Differential Diagnosis in Neurology

2.7. Genetic Aspects of Seizures

• Increase in the prevalence of epilepsy in families with epilepsy
  • 3–8% in idiopathic epilepsy
  • 0.5–15% in symptomatic epilepsy
  • Rate in the control population is 0.5%
• Seizures in close family members
  • 3.5 to 29%
• Twin studies:
  • Concordance rates 11% with acquired brain lesions; 70% in those without lesions
  • Dizygotic twins:
    • Concordance rate of 3–10%
• Pedigree analysis:
  • Mendelian pattern of metabolic disease with seizures: AR
  • Genetic causes of seizures:
    • Absence epilepsy: AD
    • Generalized spike and wave: AD
    • Febrile convulsion: AD
• Mosaicism
  • Presence of more than one distinct cell line in a single individual
  • Mutations arise post fertilization
  • Somatic mosaicism important in:
    • AD disorders
    • Sex-linked disorders
    • Survival of lethal phenotypes
    • Postzygotic alterations
    • DCX gene on Xq22

X-Linked Metabolic Disorders with Seizures

• Pyruvate dehydrogenase deficiency
• Glycerol kinase deficiency
• OTC (ornithine transcarbamylase deficiency)

Chromosomally Determined Epilepsies

• Generalized epilepsy: benign familial neonatal convulsions:
  • Genetics:
    • Chromosomes 20q, (EBN-1, KCNQ 2 genes)
    • Code for voltage gated K⁺ channel
    • Some families map to:
      • Chromosome 8q (EBN-2, KCNQ3 gene)
      • Codes for K⁺ channel gene
  • Clinical features:
    • Brief multifocal convulsions
    • Onset first week of life
    • Resolves spontaneously within six weeks
    • Some have febrile convulsions in childhood
    • 10–15% develop epilepsy in adult life
    • Normal neurologic exam
    • Positive family history for febrile convulsions or neonatal seizures
• Juvenile myoclonic epilepsy (JME)
  • Onset in adolescence or early teenage years
  • Male equals female incidence
  • Interictal generalized bursts of 3.5–6 Hz poly spike and wave on EEG
  • Genetics:
    • AD
    • AR
    • Multifactorial
    • Most families have a chromosome 6q defect
    • Some families have a chromosome 15q defect
  • Ach receptor (alpha 7 subunit dysfunction)
  • Myoclonus on awakening; associated with GCTS and absence seizures
• Mental retardation epilepsy syndrome (BNC1, CFTR and RNAseP subunit p38)
  • X chromosome (TM45F2 gene)
  • Generalized seizures
  • No regression in mentation or milestones after seizure onset
  • Macrocephaly
• Bilateral periventricular nodular heterotopia (BPNH) in boys with mental retardation and syndactyly
  • Chromosome Xq28 locus
  • Clinical features:
    • Cerebellar Hypoplasia
    • Severe Mental Retardation
    • Epilepsy
    • Syndactyly
• Idiopathic generalized seizures:
  • Chromosome 8 q (EPN2) gene locus
  • Also associated with same locus (adjacent to BFNC) benign frontal nocturnal convulsion
    • Febrile convulsions
    • JME
    • Childhood absence epilepsy
    • Asymptomatic generalized spike waves EEG activity
  • Idiopathic generalized epilepsy (IGE)
    • Specifically in occurring with JME
      • Chromosome 15q (muscarinic Ach receptor alpha 7 subunit gene)
    • ADNFLE locus (autosomal dominant frontal lobe epilepsy)
      • Ach receptor alpha 4 subunit gene
      • Chromosome 20q
      • Putative IGE locus
• Progressive Myoclonic Epilepsy (PME)
  • Unverricht–Lundberg Disease
    • Baltic myoclonus
    • Major cause of PME in North America
    • Genetics:
      • AR
      • Chromosome 21 q
      • EPM1 gene
      • Cysteine-proteinase inhibitor (cystatin B gene) is coded
      • Inactivates proteases that leak out of lysosomes
      • Dodecanes expansions of the gene
  • Point mutation in 14% of patients
  • Expansion of a dodecane nucleotide repeat:
    • Normally 2–3 copies
    • Symptomatic patients >60, copies
    • Expansion is 70 nucleotides upstream of a transcription initiation factor (5 flanking promotor)
    • results in decreased RNA for the cysteine-proteinase inhibitor
    • Paternally based (repeats more unstable during spermatogenesis)
  • Clinical features:
    • Onset between 6–15 years of age; less frequent with age
    • Progressive dementia
    • Ataxia
    • Intention tremor
    • Stimulus sensitive myoclonus
    • Photosensitivity
  • Differential Diagnosis of Photosensitivity in Epilepsy
    • Unverricht–Lundborg and Lafora body disease
    • Neuronal ceroid lipofuscinoses
    • MERRF - -
    • Sialidosis (cherry red spot epilepsy ±) with occipital lobe seizures

