Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications.

PPFIBP1 encodes for the liprin-ß1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.

Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.

Temporal subcortical T2 hypointensity on MRI in epilepsia partialis continua, a non ketotic hyperglycemia rather than herpes encephalitis.

PURPOSE: Hyperglycemia can present as many neurological problems, one of them is seizure. Different brain MRI features can be seen in focal seizures associated with nonketotic hyperglycemia that subcortical T2 hypointensity is the only characteristic one. Finding this MRI feature is highly valuable in early diagnosis and treatment. METHODS: Our patient was a 60-year-old female, a case of type 2 diabetes mellitus. She was brought to Emergency Room (ER) with focal colonic status epilepticus of right face and arm associated with confusion and drowsiness progressed over 2 weeks prior to admission. At first, acyclovir was started alongside anti-seizure medication with doubt of herpes encephalitis but antiviral was discontinued after normal LP result and characteristic MRI features. RESULTS: Subcortical T2 hypointensity in left temporal and insular lobe was seen on first MRI that was resolved on follow up MRI after she was treated. CONCLUSION: Epilepsia partialis continua in the setting of non ketotic hyperglycemia should be differentiated from that in herpes encephalitis in a diabetic patient presenting with subacute confusional state and focal status epilepticus considering characteristic MRI finding of subcortical T2 hypointensity.

The First Report of Iranian Registry of Patients with Spinal Muscular Atrophy.

BACKGROUND: Insufficient amounts of survival motor neuron protein is leading to one of the most disabling neuromuscular diseases, spinal muscular atrophy (SMA). Before the current study, the detailed characteristics of Iranian patients with SMA had not been determined. OBJECTIVE: To describe the key demographic, clinical, and genetic characteristics of patients with SMA registered in the Iranian Registry of SMA (IRSMA). METHODS: IRSMA has been established since 2018, and the demographic, clinical, and genetic characteristics of patients with SMA were recorded according to the methods of treat neuromuscular disease (TREAT-NMD) project. RESULTS: By October 1, 2022, 781 patients with 5q SMA were registered. Of them, 164 patients died, the majority of them had SMA type 1 and died during the first 20 months of life. The median survival of patients with type 1 SMA was 23 months. The consanguinity rate in 617 alive patients was 52.4%, while merely 24.8% of them had a positive family history. The most common type of SMA in live patients was type 3. Morbidities were defined as having scoliosis (44.1%), wheelchair dependency (36.8%), tube feeding (8.1%), and requiring mechanical ventilation (9.9%). Most of the registered patients had a homozygous deletion of SMN1, while the frequency of patients with higher copy numbers of SMN2, was less in more severe types of the disease. Earlier onset of the disease was significantly seen in patients with lower copy numbers of SMN2. The neuronal apoptosis inhibitory protein (NAIP) gene deletion was associated with a higher incidence of more severe types of SMA, higher dependency on ventilators, tube feeding, and earlier onset of the disease. CONCLUSIONS: The IRSMA is the first established Iranian nationwide registry of patients with SMA. Using this registry, decision-makers, researchers, and practitioners can precisely understand the epidemiology, characteristics, and genetics of patients with SMA in Iran.

Evaluation of myocardial perfusion and function in patients with asymptomatic beta-thalassemia major using myocardial gated single-photon-emission computed tomography.

This study was conducted to evaluate the cardiac perfusion and function of patients with beta-thalassemia major (TM) using99mTc-MIBI cardiac gated single-photon-emission computed tomography (SPECT) and to compare the obtained indices with echocardiographic and hematological parameters. Patients with TM who were referred for regular blood transfusion and periodic checkup were included in this study. A questionnaire containing demographic and medical data was provided for all patients by an expert pediatrician. All of the patients were on Desferal chelation therapy and none of them had clinical signs of heart failure. Myocardial gated perfusion SPECT, echocardiography, and complete blood tests were performed for each patient. In total, 24 patients including 14 men (58.3%) and 10 women (41.7%) aged 15-36 years with a mean age of 24.3 ± 6.5 years' old were enrolled in this study. Myocardial perfusion scan (MPS) was normal in all patients. The mean value of the measured left ventricular ejection fraction (LVEF) was 58.88 ± 13.45%. There was no significant association between measured LVEF on scan and echocardiography (P > 0.05). In terms of hematological results, there was a significant association between the hemoglobin and ferritin level and the amount of blood transfusion (P = 0.02 and P= 0.00, respectively). According to the results of myocardial perfusion imaging (MPI), cardiac perfusion and LVEF were within normal limits in all asymptomatic patients. In the absence of any perfusion abnormality, the use of MPI in patients with asymptomatic beta-TM is not recommended for diagnosing myocardial ischemia.

RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant.

