Severe Neonatal Presentation of Progressive Familial Intrahepatic Cholestasis Type 4 in an Omani Infant.

Progressive familial intrahepatic cholestasis type 4 (PFIC4) is a relatively newly described autosomal recessive disorder caused by biallelic mutations in the gene encoding tight junction protein 2 (TJP2) which is located in chromosome 9q21. PFIC4 is characterised by cholestasis with or without other extrahepatic manifestations. Bleeding tendency due to vitamin k deficiency is a well-known complication of cholestasis. We present a neonate who presented to the Emergency Department at a tertiary care hospital in 2021 with cholestasis and multiple intracranial bleeds. He was found to have severe coagulopathy and his genetic work up revealed a homozygous variant mutation in TJP2 gene causing PFIC4. He had persistent cholestasis that necessitated an internal biliary diversion with some clinical improvement.

Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families.

BACKGROUND: In metabolic stress, the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) enzyme is involved in energy production through the gluconeogenesis pathway. PEPCK-C deficiency is a rare childhood-onset autosomal recessive metabolic disease caused by PCK1 genetic defects. Previous studies showed a broad clinical spectrum ranging from asymptomatic to recurrent hypoglycemia with/without lactic acidosis, encephalopathy, seizures, and liver failure. RESULTS: In this article, we discuss the occurrence of PEPCK-C deficiency in four families from the United Arab Emirates and Oman. All patients presented with unexplained hypoglycemia as a common feature. Two out of the seven patients presented with episodes of encephalopathy that resulted in seizures and neuroregression leading to global developmental delay and one patient had a neonatal presentation. Observed biochemical abnormalities include elevated lactate, transaminases, and tricarboxylic acid cycle metabolites in most patients. Elevated creatine kinase was documented in two patients. Whole exome sequencing revealed two novel (c.574T > C, and c.1268 C > T) and a previously reported splice site (c.961 + 1G > A) PCK1 variant in the affected families. CONCLUSION: Patients become vulnerable during intercurrent illness; thus, prevention and prompt reversal of a catabolic state are crucial to avoid irreversible brain damage. This report will help to expand the clinical understanding of this rare disease and recommends screening for PEPCK-C deficiency in unexplained hypoglycemia.

Autosomal Recessive NOTCH3-Related Leukodystrophy in Two Siblings and Review of the Literature.

BACKGROUND: NOTCH3, a large type I transmembrane receptor expressed on arterial smooth muscle cells and capillary pericytes, features a diverse extracellular domain with 34 epidermal growth factor-like repeats. It exhibits distinct phenotypes due to variant zygosity and type; missense mutations cause CADASIL with cerebral vasculopathy, while null mutations lead to severe congenital manifestations. METHODS: This report describes two cases with homozygous loss- of- function variants in NOTCH3 along with their clinical manifestations. RESULTS: These patients presented with a severe congenital phenotype, including eye misalignment, visual impairment, epilepsy, global developmental delay, and subsequent development of pyramidal signs. Biallelic nonsense variants were discovered in both the cases (NM_000435.3:c.2203 C > T (p. [Arg735Ter]). Livedo reticularis was not reported in our cases, although it was present in previously reported patients. Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3. CONCLUSIONS: The phenotype of biallelic null variants is associated with a more severe phenotype than the dominantly inherited form of the disease.

Domino liver transplantation for maple syrup urine disease in children: A single-center case series.

BACKGROUND: Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long-term outcomes. METHODS: It was a retrospective study. All children with MSUD were paired with either recipients with end-stage liver disease (ESLD) or non-MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living-related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. RESULTS: Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split-liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type-1, one GSD type-3, and one Citrullinemia. Post-LT ICU and hospital stays were comparable (p > .05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow-up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft-related complications were seen in the post-transplant period. No occurrence of MSUD was noted in DLT recipients. CONCLUSION: DLTs have excellent post-surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage.

Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.

PURPOSE: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants. METHODS: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model. RESULTS: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. CONCLUSION: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity.

Applying whole exome sequencing in a consanguineous population with autism spectrum disorder.

This study aimed to systematically assess the impact of clinical and demographic variables on the diagnostic yield of Whole Exome Sequencing (WES) when applied to children with Autism Spectrum Disorder (ASD) from a consanguineous population. Ninety-seven children were included in the analysis, 63% were male and 37% were females. 77.3% had a suspected syndromic aetiology of which 68% had co-existent central nervous system (CNS) clinical features, while 69% had other systems involved. The diagnostic yield of WES in our cohort with ASD was 34%. Children with seizures were more likely to have positive WES results (46% vs. 31%, p = 0.042). Probands with suspected syndromic ASD aetiology showed no significant differential impact on the diagnostic yield of WES.

