Thin Corpus Callosum Research Articles

HPDL mutations identified by exome sequencing are associated with infant neurodevelopmental disorders.

BackgroundRecent research found that biallelic HPDL variants can cause neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), with only a few reports. Clinical phenotypic information on individuals with damaging HPDL variants may also be incomplete. The phenotype of NEDSWMA is characterized by severe neurodevelopmental delay, brain atrophy, and spasticity in infancy.MethodsExome sequencing was used in the proband and his parents to identify the underlying genetic cause. Candidate mutations were validated by classic Sanger sequencing. The clinical presentation of the infant who carried HPDL variants was summarized.ResultsWe identified a novel compound heterozygous variants in HPDL, c.995delC (p.T332Mfs) and c.1051C>T (p.Q351*) in the patient a 6‐month‐old boy presenting with global developmental delay, seizures, hypertonia, and limb spasticity. Brain magnetic resonance imaging (MRI) showed thin corpus callosum, ventriculomegaly, white matter volume reduction, bilateral frontotemporal subarachnoid widening, and sulcus deeping.ConclusionOur results provided important information for the associations of variants in HPDL with the neurodevelopmental disorder in infants, and broaden the genetic spectrum of HPDL‐related disease. This is the second report of the HPDL mutation causing infant neurodevelopmental disorders in a Chinese population.

Incidence, follow-up, and postnatal clinical progress of children with central nervous system anomalies on fetal MRI.

MRI is increasingly employed to assess intrauterine fetal anomalies. Central nervous system (CNS) anomalies are common structural conditions that warrant evaluation with fetal MRI and subsequent prenatal consultation with a pediatric neurosurgeon. As the use of fetal MRI increases, there is greater impetus to understand the most common CNS structural anomalies diagnosed in utero, as well as their natural histories. The authors performed a single-center retrospective review of fetal MRI evaluations performed between January 2012 and December 2020. Children who underwent both prenatal and postnatal neurosurgical evaluations of CNS anomalies were included. Specific CNS anomalies on fetal MRI, associated extra-CNS findings, and suspicion for genetic abnormality or syndromes were noted. Postnatal clinical status and interventions were assessed. Between January 2012 and December 2020, a total of 469 fetal MRI evaluations were performed; of these, 114 maternal-fetal pairs had CNS anomalies that warranted prenatal consultation and postnatal pediatric neurosurgical follow-up. This cohort included 67 male infants (59%), with a mean ± SD follow-up of 29.8 ± 25.0 months after birth. Fetal MRI was performed at 27.3 ± 5.8 weeks of gestational age. The most frequently reported CNS abnormalities were ventriculomegaly (57%), agenesis or thinning of the corpus callosum (33%), Dandy-Walker complex (DWC) (21%), neuronal migration disorders (18%), and abnormalities of the septum pellucidum (17%). Twenty-one children (18%) required neurosurgical intervention at a mean age of 2.4 ± 3.7 months. The most common surgical conditions included myelomeningocele, moderate to severe ventriculomegaly, encephalocele, and arachnoid cyst. Corpus callosum agenesis or thinning was associated with developmental delay (p = 0.02) and systemic anomalies (p = 0.05). The majority of prenatal patients referred for DWC had Dandy-Walker variants that did not require surgical intervention. The most common conditions for prenatal neurosurgical assessment were ventriculomegaly, corpus callosum anomaly, and DWC, whereas the most common surgical conditions were myelomeningocele, hydrocephalus, and arachnoid cyst. Only 18% of prenatal neurosurgical consultations resulted in surgical intervention during infancy. The majority of referrals for prenatal mild ventriculomegaly and DWC were not associated with developmental or surgical sequelae. Patients with corpus callosum abnormalities should be concurrently referred to a neurologist for developmental assessments.

Clinical and molecular genetic findings of Crisponi/cold-induced sweating syndrome (CS/CISS) spectrum in patients from Turkey.

