Disorder |
Gene(s) |
Description |
References (PMID) |
Rett syndrome |
MECP2 |
Rett syndrome is a progressive neurodevelopmental disorder affecting mostly female children; it is characterized by normal development for the first 18 months of age followed by rapid regression of developmental skills. During the regression period, individuals experience seizures, hand wringing, acquired microcephaly, ataxia, and autism-like features. Approximately 85% of females with Rett syndrome have MECP2 variants detected by sequence analysis and approximately 10% have copy number variants in the gene. The prevalence of Rett syndrome in females is estimated to be as high as 5 in 100,000. Treatment is symptomatic, although there are ongoing trials for Rett-specific medications.
Most pathogenic MECP2 variants in males cause severe neonatal encephalopathy, seizures, abnormal tone, and breathing issues; death often occurs before 2 years of age. MECP2 duplication, however, affects males less severely but still causes seizures, intellectual disability, and hypotonia. Generally, females with a heterozygous MECP2 duplication are asymptomatic but may have neuropsychiatric symptoms with normal intellectual ability. |
36642718,
37291210,
36056801,
30929312,
20301670 |
SCN1A-related disorders (incl. Dravet syndrome, developmental and epileptic encephalopathy 6B, familial febrile seizures 3A, and generalized epilepsy with febrile seizures plus, type 2) |
SCN1A |
SCN1A-related disorders are a group of epilepsy syndromes caused by pathogenic variants in SCN1A; this group ranges in severity from mild familial febrile seizures to Dravet syndrome. The phenotypic presentation can vary between family members with the same pathogenic variant. Dravet syndrome is the most common seizure disorder in this group and is characterized by intractable, or drug-resistant, epilepsy presenting before two years of age; the seizures can be easily triggered by the environment and are difficult to manage. Affected children are at increased risk for psychiatric symptoms such as anxiety and develop a crouched gait. Febrile seizures are childhood-onset seizures that are triggered by fever and often resolved by mid-childhood. Dravet syndrome is estimated to occur in approximately 1 in 15,000 children. |
20301494,
36636894,
31904117,
35002916 |
Neuronal ceroid lipofuscinosis |
CLN3, CLN5, CLN6, CLN8, TPP1 |
Neuronal ceroid lipofuscinosis (NCL) is an inherited disorder that affects the nervous system. Individuals with this disorder may experience regression in previously acquired skills or developmental delays. They can also have mild to severe intellectual disability, behavioral problems, vision impairment, seizures, and early death. Symptoms can appear starting in infancy, childhood, or in adulthood. Individuals with earlier onset often require the use of a wheelchair by late childhood and typically do not survive past adolescence. Currently, there is no cure for NCL, but medical surveillance and care may help to improve some symptoms and overall condition of life; enzyme replacement therapy is available for affected individuals with TPP1-related NCL. All types of NCL affect about 1 in 100,000 newborns worldwide. NCL is more common in Finland, where approximately 1 in 12,500 individuals have the condition. |
30877620,
34733232,
32280231,
31884868 |
POLG-related disorders |
POLG |
POLG-related disorders are a group of inherited disorders that affect the brain, nerves, muscle, and liver, and include Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), autosomal recessive progressive external ophthalmoplegia (arPEO), and autosomal dominant progressive external ophthalmoplegia (adPEO). These disorders are caused by pathogenic variants in the POLG gene and disrupt normal mitochondrial DNA synthesis. The age of onset of these disorders ranges from early childhood to adulthood and many individuals have some, but not all, of the symptoms of one or more of the individual disorders. Symptoms and their severity are not able to be predicted based on the pathogenic variant(s) identified and typically include neurological features such as epilepsy, developmental delay, ataxia, and neuropathy. Many individuals also have eye issues, failure to thrive, and high risk for liver failure. Treatment is largely based on symptoms, but valproic acid, sodium divalproate, and medications that rely heavily on liver metabolism should be avoided. POLG-related disorders are estimated to occur in 1 in 10,000 newborns and the frequency may vary greatly among populations. |
20301791,
30451971,
32391929,
36362003,
31799506 |
Angelman syndrome |
UBE3A |
Angelman syndrome is a genetic disorder characterized by normal prenatal and birth history with severe developmental delay and regression by the first year of age; affected children develop gait abnormalities, ataxia, and a unique “happy” demeanor. Other neurological findings include seizures, microcephaly, intellectual disability, and speech impairment. There is no specific treatment for Angelman syndrome and treatment is based on symptoms, although there are several therapies in preclinical or clinical development. An estimated 1 in 12,000 to 1 in 24,000 individuals have Angelman syndrome.