Ramsey Hunt Syndrome

• A form of PME
• High incidence in Mediterranean region
• Genetics:
  • Possibly mitochondrial
  • EPM1 gene

Mitochondrial Defects (Seizures and Myoclonus)

• MERRF
• Leigh's disease
• NARP
• MNGIE
• Double mutation (A8296G and Q8363A)
  • Transfer RNA for Lys
  • VIIIth nerve; cardiomyopathy; myoclonus seizures

Progressive Myoclonic Epilepsy of the Lafora Type

• Genetics:
  • AR (consanguinity)
  • Chromosome 6q 24 (Lafora)
  • Encodes for tyrosine phosphatase
• Polyglucosan storage disorder
• Clinical features:
  • Onset in late childhood or adolescence
  • Myoclonus
  • Seizures
  • Rapidly progressive dementia

Progressive Epilepsy with Mental Retardation

• Genetics: AR: chromosome 8q
• "Northern Epilepsy" (Northern Finland)
• Clinical features:
  • Age at onset 5–10 years of age
  • Early normal development
  • GTCS until adolescence
  • Cognitive decline starts later and seizures abate

Genetic Partial Epilepsies

• Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
  • Genetics chromosome 20q 13.2–13.3 alpha 4 subunit (CHRNII)
    • Gene for the RNA nicotinc Ach receptor alpha 4 subunit
    • May be allelic to EBN 1 gene
  • Childhood onset: first two decades of life
  • Clinical features:
    • Seizures occur during light sleep
    • May occur during daytime nap
    • Occur in clusters of up to 20; typically last 30–40 seconds
    • Interictal EEG is usually normal
    • Gasping; groaning, tonic stiffening, restless, agitation during seizure, changes of positions, vocalizations
• Ring Chromosome 20 Epilepsy
  • Genetics: MCR3 gene on chromosome 20
  • Clinical features:
    • Subtle nocturnal seizures
    • Semiologic variability of seizure pattern:
      • NCSE
      • GTCS
      • Simple and CPS
  • Refractory to CBZ
• Benign centrotemporal (Rolandic) and benign occipital epilepsy
  • Genetics: AD: gene and locus not identified
  • Possible phenotype variants of the same disease
  • Clinical features:
    • Onset 4–10 years of age
    • Seizures stop at age 12–14
  • Possible chromosome micro-deletions; possible chromosome deletions
  • Ach R subunit deficits
  • Chromosomes:
  • Chromosome 1 (B-2 subunit) coding for B-2 subunit of Ach receptor
  • Chromosome 8 (B3 subunit) coding for B3 subunit of Ach receptor
  • Chromosome 15 (a3, a7, B4 subunit)
  • Chromosome 15q (susceptibility locus)
• Familial temporal lobe epilepsy (FTLE)
  • Genetics: AD
    • Lateral temporal variant
      • Partial epilepsy with auditory features (ADTLEAF)
      • Chromosome 10
    • Medial temporal variant
      • Families linked to chromosome 7
      • Possible reduction of GABA-A subunit

