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Encephalopathy

MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Synonym: Unspecified encephalopathy
SNOMED CT: Encephalopathy (81308009)
 
HPO: HP:0001298

Definition

Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEncephalopathy

Conditions with this feature

Crigler-Najjar syndrome type 1
MedGen UID:
41346
Concept ID:
C0010324
Disease or Syndrome
Crigler-Najjar syndrome is a severe condition characterized by high levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). Bilirubin is produced when red blood cells are broken down. This substance is removed from the body only after it undergoes a chemical reaction in the liver, which converts the toxic form of bilirubin (called unconjugated bilirubin) to a nontoxic form called conjugated bilirubin. People with Crigler-Najjar syndrome have a buildup of unconjugated bilirubin in their blood (unconjugated hyperbilirubinemia).\n\nCrigler-Najjar syndrome is divided into two types. Type 1 (CN1) is very severe, and affected individuals can die in childhood due to kernicterus, although with proper treatment, they may survive longer. Type 2 (CN2) is less severe. People with CN2 are less likely to develop kernicterus, and most affected individuals survive into adulthood.\n\nBilirubin has an orange-yellow tint, and hyperbilirubinemia causes yellowing of the skin and whites of the eyes (jaundice). In Crigler-Najjar syndrome, jaundice is apparent at birth or in infancy. Severe unconjugated hyperbilirubinemia can lead to a condition called kernicterus, which is a form of brain damage caused by the accumulation of unconjugated bilirubin in the brain and nerve tissues. Babies with kernicterus are often extremely tired (lethargic) and may have weak muscle tone (hypotonia). These babies may experience episodes of increased muscle tone (hypertonia) and arching of their backs. Kernicterus can lead to other neurological problems, including involuntary writhing movements of the body (choreoathetosis), hearing problems, or intellectual disability.
Letterer-Siwe disease
MedGen UID:
7311
Concept ID:
C0023381
Disease or Syndrome
A multifocal, multisystem form of Langerhans-cell histiocytosis. There is involvement of multiple organ systems including the bones, skin, liver, spleen, and lymph nodes. Patients are usually infants presenting with fever, hepatosplenomegaly, lymphadenopathy, bone and skin lesions, and pancytopenia.
Juvenile myopathy, encephalopathy, lactic acidosis AND stroke
MedGen UID:
56485
Concept ID:
C0162671
Disease or Syndrome
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is a multisystem disorder with protean manifestations. The vast majority of affected individuals develop signs and symptoms of MELAS between ages two and 40 years. Common clinical manifestations include stroke-like episodes, encephalopathy with seizures and/or dementia, muscle weakness and exercise intolerance, normal early psychomotor development, recurrent headaches, recurrent vomiting, hearing impairment, peripheral neuropathy, learning disability, and short stature. During the stroke-like episodes neuroimaging shows increased T2-weighted signal areas that do not correspond to the classic vascular distribution (hence the term "stroke-like"). Lactic acidemia is very common and muscle biopsies typically show ragged red fibers.
Progressive sclerosing poliodystrophy
MedGen UID:
60012
Concept ID:
C0205710
Disease or Syndrome
POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").
Hyperglycinemia, transient neonatal
MedGen UID:
82818
Concept ID:
C0268560
Disease or Syndrome
Glutaric aciduria, type 1
MedGen UID:
124337
Concept ID:
C0268595
Disease or Syndrome
The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease – i.e., after age 6 years). Of note, the GA-1 phenotype can vary widely between untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to six years in infantile-onset GA-1 and after age six years in later-onset GA-1. Characteristically these crises result in acute bilateral striatal injury and subsequent complex movement disorders. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic; however, they may be at increased risk for other manifestations (e.g., renal disease) that are becoming apparent as the understanding of the natural history of treated GA-1 continues to evolve.
Deficiency of hydroxymethylglutaryl-CoA lyase
MedGen UID:
78692
Concept ID:
C0268601
Disease or Syndrome
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988).
D-Glyceric aciduria
MedGen UID:
452447
Concept ID:
C0342765
Disease or Syndrome
D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).
Renal carnitine transport defect
MedGen UID:
90999
Concept ID:
C0342788
Disease or Syndrome
Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. It encompasses a broad clinical spectrum including the following: Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. Childhood myopathy involving heart and skeletal muscle with onset between age two and four years. Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia. Fatigability in adulthood. Absence of symptoms. The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants.
Brown-Vialetto-van Laere syndrome 1
MedGen UID:
163239
Concept ID:
C0796274
Disease or Syndrome
Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010). Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q.
Aicardi-Goutieres syndrome 3
MedGen UID:
324389
Concept ID:
C1835916
Disease or Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Biotin-responsive basal ganglia disease
MedGen UID:
375289
Concept ID:
C1843807
Disease or Syndrome
Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in childhood, early infancy, or adulthood. The classic presentation of BTBGD occurs in childhood (age 3-10 years) and is characterized by recurrent subacute encephalopathy manifest as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia which, if left untreated, can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or stress. Simple partial or generalized seizures are easily controlled with anti-seizure medication. An early-infantile Leigh-like syndrome / atypical infantile spasms presentation occurs in the first three months of life with poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis. An adult-onset Wernicke-like encephalopathy presentation is characterized by acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia in the second decade of life. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in the childhood and adult presentations, but most with the infantile presentation have had poor outcome even after supplementation with biotin and thiamine.
Spongiform encephalopathy with neuropsychiatric features
MedGen UID:
339812
Concept ID:
C1847650
Disease or Syndrome
Infantile onset spinocerebellar ataxia
MedGen UID:
338613
Concept ID:
C1849096
Disease or Syndrome
Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness.
Progressive encephalopathy with leukodystrophy due to DECR deficiency
MedGen UID:
346552
Concept ID:
C1857252
Disease or Syndrome
2,4-Dienoyl-CoA reductase deficiency (DECRD) is a rare autosomal recessive inborn error of metabolism resulting in mitochondrial dysfunction due to impaired production of NADPH, which is an essential cofactor for several mitochondrial enzymes. Affected individuals have a variable phenotype: some may have severe neurologic symptoms and metabolic dysfunction beginning in early infancy, whereas others may present with more subtle features, such as childhood-onset optic atrophy or intermittent muscle weakness. The variable severity is putatively dependent on the effect of the mutation on the NADK2 enzyme. Biochemical analysis typically shows hyperlysinemia, due to defective activity of the mitochondrial NADP(H)-dependent enzyme AASS (605113), which is usually a benign finding. More severe cases have increased C10:2-carnitine levels, due to defective activity of the enzyme DECR (DECR1; 222745) (summary by Houten et al., 2014 and Pomerantz et al., 2018).
Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type
MedGen UID:
387801
Concept ID:
C1857355
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Combined oxidative phosphorylation defect type 4
MedGen UID:
387884
Concept ID:
C1857682
Disease or Syndrome
A rare mitochondrial disorder due to a defect in mitochondrial protein synthesis with characteristics of neonatal onset of severe metabolic acidosis and respiratory distress, persistent lactic acidosis with episodes of metabolic crises, developmental regression, microcephaly, abnormal gaze fixation and pursuit, axial hypotonia with limb spasticity and reduced spontaneous movements. Neuroimaging studies reveal polymicrogyria, white matter abnormalities and multiple cystic brain lesions, including basal ganglia, and cerebral atrophy. Decreased activity of complex I and IV have been determined in muscle biopsy.
Familial encephalopathy with neuroserpin inclusion bodies
MedGen UID:
346965
Concept ID:
C1858680
Disease or Syndrome
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant disorder characterized by progressive epilepsy and dementia. Onset of symptoms ranges from the second to fifth decades of life. Severity is variable (summary by Molinari et al., 2003).
Pyridoxal phosphate-responsive seizures
MedGen UID:
350498
Concept ID:
C1864723
Disease or Syndrome
Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B6 vitamer: pyridoxal 5'-phosphate (PLP) in about 60% of affected individuals and pyridoxine (PN) in about 40%. About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures.
Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
MedGen UID:
355842
Concept ID:
C1864840
Disease or Syndrome
Combined oxidative phosphorylation deficiency type 3 is an extremely rare clinically heterogenous disorder described in about 5 patients to date. Clinical signs included hypotonia, lactic acidosis, and hepatic insufficiency, with progressive encephalomyopathy or hypertrophic cardiomyopathy.
Congenital brain dysgenesis due to glutamine synthetase deficiency
MedGen UID:
400638
Concept ID:
C1864910
Disease or Syndrome
Congenital glutamine deficiency is a severe autosomal recessive disorder characterized by onset at birth of encephalopathy, lack of normal development, seizures, and hypotonia associated with variable brain abnormalities (summary by Haberle et al., 2011).
Ethylmalonic encephalopathy
MedGen UID:
355966
Concept ID:
C1865349
Disease or Syndrome
Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of children die in the first decade.
Severe neonatal-onset encephalopathy with microcephaly
MedGen UID:
409616
Concept ID:
C1968556
Disease or Syndrome
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.
SLC35A1-congenital disorder of glycosylation
MedGen UID:
370234
Concept ID:
C1970344
Disease or Syndrome
An extremely rare form of carbohydrate deficient glycoprotein syndrome characterized clinically in the single reported case by repeated hemorrhagic incidents, including severe pulmonary hemorrhage.
Familial acute necrotizing encephalopathy
MedGen UID:
382634
Concept ID:
C2675556
Finding
Acute necrotizing encephalopathy type 1, also known as susceptibility to infection-induced acute encephalopathy 3 or IIAE3, is a rare type of brain disease (encephalopathy) that occurs following a viral infection such as the flu.\n\nAcute necrotizing encephalopathy type 1 typically appears in infancy or early childhood, although some people do not develop the condition until adolescence or adulthood. People with this condition usually show typical symptoms of an infection, such as fever, cough, congestion, vomiting, and diarrhea, for a few days. Following these flu-like symptoms, affected individuals develop neurological problems, such as seizures, hallucinations, difficulty coordinating movements (ataxia), or abnormal muscle tone. Eventually, most affected individuals go into a coma, which usually lasts for a number of weeks. The condition is described as "acute" because the episodes of illness are time-limited.\n\nPeople with acute necrotizing encephalopathy type 1 develop areas of damage (lesions) in certain regions of the brain. As the condition progresses, these brain regions develop swelling (edema), bleeding (hemorrhage), and then tissue death (necrosis). The progressive brain damage and tissue loss results in encephalopathy.\n\nApproximately one-third of individuals with acute necrotizing encephalopathy type 1 do not survive their illness and subsequent neurological decline. Of those who do survive, about half have permanent brain damage due to tissue necrosis, resulting in impairments in walking, speech, and other basic functions. Over time, many of these skills may be regained, but the loss of brain tissue is permanent. Other individuals who survive their illness appear to recover completely.\n\nIt is estimated that half of individuals with acute necrotizing encephalopathy type 1 are susceptible to recurrent episodes and will have another infection that results in neurological decline; some people may have numerous episodes throughout their lives. Neurological function worsens following each episode as more brain tissue is damaged.
3-hydroxy-3-methylglutaryl-CoA synthase deficiency
MedGen UID:
414399
Concept ID:
C2751532
Disease or Syndrome
Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (summary by Aledo et al., 2006).
FADD-related immunodeficiency
MedGen UID:
462412
Concept ID:
C3151062
Disease or Syndrome
Immunodeficiency-90 with encephalopathy, functional hyposplenia, and hepatic dysfunction (IMD90) is a autosomal recessive complex immunologic disorder with systemic manifestations in addition to primary immunodeficiency. Affected individuals usually present in infancy or early childhood with recurrent fevers and bacterial or viral infections associated with central nervous system symptoms, including irritability, drowsiness, variable seizures, and white matter abnormalities on brain imaging. There is also liver involvement and functional hyposplenism, causing increased susceptibility to invasive pneumococcal infection, which may be fatal. Susceptibility to viral infections likely results from impaired interferon immunity, and bacterial infections likely result from splenic dysfunction. A subset of patients have congenital cardiac malformations. Most individuals demonstrate developmental delay and speech delay. Laboratory findings in affected individuals are similar to those seen in autoimmune lymphoproliferative syndrome (ALPS; 601859), including high-circulating CD4-/CD8-/TCR-alpha-beta+ (double-negative) T-cell (DNT) counts, and elevated IL10 (124092) and FASL (TNFSF6; 134638) levels, but the clinical features are somewhat different from ALPS: massive lymphadenopathy and autoimmune features are not observed in IMD90 (summary by Bolze et al., 2010, Savic et al., 2015 and Kohn et al., 2020).
Mitochondrial DNA depletion syndrome 9
MedGen UID:
462826
Concept ID:
C3151476
Disease or Syndrome
SUCLG1-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized in the majority of affected newborns by hypotonia, muscle atrophy, feeding difficulties, and lactic acidosis. Affected infants commonly manifest developmental delay / cognitive impairment, growth retardation / failure to thrive, hepatopathy, sensorineural hearing impairment, dystonia, and hypertonia. Notable findings in some affected individuals include hypertrophic cardiomyopathy, epilepsy, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, and/or hypoglycemia. Life span is shortened, with median survival of 20 months.
Mitochondrial complex V (ATP synthase) deficiency nuclear type 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
Mitochondrial encephalo-cardio-myopathy due to <i>TMEM70</i> mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.
Encephalopathy, acute, infection-induced, susceptibility to, 4
MedGen UID:
481790
Concept ID:
C3280160
Finding
