The patatin-like protein family plays an important role in various biological functions including lipid homeostasis, cellular growth, and signaling. Conserved across species, the patatin domain is shared by all 9 members of the PNPLA family without redundancy in the coding sequences. The defective function of PNPLA2, PNPLA6, and PNPLA9 are known to cause mitochondrial-related neurodegeneration. Recently, PNPLA8 has been associated with mitochondrial myopathy and poor weight gain with lactic acidosis in 3 unrelated families. Using whole-exome sequencing, we identified a homozygous novel missense variation c.1874A>G in the patatin domain of PNPLA8. The patient had prenatal-onset severe and progressive neurodegeneration with mortality in infancy.

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Peroxisome biogenesis disorders (PBDs) are a group of autosomal recessive disorders caused due to impaired peroxisome assembly affecting the formation of functional peroxisomes. PBDs are caused by a mutation in PEX gene family resulting in disease manifestation with extreme variability ranging from the onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults. Disease causing variations in PEX7 is known to cause severe rhizomelic chondrodysplasia punctata type 1 and PBD 9B, an allelic disorder resulting in a milder phenotype, often indistinguishable from that of classic Refsum disease. This case report highlights the variability of PEX7 related phenotypes and suggests that other than RCDP1 and late onset phenotype similar to Refsum disease, some cases present with cataract and neurodevelopmetal abnormalities during childhood without chondrodysplasia or rhizomelia. This report also underlines the importance of considering PBD 9B in children presenting with neurodevelopmental abnormalities especially if they have congenital cataract.

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Pontocerebellar hypoplasia (PCH) type 12 is a rare, perinatal lethal neurodegenerative genetic disorder caused by biallelic mutations in the COASY gene. Herein, we describe the clinical and neuroradiological profile of nine affected fetuses/neonates from five families identified with a common COASY: c.1486‐3C>G biallelic variant. Four of the five families were identified after data reanalysis of unresolved, severe PCH like phenotype and the fifth family through collaboration. The common antenatal phenotype was cerebellar hypoplasia. Microcephaly, arthrogryposis, and intrauterine growth restriction were the shared postnatal findings. The neurological manifestations included seizures, poor sucking, and spasticity. Novel findings of corpus callosum agenesis, simplified gyral pattern, normal sized pons, optic neuropathy, and a small thorax are reported in this series. The allele frequency of the COASY: c.1486‐3C>G variant was 0.62% in the available Asian Indian database. We describe this as a possible common Indian origin variant. To the best of our knowledge, this is the largest PCH12 series reported.

Deficiency of coagulation factor IX encoded by F9 gene (OMIM*300746) causes abnormality in the blood coagulation cascade and prolonged bleeding, known as hemophilia B (Christmas disease) (OMIM #306900). It is a rare X-linked disease, affecting around 1 in 25,000 to 30,000 live births. 1 It is diagnosed on the basis of clinical manifestations such as joint hemarthrosis, pronged bleeding; biochemical profiling of factor IX level, and family history. Hemophilia B patients are generally male with severe clinical manifestations; however, 40% to 60% of female carriers have some bleeding problems. 2 Based on residual plasma FIX activity, it is divided into severe (factor IX level <1%), moderate (factor IX level 1%-5%) and mild (factor IX level >5%-40%). 3 Molecular analysis in the F9 gene has been an area of extensive research that led to the identification of many mutations within the F9 gene. There has always been a growing interest in highlighting the differences pertaining to hemophilia mutational spectra in various populations. Genetic screening performed on familial cases reported a wide range of genetic mutations, showing large molecular heterogeneity. Till now, more than 1200 unique genetic variants have been identified in the F9 gene (www.f9-db.eahad. org). These include point mutations, small insertions/deletions, large deletions, duplications, complex rearrangements, and neutral polymorphisms. 3 Variation in mutation spectrum of F9 gene across the different populations has also been observed. [4][5][6] Molecular analysis using PCR and Sanger sequencing along with dosage analysis for detection of large deletions/duplications enables mutation detection in approximately 92% of patients. 3 This also helps in the prediction

Inherited methylenetetrahydrofolate reductase (MTHFR) deficiency is associated with a wide spectrum of disorders including homocystinuria. This study aims to describe the neurological phenotypes and molecular profiles of patients with homocystinuria caused by biallelic variants in MTHFR. We report six subjects with MTHFR deficiency who presented with variable neurological phenotypes which could be viewed as a continuous spectrum. Fatal infantile encephalopathy was observed in one family, whereas another patient presented at 27 years with acute leukoencephalopathy and recovered within 3 months. Intermediate forms presenting as complicated hereditary spastic paraparesis of variable severity were observed in four subjects. Clinical and molecular information of the 207 cases reported in literature were also retrieved and analyzed. We categorized all subjects into three categories - severe, intermediate and mild forms according to the clinical presentation. In addition, a total of 286 disease-causing variations reported to date were analyzed. These included seven disease-causing variants reported in this study of which one is novel. Some genotype-phenotype correlation could be seen which corroborated with previous observations. However, inter- and intrafamilial variability was also noted. Treatment with betaine, B12 and folic acid was started in four subjects with variable outcomes.