Genetic Syndromes with Epilepsy (Chromosomal)

• Metabolic
  • Juvenile ceroid lipofuscinosis
    • Genetics: AR; chromosomes 16p (infantile and juvenile onset and adult onset patients)
    • Over production of autofluorescent lipopigments (ceroid and lipofusion) within the brain, retina and visceral organs
    • Clinical features:
      • Onset 4–7 years of age
      • Ocular findings:
      • Retinal atrophy
      • Optic atrophy
      • Granular discoloration of the macula
      • Blindness
      • Dementia
      • Associated delusions and hallucinations
      • Dysarthria and rigidity develop over time
      • Myoclonic epilepsy begins several years after onset
      • Death within 15 years of onset
      • Skin biopsy: "Fingerprint bodies" within cytoplasm of epithelial cells
  • Sialidosis juvenile form (Type III)
    • Genetics: chromosome 10q
    • Deficiency of alpha neuraminidase (sialidoses)
    • Clinical features:
      • Type I: congenital; congestive heart failure
      • Type II: infantile form with ataxia mental retardation, myoclonus and seizures
      • Type III: (cherry red spot myoclonus)
      • Cherry red spot in the retina (absence of ganglion cells
      • Myoclonus
      • Seizures
      • Onset is late childhood
      • Urine contains oligosaccharides
      • Enzyme deficiency can be identified in cultured fibroblasts

Angelman Syndrome

• Genetics:
  • Maternally imprinted micro deletion in chromosome 15q 11–12
    • Non-deleted patients (<5%)
  • Paternal (uni parenteral) disomy (both chromosomes originate from the father)
    • Deleted area codes for GABA-A receptor-beta3 subunit
• Clinical features:
  • Seizures
  • Severe mental retardation
  • Absence of speech
  • Jerking gait and inappropriate laughter (happy puppet)
  • Enlarged jaw
  • Protruding tongue
  • Upheld arms
• Microcephaly
  • Mid face hypoplasia
  • Ataxia; tremulousness

Prader–Willi Syndrome

• Genetics: allelic to the paternally inherited defect in the same region of chromosome 15q 11–12 as Angelman Syndrome
• 70% have a deletion in paternal chromosome 15q 11–13
• Non-deletion cases (20–25%) have maternal disomy (both chromosome 15 are from the mother)
• Clinical features:
  • 1/10,000 of live births
  • Hypogonadism
  • Mental retardation
  • Severe hunger (hyperphagia)
  • Short stature
  • Massive obesity
  • Hypotonia
  • Hypotrophy of Type II muscle fibers
  • No seizures

Tuberous Sclerosis

• Genetic:
  • AD with variable expression, unrecognized affected parents in 25% of patients
  • Some families linked to chromosome 9; others to chromosome 16; tumor suppressor gene
• Clinical features:
  • Seizures; may start as infantile spasms
  • Hypopigmented oval skin nevi (18% are linden leaf shaped)
  • Shagreen spot (often over the buttocks but may be anywhere) develop in late infancy (50% of patients)
  • Angiokeratoma (adenoma sebaceum) appear over the bridge of the nose and face during childhood.
  • Retinal tumors, rhabdomyosarcoma of the heart, renal tumors (Leiomyomata) bone and liver cysts
  • MRI:
    • Subependymal nodules (usually periventricular)
    • Large poorly differentiated cortical gyri (tubers)
    • Anterior IIIrd ventricular giant cell subependymal astrocytic tumor with consequent obstructive hydrocephalus

INV Duplication 15 Syndrome

• Genetics:
  • INV (inversion) duplication of chromosome 15 results in trisomy 15P
• Clinical features:
  • Developmental delay
  • Severe seizures
  • Mental retardation
  • Stereotypies
  • Lack of interaction
  • Poor development of language
  • Down slanting palpebral fissures
  • Coarse facies
  • Hypopigmented skin areas
  • Epicanthic folds