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by episodic hyperthermia, arthrogryposis, impaired feeding ability, and respiratory distress. The classic CS/CISS is mainly associated with CRLF1 and, rarely, CLCF1. PERCHING syndrome, previously known as CS/CISS type-3 associated with biallelic pathogenic variants in KLHL7, is notable for its few overlapping manifestations. This study presents genotype-phenotype relationships in CS/CISS-like spectrum associated with CRLF1 and KLHL7. Clinical findings of 19 patients from 14 families and four patients from three families were found in association with six different CRLF1 and three different KLHL7 variants, respectively. c.167T>C and c.713delC of the CRLF1 gene and the c.642G>C of the KLHL7 were novel. The c.708_709delCCinsT allele of CRLF1 was identified in 10 families from the Mardin province of Turkey, underlining that an ancestral haplotype has become widespread. CRLF1-associated phenotypes revealed novel manifestations such as prenatal oligohydramnios, benign external hydrocephalus, previously unreported dysmorphic features emerging with advancing age, severe palmoplantar keratoderma and facial erythema, hypopigmented macules and streaks, and recurrent cardiac arrests. KLHL7 variants presented with glabellar nevus flammeus, blepharophimosis, microcephaly, thin corpus callosum, and cleft palate. Abnormalities of sweating, observed in one patient reported herein, is known to be very rare among KLHL7-related phenotypes.

Study of clinical, haematological and radiological profile of children admitted with infantile tremor syndrome to a tertiary care teaching hospital in Northern India

Background: Infantile tremor syndrome (ITS) is characterized by gradual onset of mental and psychomotor changes, pigmentary disturbances in hairs and skin, pallor, tremors and neuroregression. The aim of study was to determine clinical, haematological and radiological spectrum of children admitted with infantile tremor syndrome.Methods: It was a prospective cross-sectional study done in age group of 6 months to 5 years conducted in department of pediatrics of a tertiary care medical college with duration of 18 months. Clinical, haematological and radiological profile parameters of 36 children admitted during study period with ITS were recorded as per prepared performa and analysed. Microsoft excel was used in creating database while data was analysed by using Statistical Package for Social Sciences (SPSS) version 23.0.Results: Total 36 children were enrolled in study. Mean age was 12.33±3.89 months and mostly were male (55.6%). Most (72.2%) of children belonged to lower socioeconomic status and (83.3%) were exclusively breastfed. Only 11.1% had severe acute malnutrition (SAM). 77.77% had vitamin B12 levels below normal. Progressive paleness (88.9%), delayed development (61.1%) and developmental regression (58.3%) were most common complaints reported. 63.9% had tremors at presentation. In MRI findings, poor myelination with thinning of corpus callosum (16.7%) and uniform thinning of corpus callosum with subtle hypomyelination in bilateral frontal lobes (8.3%) were major findings. In majority of children tremor disappeared in 11-15 days (30.6%) after starting treatment.Conclusions: ITS should to be considered as a differential diagnosis in an infant on exclusive breast feeding with vegetarian mother with poor weaning practices presenting with neuroregression, tremor and malnutrition with skin changes.

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family.

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

18. Trisomy 18p detected in DNA from saliva but absent in DNA from blood

Molecular diagnostic testing using DNA from saliva specimens markedly increased recently due to the ease of sample collection, compared to peripheral blood, during the COVID-19 pandemic. Published literature suggests that DNA from saliva is primarily composed of epithelial cells (70-90%), with the remainder being primarily leukocytes (10-30%). Here, we describe a case followed by our clinicians since 2007 characterized by developmental delay, autism, a somewhat coarse face with full cheeks, up-slanting palpebral fissures, thin corpus callosum, and a full-scale IQ of 60.

Pontocerebellar Hypoplasia Type 9: A New Case with a Novel Mutation and Review of Literature.