MLIP-Associated Myopathy: A Case Report and Review of the Literature.

BACKGROUND: Muscular A-type lamin-interacting protein (MLIP) has a regulatory role in myoblast differentiation and organization of myonuclear positioning in skeletal muscle. It is ubiquitously expressed but abundantly in cardiac, skeletal, and smooth muscles. Recently, two studies confirmed the causation of biallelic pathogenic variants in the MLIP gene of a novel myopathy phenotype. OBJECTIVE: Description of the phenotypic spectrum and features of MLIP-related myopathy. METHODS: report a patient with biallelic variants in MLIP gene with the clinical features, and histomorphological findings of MLIP-related myopathy and provide a literature review of the previously reported 12 patients. RESULTS: MLIP-related myopathy is characterized by episodes of rhabdomyolysis, myalgia triggered by mild to moderate exercise, mild muscle weakness, and sometimes cardiac involvement characterized by cardiomyopathy and cardiac rhythm abnormalities. CONCLUSIONS: This report reviews and extends the clinical features of a novel myopathy caused by biallelic pathogenic variants in the MLIP gene.

Genetic Causes, Clinical Features, and Survival of Underlying Inborn Errors of Immunity in Omani Patients: a Single-Center Study.

PURPOSE: Early identification of inborn errors of immunity (IEIs) is crucial due to the significant risk of morbidity and mortality. This study aimed to describe the genetic causes, clinical features, and survival rate of IEIs in Omani patients. METHODS: A prospective study of all Omani patients evaluated for immunodeficiency was conducted over a 17-year period. Clinical features and diagnostic immunological findings were recorded. Targeted gene testing was performed in cases of obvious immunodeficiency. For cases with less conclusive phenotypes, a gene panel was performed, followed by whole-exome sequencing if necessary. RESULTS: A total of 185 patients were diagnosed with IEIs during the study period; of these, 60.5% were male. Mean ages at symptom onset and diagnosis were 30.0 and 50.5 months, respectively. Consanguinity and a family history of IEIs were present in 86.9% and 50.8%, respectively. Most patients presented with lower respiratory infections (65.9%), followed by growth and development manifestations (43.2%). Phagocytic defects were the most common cause of IEIs (31.9%), followed by combined immunodeficiency (21.1%). Overall, 109 of 132 patients (82.6%) who underwent genetic testing received a genetic diagnosis, while testing was inconclusive for the remaining 23 patients (17.4%). Among patients with established diagnoses, 37 genes and 44 variants were identified. Autosomal recessive inheritance was present in 81.7% of patients with gene defects. Several variants were novel. Intravenous immunoglobulin therapy was administered to 39.4% of patients and 21.6% received hematopoietic stem cell transplantation. The overall survival rate was 75.1%. CONCLUSION: This study highlights the genetic causes of IEIs in Omani patients. This information may help in the early identification and management of the disease, thereby improving survival and quality of life.

Expanding the spectrum of EEF1D neurodevelopmental disorders: Biallelic variants in the guanine exchange domain.

Protein translation is an essential cellular process and dysfunctional protein translation causes various neurodevelopmental disorders. The eukaryotic translation elongation factor 1A (eEF1A) delivers aminoacyl-tRNA to the ribosome, while the eEF1B complex acts as a guanine exchange factor (GEF) of GTP for GDP indirectly catalyzing the release of eEF1A from the ribosome. The gene EEF1D encodes the eEF1Bδ subunit of the eEF1B complex. EEF1D is alternatively spliced giving rise to one long and three short isoforms. Two different homozygous, truncating variants in EEF1D had been associated with severe intellectual disability and microcephaly in two families. The published variants only affect the long isoform of EEF1D that acts as a transcription factor of heat shock element proteins. By exome sequencing, we identified two different homozygous variants in EEF1D in two families with severe developmental delay, severe microcephaly, spasticity, and failure to thrive with optic atrophy, poor feeding, and recurrent aspiration pneumonia. The EEF1D variants reported in this study are localized in the C-terminal GEF domain, suggesting that a disturbed protein translation machinery might contribute to the neurodevelopmental phenotype. Pathogenic variants localized in both the alternatively spliced domain or the GEF domain of EEF1D cause a severe neurodevelopmental disorder with microcephaly and spasticity.

