epilepsy

Epileptic Encephalopathy, Early Infantile 47

Clinical Characteristics
Ocular Features: 

The fundus is normal early but optic atrophy with narrowed vessels develops eventually.  Cerebral visual impairment has been described.  VEPs were normal at 4 months of age in one patient.

Systemic Features: 

Tonic seizures have their onset in the first month of life.  These become refractory as documented by the EEG which shows severe background slowing, multifocal origins, and hypsarrhythmia.  Psychomotor development is severely delayed and accompanied by profound intellectual disability.  The two reported children were unable to stand and never developed speech.  Feeding difficulties requires tube feeding.  Microcephaly eventually develops along with axial hypotonia and limb ataxia.

Brain MRI was normal at 5 months of age in one individual but at 6 years old showed cerebellar atrophy.  Her younger male sibling at 2 months of age had a normal MRI but cerebellar atrophy was present at 3 years of age.  He died at 3.5 years while his older sib died at age 7 years.

Genetics

Heterozygous mutations in the FGF12 gene (3q28-q29) are responsible for this condition.  One family with 2 affected children has been reported but neither parent carried the mutation in somatic cells suggesting germline mosaicism.

For autosomal recessive forms of early onset epileptic encephalopathy in this database see Epileptic Encephalopathy, Early Infantile 28 (616211) and Epileptic Encephalopathy, Early Infantile 48 (617276).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the general condition.  Complete supportive care is required.  Seizures are described as 'refractory' to treatment.

References
Article Title: 

GM3 Synthase Deficiency

Clinical Characteristics
Ocular Features: 

Profound optic atrophy is the primary ocular feature in this disorder.  ERG amplitudes are normal.  Visual impairment is pronounced with no reactions to environmental stimuli but it is not possible to determine how much of this is due to general CNS disease.  Eye movements are random and uncoordinated. 

Systemic Features: 

Infants may appear normal at birth but within a few months develop signs of developmental stagnation with onset of tonic-clonic seizures.  Irritability, poor feeding, vomiting and failure to thrive are important features.  Generalized hypotonia is evident but lower limb deep tendon reflexes may be present.  Normal developmental milestones are never achieved and patients are unresponsive to their environment.  Older individuals develop non-purposeful choreothetoid movements.  The EEG shows multifocal epileptiform discharges and brain MRIs show diffuse atrophy in older patients.         

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in (ST3GAL5) (2p11.2) encoding sialytransferase (SIAT9).

The nonsense mutation results in a deficiency of functional GM3 synthase important in the utilization of lactosylceramide necessary for the production of downstream gangliosides.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no known treatment for the enzyme deficiency.  Seizures respond poorly to anti-epileptic medications.

References
Article Title: 

Mowat-Wilson Syndrome

Clinical Characteristics
Ocular Features: 

Most reports of Mowat-Wilson disorders provide only incomplete ocular findings and the full phenotype remains to be described.  Most of the reported findings are part of the facial phenotype, such as downward slanting palpebral fissures, and ‘wedge-shaped’ eyebrows with the medial portion visibly wider than the temporal region.  Hypertelorism, strabismus and telecanthus have also been noted.  However, optic nerve atrophyor aplasia, RPE atrophy, microphthalmia, ptosis, and cataracts are sometimes present while strabismus is more common.  Iris and other uveal colobomas may be present and at least one patient has been reported with retinal aplasia.  There may be considerable asymmetry in the features among the two eyes.

Systemic Features: 

This is a highly complex dysmorphic developmental disorder with unusual progression of facial features.  Birth weight and length are usually normal but later there is general somatic and mental growth delay with microcephaly (pre- and post natal), short stature, intellectual disability, and epilepsy (70%).  Hypotonia has been noted at birth.  A significant proportion (~50%) of patients have Hirschsprung disease with megacolon.  Congenital heart defects are common, many involving septal openings.  Hypospadias is often present with or without other genitourinary anomalies.  Teeth are often crowded and crooked.  The earlobes may be flattened and may have a central depression.

The facial features are present in early childhood but as they mature the upper half of the nasal profile becomes convex, while the nasal tip becomes longer and overhangs the philtrum.  The eyes appear more deeply set.  The chin lengthens and prognathism becomes apparent.  IQ levels cannot be determined but many individuals exhibit behavioral or emotional disturbances.

Genetics

Heterozygous mutations in ZEB2 (2q22.3) are responsible for most cases (81%) of this disorder.  A large number of molecular mutations, many of the nonsense type, have been reported. About 2-4% of patients have cytogenetic alterations involving the 2q22 region.

Another disorder with microcephaly, intellectual disability and Hirschsprung disease is Goldberg-Shprintzen syndrome (609460) with mutations in the KIAA1279 gene.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment may be directed at specific defects but there is no treatment for the general disorder. Individuals can live to adulthood. Treatment is largely symptomatic.  Physical and speech treatment can be helpful if initiated early.