Trisomy 9P Syndrome

• Genetics:
  • Trisomy 9P
    • Multifocal independent spike foci
  • Association of trisomy 9P
    • Band heterotopia
• Clinical features:
  • Microcephaly
  • Short stature
  • Kyphosis
  • Severe seizures
• Dysmorphisms:
  • Prominent brow and nose coarseness
  • Maxillary hypoplasia
  • High arched palate
  • Down turned mouth
  • Small chin
  • Blunt fingers and toes
  • Hypoplastic nails
• MRI:
  • Hippocampal formation abnormalities
  • Hypoplastic cerebellar vermis
  • Dilatation of IVth ventricle
  • Normal to hypoplastic brainstem
  • Syringomyelia
  • Myelomeningocele
  • Gliosis of the centrum semiovale
  • Atrophy of the corpus callosum

Trisomy 12P Syndrome

• Trisomy 12P:
  • generalized 3 Hz spike and wave
  • 2/3 of patients have myoclonic seizures

Grey–Matter heterotopias

• Heteropsia are secondary to improper migration of neurons from the subependymal ventricular zone
• Over migration of neurons is implicated in:
  • Seizure disorders
  • Fetal alveolar syndrome
  • 18p-syndrome
  • Some congential muscular dystrophies
• The three major forms of heterotopia are:
  • Subependymal (SEH); nodular
  • Band heterotopia (double cortex)
  • Subcortical
• Subependymal heterotopia
  • In symptomatic women:
    • Partial complex seizures that start in the second decade
  • In symptomatic males:
    • xq28: gene is filamin 1 (FLN1)
      • Actin filament (is coded)
      • Links membrane protein to actin
    • Clinical features:
      • Strokes in early life
      • Neurodevelopmental delay
      • Seizure patterns:
      • Temporal lobe (mesial and neocortical)
      • Parietal and occipital foci

Subependymal Band Heterotopias (SBH) in Women

• Genetics: mutation of the DCX gene
  • Missense mutations in familial patients
  • Sporadic mutations:
    • Protein truncation mutations
  • DCX carrier mothers (not including germline or mosaicism mutations)
    • Minimally affected
    • Milder SBH phenotype
    • Mutations are R196H of exon 5 (pep-2) repeat on X chromosome
    • Majority of DCX mutations are (pep 1/2)
• Clinical features:
  • Mental retardation
  • Developmental delay
  • Complex partial seizures
  • Atypical absence seizures
  • Severely affected patients suffer drop attacks
  • Sporadic cases more severely affected than familial
  • Most severely affected women:
    • Mental retardation
    • CPS
    • Demonstrate the ILS (isolated lissencephaly) sequence
• Males with mutations of the X lissencephaly (XLIS) or double cortin DCX gene
  • Suffer severe brain anomalies
  • Die in utero (in general)
  • X-linked isolated lissencephaly/SBH
    • Genetics: mutations within the DCX gene
      • Familial form
      • Sporadic -80% are females
      • Allelic-ILS/SBH
    • ILS in boys
    • SBH in girls

Males with Epilepsy, Complete Subcortical Band Heterotopia and Somatic Mosaicism for DCX Gene

• Genetics:
  • Mutation in the double cortin gene (DCX or XLIS gene on the X chromosome)
  • Bilateral symmetric bands of grey matter in central white matter of cerebral hemispheres
• Females with DCX mutation
  • Complete subcortical heterotopic bands (double cortex)
    • Small amount of polygyria
    • Normal gyrational pattern
  • Clinical features:
    • Mild mental retardation
    • Complex partial seizures
• Males with DCX mutations
  • SBH is not observed
  • Classic lissencephaly noted:
    • Complex partial seizures
    • Mental retardation
  • Mutated gene is on the inactivated X-chromosome
    • This single copy of the mutated DCX gene affects all developing neurons-lissencephaly is produced
  • SBH can occur in males who have a somatic mosaicism