Congenital Hyperinsulinism and Maple Syrup Urine Disease: A Challenging Combination

Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. CHI is a challenging disease to diagnose and manage. Moreover, complicating the course of the disease with another metabolic disease, in this case maple syrup urine disease (MSUD), adds more challenges to the already complex management. We report a term neonate who developed symptomatic, non-ketotic hypoglycemia with a blood glucose (BG) level of 1.9 mmol/L at 21-hours of life. A critical sample at that time showed high serum insulin and C-peptide levels confirming the diagnosis of CHI. Tandem mass spectrometry done at the same time was suggestive of MSUD which was confirmed by high performance liquid chromatography. The diagnosis of both conditions was subsequently confirmed by molecular genetic testing. His hypoglycemia was managed with high glucose infusion with medical therapy for CHI and branched chain amino acids (BCAA) restricted medical formula. At the age of four months, a near-total pancreatectomy was done, due to the failure of conventional therapy. Throughout his complicated course, he required meticulous monitoring of his BG and modified plasma amino acid profile aiming to maintain the BG at ≥3.9 mmol/L and levels of the three BCAAs at the disease therapeutic targets for his age. The patient is currently 29 months old and has normal growth and development. This patient is perhaps the only known case of the co-occurrence of CHI with MSUD. Both hypoglycemia and leucine encephalopathy can result in death or permanent neurological damage. The management of CHI and MSUD in combination is very challenging.

Joint Analysis of Phenotypic and Genomic Diversity Sheds Light on the Evolution of Xenobiotic Metabolism in Humans.

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families.

Global Developmental Delay/Intellectual disability (ID) is the term used to describe various disorders caused by abnormal brain development and characterized by impairments in cognition, communication, behavior, or motor skills. In the past few years, whole-exome sequencing (WES) has been proven to be a powerful, robust, and scalable approach for candidate gene discoveries in consanguineous populations. In this study, we recruited 215 patients affected with ID from 118 Middle Eastern families. Whole-exome sequencing was completed for 188 individuals. The average age at which WES was completed was 8.5 years. Pathogenic or likely pathogenic variants were detected in 32/118 families (27%). Variants of uncertain significance were seen in 33/118 families (28%). The candidate genes with a possible association with ID were detected in 32/118 (27%) with a total number of 64 affected individuals. These genes are novel, were previously reported in a single family, or cause strikingly different phenotypes with a different mode of inheritance. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOC8, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SMG8, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28. During the 5 years of the study and through gene matching databases, several of these genes have now been confirmed as causative of ID. In conclusion, understanding the causes of ID will help understand biological mechanisms, provide precise counseling for affected families, and aid in primary prevention.

Establishment and Validation of Reference Values for Amino Acids and Acylcarnitines in Dried Blood Spots for Omani Newborns Using Tandem Mass Spectrometry.

Objectives: To establish a reference range for acylcarnitines (ACs) and amino acids (AAs) concentrations in dried blood spot (DBS) samples of Omani neonates to detect inborn errors of metabolism (IEM), and to evaluate the effect of age and sex on ACs and AAs. Methods: Electrospray-ionization tandem mass spectrometry (+ESI-MS/MS) was used to determine ACs and AAs concentrations in DBS samples collected from 1302 healthy newborns (0-7 days) delivered at Sultan Qaboos University Hospital between August 2008 and May 2009. Results: More than fifty biomarkers that allow diagnosis of various IEMs were measured, their 1stand 99thpercentile values determined, and compared with published international data. Our results were comparable with the corresponding figures from Collaborative Laboratory Integrated Report, despite a much smaller sample size. We found that age had a significant effect on most ACs and AAs except decadienoylcarnitin, decenoylcarnitine, adipylcarnitine, palmitoylcarnitine, steatoylcarnitine, tyrosin, phenylalanine, and valine. Sex of the neonate had insignificant effect on most ACs and AAs except free-carnitine, acetylcarnitine, hexanoylcarnitine, octanoylcarnitine, malonylcarnitine, decanoylcarnitine, dodecenoylcarnitine, dodecanoylcarnitine, and tetradecanoylcarnitine. Conclusions: Tandem mass spectrometer is a highly effective tool for high throughput screening of IEM. This study is the first to publish reference intervals for ACs and AAs from DBS samples of Omani newborns. The results may prove to be of significance when determining cut-off values for newborn screening in the near future.

Further phenotypic delineation of Alazami syndrome.

Alazami syndrome (AS) is an autosomal recessive condition characterized by the cardinal features of severe growth restriction, moderate to severe intellectual disability, and distinctive facial features. Biallelic pathogenic variants of the LARP7, encoding a chaperone of 7SK noncoding RNA, is implicated in this disease. There are <35 reported cases in the literature. All reported cases share the same three cardinal features of the syndrome. Herein, we report on 12 patients with a confirmed diagnosis of AS from eight unrelated families. The cohort shares the same key feature of the syndrome. Moreover, we report additional phenotypic features, including genito-renal anomalies, ophthalmological abnormalities, and congenital heart disease. Whole-exome sequencing was used in all reported cases, implicating a clinical under-recognition of the syndrome. This report further expands the clinical and molecular characteristics of Alazami syndrome.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation.

Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases.

Uptake of prenatal genetic diagnosis and termination of pregnancy by Omani Muslim families at risk of genetic disorders: experience over a 9-year period.

Studies on the acceptance of prenatal diagnosis and termination of pregnancy for single gene disorders within Islamic societies in the Middle East are limited. A few have examined the attitudes toward pregnancy termination for fetal indications, but a dearth of published data exists on actual behavior and uptake. This study reports on all prenatal diagnosis requests for single gene disorders, from the Sultanate of Oman, over 9 years. A retrospective study was conducted during which the medical records of all women who performed prenatal diagnoses for single gene disorders were reviewed. A total of 148 invasive procedures were performed for 114 families. The total number of yearly requests for prenatal diagnosis increased exponentially from three in 2012 to 21 in 2020. Sixty-four different diagnoses were tested for with the majority being autosomal recessive in nature. Seventy-one percent (28/39) of cases where an affected pregnancy was identified were terminated. Fifty-two of the 114 women (45.6%) repeated prenatal diagnosis in a future pregnancy. Seventy-two couples (63%) were consanguineous parents related as second cousins or closer. The majority of tests performed were for couples from Muscat (27%), Albatinah (27%), and Alsharqiya (20.3%) governorates in Oman. The findings of this study provide evidence that prenatal diagnosis is an acceptable reproductive option to prevent the occurrence of genetic disorders that meet termination eligibility criteria as outlined by the Islamic Jurisprudence (Fiqh) Council Fatwa, among Omani Muslim couples.

Mucolipidosis Type IV in Omani Families with a Novel MCOLN1 Mutation: Search for Evidence of Founder Effect.

Mucolipidosis Type IV (MLIV) is caused by a deficiency of the mucolipin cation channel encoded by Mucolipin TRP Cation Channel 1 gene (MCOLN1). It is a slowly progressive neurodevelopmental and neurodegenerative disorder causing severe psychomotor developmental delay and progressive visual impairment, which is often misdiagnosed as cerebral palsy. We describe six patients with MLIV from two Omani families with a novel c.237+5G>A mutation in the MCOLN1 gene predicted to affect mRNA splicing. Mutation screening with a high-resolution melting (HRM) assay in a large population sample did not detect this mutation in control subjects. This report highlights the importance of considering MLIV in the differential diagnosis of patients in a pediatric age group with cerebral palsy-like presentation. Although the same rare mutation was seen in two apparently unrelated families, this was not seen in the sample screened from the general population. The HRM assay provides a cost-effective assay for population screening for the c.237+5G>A mutation.

Hypoketotic hypoglycemia without neuromuscular complications in patients with SLC25A32 deficiency.

Mitochondrial flavin adenine dinucleotide (FAD) transporter deficiencies are new entities recently reported to cause a neuro-myopathic phenotype. We report three patients from two unrelated families who presented primarily with hypoketotic hypoglycemia. They all had acylcarnitine profiles suggestive of multiple acyl-CoA dehydrogenase deficiency (MADD) with negative next-generation sequencing of electron-transfer flavoprotein genes (ETFA, ETFB, and ETFDH). Whole exome sequencing revealed a homozygous c.272 G > T (p.Gly91Val) variant in exon 2 of the SLC25A32 gene. The three patients shared the same variant, and they all demonstrated similar clinical and biochemical improvement with riboflavin supplementation. To date, these are the first patients to be reported with hypoketotic hypoglycemia without the neuromuscular phenotype previously reported in patients with SLC25A32 deficiency.

EEG Pattern in Neonatal Maple Syrup Urine Disease: Description and Clinical Significance.

Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder characterized by deficiency of branched-chain keto acid dehydrogenase complex, which is required to metabolize the three branched chain amino acids (BCAAs), leucine, isoleucine and valine. This metabolic dysfunction results in progressive encephalopathy manifesting with lethargy, vomiting, posturing and abnormal movements during the neonatal period in the classic form of the disease. If untreated, progressive brain damage causes coma, seizures and death usually within a few weeks. EEG is an essential investigation in a neonate with progressive encephalopathy and seizures. EEG abnormalities in neonatal encephalopathies due to inborn error of metabolism (IEM) are widely variable depending on the severity. Central comb-like rhythm is an EEG marker of neonatal MSUD in appropriate clinical context. This pattern should not be mistaken for epileptic abnormalities, sleep spindles or other similar nonspecific activities. We describe a patient with classic MSUD who presented with an EEG pattern of comb-like rhythm. Background abnormalities and epileptic discharges are common along comb-like rhythm in MSUD patients. EEG technologists and interpreters should be able to identify this pattern to support the early diagnosis and treatment of MSUD.