Acute encephalopathy is a severe neurologic complication of an infection that usually occurs in children. It is characterized by a high-grade fever accompanied within 12 to 48 hours by febrile convulsions, often leading to coma, multiple-organ failure, brain edema, and high morbidity and mortality. The infections are usually viral, particularly influenza, although other viruses and even mycoplasma have been found to cause the disorder (summary by Chen et al., 2005; Shinohara et al., 2011). For a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1
MedGen UID:
482290
Concept ID:
C3280660
Disease or Syndrome
Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36.
Childhood encephalopathy due to thiamine pyrophosphokinase deficiency
MedGen UID:
482496
Concept ID:
C3280866
Disease or Syndrome
Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Lipoic acid synthetase deficiency
MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Hyperglycinemia, lactic acidosis, and seizures (HGCLAS) is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
Aicardi-Goutieres syndrome 2
MedGen UID:
483677
Concept ID:
C3489724
Disease or Syndrome
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
Coenzyme Q10 deficiency, primary, 1
MedGen UID:
764868
Concept ID:
C3551954
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
MedGen UID:
766288
Concept ID:
C3553374
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Mitochondrial pyruvate carrier deficiency
MedGen UID:
766521
Concept ID:
C3553607
Disease or Syndrome
Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
MedGen UID:
767448
Concept ID:
C3554534
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 6 (MC4DN6) is an autosomal recessive multisystem metabolic disorder with a highly variable phenotype. Some patients present in the neonatal period with encephalomyopathic features, whereas others present later in the first year of life with developmental regression. Manifestations include hypotonia, feeding difficulties, and global developmental delay. Many, but not all, patients develop hypertrophic cardiomyopathy, which may result in early death. Additional more variable features may include poor overall growth, microcephaly, seizures, neurodegeneration, spasticity, visual defects, retinopathy, and hepatic steatosis. Brain imaging in some patients shows features consistent with Leigh syndrome (see 256000). Laboratory studies show increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV (summary by Kennaway et al., 1990 and Oquendo et al., 2004). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex V (ATP synthase) deficiency nuclear type 4B
MedGen UID:
815229
Concept ID:
C3808899
Disease or Syndrome
Mitochondrial complex V deficiency is a shortage (deficiency) of a protein complex called complex V or a loss of its function. Complex V is found in cell structures called mitochondria, which convert the energy from food into a form that cells can use. Complex V is the last of five mitochondrial complexes that carry out a multistep process called oxidative phosphorylation, through which cells derive much of their energy.\n\nMitochondrial complex V deficiency can cause a wide variety of signs and symptoms affecting many organs and systems of the body, particularly the nervous system and the heart. The disorder can be life-threatening in infancy or early childhood. Affected individuals may have feeding problems, slow growth, low muscle tone (hypotonia), extreme fatigue (lethargy), and developmental delay. They tend to develop elevated levels of lactic acid in the blood (lactic acidosis), which can cause nausea, vomiting, weakness, and rapid breathing. High levels of ammonia in the blood (hyperammonemia) can also occur in affected individuals, and in some cases result in abnormal brain function (encephalopathy) and damage to other organs.\n\nAnother common feature of mitochondrial complex V deficiency is hypertrophic cardiomyopathy. This condition is characterized by thickening (hypertrophy) of the heart (cardiac) muscle that can lead to heart failure. People with mitochondrial complex V deficiency may also have a characteristic pattern of facial features, including a high forehead, curved eyebrows, outside corners of the eyes that point downward (downslanting palpebral fissures), a prominent bridge of the nose, low-set ears, thin lips, and a small chin (micrognathia).\n\nSome people with mitochondrial complex V deficiency have groups of signs and symptoms that are classified as a specific syndrome. For example, mitochondrial complex V deficiency can cause a condition called neuropathy, ataxia, and retinitis pigmentosa (NARP). NARP causes a variety of signs and symptoms chiefly affecting the nervous system. Beginning in childhood or early adulthood, most people with NARP experience numbness, tingling, or pain in the arms and legs (sensory neuropathy); muscle weakness; and problems with balance and coordination (ataxia). Many affected individuals also have cognitive impairment and an eye disorder called retinitis pigmentosa that causes vision loss.\n\nA condition called Leigh syndrome can also be caused by mitochondrial complex V deficiency. Leigh syndrome is characterized by progressive loss of mental and movement abilities (developmental or psychomotor regression) and typically results in death within 2 to 3 years after the onset of symptoms. Both NARP and Leigh syndrome can also have other causes.
Multiple mitochondrial dysfunctions syndrome 3
MedGen UID:
815495
Concept ID:
C3809165
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome-3 (MMDS3) is an autosomal recessive severe neurodegenerative disorder characterized by loss of previously acquired developmental milestones in the first months or years of life. Some affected patients have normal development in early infancy before the onset of symptoms, whereas others show delays from birth. Features included loss of motor function, spasticity, pyramidal signs, loss of speech, and cognitive impairment. The disease course is highly variable: some patients die of respiratory failure early in childhood, whereas some survive but may be bedridden with a feeding tube. Less commonly, some patients may survive and have a stable course with motor deficits and mild or even absent cognitive impairment, although there may be fluctuating symptoms, often in response to infection. Other variable features include visual problems and seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Laboratory studies tend to show increased lactate and CSF glycine, and decreased activity of mitochondrial complexes I and II, although these findings are also variable. There may be additional biochemical evidence of mitochondrial dysfunction (summary by Liu et al., 2018). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).
Mitochondrial complex III deficiency nuclear type 6
MedGen UID:
815883
Concept ID:
C3809553
Disease or Syndrome
Mitochondrial complex III deficiency nuclear type 6 (MC3DN6) is an autosomal recessive disorder caused by mitochondrial dysfunction. It is characterized by onset in early childhood of episodic acute lactic acidosis, ketoacidosis, and insulin-responsive hyperglycemia, usually associated with infection. Laboratory studies show decreased activity of mitochondrial complex III. Psychomotor development is normal (summary by Gaignard et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Mitochondrial DNA depletion syndrome 13
MedGen UID:
815922
Concept ID:
C3809592
Disease or Syndrome
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome
MedGen UID:
816301
Concept ID:
C3809971
Disease or Syndrome
Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern.
Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
MedGen UID:
816734
Concept ID:
C3810404
Disease or Syndrome
Most children with carbonic anhydrase VA (CA-VA) deficiency reported to date have presented between day 2 of life and early childhood (up to age 20 months) with hyperammonemic encephalopathy (i.e., lethargy, feeding intolerance, weight loss, tachypnea, seizures, and coma). Given that fewer than 20 affected individuals have been reported to date, the ranges of initial presentations and long-term prognoses are not completely understood. As of 2021 the oldest known affected individual is an adolescent. Almost all affected individuals reported to date have shown normal psychomotor development and no further episodes of metabolic crisis; however, a few have shown mild learning difficulties or delayed motor skills.
