Mohammad Kabiraj - Academia.edu (original) (raw)

Papers by Mohammad Kabiraj

Research paper thumbnail of Postictal hemiatrophy: Hemiconvulsion-hemiplegia-epilepsy syndrome

Pediatric Neurology, 1994

Research paper thumbnail of Postictal cerebral hemiatrophy: Hemiconvulsion-hemiplegia-epilepsy syndrome

Research paper thumbnail of C19orf12 mutation leads to a pallido-pyramidal syndrome

Gene 537 352 356, Mar 10, 2014

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part ... more Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Research paper thumbnail of Evoked and event related potentials in chronic respiratory failure

Research paper thumbnail of Evoked and event related potentials in chronic respiratory failure

Neurosciences (Riyadh, Saudi Arabia), 2002

To assess the value of brainstem auditory evoked potentials and event related evoked potential (3... more To assess the value of brainstem auditory evoked potentials and event related evoked potential (3rd positive component of evoked related potentials with latency of 300 millisecond, in evaluating cognitive dysfunction in patients with chronic respiratory failure. Thirty-two patients with chronic obstructive pulmonary disease and respiratory failure of mild to moderate severity, were assessed regarding their mental function, utilizing mini-mental state examination, arterial blood gases including PH, partial pressure of carbon dioxide, partial pressure of oxygen, and both brainstem auditory evoked potentials and event related evoked potential response. Twenty-five normal subjects, matched for age and sex, were also studied as a control group. The study was carried out during the year 1999 to 2000 in 3 hospitals; King Khalid University Hospital, King AbdulAziz University Hospital and Sahara Hospital, Riyadh, Kingdom of Saudi Arabia. There were significant delay of event related evoked p...

Research paper thumbnail of Conferences and Symposia

Research paper thumbnail of Stroke in Saudi children. Epidemiology, clinical features and risk factors

Saudi medical journal, 2006

To describe the epidemiology and clinical features of stroke in a prospective and retrospective c... more To describe the epidemiology and clinical features of stroke in a prospective and retrospective cohort of Saudi children and ascertain the causes, pathogenesis, and risk factors. The Retrospective Study Group (RSG) included children with stroke who were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the period July 1992 to February 2001. The Prospective Study Group (PSG) included those seen between February 2001 and March 2003. During the combined study periods of 10 years and 7 months, 117 children (61 males and 56 females, aged one month-12 years) were evaluated; the majority (89%) of these were Saudis. The calculated annual hospital frequency rate of stroke was 27.1/100,000 of the pediatric (1 month-12 years) population. The mean age at onset of the initial stroke in the 104 Saudi children was 27.1 months (SD = 39.3 months) and median was 6 months. ...

Research paper thumbnail of Diagnostic role of brain-stem auditory evoked potentials in neurobrucellosis

Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section, 1992

Evoked potential audiometry and brain-stem auditory evoked potentials were evaluated in 15 patien... more Evoked potential audiometry and brain-stem auditory evoked potentials were evaluated in 15 patients with systemic brucellosis in whom brucella meningitis was suspected clinically. In 8 patients cerebrospinal fluid (CSF) was abnormal with high brucella titre, and evoked potentials were abnormal in all of them. In 7 patients the CSF was normal and evoked potentials were also normal. Brain-stem auditory evoked potential abnormalities were categorised into 4 types: (1) abnormal wave I, (2) abnormal wave V, both irreversible, (3) prolonged I-III interpeak latencies, and (4) prolonged I-V interpeak latencies, both reversible. These findings are of important diagnostic value and correlate well with the clinical features, aetiopathogenesis and final outcome.

