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Unspecified encephalopathy

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

Definition

A functional and/or structural disorder of the brain caused by diseases (e.g. liver disease, kidney disease), medications, chemicals, and injuries. [from NCI]

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).Bilirubin 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.Crigler-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.
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 syndrome, comprising mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with a variable clinical phenotype. The disorder is accompanied by features of central nervous system involvement, including seizures, hemiparesis, hemianopsia, cortical blindness, and episodic vomiting (Pavlakis et al., 1984; Montagna et al., 1988). Other mitochondrial encephalomyopathies include Leigh syndrome (LS; 256000), Kearns-Sayre syndrome (KSS; 530000), MERRF syndrome (545000), and Leber optic atrophy (535000).
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: 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.
Non-ketotic hyperglycinemia
MedGen UID:
155625
Concept ID:
C0751748
Disease or Syndrome
Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism defined by deficient activity of the glycine cleavage enzyme and, as a consequence, accumulation of large quantities of glycine in all body tissues including the brain. The majority of glycine encephalopathy presents in the neonatal period (85% as the neonatal severe form and 15% as the neonatal attenuated form). Of those presenting in infancy, 50% have the infantile attenuated form and 50% have the infantile severe form. Overall, 20% of all children presenting as either neonates or infants have a less severe outcome, defined as developmental quotient greater than 20. A minority of patients have mild or atypical forms of glycine encephalopathy. The neonatal form manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death. Surviving infants have profound intellectual disability and intractable seizures. The infantile form is characterized by hypotonia, developmental delay, and seizures. The atypical forms range from milder disease, with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset.
Crome syndrome
MedGen UID:
167082
Concept ID:
C0795914
Disease or Syndrome
A lethal combination of manifestations including short stature, congenital cataracts, encephalopathy with epileptic fits and postmortem confirmation of nephropathy (renal tubular necrosis). The combination has been described in 2 female infant children of first cousin parents. The infants did not survive beyond 4 and 8 months respectively. There have been no further descriptions in the literature since 1963.
Deficiency of glycerate kinase
MedGen UID:
226941
Concept ID:
C1291386
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).
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.
Basal ganglia disease, biotin-responsive
MedGen UID:
375289
Concept ID:
C1843807
Disease or Syndrome
Biotin-thiamine-responsive basal ganglia disease (BTBGD) 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 surgery. Less frequently, BTBGD presents as chronic or slowly progressive dystonia, seizures, and/or psychomotor delay. Although onset is usually in childhood (ages three to ten 10 years), it is extremely variable, ranging from the newborn period to adulthood. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days.
Coenzyme Q10 deficiency, primary 1
MedGen UID:
334528
Concept ID:
C1843920
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.
Spongiform encephalopathy with neuropsychiatric features
MedGen UID:
339812
Concept ID:
C1847650
Disease or Syndrome
Encephalopathy with intracranial calcification, growth hormone deficiency, microcephaly, and retinal degeneration
MedGen UID:
346482
Concept ID:
C1856973
Disease or Syndrome
2,4-Dienoyl-CoA reductase deficiency
MedGen UID:
346552
Concept ID:
C1857252
Disease or Syndrome
DECR deficiency is a rare autosomal recessive inborn error of metabolism resulting in mitochondrial dysfunction. Affected individuals have a severe encephalopathy with neurologic and metabolic dysfunction beginning in early infancy. Laboratory studies show decreased activity of the mitochondrial NADP(H)-dependent enzymes DECR1 (222745) and AASS (605113), resulting in increased C10:2-carnitine levels and hyperlysinemia (summary by Houten et al., 2014).
Combined oxidative phosphorylation deficiency 4
MedGen UID:
387884
Concept ID:
C1857682
Disease or Syndrome
Encephalopathy, familial, with neuroserpin inclusion bodies
MedGen UID:
346965
Concept ID:
C1858680
Disease or Syndrome
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a disorder that causes progressive dysfunction of the brain (encephalopathy). It is characterized by a loss of intellectual functioning (dementia) and seizures. At first, affected individuals may have difficulty sustaining attention and concentrating. They may experience repetitive thoughts, speech, or movements. As the condition progresses, their personality changes and judgment, insight, and memory become impaired. Affected people lose the ability to perform the activities of daily living, and most eventually require comprehensive care.The signs and symptoms of FENIB vary in their severity and age of onset. In severe cases, the condition causes seizures and episodes of sudden, involuntary muscle jerking or twitching (myoclonus) in addition to dementia. These signs can appear as early as a person's teens. Less severe cases are characterized by a progressive decline in intellectual functioning beginning in a person's forties or fifties.
Pyridoxal 5'-phosphate-dependent epilepsy
MedGen UID:
350498
Concept ID:
C1864723
Disease or Syndrome
PNPOD is an autosomal recessive inborn error of metabolism resulting in vitamin B6 deficiency that manifests as neonatal-onset severe seizures and subsequent encephalopathy. Patients with PNPO mutations tend to respond better to treatment with pyridoxal 5-prime phosphate (PLP) than with pyridoxine (summary by Plecko et al., 2014).
Combined oxidative phosphorylation deficiency 3
MedGen UID:
355842
Concept ID:
C1864840
Disease or Syndrome
Glutamine deficiency, congenital
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
MECP2-related disorders in females include classic Rett syndrome, variant Rett syndrome, and mild learning disabilities. A pathogenic MECP2 variant in a male is presumed to most often be lethal; phenotypes in rare surviving males are primarily severe neonatal encephalopathy and manic-depressive psychosis, pyramidal signs, Parkinsonian, and macro-orchidism (PPM-X syndrome). 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. Atypical Rett syndrome is observed increasingly as MECP2 variants are identified in individuals previously diagnosed with: clinically suspected but molecularly unconfirmed Angelman syndrome; intellectual disability with spasticity or tremor; mild learning disability; or (rarely) autism. Severe neonatal encephalopathy resulting in death before age two years is the most common phenotype observed in affected males.