Mitochondrial complex III deficiency nuclear type 8
MedGen UID:
862877
Concept ID:
C4014440
Disease or Syndrome
Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Severe neurodegenerative syndrome with lipodystrophy
MedGen UID:
863137
Concept ID:
C4014700
Disease or Syndrome
The spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and pes cavus and other foot deformities. Disease severity is variable among and within families.
Combined oxidative phosphorylation deficiency 22
MedGen UID:
863499
Concept ID:
C4015062
Disease or Syndrome
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
MedGen UID:
873604
Concept ID:
C4040739
Disease or Syndrome
The phenotypic spectrum of SERAC1 deficiency comprises MEGD(H)EL syndrome (3-methylglutaconic aciduria with deafness-dystonia, [hepatopathy], encephalopathy, and Leigh-like syndrome), juvenile-onset complicated hereditary spastic paraplegia (in 1 consanguineous family), and adult-onset generalized dystonia (in 1 adult male). MEGD(H)EL syndrome is characterized in neonates by hypoglycemia and a sepsis-like clinical picture for which no infectious agent can be found. During the first year of life feeding problems, failure to thrive, and/or truncal hypotonia become evident; many infants experience (transient) liver involvement ranging from undulating transaminases to prolonged hyperbilirubinemia and near-fatal liver failure. By age two years progressive deafness, dystonia, and spasticity prevent further psychomotor development and/or result in loss of acquired skills. Affected children are completely dependent on care for all activities of daily living; speech is absent.
Developmental and epileptic encephalopathy, 35
MedGen UID:
904159
Concept ID:
C4225256
Disease or Syndrome
Developmental and epileptic encephalopathy-35 (DEE35) is an autosomal recessive neurodegenerative disorder characterized by onset of seizures in the first months of life associated with essentially no normal development. Brain imaging shows a characteristic pattern consistent with lack of myelination of early structures, including the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices. Many patients die in early childhood (summary by Kevelam et al., 2015) For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection
MedGen UID:
904009
Concept ID:
C4225260
Disease or Syndrome
Immunodeficiency-44 (IMD44) is an autosomal recessive primary immunodeficiency characterized by increased susceptibility to viral infections and adverse multisystemic reaction to vaccination in some patients. Affected individuals appear to have defects in mitochondrial fission and fusion (summary by Shahni et al., 2015).
Developmental and epileptic encephalopathy, 30
MedGen UID:
898954
Concept ID:
C4225360
Disease or Syndrome
Developmental and epileptic encephalopathy-30 (DEE30) is a severe neurologic disorder characterized by onset of refractory seizures soon after birth or in the first months of life. Seizure types include early myoclonic encephalopathy (EME), Ohtahara syndrome, and infantile spasms; most are refractory to treatment. Patients with earlier seizure onset make essentially no developmental progress and may die in infancy. Those with later onset show profoundly impaired global development with absent speech, poor eye contact, inability to walk, behavioral abnormalities, and feeding difficulties that may require a feeding tube (summary by Hansen et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Glutamate pyruvate transaminase 2 deficiency
MedGen UID:
906606
Concept ID:
C4225388
Disease or Syndrome
Neurodevelopmental disorder with spastic paraplegia and microcephaly (NEDSPM) is an autosomal recessive neurologic syndrome characterized by delayed psychomotor development with delayed walking, moderately to severely impaired intellectual development, and poor or absent speech. More severely affected individuals show poor overall growth with progressive microcephaly, axial hypotonia, oromotor dysfunction with drooling, joint contractures, and spastic paraplegia resulting in walking difficulties. Some patients may develop seizures; nonspecific dysmorphic features have also been reported (summary by Hengel et al., 2018 and Ouyang et al., 2019).
Neurodevelopmental disorder with hypotonia, seizures, and absent language
MedGen UID:
934610
Concept ID:
C4310643
Disease or Syndrome
Encephalopathy, progressive, with amyotrophy and optic atrophy
MedGen UID:
934634
Concept ID:
C4310667
Disease or Syndrome
Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO) is a severe autosomal recessive neurodegenerative disorder characterized by delayed development with hypotonia apparent in infancy and subsequent motor regression. Most affected individuals are unable to or lose the ability to sit and show distal amyotrophy and weakness of all 4 limbs. The patients are cognitively impaired and unable to speak or have severe dysarthria. Additional features include optic atrophy, thin corpus callosum, and cerebellar atrophy (Sferra et al., 2016).
Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome
MedGen UID:
934638
Concept ID:
C4310671
Disease or Syndrome
PEBAT is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development apparent soon after birth or in infancy, profound intellectual disability, poor or absent speech, and seizures. Most patients are never able to walk due to hypotonia or spasticity. Brain imaging shows cerebral and cerebellar atrophy, thin corpus callosum, and secondary hypomyelination. The disorder shows progressive features, including microcephaly, consistent with a neurodegenerative process (summary by Miyake et al., 2016; Flex et al., 2016).
Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1
MedGen UID:
934642
Concept ID:
C4310675
Disease or Syndrome
Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by Kremer et al., 2016). Genetic Heterogeneity of PEBEL See also PEBEL2 (618321), caused by mutation in the NAXD gene (615910) on chromosome 13q34.
Atypical glycine encephalopathy
MedGen UID:
934910
Concept ID:
C4310943
Disease or Syndrome
GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity can be observed. Generalized hypotonia develops later into axial hypotonia with limb hypertonicity and a startle-like response to vocal and visual stimuli which should not be confused with seizures. To date, three of the six affected children reported from three families died between ages two days and seven months; the oldest reported living child is severely globally impaired at age three years. Because of the limited number of affected individuals reported to date, the phenotype has not yet been completely described.
Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities
MedGen UID:
1624694
Concept ID:
C4540052
Disease or Syndrome
NELABA is a severe autosomal recessive metabolic disorder characterized by onset at birth of progressive encephalopathy associated with increased serum lactate. Affected individuals have little or no psychomotor development and show brain abnormalities, including cerebral atrophy, cysts, and white matter abnormalities. Some patients die in infancy (summary by Habarou et al., 2017).
Hyperekplexia 4
MedGen UID:
1642659
Concept ID:
C4693933
Disease or Syndrome
Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures, and many have inguinal or umbilical hernia. Most patients die in the first months of life due to respiratory failure or other complications (summary by Piard et al., 2018). For a general description and a discussion of genetic heterogeneity of hyperekplexia, see HKPX1 (149400).
Combined oxidative phosphorylation defect type 13
MedGen UID:
1631854
Concept ID:
C4706283
Disease or Syndrome