Pontocerebellar hypoplasia type 9 (PCH-9) is a very rare autosomal recessive neurodegenerative disorder. Affected infants present early with severe developmental delay, spasticity, with the unique magnetic resonance imaging picture of thin corpus callosum, atrophied pons, and cerebellum. It is caused by loss of function mutations in the AMPD2 gene, encoding for the adenosine monophosphate deaminase enzyme-paralog 2. This gene is expressed in different somatic tissues with high level of expression in cerebellum and its encoded enzyme catalyzes a critical step in de novo biosynthesis of purines and its deficiency in the developing neurons severely affects neuronal differentiation and cell viability. We clinically evaluated an Emirati patient presented with severe developmental and growth delay, as well as corpus callosum agenesis and atrophy of brainstem and cerebellum. We performed exome sequencing, Sanger sequencing, and segregation analysis to identify the genetic cause of the phenotype, followed by in silico and in vitro analysis. We identified the novel variant (NM_004037.9:c.1471G > A) in AMPD2 gene leading to a single amino acid substitution (p.Gly491Arg) in adenosine monophosphate deaminase-2 enzyme. This variant is predicted to be pathogenic using several in silico tools, and resulted in a decrease in the enzyme function in the patient's polymorphonuclear cells by 82% (95% confidence interval: 73.3-91.7%, p = 0.029) compared with the control. This data establishes that the affected child is affected by PCH-9. Furthermore, we review all reported cases in literature to summarize the main clinical features of this rare disease.

A syndrome of severe intellectual disability, hypotonia, failure to thrive, dysmorphism, and thinning of corpus callosum maps to chromosome 7q21.13-q21.3.

Six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, unique dysmorphism, skeletal abnormalities, and severe failure to thrive with normal birth weights. Patients had a profound intellectual disability and cognitive impairment with almost no acquired developmental milestones by 12 months. Early‐onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia. Craniofacial dysmorphism consisted of a triangular face with a prominent forehead and midface hypoplasia. Magnetic resonance imaging (MRI) demonstrated thinning of the corpus callosum and paucity of white matter. Genome‐wide linkage analysis identified a single ~4 Mbp disease‐associated locus on chromosome 7q21.13‐q21.3 (LOD score>5). Whole‐exome and genome sequencing identified no nonsynonymous pathogenic biallelic variants in any of the genes within this locus. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.

Second report of SHMT2 related neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB; MIM# 619121) is a recently described metabolic disorder with characteristic features of mild dysmorphism, intellectual disability, spasticity, peripheral neuropathy, cardiomyopathy, and thin corpus callosum. Biallelic variants in SHMT2 (MIM 138450), encoding mitochondrial serine hydroxymethyltransferase enzyme, have been recently linked to this disorder. Till now, a total of seven variants including six missense and one deletion-insertion has been reported in SHMT2. We hereby report an additional individual with novel homozygous missense variant c.1133A > G in SHMT2 (NM_005412.6) identified by exome sequencing and review the phenotype and genotype of the previously reported individuals with NEDCASB.

Expansion of the mutation and phenotypic spectrum of hereditary spastic paraplegia

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts, and more than 80 HSP loci have been mapped to cause HSP. In this study, we aim to perform a genetic and clinical study of ten (6 male, 4 female) sporadic Chinese HSP patients. Next-generation sequencing (NGS) gene panels combined with multiplex ligation-dependent probe amplification assay (MLPA) analysis and the trinucleotide repeat dynamic mutation detection are available for the ten patients. Among the 10 patients, one SPG7 patient, one SPG11 patient, and one pure SPG31 patient were detected. Two variants (deletion of exon 3-9 of SPG7 gene and the heterozygous mutation c.1861C > T/p.Q621* of SPG11 gene) were novel and three (c.1150_1150 + 1insCTAC/p.G384Afs*13 in SPG7 gene, c.3075dupA/p.E1026Rfs*4 in SPG11 gene, and c.478delA/p.R160Gfs*63 of REEP1 gene/SPG31) were previously reported. The SPG11 patient presented mild intellectual with peripheral neuropathy and thin corpus callosum (TCC) with no white matter abnormalities (WMA). The SPG7 patient detected in this study is the third SPG7 family reported in China; he manifested peripheral neuropathy, scoliosis, and polydactyly which expand the phenotype spectrum of SPG7. The AAO overlapped among each HSP subtype, which limited the ability to predict the subtype of HSP from AAO. Compared with non-Asian patients, the mutation frequency of SPG7 is relatively low in Asian populations. Considering the varieties of mutation types of HSP, we suggested targeted sequencing gene panels should be combined with MLPA for diagnosis of HSP.