Congenital disorder of glycosylation type 2H
MedGen UID:
409971
Concept ID:
C1970021
Disease or Syndrome
Syndrome with characteristics of severe psychomotor retardation, failure to thrive and intolerance to wheat and dairy products. So far, only two cases have been described. The disease is caused by mutations in the COG8 gene, which encodes a subunit of the COG complex. This complex is involved vesicle transport in the Golgi apparatus.
Acyl-CoA dehydrogenase family, member 9, deficiency of
MedGen UID:
370195
Concept ID:
C1970173
Disease or Syndrome
ACAD9 deficiency 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 general description and a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Pitt-Hopkins syndrome
MedGen UID:
370910
Concept ID:
C1970431
Disease or Syndrome
Pitt-Hopkins syndrome (PTHS) is characterized by significant global developmental delays with moderate to severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.
Encephalopathy, acute, infection-induced, 3, suceptibility to
MedGen UID:
382634
Concept ID:
C2675556
Finding
Infection-induced acute encephalopathy 3 (IIAE3) is the susceptibility to recurrent acute necrotizing encephalopathy (ANE) caused by a heterozygous pathogenic variant in RANBP2. ANE refers to the specific neurologic presentation in which bilateral symmetric thalamic, midbrain, and/or hindbrain lesions occur within days following the onset of an acute viral illness caused by influenza A, influenza B, parainfluenza II, human herpes virus 6, coxsackie virus, or an enterovirus. Although most IIAE3 occurs before age six years, first episodes have been observed in teenagers and adults. ANE begins within 12 hours to three or four days of the first awareness of viral symptoms (fever, cough, rhinorrhea, vomiting, diarrhea, and malaise). The most common sign of ANE is lethargy that progresses to coma (which may last for weeks) and seizures (in 50%). One third of affected individuals die during the acute phase of the encephalopathy; of the survivors, one half have permanent neurologic damage and the remainder have no discernible residual symptoms. Fifty per cent of persons with IIAE3 will have at least one repeat episode and some will have multiple repeat episodes
Combined d-2- and l-2-hydroxyglutaric aciduria
MedGen UID:
412535
Concept ID:
C2746066
Disease or Syndrome
Combined D-2- and L-2-hydroxyglutaric aciduria (D-2-HG and L-2-HG) 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 (summary by Muntau et al., 2000). See also isolated L-2-hydroxyglutaric aciduria (236792) and isolated D-2-hydroxyglutaric aciduria (see 600721).
Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovascular malformations
MedGen UID:
462412
Concept ID:
C3151062
Disease or Syndrome
Mitochondrial DNA depletion syndrome 9 (encephalomyopathic with methylmalonic aciduria)
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 DNA-depletion syndrome 3, hepatocerebral
MedGen UID:
462863
Concept ID:
C3151513
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.
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
Encephalopathy, acute, infection-induced, 4, susceptibility to
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.
Pyruvate dehydrogenase lipoic acid synthetase deficiency
MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Hyperglycinemia, lactic acidosis, and seizures 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, 5
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.
3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome
MedGen UID:
766511
Concept ID:
C3553597
Disease or Syndrome
MEGDEL (3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like) 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.
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2
MedGen UID:
767448
Concept ID:
C3554534
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome 3
MedGen UID:
815495
Concept ID:
C3809165
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome is characterized by impairment of cellular structures called mitochondria, which are the energy-producing centers of cells. While certain mitochondrial disorders are caused by impairment of a single stage of energy production, individuals with multiple mitochondrial dysfunctions syndrome have reduced function of more than one stage. The signs and symptoms of this severe condition begin early in life, and affected individuals usually do not live past infancy.Affected infants typically have severe brain dysfunction (encephalopathy), which can contribute to weak muscle tone (hypotonia), seizures, and delayed development of mental and movement abilities (psychomotor delay). These infants often have difficulty growing and gaining weight at the expected rate (failure to thrive). Most affected babies have a buildup of a chemical called lactic acid in the body (lactic acidosis), which can be life-threatening. They may also have high levels of a molecule called glycine (hyperglycinemia) or elevated levels of sugar (hyperglycemia) in the blood. Some babies with multiple mitochondrial dysfunctions syndrome have high blood pressure in the blood vessels that connect to the lungs (pulmonary hypertension) or weakening of the heart muscle (cardiomyopathy).
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
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 global 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 global 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.
Pontocerebellar hypoplasia, type 10
MedGen UID:
862784
Concept ID:
C4014347
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).
Combined oxidative phosphorylation deficiency 22
MedGen UID:
863499
Concept ID:
C4015062
Disease or Syndrome
Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
MedGen UID:
894421
Concept ID:
C4225161
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).
Epileptic encephalopathy, early infantile, 35
MedGen UID:
904159
Concept ID:
C4225256
Disease or Syndrome
Early infantile epileptic encephalopathy-35 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 EIEE, see 308350.
Mental retardation, autosomal recessive 49
MedGen UID:
906606
Concept ID:
C4225388
Mental or Behavioral Dysfunction
Encephalopathy, progressive, with amyotrophy and optic atrophy
MedGen UID:
934634
Concept ID:
C4310667
Disease or Syndrome
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 (summary by Sferra et al., 2016).
Encephalopathy, progressive, early-onset, with brain atrophy and thin corpus callosum
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).
Epileptic encephalopathy, early infantile, 44
MedGen UID:
934667
Concept ID:
C4310700
Disease or Syndrome
Glycine encephalopathy with normal serum glycine
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.
Crigler-Najjar syndrome
MedGen UID:
468484
Concept ID:
CN119421
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).Bilirubin 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.Crigler-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.