Miller-Deiker syndrome (deletion involving chromosome 17p 13.3)

• Defects in the lissencephaly gene (LIS1)
• Both males and females
• Posterior greater than anterior brain malformations compared to SBH/DCX mutations

Bilateral Diffuse Heterotopia

• Genetics: Xq 28
• Clinical features:
  • May have normal IQ
  • Mental retardation is usual
  • Seizure type as noted with unilateral Xq 28 syndrome
  • Cerebellar hypoplasia
  • Syndactyly
  • Short gut syndrome
  • Frontonasal dysplasia
  • Congenital nephrosis
• Associated malformations:
  • Megalencephaly
  • Hemimeganencephaly
  • Encephaloceles
  • Polymicrogyria
• Variants
  • Bilateral periventricular nodular heterotopia (BPNH) with associated MR
    • Genetics: micro deletions/micro duplications in Xq28
  • BPNH
    • Associated with Ehlers–Danlos
  • BPNH
    • VLes absence of the corpus callosum syndrome; X-linked
  • Clinical features:
    • MR
    • Pyramidal tract signs

MASA Syndrome

• Genetics: LICAM gene mutation
• Clinical features:
  • Adducted thumbs
  • Spasticity
  • Aphasia

Isolated Subependymal Heterotopia (SE)

• X-linked and non X-linked
• Unilateral focal group
  • Seizures
  • Decreased cognition

Associations of Subependymal Heterotopia

• Chiari II malformations
• Basilar cephaloceles
• Agenesis of the corpus callosum
• Metabolic disorders
  • Zellweger Syndrome
  • Neonatal adrenoleukodystrophy

AD Subependymal Heterotopia in Males

• Similar to female presentations of SEH

Subcortical Heterotopias

• Males and females are equally affected
• Congenital defects
• Complex partial seizures
  • start at age 15–20 years

Bilateral periventricular nodular heterotopia (BPNH)

• Genetics:
  • Xq28 (females)
  • Distal arms of Xq28 (males)
• Clinical features in female children:
  • Epilepsy
  • Normal intelligence
• Clinical features in male children:
  • Seizures
  • Syndactyly
  • Mental retardation
• Clinical male variants of BPNH associated with:
  • Short gut
  • Congenital nephrosis
• BPNH with fronto nasal malformations; clinical features:
  • Anterior cranium bifidum occultum
  • Hypertelorism
  • Broad neck
  • Poorly formed nasal tip
  • Widows peak
  • Frontal bossing
  • Low set eyes
  • High arched palate/cleft palate
  • Strabismus
  • Epicanthal folds
  • Micropenis
  • Triorchidism
  • Proximal implantation of 5th toe
  • Clinodactyly
  • Mental retardation
• MRI
  • Cortical dysplasia
  • Ventriculomegaly
  • Atrophic vermis
• Associated intracranial cystic malformations
  • Midline brain defects
  • Hematoma and lipoma of corpus callosum
  • Anterior encephalocele
  • Holoprosencephaly
• Pathology (25 syndromes with BPNH)
  • Abnormalities of glial proliferation
  • Neuronal migration disorder
  • Dysplasia of cortical organizations

Familial Partial Epilepsy with Variable Foci

• Genetics: chromosome 2q; penetrance 60%
• Clinical features:
  • Onset a 13–43 years of age
  • Distinguished from other inherited epilepsies because partial seizures may have different orgin (frontal, temporal, parietal or occipital) in different members of the same family
  • Familial temporal lobe epilepsy:
    • Affected members have a medial or lateral origin
    • Medial temporal lobe: chromosome: 10
    • Lateral temporal lobe with auditory features: AD