SPG11: clinical and genetic features of seven Czech patients and literature review

ABSTRACT SPG11 is one of the most frequent autosomal recessively inherited types of hereditary spastic paraplegias (HSP or SPG). We describe the first seven patients from the Czech Republic with biallelic pathogenic variants in the SPG11. The typical HSP neurological findings are present in all the described patients in that the signs of a complicated phenotype develop slowly. The speed of disease progression, and the severity of gait impairment, was fast in all patients but the phenotype varied from patient to patient. Thin corpus callosum was not observed in two patients. Two Czech SPG11 patients had unusual late onset of disease and both were compound heterozygotes for the c.5381T>C variant. Therefore, we looked for a potential ralationship between the type of variant in the SPG11 gene and the age of disease onset. By reviewing all described SPG11 patients carrying at least one missense pathogenic variant in the SPG11 gene we did not found any relationship between the age of onset and the type of variant. Together twelve pathogenic variants, including gross deletions, were found in the SPG11 gene the Czech SPG11 patients, the c.3454-2A>G variant is novel.

Novel SEPSECS Pathogenic Variants Featuring Unusual Phenotype of Complex Movement Disorder With Thin Corpus Callosum: A Case Report.

ObjectivesTo report a novel association between pathogenic variants in the SEPSECS gene and complex movement disorder with thin corpus callosum (TCC).MethodsClinical exome sequencing was performed in an adult patient with a genetically unsolved neurodegenerative disorder. The main clinical, neuroimaging, and genetic data were described.ResultsThe c.865C > T (p.P289S) and c.1297T > C (p.Y433H) missense variants in SEPSECS (NM_016,955.3) were discovered.DiscussionThis case represents a novel form of early-onset pyramidal syndrome with optic nerve hypoplasia, which slowly evolved to extrapyramidal syndrome featuring dystonia-parkinsonism, associated with TCC, caused by SEPSECS pathogenic variants. This form enlarges the group of the so-called pyramidal-extrapyramidal syndromes, as well as complex hereditary spastic paraparesis with TCC.

EP262: De novo heterozygous variant in the RAB11B gene presenting with combined cardiac defect and neurodevelopmental disorder: A case report

The RAB11B gene (OMIM: 604198) encodes for a GTP-binding protein within the Rab11 GTPase subfamily which is associated with the regulation of exocytic and endocytic pathways. It also plays an essential role in ciliogenesis and vesicular trafficking. Pathogenic variants in RAB11B were first described in five patients in 2017. Subsequently, an additional patient was diagnosed through the Korean Undiagnosed Diseases Program (KUDP) in 2019. Clinical features shared by these patients were predominantly a neurological phenotype, including global developmental delay, epilepsy, hypotonia and gait disturbances. Ophthalmological, musculoskeletal, dermatological, and urological findings were also reported in some patients. MRI brain abnormalities were present in many of these patients and include decrease in white matter volume, patchy white matter signals, cerebellar hypoplasia, ventriculomegaly, thin corpus callosum and atypical partial rhombencephalosynapsis. Here we describe a 6-year-old male with previously unreported clinical findings of congenital heart defect in this disorder. A 5-year-old term male presented with prenatal complications of fetal congenital heart disease, maternal hypertension and maternal gestational diabetes. Fetal echocardiogram identified a tetralogy of Fallot (TOF) and post-natal echocardiogram confirmed the TOF with pulmonary valve atresia and 2 aorto-pulmonary collateral vessels from the descending aorta. Clinical examination at birth revealed bilateral congenital vertical talus but no other dysmorphic features. Fluorescent in-situ hybridization test for 22q11.2 deletion was negative. Chromosomal microarray analysis revealed a 133kb deletion of uncertain significance on chromosome 5q14.3. A head and renal ultrasound was normal at birth. He was diagnosed with congenital nystagmus and microcoria at 6 months of age with low amplitude on visual evoked potential testing. MRI brain revealed an extremely hypoplastic corpus callosum and brainstem, bilateral optic nerve hypoplasia, marked depletion of white matter and delayed myelination. He requires a G-tube for feeding. He has significant global developmental delays and is non-verbal. A clinical trio exome sequencing revealed a de novo, heterozygous, missense variant of unknown significance in the RAB11B gene (c.64 G>A; p.al22Met). This variant has since been re-classified as a pathogenic variant based on the published case series of 6 other individuals with similar phenotype. Given the fact that RAB11B is highly expressed in brain, cardiac and testicular tissue with various roles in ciliogenesis and vesicular trafficking, this patient’s cardiac defect is likely secondary to the pathogenic variant the RAB11B gene. We present this case of a de novo, heterozygous RAB11B variant presenting with a congenital heart defect in addition to a neurodevelopmental phenotype, thus expanding the phenotypic spectrum of this rare disorder.