Research paper thumbnail of Nocturnal epilepsies in adults

Seizure, 1997

We evaluated the clinical characteristics and the electroencephalographic (EEG) findings by long ... more We evaluated the clinical characteristics and the electroencephalographic (EEG) findings by long video-EEG monitoring in 64 successive patients with definite nocturnal seizures. Mental state, neurological examination, neuroimaging and EEG background were normal in all patients. Classification of epilepsies was possible in 42 out of 64 (66%) patients according to the revised Classification of Epilepsies and Epileptic Syndromes by the Commission on Classification and Terminology of International League Against Epilepsy (1989). Out of those 42 patients, 33 (79%) had partial epilepsies, while 9 (21%) had generalized epilepsies. Response to antiepileptic drugs was excellent and only 4 (6%) patients had one seizure attack per year, two of them were on two antiepileptic drugs while the others were free of seizure on a single drug during the 2 years of follow-up. It seems that nocturnal seizures in adults form a new distinctive partial epileptic syndrome of a benign entity.

Research paper thumbnail of New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

PLoS ONE, 2013

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrop... more Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Research paper thumbnail of Correction: New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

PLoS ONE, 2013

[This corrects the article on p. e76831 in vol. 8.].

Research paper thumbnail of Postictal hemiatrophy: Hemiconvulsion-hemiplegia-epilepsy syndrome

Pediatric Neurology, 1994

Research paper thumbnail of Can cytotoxic drugs ameliorate subacute sclerosing panencephalitis?

Pediatric Neurology, 1994

Research paper thumbnail of Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity

Neuromuscular Disorders, 2000

We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropa... more We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropathy (HMSN). Four individuals were affected including two children (a boy and a girl) and a 23-year-old man. The fourth (a female) died at the age of 14 years. Onset of the disease was early (< 2 years) and the clinical and neurophysiological features were, generally, quite similar to those of an Italian family linked to chromosome 11q23. The peculiar pathologic pattern was irregular and redundant loops associated with folding of the myelin sheaths. The genetic study confirmed linkage to chromosome 11q23 and refined the location of the gene between D11S1311 and D11S917, a 3.3 cM region. These findings support the existence of a homogeneous and distinct entity within the form of HMSN associated with focally folded myelin sheaths.

Research paper thumbnail of PO19-WE-05 Linkage analysis and mutation screening in PANK2 and PLA2G6 genes in 7 consanguineous Saudi Arabian families with Karak syndrome

Journal of the Neurological Sciences, 2009

Research paper thumbnail of C19orf12 mutation leads to a pallido-pyramidal syndrome

Gene, 2014

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part ... more Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Research paper thumbnail of Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes

Research paper thumbnail of A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23

Research paper thumbnail of Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia

Brain, 2010

We have identified a novel form of recessive ataxia that segregates in three children of a large ... more We have identified a novel form of recessive ataxia that segregates in three children of a large consanguineous Saudi Arabian family. The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years. Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation. Linkage studies allowed us to identify a single locus that segregated with the disease on chromosome 3q28-qter. Mutation screening of all coding sequences revealed a single nucleotide deletion, 2927delC, in exon 19 of the KIAA0226 gene, which results in a frame shift of the C-terminal domain (p.Ala943ValfsX146). The KIAA0226 gene encodes a protein that we named rundataxin, with two conserved domains: an N-terminal RUN domain and a C-terminal domain containing a diacylglycerol binding-like motif. The closest paralogue of rundataxin, the plekstrin homology domain family member M1, has been shown to colocalize with Rab7, a small GTPase associated with late endosomes/lysosomes, suggesting that rundataxin may also be associated with vesicular trafficking and signalling pathways through its RUN and diacylglycerol binding-like domains. The rundataxin pathway appears therefore distinct from the ataxia pathways involving deficiency in mitochondrial or nuclear proteins and broadens the range of mechanisms leading to recessive ataxias.

Research paper thumbnail of SLC25A22 is a novel gene for migrating partial seizures in infancy

Annals of Neurology, 2013

Objective: To identify a genetic cause for migrating partial seizures in infancy (MPSI). Methods:... more Objective: To identify a genetic cause for migrating partial seizures in infancy (MPSI). Methods: We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22. Results: In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport. Interpretation: We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome View this article online at wileyonlinelibrary.com.