The Epileptic Spectrum in the Congenital Bilateral Perisylvian Syndrome

• Clinical features:
  • Pseudobulbar palsy
  • Bilateral perisylvian polymicrogyria
  • Onset of illness: age 4–12
  • Seizures in 87% of patients:
    • Atypical absence with atonic component
    • Tonic clonic
    • Partial 26%
    • Drop attacks
    • Bilateral focal seizure involving the lips
  • Facio-pharyngeal-masticatory diplegia (opercular syndrome of Foix–Chavany–Marie)
  • Mental retardation

Epilepsy in the Nevoid Basal Cell Carcinoma Syndrome (Gorlin's' Syndrome)

• Genetics:
  • AD
  • Chromosome 9q 22.3–q31 full penetrance
• Clinical features:
  • Onset: puberty to early adulthood
  • 80% of patients, one basal cell tumor by age 20
  • Planar plantar pits
  • Odontogenic cysts in the mandible
  • Optic nerve compression
  • Facial paresthesiae
  • Abnormal taste
• Dysmorphism:
  • Large stature
  • Macrocephaly; broad nasal root
  • Frontoparietal bossing
  • High arched palate
  • Sloping narrow shoulders
  • Bifid hypoplastic ribs
  • Polydactyly syndactyly
  • Calcified bilateral ovarian cysts
  • Pseudocystic bone lesions
  • Cardiac fibroma
  • Spina bifida
  • Agenesis of the odontoid
• Central nervous system associations:
  • Intracranial calcifications of the:
    • Falx
    • Diaphragma sella
    • Petroclinoid ligament
  • Meningioma
  • Medulloblastoma (3–5%)
  • Agenesis of the corpus callosum
  • Seizures
  • Fusion of the hemispheres
  • Thick cortical mantle

Progressive Facial Hemiatrophy and Epilepsy (Parry–Romberg Syndrome)

• Age of onset 24–70 years of age
• Clinical features:
  • Facial dysmorphism
  • Upper face affected; subcutaneous tissue and bone atrophy
  • Starts first two decades
  • Possibly localized linear scleroderma
  • Seizures prior to age 20; simple or complex partial seizures; masticatory spasms
  • Vascular proliferation
  • Cystic infarcts of the brain underneath the focal mesodermal lesions
• Pathology:
  • Cortical laminar disruption under the skull defect
  • Intracranial calcification
  • Midline non-specific gliosis
  • Leptomeningeal abnormalities
  • Dysgenetic embryoplastic neuroepithelial tissue (DNT)
    • Focal glial cortical neoplasia
    • Intracortical or subcortical heterogenous lesions

Adult and Adolescent Chronic Encephalitis and Epilepsy (Variant of Rasmussen's Syndrome)

• Mechanism
  • Persistent viral infection
  • Viral infection with local immune response; antibodies to GLUR3 receptor
• Clinical manifestations:
  • Epilepsia partialis continue 50% of patients
  • Simple partial seizures
  • 85% of patients have seizure prior to age 10
• Adult patients:
  • More benign course
  • More occipital lobe involvement
  • May be bilateral

Epilepsy Syndromes with Single Gene Mutations

• Generalized epilepsy with febrile seizures plus (GEFS+) gene
  • SCN 1B – sodium channel subunit
  • SCN 1A – sodium channel subunit
  • SCN 2A – sodium channel subunit
  • GABRG2 – GABA_A – receptor subunit
• Benign familial neonatal convulsions gene
  • KCN Q2 – potassium channel
  • KCN Q3 – potassium channel
• Autosomal Dominant Neuronal Frontal Lobe Epilepsy Gene
  • CHRNA4 – Neuronal nicotinic acetylcholine receptor subunit
  • CHRNB2 – Neuronal nicotinic acetylcholine receptor subunit
• Childhood absence epilepsy and febrile seizures gene
  • GABRG2 – GABA – receptor subunit
• Autosomal dominant partial epilepsy with auditory feature gene (ADTLEAF)
  • LG IV
  • Leucine rich transmembrane protein