenotypic features representing the cardinal characteristics of this syndrome combine brain atrophy with clubfoot and arthrogryposis. Affected individuals present with cerebral parenchymal underdevelopment, ranging from major cerebral parenchymal thinning with lissencephalic aspect to moderate parenchymal rarefaction, severe to mild ventriculomegaly, cerebellar hypoplasia with brainstem dysgenesis, and cardiac and ophthalmologic anomalies, such as microphthalmia and cataract. Severe loss-of-function cases were incompatible with life, whereas those individuals with milder missense variants presented with severe global developmental delay, syndactyly of 2nd and 3rd toes, and severe muscle hypotonia resulting in incapacity to stand without support. Consistent with a causative role for KIAA1109 loss-of-function/hypomorphic variants in this syndrome, knockdowns of the zebrafish orthologous gene resulted in embryos with hydrocephaly and abnormally curved notochords and overall body shape, whereas published knockouts of the fruit fly and mouse orthologous genes resulted in lethality or severe neurological defects reminiscent of the probands\' features.