Research paper thumbnail of Postictal hemiatrophy: Hemiconvulsion-hemiplegia-epilepsy syndrome

Pediatric Neurology, 1994

Research paper thumbnail of Postictal cerebral hemiatrophy: Hemiconvulsion-hemiplegia-epilepsy syndrome

Research paper thumbnail of C19orf12 mutation leads to a pallido-pyramidal syndrome

Gene 537 352 356, Mar 10, 2014

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part ... more Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Research paper thumbnail of Evoked and event related potentials in chronic respiratory failure

Research paper thumbnail of Evoked and event related potentials in chronic respiratory failure

Neurosciences (Riyadh, Saudi Arabia), 2002

To assess the value of brainstem auditory evoked potentials and event related evoked potential (3... more To assess the value of brainstem auditory evoked potentials and event related evoked potential (3rd positive component of evoked related potentials with latency of 300 millisecond, in evaluating cognitive dysfunction in patients with chronic respiratory failure. Thirty-two patients with chronic obstructive pulmonary disease and respiratory failure of mild to moderate severity, were assessed regarding their mental function, utilizing mini-mental state examination, arterial blood gases including PH, partial pressure of carbon dioxide, partial pressure of oxygen, and both brainstem auditory evoked potentials and event related evoked potential response. Twenty-five normal subjects, matched for age and sex, were also studied as a control group. The study was carried out during the year 1999 to 2000 in 3 hospitals; King Khalid University Hospital, King AbdulAziz University Hospital and Sahara Hospital, Riyadh, Kingdom of Saudi Arabia. There were significant delay of event related evoked p...

Research paper thumbnail of Conferences and Symposia

Research paper thumbnail of Stroke in Saudi children. Epidemiology, clinical features and risk factors

Saudi medical journal, 2006

To describe the epidemiology and clinical features of stroke in a prospective and retrospective c... more To describe the epidemiology and clinical features of stroke in a prospective and retrospective cohort of Saudi children and ascertain the causes, pathogenesis, and risk factors. The Retrospective Study Group (RSG) included children with stroke who were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the period July 1992 to February 2001. The Prospective Study Group (PSG) included those seen between February 2001 and March 2003. During the combined study periods of 10 years and 7 months, 117 children (61 males and 56 females, aged one month-12 years) were evaluated; the majority (89%) of these were Saudis. The calculated annual hospital frequency rate of stroke was 27.1/100,000 of the pediatric (1 month-12 years) population. The mean age at onset of the initial stroke in the 104 Saudi children was 27.1 months (SD = 39.3 months) and median was 6 months. ...

Research paper thumbnail of Diagnostic role of brain-stem auditory evoked potentials in neurobrucellosis

Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section, 1992

Evoked potential audiometry and brain-stem auditory evoked potentials were evaluated in 15 patien... more Evoked potential audiometry and brain-stem auditory evoked potentials were evaluated in 15 patients with systemic brucellosis in whom brucella meningitis was suspected clinically. In 8 patients cerebrospinal fluid (CSF) was abnormal with high brucella titre, and evoked potentials were abnormal in all of them. In 7 patients the CSF was normal and evoked potentials were also normal. Brain-stem auditory evoked potential abnormalities were categorised into 4 types: (1) abnormal wave I, (2) abnormal wave V, both irreversible, (3) prolonged I-III interpeak latencies, and (4) prolonged I-V interpeak latencies, both reversible. These findings are of important diagnostic value and correlate well with the clinical features, aetiopathogenesis and final outcome.

Research paper thumbnail of Nocturnal epilepsies in adults

Seizure, 1997

We evaluated the clinical characteristics and the electroencephalographic (EEG) findings by long ... more We evaluated the clinical characteristics and the electroencephalographic (EEG) findings by long video-EEG monitoring in 64 successive patients with definite nocturnal seizures. Mental state, neurological examination, neuroimaging and EEG background were normal in all patients. Classification of epilepsies was possible in 42 out of 64 (66%) patients according to the revised Classification of Epilepsies and Epileptic Syndromes by the Commission on Classification and Terminology of International League Against Epilepsy (1989). Out of those 42 patients, 33 (79%) had partial epilepsies, while 9 (21%) had generalized epilepsies. Response to antiepileptic drugs was excellent and only 4 (6%) patients had one seizure attack per year, two of them were on two antiepileptic drugs while the others were free of seizure on a single drug during the 2 years of follow-up. It seems that nocturnal seizures in adults form a new distinctive partial epileptic syndrome of a benign entity.

