HHHS
MCID: HYP774
MIFTS: 55

Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (HHHS)

Categories: Genetic diseases, Metabolic diseases, Rare diseases

Aliases & Classifications for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

MalaCards integrated aliases for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

Name: Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome 56 24 52 25 58 73 36 29 6
Hhh Syndrome 56 12 74 24 52 25 58 73 54 71
Ornithine Translocase Deficiency 56 12 52 25 58 15
Hyperornithinemia-Hyperammonemia-Homocitrullinemia Syndrome 56 25 13 39
Triple H Syndrome 25 58
Hhhs 56 52
Hhh 56 52
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome 12
Hyperornithinemia, Hyperammonemia, Homocitrullinuria Syndrome 74
Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria Syndrome 25
Ornithine Translocase Deficiency Syndrome 52
Ornithine Carrier Deficiency 58
Hhh Syndrome; Hhh 56
Ornt1 Deficiency 58

Characteristics:

Orphanet epidemiological data:

58
hyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Inheritance: Autosomal recessive; Prevalence: 1-5/10000 (Europe); Age of onset: Adolescent,Adult,Childhood,Infancy,Neonatal; Age of death: infantile;

OMIM:

56
Miscellaneous:
phenotypic variability
onset in first months or years of life
increased prevalence in the french-canadian population

Inheritance:
autosomal recessive


HPO:

31
hyperornithinemia-hyperammonemia-homocitrullinuria syndrome:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Inborn errors of metabolism


Summaries for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 415 Definition A rare, genetic disorder of urea cycle metabolism characterized by either a neonatal-onset with manifestations of lethargy, poor feeding, vomiting and tachypnea or, more commonly, presentations in infancy, childhood or adulthood with chronic neurocognitive deficits, acute encephalopathy and/or coagulation defects or other chronic liver dysfunction. Epidemiology More than 100 cases have been reported in the literature to date. The prevalence in Northern Saskatchewan, Canada is especially high due to a founder effect and is estimated in this population at 1/1550 live births. Clinical description Age of onset can range from the neonatal period to adulthood and a wide phenotypic spectrum is noted. The neonatal presentation usually begins a few days after birth with lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures . Onset of symptoms (ranging from mild to severe) in the majority of patients occurs in infancy, childhood and adulthood with episodes of confusion, forgetfulness, hyperammonemic coma, intellectual disability , developmental delay , spastic paraplegia, cerebellar ataxia , learning difficulties, unexplained seizures, liver dysfunction (rarely failure) and coagulopathy with factor VII-, IX- and X-deficiencies. An aversion to protein -rich foods before diagnosis is often reported. Etiology The syndrome is due to mutations in the SLC25A15 gene (13q14) encoding the mitochondrial ornithine transporter 1 (ORNT1) which plays a role in ornithine transport across the mitochondrial membrane and consecutively in mitochondrial protein synthesis, metabolism of arginine and lysine, and synthesis of polyamines. Mutations in this protein disrupt the urea cycle, resulting in hyperornithinemia, hyperammonemia and homocitrullinuria. Patients with a complete ORNT1 deficiency present in the neonatal period with severe hyperammonemia whereas those with a partial deficiency present later, between infancy to adulthood. Diagnostic methods Diagnosis is based on clinical findings and specific metabolic abnormalities. Laboratory tests usually reveal increased urinary excretion of orotic acid, homocitrulline and uracil , and a rise in the levels of plasma polyamines, ornithine, glutamine, alanine, and liver transaminases. Plasma ammonia levels are elevated episodically or postprandially and plasma ornithine is chronically elevated and is a hallmark of the disease as is the presence of homocitrulline in urine. Molecular genetic testing confirms diagnosis. Differential diagnosis Differential diagnosis includes other urea cycle disorders as well as lysinuric protein intolerance. Hyperinsulinism-hyperammonemia syndrome, pyruvate carboxylase deficiency and secondary causes of hyperammonemia should also be considered. Antenatal diagnosis Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles . Genetic counseling The pattern of inheritance is autosomal recessive ; where both parents are unaffected carriers , there is a 25% risk of inheriting the disease. Management and treatment Treatment involves the adherence to a low protein diet along with citrulline or arginine supplementation. In resistant cases, sodium benzoate and/or sodium or glycerol phenylbutyrate may be necessary for control of plasma ammonia levels. Patients should be monitored during times of stress (e.g. pregnancy, surgery, intercurrent infections) and when taking certain medications (i.e. corticosteroids ) as they can trigger an episode of hyperammonemia. Hyperammonemic coma is treated in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration), ammonia scavenger therapy implemented, catabolism reversed (with glucose and lipid infusions) and special care taken to reduce the risk of neurological damage. Prognosis With early diagnosis and proper adherence to treatment protocol the prognosis is better than for most other urea cycle defects. However, patients remain at risk for metabolic decompensation throughout life and irreversible neurological complications can occur if treatment is delayed. Visit the Orphanet disease page for more resources.