BACKGROUND: Ribonucleases (RNases) are crucial for degradation of ribosomal RNA (rRNA). RNASET2 as a subtype of RNASEs is a 256 amino acid protein, encoded by RNASET2 gene located on chromosome six. Defective RNASET2 leads to RNASET2-deficient leukoencephalopathy, a rare autosomal recessive neurogenetic disorder with psychomotor delay as its main clinical symptom. The clinical findings can be similar to congenital cytomegalovirus (CMV) infection and Aicardi-Goutieres syndrome (AGS). METHODS: Herein, we presented a patient with motor delay, neurological regression, infrequent seizures and microcephaly at 5 months of age. Brain imaging showed white matter involvement, calcification and anterior temporal cysts. Basic metabolic tests, serum and urine CMV polymerase chain reaction (PCR) were requested. According to clinical and imaging findings, screening of RNASET2 and RMND1 genes were performed. The clinical data and magnetic resonance imaging (MRI) findings of previous reported individuals with RNASET2-deficient leukodystrophy were also reviewed and compared to the findings of our patient. RESULTS: Brain MRI findings were suggestive of RNASET2-deficient leukoencephalopathy, AGS and CMV infection. Basic metabolic tests were normal and CMV PCR was negative. Molecular study revealed a novel homozygous variant of c.233C > A; p.Ser78Ter in exon 4 of RNASET2 gene compatible with the diagnosis of RNASET2-deficient leukoencephalopathy. CONCLUSIONS: RNASET2-deficiency is a possible diagnosis in an infant presented with a static leukoencephalopathy and white matter involvement without megalencephaly. Due to overlapping clinical and radiologic features of RNASET2-deficient leukoencephalopathy, AGS and congenital CMV infections, molecular study as an important and helpful diagnostic tool should be considered to avoid misdiagnosis.

Urinary arsenic, cadmium, manganese, nickel, and vanadium levels of schoolchildren in the vicinity of the industrialised area of Asaluyeh, Iran.

Asaluyeh is one of the most heavily industrialised areas in the world where gas, petrochemical, and many downstream industries are located. This study aims to survey the biomonitoring of four metals and one metalloid in children living in the vicinity of Asaluyeh area. To do this, we analysed the creatinine-adjusted urinary levels of arsenic (As), cadmium (Cd), vanadium (V), manganese (Mn), and nickel (Ni) in 184 elementary schoolchildren (99 boys and 85 girls) living in Asaluyeh and compared them with a reference population. The comparisons were done for two seasons (spring and fall). The results showed that in the case area (Asaluyeh), the levels of As, V, Mn, and Ni were significantly higher and that of Cd was not significantly higher than the reference city for both seasons. The mean concentration of metal(loid)s in Asaluyeh (case) and Sadabad (reference) area as µg g-1 creatinine was As 2.90 and 2.24, V 0.06 and 0.03, Mn 0.28 and 0.25, Ni 0.54 and 0.29, and Cd 0.31 and 0.28 in spring and As 3.08 and 2.28, V 0.07 and 0.03, Mn 0.30 and 0.26, Ni 0.91 and 0.30, and Cd 0.36 and 0.31 in the fall. Seasonal variations played a key role in determining urinary metal(loid) concentration, as we saw the significant level of As, Cd, V, and Ni in fall than in spring. With regard to the impact of gender on the absorption and accumulation of urinary metal(loid)s, boys showed higher levels of the studied elements, especially for As, than girls as outdoor activities are more popular among boys. Due to the values being lower than those reported in literature, more research is needed on various population groups and other exposure sources in order to judge whether living in the vicinity of the gas and petrochemical industries in Asaluyeh is a threat to nearby residents.

Precision medicine and molecular imaging: new targeted approaches toward cancer therapeutic and diagnosis.

This paper presents a review of the importance and role of precision medicine and molecular imaging technologies in cancer diagnosis with therapeutics and diagnostics purposes. Precision medicine is progressively becoming a hot topic in all disciplines related to biomedical investigation and has the capacity to become the paradigm for clinical practice. The future of medicine lies in early diagnosis and individually appropriate treatments, a concept that has been named precision medicine, i.e. delivering the right treatment to the right patient at the right time. Molecular imaging is quickly being recognized as a tool with the potential to ameliorate every aspect of cancer treatment. On the other hand, emerging high-throughput technologies such as omics techniques and systems approaches have generated a paradigm shift for biological systems in advanced life science research. In this review, we describe the precision medicine, difference between precision medicine and personalized medicine, precision medicine initiative, systems biology/medicine approaches (such as genomics, radiogenomics, transcriptomics, proteomics, and metabolomics), P4 medicine, relationship between systems biology/medicine approaches and precision medicine, and molecular imaging modalities and their utility in cancer treatment and diagnosis. Accordingly, the precision medicine and molecular imaging will enable us to accelerate and improve cancer management in future medicine.