Combined oxidative phosphorylation deficiency-13 (COXPD13) is an autosomal recessive multisystem disorder resulting from mitochondrial dysfunction. Affected individuals develop severe neurologic impairment in the first months of life, including hypotonia, abnormal dystonic movements, hearing loss, poor feeding, global developmental delay, and abnormal eye movements. Brain imaging shows signal abnormalities in putamen, basal ganglia, caudate nuclei, or corpus callosum, as well as delayed myelination. Analysis of patient tissues shows multiple defects in enzymatic activities of the mitochondrial respiratory chain, although some tissues may show normal values since tissue expression of the mitochondrial defect and metabolic needs of specific tissues are variable (summary by Vedrenne et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Acyl-CoA dehydrogenase 9 deficiency
MedGen UID:
1648400
Concept ID:
C4747517
Disease or Syndrome
MC1DN20 is an autosomal recessive multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Mitochondrial complex 5 (ATP synthase) deficiency nuclear type 5
MedGen UID:
1648429
Concept ID:
C4748269
Disease or Syndrome
Developmental and epileptic encephalopathy, 68
MedGen UID:
1648479
Concept ID:
C4748688
Disease or Syndrome
Developmental and epileptic encephalopathy-68 (DEE68) is an autosomal recessive neurologic disorder characterized by onset of twitching and/or myoclonic jerks in infancy. The disorder progresses to refractory generalized tonic-clonic seizures, often resulting in status epilepticus, loss of developmental milestones, and early death. Other features include delayed development, axial hypotonia, spasticity of the limbs, and clonus. Brain imaging may show cortical atrophy (summary by Barel et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Inflammatory bowel disease, immunodeficiency, and encephalopathy
MedGen UID:
1648434
Concept ID:
C4748708
Disease or Syndrome
A rare genetic disease characterized by infantile onset of severe inflammatory bowel disease manifesting with bloody diarrhea and failure to thrive, and central nervous system disease with global developmental delay and regression, impaired speech, hypotonia, hyperreflexia, and epilepsy. Brain imaging shows global cerebral atrophy, thin corpus callosum, delayed myelination, and posterior leukoencephalopathy. Cases with recurrent infections and impaired T-cell responses to stimulation, as well as decreased T-cell subsets, have been reported.
Mitochondrial complex 1 deficiency, nuclear type 3
MedGen UID:
1648346
Concept ID:
C4748752
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 7
MedGen UID:
1648484
Concept ID:
C4748760
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 8
MedGen UID:
1648411
Concept ID:
C4748766
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 9
MedGen UID:
1648447
Concept ID:
C4748767
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 10
MedGen UID:
1648426
Concept ID:
C4748768
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 11
MedGen UID:
1648356
Concept ID:
C4748769
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 13
MedGen UID:
1648370
Concept ID:
C4748770
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 14
MedGen UID:
1648440
Concept ID:
C4748777
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 15
MedGen UID:
1648320
Concept ID:
C4748778
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 25
MedGen UID:
1648366
Concept ID:
C4748806
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 33
MedGen UID:
1648420
Concept ID:
C4748840
Disease or Syndrome
Ferro-cerebro-cutaneous syndrome
MedGen UID:
1658844
Concept ID:
C4751570
Disease or Syndrome
A rare genetic metabolic liver disease with characteristics of progressive neurodegeneration, cutaneous abnormalities including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations including microdontia, widely spaced and pointed teeth with delayed eruption and gingival overgrowth.
Pontocerebellar hypoplasia type 10
MedGen UID:
1676575
Concept ID:
C5190575
Disease or Syndrome
Pontocerebellar hypoplasia type 10 is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by severely delayed psychomotor development, progressive microcephaly, spasticity, seizures, and brain abnormalities, including brain atrophy and delayed myelination. Some patients have dysmorphic features and an axonal sensorimotor neuropathy (summary by Karaca et al., 2014 and Schaffer et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).
Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)
MedGen UID:
1682503
Concept ID:
C5191055
Disease or Syndrome
The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and psychomotor retardation) evident within weeks of birth. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.
NAD(P)HX dehydratase deficiency
MedGen UID:
1681210
Concept ID:
C5193026
Disease or Syndrome
Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-2 (PEBEL2) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, and sometimes seizures, resulting in death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by Van Bergen et al., 2019). For a discussion of genetic heterogeneity of PEBEL, see PEBEL1 (617186).
Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal
MedGen UID:
1716458
Concept ID:
C5394137
Disease or Syndrome
Neonatal lethal pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome (PHRINL) is an autosomal recessive multisystem disorder with onset in utero and death in the neonatal period. Rare patients may survive a few months. Affected infants show respiratory insufficiency and almost no spontaneous movement at birth, usually requiring mechanical ventilation and admission to the neonatal intensive care unit. Additional features include corneal clouding, seizures, dysmorphic facies, contractures, and progressive pontocerebellar hypoplasia with simplified gyral pattern and white matter abnormalities. Some patients may have cardiac anomalies or cardiac hypertrophy. Laboratory studies show evidence consistent with mitochondrial defects and/or abnormal cholesterol or lipid metabolism. Depending on the type of mutation or deletion, some patients may have a less severe disorder (see GENOTYPE/PHENOTYPE CORRELATIONS) (summary by Desai et al., 2017).
Chromosome 1p36.33 duplication syndrome, atad3 gene cluster, autosomal dominant
MedGen UID:
1708515
Concept ID:
C5394150
Disease or Syndrome
Autosomal dominant chromosome 1p36.33 duplication syndrome is a severe multisystemic disorder characterized by neonatal respiratory insufficiency, hypotonia, and cardiomyopathy, resulting in death in the first weeks of life. Affected infants may also have seizures, contractures, and corneal opacities. Brain imaging shows variable anomalies, such as white matter changes, and laboratory studies suggest that the phenotype results from metabolic defects in mitochondrial and cholesterol homeostasis (summary by Gunning et al., 2020).
Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity
MedGen UID:
1711516
Concept ID:
C5394423
Disease or Syndrome
Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (NEDBASS) is an autosomal recessive neurologic disorder characterized by global developmental delay apparent from early infancy, poor overall growth often with microcephaly, impaired intellectual development with delayed or absent speech, axial hypotonia, and peripheral spasticity. Additional common but variable features include early-onset seizures, optic atrophy with poor visual fixation, and dysmorphic facial features. Brain imaging shows cerebral atrophy, poor or absent myelination with loss of white matter volume, and often hypoplasia of the corpus callosum and/or cerebellum. Early death may occur (summary by Bend et al., 2020).
Episodic ataxia, type 9
MedGen UID:
1714171
Concept ID:
C5394520
Disease or Syndrome