Recent clinical studies

Etiology

Skuja S, Zieda A, Ravina K, Chapenko S, Roga S, Teteris O, Groma V, Murovska M
PLoS One 2017;12(1):e0170071. Epub 2017 Jan 10 doi: 10.1371/journal.pone.0170071. PMID: 28072884Free PMC Article
Chapenko S, Roga S, Skuja S, Rasa S, Cistjakovs M, Svirskis S, Zaserska Z, Groma V, Murovska M
J Neurovirol 2016 Aug;22(4):488-97. Epub 2016 Jan 4 doi: 10.1007/s13365-015-0417-0. PMID: 26727906
Absoud M, Parslow RC, Wassmer E, Hemingway C, Duncan HP, Cummins C, Lim MJ; UK & Ireland Childhood CNS Inflammatory Demyelination Working Group and the the Paediatric Intensive Care Audit Network.
Mult Scler 2011 Oct;17(10):1258-61. Epub 2010 Sep 27 doi: 10.1177/1352458510382554. PMID: 20876155

Diagnosis

Chapenko S, Roga S, Skuja S, Rasa S, Cistjakovs M, Svirskis S, Zaserska Z, Groma V, Murovska M
J Neurovirol 2016 Aug;22(4):488-97. Epub 2016 Jan 4 doi: 10.1007/s13365-015-0417-0. PMID: 26727906
Absoud M, Parslow RC, Wassmer E, Hemingway C, Duncan HP, Cummins C, Lim MJ; UK & Ireland Childhood CNS Inflammatory Demyelination Working Group and the the Paediatric Intensive Care Audit Network.
Mult Scler 2011 Oct;17(10):1258-61. Epub 2010 Sep 27 doi: 10.1177/1352458510382554. PMID: 20876155

Clinical prediction guides

Skuja S, Zieda A, Ravina K, Chapenko S, Roga S, Teteris O, Groma V, Murovska M
PLoS One 2017;12(1):e0170071. Epub 2017 Jan 10 doi: 10.1371/journal.pone.0170071. PMID: 28072884Free PMC Article

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