MalaCards based summary : Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome, also known as hhh syndrome, is related to lysinuric protein intolerance and gyrate atrophy of choroid and retina, and has symptoms including seizures, clonus and lethargy. An important gene associated with Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome is SLC25A15 (Solute Carrier Family 25 Member 15), and among its related pathways/superpathways are Metabolism and Viral mRNA Translation. Affiliated tissues include liver, brain and testes, and related phenotypes are cognitive impairment and neurodevelopmental delay

Disease Ontology : 12 An amino acid metabolic disorder that has material basis in deficiency of ornithine translocase resulting in the accumulation of ammonia in the blood.

Genetics Home Reference : 25 Ornithine translocase deficiency is an inherited disorder that causes ammonia and other substances to build up (accumulate) in the blood. Ammonia, which is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is especially sensitive to the effects of excess ammonia. Ornithine translocase deficiency varies widely in its severity and age of onset. Affected infants show signs and symptoms of ornithine translocase deficiency within days after birth. In most affected individuals, however, signs and symptoms of ornithine translocase deficiency do not appear until later in life, with health problems first appearing anytime from childhood to adulthood. Later-onset forms of ornithine translocase deficiency are usually less severe than the infantile form. Infants with ornithine translocase deficiency may lack energy (be lethargic), refuse to eat, vomit frequently, or have poorly controlled breathing or body temperature. Seizures or unusual body movements are common in these individuals. Some people with this condition have intellectual disability or developmental delay, but others have normal intelligence. Severe cases may result in coma. Some people with later-onset ornithine translocase deficiency have episodes of vomiting, lethargy, problems with coordination (ataxia), vision problems, episodes of brain dysfunction (encephalopathy), developmental delay, learning disabilities, or stiffness caused by abnormal tensing of the muscles (spasticity). Affected individuals may have chronic liver problems and mild abnormal bleeding. Individuals with ornithine translocase deficiency often cannot tolerate high-protein foods, such as meat. Occasionally, high-protein meals or stress caused by illness or periods without food (fasting) may cause ammonia to accumulate more quickly in the blood. This rapid increase of ammonia likely leads to the signs and symptoms of ornithine translocase deficiency. While the signs and symptoms of ornithine translocase deficiency can vary greatly among affected individuals, proper treatment can prevent some complications from occurring and may improve quality of life.

OMIM : 56 Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHHS) is an autosomal recessive, chronic and progressive disorder of the urea cycle with typical age of onset in early life. The acute phase is characterized by hyperammonemia accompanied by vomiting, ataxia, lethargy, confusion, and coma. Chronically, aversion to protein-rich foods, coagulation abnormalities, hypotonia, developmental delay, progressive encephalopathy with mental regression, and signs of motor dysfunction are present. About 95% of patients survive after diagnosis and therapy is established. However, in early adulthood most patients develop signs of pyramidal tract dysfunction (summary by Tessa et al., 2009). (238970)

KEGG : 36 Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder, characterized by mental retardation, progressive spastic paraparesis, seizures, and myoclonus epilepsy. This disease varies widely in its severity and age of onset. The HHH syndrome is thought to be caused by the defective activities of the mitochondrial carrier responsible for transporting ornithine from the cytoplasm into the inner mitochondrial membrane. Mutations in the SLC25A15 gene, that encodes the mitochondrial ornithine transporter have been shown to be correlated with the HHH syndrome.

UniProtKB/Swiss-Prot : 73 Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: Autosomal recessive disorder resulting in various neurologic symptoms, including mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia, and episodic disturbance of consciousness or coma caused by hyperammonemia. It causes a functional impairment of the urea cycle.

Wikipedia : 74 Ornithine translocase deficiency, also called hyperornithinemia-hyperammonemia-homocitrullinuria (HHH)... more...