Episodic ataxia type 9 (EA9) is a neurologic disorder characterized by onset of ataxic episodes in the first years of life. Features may include difficulty walking, dizziness, slurred speech, headache, vomiting, and pain. The ataxic episodes vary in frequency and duration; most tend to occur every few weeks or months and last minutes to hours. Prior to the EA, most patients have neonatal- or infantile-onset tonic or generalized tonic-clonic (GTC) seizures that may be severe and refractory to medication, but remit later in infancy or early childhood, either spontaneously or concurrently with medication. Some patients have mildly delayed development with speech delay and/or autistic features or mildly impaired intellectual development. However, others show normal psychomotor development. Treatment of the ataxic episodes with acetazolamide is effective in about 50% of patients (summary by Schwarz et al., 2019). For a phenotypic description and discussion of genetic heterogeneity of episodic ataxia, see EA1 (160120).
Mitchell syndrome
MedGen UID:
1714342
Concept ID:
C5394554
Disease or Syndrome
Mitchell syndrome (MITCH) is a progressive disorder characterized by episodic demyelination, sensorimotor polyneuropathy, and hearing loss (Chung et al., 2020).
Coenzyme q10 deficiency, primary, 9
MedGen UID:
1740444
Concept ID:
C5436638
Disease or Syndrome
Coenzyme Q10 deficiency-9 (COQ10D9) is an autosomal recessive disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in the first decade of life. Some patients may have additional neurologic signs and symptoms, including intellectual disability and seizures. Treatment with CoQ10 may offer clinical benefit (summary by Malicdan et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of primary coenzyme Q10 deficiency, see COQ10D1 (607426).
Mitochondrial complex IV deficiency, nuclear type 22
MedGen UID:
1786100
Concept ID:
C5543491
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 22 (MC4DN22) is an autosomal recessive metabolic disorder characterized by neonatal hypertrophic cardiomyopathy, encephalopathy, and severe lactic acidosis with fatal outcome (Wintjes et al., 2021). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Spinocerebellar ataxia, autosomal recessive 31
MedGen UID:
1786855
Concept ID:
C5543627
Disease or Syndrome
Autosomal recessive spinocerebellar ataxia-31 (SCAR31) is a complex neurodevelopmental disorder characterized by global developmental delay with hypotonia and variably impaired intellectual and language development. Affected individuals have an ataxic gait, tremor, and dysarthria; more severely affected patients also have spasticity with inability to walk. Most have optic atrophy. Brain imaging shows cerebellar hypoplasia, enlarged ventricles, and atrophy of the posterior corpus callosum. Additional features may include retinitis pigmentosa, sensorineural deafness, dysmorphic facial features, and possibly endocrine dysfunction (summary by Collier et al., 2021).
Neurodevelopmental disorder with impaired language and ataxia and with or without seizures
MedGen UID:
1794216
Concept ID:
C5562006
Disease or Syndrome
Neurodevelopmental disorder with impaired language and ataxia and with or without seizures (NEDLAS) is characterized by axial hypotonia and global developmental delay apparent in early infancy. Affected individuals have delayed walking with gait ataxia and poor language development. Behavioral abnormalities also commonly occur. The severity is highly variable: a subset of patients have a more severe phenotype with early-onset seizures resembling epileptic encephalopathy, inability to walk or speak, and hypomyelination on brain imaging (summary by Stolz et al., 2021).
Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome
MedGen UID:
1798652
Concept ID:
C5567229
Disease or Syndrome
A rare genetic neurological disorder with characteristics of early-onset severe global developmental delay with regression, congenital or acquired microcephaly, hearing loss, truncal hypotonia, appendicular spasticity, and dystonia and/or myoclonus. Additional reported manifestations include seizures, optic atrophy, cortical visual impairment, scoliosis, and dysphagia. Brain imaging shows pontine hypoplasia, partial agenesis of the corpus callosum, and diffuse cerebral atrophy with relative sparing of the cerebellum.
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
MedGen UID:
1798903
Concept ID:
C5567480
Disease or Syndrome
Infantile hypotonia with psychomotor retardation and characteristic facies-3 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Most affected individuals show very poor, if any, normal psychomotor development, poor speech, and inability to walk independently (summary by Bhoj et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).
Pyruvate dehydrogenase E3 deficiency
MedGen UID:
1805500
Concept ID:
C5574660
Disease or Syndrome
The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset liver involvement and, rarely, a myopathic presentation. Early-onset DLD deficiency typically manifests in infancy as hypotonia with lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die within the first few years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits (intellectual disability, spasticity, ataxia, and seizures). In contrast, isolated liver involvement can present as early as the neonatal period and as late as the third decade. Evidence of liver injury/failure is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes affected individuals frequently return to baseline with no residual neurologic deficit or intellectual disability. Liver failure can result in death, even in those with late-onset disease. Individuals with the myopathic presentation may experience muscle cramps, weakness, and an elevated creatine kinase.
D,L-2-hydroxyglutaric aciduria
MedGen UID:
1802316
Concept ID:
C5574940
Disease or Syndrome
Combined D-2- and L-2-hydroxyglutaric aciduria (D2L2AD) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (Muntau et al., 2000). See also isolated L-2-hydroxyglutaric aciduria (236792) and isolated D-2-hydroxyglutaric aciduria (see 600721).
Atelis syndrome 2
MedGen UID:
1824055
Concept ID:
C5774282
Disease or Syndrome
Atelis syndrome-2 (ATELS2) is an autosomal recessive disorder characterized by poor overall growth with microcephaly and short stature, dysmorphic facial features, and congenital cardiac defects. Additional more variable features may include hematologic abnormalities, variable ocular abnormalities, motor delay, and anxiety. Patient cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy (Grange et al., 2022). See also ATELS1 (620184), caused by mutation in the SLF2 gene (610348). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).
Encephalitis, acute, infection-induced, susceptibility to, 12
MedGen UID:
1846830
Concept ID:
C5882673
Finding
Infection-induced acute encephalitis-12 (IIAE12) is an autosomal recessive disorder characterized by episodic acute encephalopathy associated with infections and febrile illness. Patients present with neurologic symptoms in the first months or years of life, usually after normal early development. Brain imaging in the acute episodes shows restriction on diffusion-weighted imaging (DWI) and T2-weighted abnormalities in the periventricular and subcortical regions, which progresses to cavitation of previously affected areas. The long-term outcome is highly variable, even within families, ranging from death to severe neurologic deficits to normal outcomes (Shashi et al., 2023). For a discussion of genetic heterogeneity of susceptibility to acute infection-induced encephalopathy, see 610551.
Xerosis and growth failure with immune and pulmonary dysfunction syndrome
MedGen UID:
1848919
Concept ID:
C5882692
Disease or Syndrome
Xerosis and growth failure with immune and pulmonary dysfunction syndrome (XGIP) is characterized by premature birth, intrauterine and postnatal growth retardation, and collodion membrane or collodion-like skin at birth with dry skin thereafter. Patients also exhibit bronchopulmonary disease and thrombocytopenia and neutropenia. Variable features include cardiac anomalies, seizures, encephalopathy, and cholestasis, and cataract has been observed. Affected individuals die within the first year of life (Shamseldin et al., 2023).