Angelman syndrome follows non-Mendelian inheritance. It is an imprinting disorder caused by absence of the maternally derived 15q11.2-q13 chromosome region, and most patients with AS (80-84%) will exhibit abnormal DNA methylation pattern showing only the paternally inherited allele. 7% have paternal uniparental disomy 15 (UPD), 3% have an imprinting center sequence variant, and UBE3A sequence analysis detects pathogenic variants in approximately 11% of individuals. |
20301323,
36947593,
32893075,
34112038 |
Developmental and epileptic encephalopathy |
ARX, CAD, CDKL5, GABRA1, GABRB3, GABRG2, GRIN1, GRIN2B, GRIN2D, KCNQ2, KCNT1, PCDH19, SCN1A, SCN1B, SCN2A, SCN8A, SPTAN1, STXBP1 |
Developmental and epileptic encephalopathy (DEE) refers to a group of disorders characterized by epilepsy and encephalopathy. Pathogenic variants in several genes can cause DEE. Age of onset is typically shortly after birth with frequent and often drug-resistant seizures. Individuals are significantly developmentally delayed and may regress even when seizures are controlled. Electroencephalograms show abnormalities such as background slowing. Novel therapies such as antisense oligonucleotides and repurposed drugs are under investigation for treatment of the disease. DEE is thought to be extremely common, occurring in as many as 1 in 600 children. |
33632673,
33638459,
33279965,
33632673,
35951482,
36581463 |
Menkes disease |
SMARCA4,
ARID1A,
ARID1B,
SMARCB1 |
Menkes disease is an inherited disorder affecting copper levels in the body and caused by pathogenic variants in ATP7A. Menkes disease is inherited in an X-linked manner, meaning primarily males are affected. Symptoms begin in the first few months of life with developmental regression, weak muscle tone, seizures, and failure to thrive due to low copper and ceruloplasmin levels. A hallmark feature of the condition is light-colored, sparse, and twisted hair. Early treatment with copper histidinate can improve symptoms and survival by increasing serum copper concentration; without treatment, children pass away in early childhood. Most female carriers are unaffected but may have characteristic hair abnormalities called pili torti. Some individuals with pathogenic ATP7A variants present in childhood with occipital horn syndrome (OHS) or as an adult with distal motor neuropathy (DMN). Individuals with OHS have distinctive findings in the skull on x-ray, mild intellectual disability, and skin and joint abnormalities. Adults with DMN have weakness in the hands and feet, and some have absent reflexes which can affect the ability to walk over time. Menkes disease and OHS are estimated to occur in 1 in 100,000 newborns worldwide. |
20301586,
30594472,
33137485 |
Tuberous sclerosis complex |
TSC1, TSC2 |
Tuberous sclerosis complex (TSC) is a multisystem disorder caused by pathogenic variants in the TSC1 or TSC2 gene. Almost 100% of affected individuals have characteristic skin lesions such as hypomelanotic macules, facial angiofibromas, and shagreen patches. Most individuals have renal and central nervous system tumors; subependymal giant cell astrocytomas, or SEGAs, occur in one-fifth of individuals. Other significant neurological symptoms include seizures, developmental delay, intellectual disability, and psychiatric issues. Treatment is based on symptoms and includes surgical removal of tumors, mTOR inhibitors, and antiepileptic drugs. TSC occurs in approximately 1 in 6,000 to 1 in 10,000 individuals. |
20301399,
34399110,
35246210, 31018109, 35963265, 33180985 |