Novel RAB3GAP1 Mutation in the First Tunisian Family With Warburg Micro Syndrome.

Warburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.We applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.We reveal a new variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 (NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.WES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 (NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects

BackgroundGoltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants.ResultsWe report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes.ConclusionsOur combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.

Mast Syndrome Outside the Amish Community: SPG21 in Europe.

Background:Mast syndrome is a rare disorder belonging to the group of hereditary spastic paraplegias (HSPs). It is caused by bi-allelic mutations in the ACP33 gene, and is originally described in Old Order Amish. Outside this population, only one Japanese and one Italian family have been reported. Herein, we describe five subjects from the first three SPG21 families of German and Austrian descent.Methods:Five subjects with complicated HSP were referred to our centers. The workup consisted of neurological examination, neurophysiological and neuropsychological assessments, MRI, and genetic testing.Results:Onset varied from child- to adulthood. All patients exhibited predominant spastic para- or tetraparesis with positive pyramidal signs, pronounced cognitive impairment, ataxia, and extrapyramidal signs. Neurophysiological workup showed abnormal motor and sensory evoked potentials in all the patients. Sensorimotor axonal neuropathy was present in one patient. Imaging exhibited thin corpus callosum and global brain atrophy. Genetic testing revealed one heterozygous compound and two homozygous mutations in the ACP33 gene.Conclusion:Herein, we report the first three Austrian and two German patients with SPG21, presenting a detailed description of their clinical phenotype and disease course. Our report adds to the knowledge of this extremely rare disorder, and highlights that SPG21 must also be considered in the differential diagnosis of complicated HSP outside the Amish community.

An autopsied case report of spastic paraplegia with thin corpus callosum carrying a novel mutation in the SPG11 gene: widespread degeneration with eosinophilic inclusions

BackgroundThe detailed neuropathological features of patients with autosomal recessive hereditary spastic paraplegia with a thin corpus callosum (TCC) and SPG11 mutations are poorly understood, as only a few autopsies have been reported. Herein, we describe the clinicopathological findings of a patient with this disease who received long-term care at our medical facility.Case presentationA Japanese man exhibited a mild developmental delay in early childhood and intellectual disability, followed by the appearance of a spastic gait by age 13. At the age of 25 years, he became bedridden and needed a ventilator. Genetic analysis revealed a homozygous splice site variant in the SPG11 gene (c. 4162–2A > G) after the provision of genetic counselling and acquisition of informed consent from his parents. He died of pneumonia at the age of 44. His brain weighed 967 g and was characterized by a TCC, and his spinal cord was flattened. Microscopically, degeneration was observed in the posterior spinocerebellar tract, the gracile fasciculus, and the posterior column in addition to the corticospinal tract. Marked neuronal loss and gliosis were observed in the anterior horn, Clarke’s column, and hypoglossal and facial nuclei. Various types of neurons, in addition to motor neurons, showed coarse eosinophilic granules that were immunoreactive for p62. The loss of pigmented neurons with gliosis was apparent in both the substantia nigra and locus coeruleus. Lateral geniculate body degeneration was a characteristic feature of this patient. Furthermore, peripheral Lewy body-related α-synucleinopathy and scattered α-synuclein–immunoreactive neurites in the locus coeruleus and reticular formation of the brainstem were observed.ConclusionsIn patients with hereditary spastic paraplegia with SPG11 mutations, a variety of clinical phenotypes develop due to widespread lesions containing p62-immunoreactive neuronal cytoplasmic inclusions. We herein report the lateral geniculate body as another degenerative site related to SPG11-related pathologies that should be studied in future investigations.