Professional guidelines

PubMed

Olofsson P
Am J Obstet Gynecol 2023 May;228(5S):S1222-S1240. Epub 2023 Mar 19 doi: 10.1016/j.ajog.2022.07.001. PMID: 37164495
Adrogué HJ, Tucker BM, Madias NE
JAMA 2022 Jul 19;328(3):280-291. doi: 10.1001/jama.2022.11176. PMID: 35852524
Smith A, Baumgartner K, Bositis C
Am Fam Physician 2019 Dec 15;100(12):759-770. PMID: 31845776

Recent clinical studies

Etiology

Fox A, Doyle E, Geary M, Hayes B
Int J Gynaecol Obstet 2023 Jan;160(1):22-27. Epub 2022 Jul 3 doi: 10.1002/ijgo.14301. PMID: 35694848Free PMC Article
Moran S, López-Sánchez M, Milke-García MDP, Rodríguez-Leal G
World J Gastroenterol 2021 Jun 14;27(22):3050-3063. doi: 10.3748/wjg.v27.i22.3050. PMID: 34168407Free PMC Article
Krishnarao A, Gordon FD
Clin Liver Dis 2020 May;24(2):219-229. Epub 2020 Mar 2 doi: 10.1016/j.cld.2020.01.004. PMID: 32245529
Elsaid MI, Rustgi VK
Clin Liver Dis 2020 May;24(2):157-174. Epub 2020 Mar 2 doi: 10.1016/j.cld.2020.01.001. PMID: 32245524
Erkkinen MG, Berkowitz AL
Am J Med 2019 Oct;132(10):1142-1147. Epub 2019 Jul 19 doi: 10.1016/j.amjmed.2019.07.001. PMID: 31330129

Diagnosis

Rudler M, Weiss N, Bouzbib C, Thabut D
Clin Liver Dis 2021 May;25(2):393-417. Epub 2021 Mar 11 doi: 10.1016/j.cld.2021.01.008. PMID: 33838857
Russ JB, Simmons R, Glass HC
Neoreviews 2021 Mar;22(3):e148-e162. doi: 10.1542/neo.22-3-e148. PMID: 33649088
Mazeraud A, Righy C, Bouchereau E, Benghanem S, Bozza FA, Sharshar T
Neurotherapeutics 2020 Apr;17(2):392-403. doi: 10.1007/s13311-020-00862-1. PMID: 32378026Free PMC Article
Erkkinen MG, Berkowitz AL
Am J Med 2019 Oct;132(10):1142-1147. Epub 2019 Jul 19 doi: 10.1016/j.amjmed.2019.07.001. PMID: 31330129
Patidar KR, Bajaj JS
Clin Gastroenterol Hepatol 2015 Nov;13(12):2048-61. Epub 2015 Jul 9 doi: 10.1016/j.cgh.2015.06.039. PMID: 26164219Free PMC Article

