Case#:Patient 7, male, 5 years old

DiseaseAssertion:Neonatal/Infantile Epileptic Encephalopathy (NIEE)

FamilyInfo:The family is French/Chinese

ParentalGenotype:The variant was inherited from Patient 7's asymptomatic mother.

CasePresentingHPOs:HP:0010864, HP:0012758, HP:0000729, HP:0007359, HP:0002069, HP:0032794, HP:0001250, HP:0000252.

CaseHPOFreeText:Patient 7 presents with severe intellectual disability, developmental slowdown, and various seizure types. Patient 7 has Autistic Spectrum Disorder (ASD) and microcephaly.

Patient History

@ 12 months - Patient 7 presented with seizures.

Patient 7 developed additional seizure types including: focal seizures with/without generalization, generalized tonic/clonic/tonic-clonic seizures, myoclonic seizures, and hypomotor seizures.

Patient 7 was on two antiepileptic drugs at most recent followup visit which reduced seizure frequency by >50%.

CaseNotHPOs:Not provided

CaseNotHPOFreeText:Not provided

CasePreviousTesting:The authors selected a cohort of 31 patients with seizure cryptogenic Neonatal/Infantile Epileptic Encephalopathy (NIEE) and seizure onset before 24 months.

Exclusion criteria included: (1) Patients with a definite history of brain insult, malformation of cortical development, neurocutaneous and syndromal disorders, and confirmed or highly suspected neurometabolic disorders based on clinical and biochemical markers. (2) Patients with Dravet syndrome and epilepsy at infancy with migrating focal seizure were also excluded because the majority of variants are detected in the SCN1A (>85%) and KCNT1 (approximately 50%) genes.

Formal neuropsychological testing or best clinical assessment was used to classify patient development or intelligence.

PreviouslyPublished:Not previously published

GenotypingMethod:Whole Exome Sequencing (WES) variant results were filtered in a panel of 430 epilepsy-associated genes. After selection of variants from the 430-gene panel, the synonymous variants, variants with variant frequency <10%, and variants with allele frequency >1% were removed.

Gene:SLC9A6

Variant:Hemizygous splice site NM_001042537.1 c. 794-2A>G was assessed by the authors to be likely pathogenic.

HGVS:Not provided

ClinVarID:Not found

CAID:CA414750320

gnomAD:Not found

MultipleGeneVariants:Not provided

Case#: Index patient, 6 years old (age at report), caucasian, male

DiseaseAssertion: Creatine transporter deficiency

FamilyInfo: Mother and maternal grandmother have history of learning disabilities, severely retarded uncle, unnaffected aunt

CasePresentingHPOs: HP:0001290 , HP:0006863, HP:0000750, HP:0001256 (Hypotonia, severe expressive language delay, severe speech delay, mild mental retardation)

CaseHPOFreeText: N/A

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

Biochemical analyte testing: Increased creatine levels in urine and plasma

Brain Magnetic Resonance Spectroscopy (MRS): Brain proton MRS revealed an almost complete absence of the creatine signal.

Creatine uptake assay: Creatine uptake was measured in total cell lysates, creatine concentration of 25 μM uptake level was negligible, and creatine concentration of1 25 μM uptake level was negligible.

Variant: No varient ID directly identified. Hemizygous nonsense mutation, A 1539C→T transition in SLC6A8 (GenBank accession number NM_005629) resulted in the substitution of an arginine codon by a termination codon (R514→X).

ClinVarID: N/A

CAID: N/A

gnomAD: N/A

Zygosity: Hemizygous

MaternalGenotype: grandmother aunt, and mother heterozygous for mutation

AdditionalParentalTesting: N/A

AlsoPublished: PMID: 11261517