Research paper thumbnail of New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

PLoS ONE, 2013

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrop... more Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Research paper thumbnail of Correction: New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

PLoS ONE, 2013

[This corrects the article on p. e76831 in vol. 8.].

Research paper thumbnail of Postictal hemiatrophy: Hemiconvulsion-hemiplegia-epilepsy syndrome

Pediatric Neurology, 1994

Research paper thumbnail of Can cytotoxic drugs ameliorate subacute sclerosing panencephalitis?

Pediatric Neurology, 1994

Research paper thumbnail of Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity

Neuromuscular Disorders, 2000

We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropa... more We describe a six generation Saudi kindred, with a recessive hereditary motor and sensory neuropathy (HMSN). Four individuals were affected including two children (a boy and a girl) and a 23-year-old man. The fourth (a female) died at the age of 14 years. Onset of the disease was early (< 2 years) and the clinical and neurophysiological features were, generally, quite similar to those of an Italian family linked to chromosome 11q23. The peculiar pathologic pattern was irregular and redundant loops associated with folding of the myelin sheaths. The genetic study confirmed linkage to chromosome 11q23 and refined the location of the gene between D11S1311 and D11S917, a 3.3 cM region. These findings support the existence of a homogeneous and distinct entity within the form of HMSN associated with focally folded myelin sheaths.

Research paper thumbnail of PO19-WE-05 Linkage analysis and mutation screening in PANK2 and PLA2G6 genes in 7 consanguineous Saudi Arabian families with Karak syndrome

Journal of the Neurological Sciences, 2009

Research paper thumbnail of C19orf12 mutation leads to a pallido-pyramidal syndrome

Gene, 2014

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part ... more Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Research paper thumbnail of Clinical and molecular genetic findings in COLQ-mutant congenital myasthenic syndromes

Research paper thumbnail of A new form of childhood onset, autosomal recessive spinocerebellar ataxia and epilepsy is localized at 16q21-q23

Research paper thumbnail of Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia

Brain, 2010

We have identified a novel form of recessive ataxia that segregates in three children of a large ... more We have identified a novel form of recessive ataxia that segregates in three children of a large consanguineous Saudi Arabian family. The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years. Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation. Linkage studies allowed us to identify a single locus that segregated with the disease on chromosome 3q28-qter. Mutation screening of all coding sequences revealed a single nucleotide deletion, 2927delC, in exon 19 of the KIAA0226 gene, which results in a frame shift of the C-terminal domain (p.Ala943ValfsX146). The KIAA0226 gene encodes a protein that we named rundataxin, with two conserved domains: an N-terminal RUN domain and a C-terminal domain containing a diacylglycerol binding-like motif. The closest paralogue of rundataxin, the plekstrin homology domain family member M1, has been shown to colocalize with Rab7, a small GTPase associated with late endosomes/lysosomes, suggesting that rundataxin may also be associated with vesicular trafficking and signalling pathways through its RUN and diacylglycerol binding-like domains. The rundataxin pathway appears therefore distinct from the ataxia pathways involving deficiency in mitochondrial or nuclear proteins and broadens the range of mechanisms leading to recessive ataxias.

Research paper thumbnail of SLC25A22 is a novel gene for migrating partial seizures in infancy

Annals of Neurology, 2013

Objective: To identify a genetic cause for migrating partial seizures in infancy (MPSI). Methods:... more Objective: To identify a genetic cause for migrating partial seizures in infancy (MPSI). Methods: We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22. Results: In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport. Interpretation: We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome View this article online at wileyonlinelibrary.com.