Therapy

Tapper EB, Parikh ND
JAMA 2023 May 9;329(18):1589-1602. doi: 10.1001/jama.2023.5997. PMID: 37159031Free PMC Article
Goetzl L
Am J Obstet Gynecol 2023 May;228(5S):S1274-S1282. Epub 2023 Mar 20 doi: 10.1016/j.ajog.2022.11.002. PMID: 36997396
Ziobro JM, Eschbach K, Shellhaas RA
Neurotherapeutics 2021 Jul;18(3):1564-1581. Epub 2021 Aug 12 doi: 10.1007/s13311-021-01085-8. PMID: 34386906Free PMC Article
Graham NS, Sharp DJ
J Neurol Neurosurg Psychiatry 2019 Nov;90(11):1221-1233. Epub 2019 Sep 21 doi: 10.1136/jnnp-2017-317557. PMID: 31542723Free PMC Article
Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG
Cochrane Database Syst Rev 2013 Jan 31;2013(1):CD003311. doi: 10.1002/14651858.CD003311.pub3. PMID: 23440789Free PMC Article

Prognosis

Rudler M, Weiss N, Bouzbib C, Thabut D
Clin Liver Dis 2021 May;25(2):393-417. Epub 2021 Mar 11 doi: 10.1016/j.cld.2021.01.008. PMID: 33838857
Del Rosario C, Slevin M, Molloy EJ, Quigley J, Nixon E
Arch Dis Child Educ Pract Ed 2021 Apr;106(2):108-112. Epub 2020 Aug 28 doi: 10.1136/archdischild-2020-319063. PMID: 32859738
Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, Giovo I, Uschner FE, Jimenez C, Mookerjee R, Gustot T, Albillos A, Bañares R, Janicko M, Steib C, Reiberger T, Acevedo J, Gatti P, Bernal W, Zeuzem S, Zipprich A, Piano S, Berg T, Bruns T, Bendtsen F, Coenraad M, Merli M, Stauber R, Zoller H, Ramos JP, Solè C, Soriano G, de Gottardi A, Gronbaek H, Saliba F, Trautwein C, Özdogan OC, Francque S, Ryder S, Nahon P, Romero-Gomez M, Van Vlierberghe H, Francoz C, Manns M, Garcia E, Tufoni M, Amoros A, Pavesi M, Sanchez C, Curto A, Pitarch C, Putignano A, Moreno E, Shawcross D, Aguilar F, Clària J, Ponzo P, Jansen C, Vitalis Z, Zaccherini G, Balogh B, Vargas V, Montagnese S, Alessandria C, Bernardi M, Ginès P, Jalan R, Moreau R, Angeli P, Arroyo V; PREDICT STUDY group of the EASL-CLIF Consortium
J Hepatol 2020 Oct;73(4):842-854. Epub 2020 Jul 13 doi: 10.1016/j.jhep.2020.06.013. PMID: 32673741
Elsaid MI, Rustgi VK
Clin Liver Dis 2020 May;24(2):157-174. Epub 2020 Mar 2 doi: 10.1016/j.cld.2020.01.001. PMID: 32245524
Zambrano MD, Miller EC
Curr Atheroscler Rep 2019 Jun 22;21(9):33. doi: 10.1007/s11883-019-0798-2. PMID: 31230137Free PMC Article

Clinical prediction guides

Uematsu K, Matsumoto H, Zaha K, Mizuguchi M, Nonoyama S
Brain Dev 2023 Feb;45(2):93-101. Epub 2022 Oct 31 doi: 10.1016/j.braindev.2022.10.004. PMID: 36328834
Tang L, Liu S, Xiao Y, Tran TML, Choi JW, Wu J, Halsey K, Huang RY, Boxerman J, Patel SH, Kung D, Liu R, Feldman MD, Danoski DD, Liao WH, Kasner SE, Liu T, Xiao B, Zhang PJ, Reznik M, Bai HX, Yang L
CNS Neurosci Ther 2021 Oct;27(10):1127-1135. Epub 2021 Jun 16 doi: 10.1111/cns.13687. PMID: 34132473Free PMC Article
Faille LD, Fieuws S, Van Paesschen W
Acta Neurol Belg 2017 Jun;117(2):469-475. Epub 2017 Jan 31 doi: 10.1007/s13760-017-0750-6. PMID: 28144796Free PMC Article
Dupre CM, Libman R, Dupre SI, Katz JM, Rybinnik I, Kwiatkowski T
J Stroke Cerebrovasc Dis 2014 Feb;23(2):374-8. Epub 2013 Aug 15 doi: 10.1016/j.jstrokecerebrovasdis.2013.07.015. PMID: 23954604
Stevens RD, Sutter R
Crit Care Med 2013 Apr;41(4):1104-23. doi: 10.1097/CCM.0b013e318287ee79. PMID: 23528755

Recent systematic reviews

Caramelo I, Coelho M, Rosado M, Cardoso CMP, Dinis A, Duarte CB, Grãos M, Manadas B
World J Pediatr 2023 Jun;19(6):505-548. Epub 2023 Apr 21 doi: 10.1007/s12519-023-00698-7. PMID: 37084165Free PMC Article
Astarita A, Covella M, Vallelonga F, Cesareo M, Totaro S, Ventre L, Aprà F, Veglio F, Milan A
J Hypertens 2020 Jul;38(7):1203-1210. doi: 10.1097/HJH.0000000000002372. PMID: 32510905
Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG, Fraser GL
Crit Care 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1. PMID: 29137682Free PMC Article
Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG
Cochrane Database Syst Rev 2013 Jan 31;2013(1):CD003311. doi: 10.1002/14651858.CD003311.pub3. PMID: 23440789Free PMC Article
Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser WA
Epilepsia 2010 Apr;51(4):671-5. Epub 2009 Sep 3 doi: 10.1111/j.1528-1167.2009.02285.x. PMID: 19732133

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