Novel insights into the genetic profile of hereditary spastic paraplegia in India

The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5–49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.

Corpus Callosal Morphometry in Mid-sagittal Plane MRI in Patients of Different Age Groups: A Retrospective Study

Introduction: Corpus callosum is the largest and most important of the forebrain commissural tracts connecting the two cerebral hemispheres. This white matter tract plays essential role in sensory, motor, and cognitive signal transmission across the right and left cerebral hemispheres. Hence, corpus callosal thickness and morphology reflects the hemispheric volume and functional ability of the brain. Thinning of corpus callosum which can be due to abnormal or absent myelination, demyelinating conditions, hypoxic-ischemic encephalopathy and metabolic diseases affecting the white matter can lead to developmental impairment and behavioural disorders which need to be properly evaluated. Aim: To identify possible age-associated variability in the anteroposterior diameter and the thickness of different parts of the corpus callosum. Materials and Methods: A retrospective cross-sectional study of 420 patients over a period of two years from January 2019 to December 2020 done at Dr. PSIMS and RF, Gannavaram, Andhra Pradesh. Magnetic Resonance (MR) examinations were performed with 1.5T Philips Healthcare Magnetic Resonance Imaging (MRI) scanner. The subjects who underwent MRI for various suspected or known central nervous system diseases were included in the study. The thickness of various parts along with the anteroposterior diameter of the corpus callosum were measured with mid-sagittal T1 weighted MR sequence and the mean and standard deviation was calculated. Results: The anteroposterior diameter of the corpus callosum was more in older adults (61-70 age group) than in children and younger adults. The mean thickness of genu, body and isthmus was found to be significantly more in younger adults (21-30 age group), whereas thickness of splenium was more significant in the age group of 31-40 years. Conclusion: The anteroposterior diameter was more in the elderly age group, whereas the thickness of corpus callosal regions was more in the young adult age group. Therefore, variations in corpus callosal thickness would help in the diagnosis of disease presence and progression.

Abstract- Poster

Marchiafava - Bignami disease is a progressive alcoholism related neurologic disease characterized by corpus callosum demyelination, necrosis and subsequent atrophy which occasionally occurs in non alcoholics but chronically malnourished. Among the many brain alterations promoted by chronic ethanol consumption, brain shrinkage due to cortical atrophy is the most striking one, it is related to alcoholic dementia and to atrophy of the corpus callosum. Although clearly dependent on age, brain shrinkage is more intense among heavy drinkers. MBD is a rare complication of chronic alcoholism and malnutrition which is most prevalent in men between 40 and 60 years of age. We are presenting here a case of 32year old alcoholic came to us with chief complaints of memory disturbances, decreased selfcare, decreased interaction with family members, provoked anger, sleep disturbances and disoriented to time and place for 2 months, with history of chronic alcohol consumption. A provisional diagnosis of Delirium was made and started him on Tab. Haloperidol 1.5 mg HS, T. Pregabalin 75 mg BD, T. Memantine 5mg OD, Thiamine and folic acid supplements for 7 days which showed no improvement in symptoms, on imaging found to have thinning of Corpus Callosum.