Oculocerebrorenal syndrome (Lowe syndrome) is a rare X-linked disorder affecting 1/500,000 males that most frequently affects the eyes, central nervous system, and kidneys. Phenotypic presentation includes congenital cataracts, developmental delay, intellectual disability, and Fanconi-type renal dysfunction. Lowe Syndrome is caused by hemizygous loss of function variants in the OCRL gene. While individuals may live into the third and fourth decade of life, some will die in the first few years of either renal failure or infection. While early diagnosis is important, few cases have documented the prenatal phenotype of this condition, which has included bilateral cataracts and variable neurological abnormalities. We report a case of a family with an extensive history of congenital cataracts, immune compromise, and neonatal death in male members. The fetus was found to have a unilateral cataract, mild ventriculomegaly, vertebral anomalies, and an underlying diagnosis of Lowe Syndrome with a mutation in OCRL at c.2582-1G>C (IVS23-1G>C).

NUDT2 is an enzyme important for maintaining the intracellular level of the diadenosine tetraphosphate (Ap4A). Bi-allelic loss of function variants in NUDT2 has recently been reported as a rare cause of intellectual disability (ID). Herein, we describe a Chinese girl with ID, attention deficit hyperactivity disorder (ADHD), and motor delays with abnormal walking posture and difficulty climbing stairs, who bears compound heterozygous variants c.34 C > T (p.R12*) and c.194T > G (p.I65R) in NUDT2. Homozygous variants c.34 C > T (p.R12*) or c.186del (p.A63Qfs*3) in NUDT2 were previously reported to cause ID. This is the first patient with ID due to compound heterozygous variants in NUDT2 and p.I65R is a novel missense variant. This study enriched the genotype and phenotype of NUDT2-related ID and supported the critical developmental involvement of NUDT2.

Joubert syndrome (JS) is a recessive disorder that is characterized by midbrain-hindbrain malformation and shows the \"molar tooth sign\" on magnetic resonance imaging. Mutations in 40 genes, including Abelson helper integration site 1 (AHI1), inositol polyphosphate-5-phosphatase (INPP5E), coiled-coil and c2 domain-containing protein 2A (CC2D2A), and ARL2-like protein 1 (ARL13B), can cause JS. Classic JS is a part of a group of diseases associated with JS, and its manifestations include various neurological signs such as skeletal abnormalities, ocular coloboma, renal disease, and hepatic fibrosis. Here, we present a proband with the molar tooth sign, ataxia, and developmental and psychomotor delays in a Dagestan family from Russia. Molecular genetic testing revealed two novel heterozygous variants, c.2924G>A (p.Arg975His) in exon 28 and c.1241C>G (p.Pro414Arg) in exon 12 of the transmembrane protein 67 (TMEM67) gene. These TMEM67 gene variants significantly affected the development of JS type 6. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of children with complex motor and psycho-language delays. This case also expands the clinical phenotype and genotype of TMEM67-associated diseases.

Joubert syndrome (JS) is a group of rare ciliopathies, mainly characterized by cerebellar dysplasia representing the \"molar tooth sign (MTS)\" on neuroimaging, hypotonia, and developmental delay. Having a complicated genotype-phenotype correlation due to its rich genetic heterogeneity, JS is usually combined with other organic defects affecting the retina, kidney, and liver. This report aimed to present new cases and novel variants of JS.
Five unrelated patients who were diagnosed with JS, with or without typical clinical characteristics, received integrated examinations, including whole-exome sequencing (WES) and Sanger sequencing. We identified nine pathogenic variants in the TCTN2, CPLANE1, INPP5E, NPHP1, and CC2D2A genes.
Four novel pathogenic mutations in the TCTN2, CPLANE1, and INPP5E genes were reported. The findings broadened the genotypic spectrum of JS and contributed to a better understanding of genotype-phenotype correlation.

暂无摘要。

Prune exopolyphosphatase-1 (PRUNE1) encodes a member of the aspartic acid-histidine-histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss-of-function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1-related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous PRUNE1 NM_021222.2:c.933G>A synonymous variant identified in a 6-year-old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the PRUNE1 NM_021222.1:c.933G>A variant resulted in an in-frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH-associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in PRUNE1-related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations.

A 7-year-old boy visited our hospital for a detailed examination of proteinuria identified in a school urinary test. He had short stature, misaligned teeth, and mild intellectual disability. A urinary examination identified mild proteinuria and extremely high levels of beta-2 microglobulin. On blood examination, his protein, albumin, and creatinine levels were found to be normal; however, his lactate dehydrogenase and creatinine phosphokinase levels were slightly elevated. Upon histological examination, no abnormalities in glomeruli or tubules were found. Considering these results, we diagnosed our patient with Dent disease type 2 (DD2). Although the whole exome sequencing revealed large deletion of OCRL, which was seen only in Lowe syndrome and not in DD2 previously, our final diagnosis for the patient is DD2. A phenotypic continuum exists between Dent disease and Lowe syndrome, and several factors modify the phenotypes caused by defects in OCRL. Although patients have thus far been diagnosed with DD2 or Lowe syndrome on the basis of their symptoms, accumulation and analysis of cases with OCRL defects may hereafter enable more accurate diagnoses.

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug\'s neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium\'s neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug\'s inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium\'s neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer\'s disease (AD) and in patients, discussing the rationale for the drug\'s use in the treatment of AD.

The molecular function of a protein relies on its structure. Understanding how variants alter structure and function in multidomain proteins is key to elucidate the generation of a pathological phenotype. However, one may fall into the logical bias of assessing protein damage only based on the variants that are visible (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with both kinase and phosphatase function. Most variants in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerability to variation, we evaluated whether variants in PNKP are under survivorship bias. Here, we provide the evidence that supports a higher tolerance in the kinase domain even when all variants reported are deleterious. Instead, the phosphatase domain is less tolerant due to its lower variant rates, a higher degree of sequence conservation, lower dN/dS ratios, and the presence of more disease-propensity hotspots. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Finally, we propose the term \"Wald\'s domain\" for future studies analyzing the possible survivorship bias in multidomain proteins.

The oculocerebrorenal (OCRL) syndrome, also known as Lowe syndrome (LS), is an X-linked recessive disorder that predominantly affects males and is characterized by growth and mental retardation, congenital cataract and renal Fanconi syndrome. OCRL1 is the gene responsible for LS and encodes an inositol polyphosphate-5-phosphatase. We report a male child from North India, with LS with missense mutation in exon 14 of the OCRL gene.