References
Article Title: 

Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome

Bourchany A, Giurgea I, Thevenon J, Goldenberg A, Morin G, Bremond-Gignac D, Paillot C, Lafontaine PO, Thouvenin D, Massy J, Duncombe A, Thauvin-Robinet C, Masurel-Paulet A, Chehadeh SE, Huet F, Bron A, Creuzot-Garcher C, Lyonnet S, Faivre L. Clinical spectrum of eye malformations in four patients with Mowat-Wilson syndrome. Am J Med Genet A. 2015 Apr 21. [Epub ahead of print]

PubMed ID: 
25899569

The behavioral phenotype of Mowat-Wilson syndrome

Evans E, Einfeld S, Mowat D, Taffe J, Tonge B, Wilson M. The behavioral phenotype of Mowat-Wilson syndrome. Am J Med Genet A. 2012 Feb;158A(2):358-66. doi: 10.1002/ajmg.a.34405.

PubMed ID: 
22246645

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature

Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti L, Bergamaschi R, De Brasi D, Sperandeo MP, Mari F, Uliana V, Mostardini R, Cecconi M, Grasso M, Sassi S, Sebastio G, Renieri A, Silengo M, Bernasconi S, Wakamatsu N, Neri G. Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature. Am J Med Genet A. 2009 Mar;149A(3):417-26. Review.

PubMed ID: 
19215041

Clinical and mutational spectrum of Mowat-Wilson syndrome

Zweier C, Thiel CT, Dufke A, Crow YJ, Meinecke P, Suri M, Ala-Mello S, Beemer F, Bernasconi S, Bianchi P, Bier A, Devriendt K, Dimitrov B, Firth H, Gallagher RC, Garavelli L, Gillessen-Kaesbach G, Hudgins L, K?SS?SSri?SSinen H, Karstens S, Krantz I, Mannhardt A, Medne L, M?ocke J, Kibaek M, Krogh LN, Peippo M, Rittinger O, Schulz S, Schelley SL, Temple IK, Dennis NR, Van der Knaap MS, Wheeler P, Yerushalmi B, Zenker M, Seidel H, Lachmeijer A, Prescott T, Kraus C, Lowry RB, Rauch A. Clinical and mutational spectrum of Mowat-Wilson syndrome. Eur J Med Genet. 2005 Apr-Jun;48(2):97-111

PubMed ID: 
16053902

Organoid Nevus Syndrome

Clinical Characteristics
Ocular Features: 

The sebaceous nevi often involve the eyelids, cornea, and conjunctiva.  Dermoids and lipodermoids are also seen.  Iris and choroidal colobomas are often present.  The sclerae may contain cartilage and bone which can be visible on CAT scans.  Depending upon the structures involved, patients may have strabismus, nystagmus, ptosis, exposure keratitis, and nerve palsies.

 

Systemic Features: 

Phakomatous lesions on the skin seem to preferentially occur on the upper part of the body including the face, neck and scalp but they may occur anywhere on the body including the oral cavity.  Initially they appear as papules but become verrucous around puberty.  Malignant transformation is seen in 15-20 per cent of patients.

Mental retardation and seizures are often seen in the first year of life.  Milestones achieved during that time are often lost subsequently.  Generalized weakness, osteopenia, and intracranial aneurysms are features in some patients.  Bone involvement may be highly asymmetrical.

Biopsies of conjunctival lesions show choristomas containing hyperplastic sebaceous and apocrine glands along with hair follicles.

Genetics

No clear genetic basis exists for this disease.  However, several families with multigenerational involvement have been reported in an autosomal dominant pattern.  It has been suggested that the disorder may result from a dominant lethal gene that allows some patients to survive by chance mosaicism.

Treatment
Treatment Options: 

No treatment is available for the generalized disease but therapy for specific symptoms such as epilepsy may be helpful.

References
Article Title: 

Ophthalmic features of the organoid nevus syndrome

Shields JA, Shields CL, Eagle RC Jr, Arevalo F, De Potter P. Ophthalmic features of the organoid nevus syndrome. Trans Am Ophthalmol Soc. 1996;94:65-86; discussion 86-7. Review.

PubMed ID: 
8981690

Pantothenate Kinase-Associated Neurodegeneration

Clinical Characteristics
Ocular Features: 

Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals.  However, when combined with ERG evidence the proportion rises to 68%.  When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration.  Some patients have a fleck-like retinopathy.  Optic atrophy may be present in advanced cases.

Systemic Features: 

This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation.  There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years.  Others with atypical disease may not have symptoms until the second or third decades.  Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms.  Motor tics are often seen.  Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well.  Swallowing difficulties may be severe sometimes leading to malnutrition.  Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow.  Independent ambulation is lost in the majority of patients within one to two decades.    Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.

Genetics

Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder. 

This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs.  The group is genetically heterogeneous with many overlapping features.  Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Pharmacologic treatment is aimed at alleviation of specific symptoms such as dystonia and spasticity.  Some symptoms may improve with deep brain stimulation.

References
Article Title: 
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