Epileptic Encephalopathy, Early Infantile 47 Clinical CharacteristicsOcular 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. GeneticsHeterozygous 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 dominantTreatmentTreatment Options: No treatment is available for the general condition. Complete supportive care is required. Seizures are described as 'refractory' to treatment. ReferencesArticle Title: Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy Siekierska A, Isrie M, Liu Y, Scheldeman C, Vanthillo N, Lagae L, de Witte PA, Van Esch H, Goldfarb M, Buyse GM. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology. 2016 Jun 7;86(23):2162-70. PubMed ID: 27164707 Read more about Epileptic Encephalopathy, Early Infantile 47
Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy Siekierska A, Isrie M, Liu Y, Scheldeman C, Vanthillo N, Lagae L, de Witte PA, Van Esch H, Goldfarb M, Buyse GM. Gain-of-function FHF1 mutation causes early-onset epileptic encephalopathy with cerebellar atrophy. Neurology. 2016 Jun 7;86(23):2162-70. PubMed ID: 27164707
Spinocerebellar Ataxia 42 Clinical CharacteristicsOcular Features: Saccadic eye movements with nystagmus and diplopia have been reported (7 of 10 reported patients). Systemic Features: Cerebellar signs usually have their onset in midlife or later with slow progression. Most patients are mildly to moderately disabled. Dysarthria, dysphagia, and a spastic gait are experienced by the majority of individuals. Hyperreflexia and a positive Babinski sign are commonly presently. Mild cognitive impairment and depression have been seen in a minority of patients. Brain MRIs show cerebellar hemispheric and vermian atrophy. The cerebral cortex appeared histologically normal in one deceased patient. GeneticsThis disorder is caused by heterozygous mutations in the CACNA1G gene (17q21.33). Pedigree: Autosomal dominantTreatmentTreatment Options: No treatment has been reported. ReferencesArticle Title: A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia Morino H, Matsuda Y, Muguruma K, Miyamoto R, Ohsawa R, Ohtake T, Otobe R, Watanabe M, Maruyama H, Hashimoto K, Kawakami H. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Mol Brain. 2015 Dec 29;8:89. PubMed ID: 26715324 A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia Coutelier M, Blesneac I, Monteil A, Monin ML, Ando K, Mundwiller E, Brusco A, Le Ber I, Anheim M, Castrioto A, Duyckaerts C, Brice A, Durr A, Lory P, Stevanin G. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. Am J Hum Genet. 2015 Nov 5;97(5):726-37. PubMed ID: 26456284 Read more about Spinocerebellar Ataxia 42
A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia Morino H, Matsuda Y, Muguruma K, Miyamoto R, Ohsawa R, Ohtake T, Otobe R, Watanabe M, Maruyama H, Hashimoto K, Kawakami H. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Mol Brain. 2015 Dec 29;8:89. PubMed ID: 26715324
A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia Coutelier M, Blesneac I, Monteil A, Monin ML, Ando K, Mundwiller E, Brusco A, Le Ber I, Anheim M, Castrioto A, Duyckaerts C, Brice A, Durr A, Lory P, Stevanin G. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. Am J Hum Genet. 2015 Nov 5;97(5):726-37. PubMed ID: 26456284
Epileptic Encephalopathy, Early Infantile 28 Clinical CharacteristicsOcular Features: Infants with this lethal neuropathy often have minimal or absent eye contact from birth. Responses to visual stimuli are often but not always absent. Optic atrophy may be present and the ERG is abnormal in some individuals. The retinas may have "abnormal" pigmentation while scotopic and photopic flash ERG responses are reduced as are visual evoked potentials indicating delayed visual maturation with severe macular and optic nerve dysfunction. Systemic Features: Seizures begin within weeks after birth and are resistant to pharmacological treatment. There is no spontaneous motility and little or no psychomotor development. Normal developmental milestones are usually not achieved. Spasticity and hyperreflexia are often present but some newborn infants are hypotonic. MRI imaging reveals cortical atrophy with hippocampal hypoplasia and a hypoplastic corpus callosum. Progressive microcephaly has been described. Infants generally do not live beyond two years of age and may die within weeks or a few months. Pulmonary dysfunction can be a significant cause of morbidity. GeneticsThe transmission pattern is consistent with autosomal recessive inheritance. Homozygous and compound heterozygous mutations in the WWOX gene (16q23) have been found in several families. Among the limited number of patients reported, at least two with compound heterozygous mutations had normal brain imaging, appropriate visual responses, and some ability to interact with their environment. Profound psychomotor delays, however, remained. Hypotonia replaced spasticity as a neurological feature in some infants. The same gene is mutated in autosomal recessive spinocerebellar ataxia 12 (614322), a less severe condition in which gaze-evoked nystagmus occurs. Other forms of epileptic encephalopathy have been reported (see 617105, 617106, and 617113) including Early Onset Epileptic Encephalopathy 48 (617276). For an autosomal dominant form of epileptic encephalopathy in this database, see Epileptic Encephalopathy, Early Onset 47 (617166). Pedigree: Autosomal recessiveTreatmentTreatment Options: No treatment is known for this condition. ReferencesArticle Title: WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation Mignot C, Lambert L, Pasquier L, Bienvenu T, Delahaye-Duriez A, Keren B, Lefranc J, Saunier A, Allou L, Roth V, Valduga M, Moustaine A, Auvin S, Barrey C, Chantot-Bastaraud S, Lebrun N, Moutard ML, Nougues MC, Vermersch AI, Heron B, Pipiras E, Heron D, Olivier-Faivre L, Gueant JL, Jonveaux P, Philippe C. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015 Jan;52(1):61-70.. PubMed ID: 25411445 The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration Abdel-Salam G, Thoenes M, Afifi HH, Korber F, Swan D, Bolz HJ. The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration. Orphanet J Rare Dis. 2014 Jan 23;9:12.. PubMed ID: 24456803 Read more about Epileptic Encephalopathy, Early Infantile 28
WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation Mignot C, Lambert L, Pasquier L, Bienvenu T, Delahaye-Duriez A, Keren B, Lefranc J, Saunier A, Allou L, Roth V, Valduga M, Moustaine A, Auvin S, Barrey C, Chantot-Bastaraud S, Lebrun N, Moutard ML, Nougues MC, Vermersch AI, Heron B, Pipiras E, Heron D, Olivier-Faivre L, Gueant JL, Jonveaux P, Philippe C. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015 Jan;52(1):61-70.. PubMed ID: 25411445
The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration Abdel-Salam G, Thoenes M, Afifi HH, Korber F, Swan D, Bolz HJ. The supposed tumor suppressor gene WWOX is mutated in an early lethal microcephaly syndrome with epilepsy, growth retardation and retinal degeneration. Orphanet J Rare Dis. 2014 Jan 23;9:12.. PubMed ID: 24456803