GeneReviews: NBK97260

Related Diseases for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Diseases related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 62)
# Related Disease Score Top Affiliating Genes
1 lysinuric protein intolerance 30.6 OTC NAGS ASS1 ASL
2 gyrate atrophy of choroid and retina 30.5 SLC25A15 OAT
3 carbonic anhydrase va deficiency, hyperammonemia due to 30.4 SLC25A20 SLC25A15 SLC25A13 OTC NAGS CPS1
4 spastic paraparesis 30.3 SLC25A15 ALDH18A1
5 urea cycle disorder 29.7 SLC25A2 SLC25A15 SLC25A13 OTC NAGS CPS1
6 argininemia 29.6 SLC25A15 SLC25A13 OTC NAGS CPS1 ASS1
7 ornithinemia 11.2
8 autosomal recessive disease 10.8
9 ocular motor apraxia 10.7
10 ataxia and polyneuropathy, adult-onset 10.5
11 yemenite deaf-blind hypopigmentation syndrome 10.5
12 alacrima, achalasia, and mental retardation syndrome 10.5
13 paraplegia 10.5
14 night blindness 10.5
15 learning disability 10.5
16 cerebral atrophy 10.5
17 hypotonia 10.5
18 spasticity 10.5
19 acute liver failure 10.5
20 postpartum psychosis 10.2 OTC ASS1
21 helix syndrome 10.2
22 sleep apnea 10.2
23 hereditary spastic paraplegia 10.2
24 inherited metabolic disorder 10.2
25 encephalopathy 10.2
26 acyl-coa dehydrogenase deficiency 10.1 OTC ASS1
27 isovaleric acidemia 10.0 NAGS CPS1
28 tyrosinemia, type i 10.0 OTC NAGS ASL
29 branchiootic syndrome 1 10.0
30 heart disease 10.0
31 polyneuropathy 10.0
32 liver disease 10.0
33 dystonia 10.0
34 peripheral nervous system disease 10.0
35 congestive heart failure 10.0
36 hyperthyroidism 10.0
37 neuropathy 10.0
38 meningitis 10.0
39 diastolic heart failure 10.0
40 tuberculous meningitis 10.0
41 tremor 10.0
42 rare peripheral neuropathy 10.0
43 spastic paraplegia 9b, autosomal recessive 10.0 OTC ALDH18A1
44 maple syrup urine disease 10.0 OTC NAGS ASL
45 spastic paraplegia 9a, autosomal dominant 10.0 OTC ALDH18A1
46 methylmalonic acidemia 9.9 OTC NAGS CPS1
47 pyrimidine metabolic disorder 9.9 OTC NAGS ASS1 ASL
48 reye syndrome 9.8 OTC OAT ASS1
49 epileptic encephalopathy, early infantile, 39 9.8 SLC25A48 SLC25A22 SLC25A13
50 alopecia universalis congenita 9.8

Graphical network of the top 20 diseases related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:



Diseases related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Symptoms & Phenotypes for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Human phenotypes related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

58 31 (show all 49)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 cognitive impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0100543
2 neurodevelopmental delay 58 31 hallmark (90%) Very frequent (99-80%) HP:0012758
3 hyperammonemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001987
4 hyperornithinemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0012026
5 abnormal circulating citrulline concentration 31 hallmark (90%) HP:0011965
6 intellectual disability 58 31 frequent (33%) Frequent (79-30%) HP:0001249
7 hepatomegaly 58 31 frequent (33%) Frequent (79-30%) HP:0002240
8 failure to thrive 58 31 frequent (33%) Frequent (79-30%) HP:0001508
9 abnormal pyramidal sign 58 31 frequent (33%) Frequent (79-30%) HP:0007256
10 feeding difficulties 58 31 frequent (33%) Frequent (79-30%) HP:0011968
11 hepatitis 58 31 frequent (33%) Frequent (79-30%) HP:0012115
12 specific learning disability 58 31 frequent (33%) Frequent (79-30%) HP:0001328
13 elevated hepatic transaminase 58 31 frequent (33%) Frequent (79-30%) HP:0002910
14 cerebral cortical atrophy 58 31 frequent (33%) Frequent (79-30%) HP:0002120
15 clonus 58 31 frequent (33%) Frequent (79-30%) HP:0002169
16 spastic paraplegia 58 31 frequent (33%) Frequent (79-30%) HP:0001258
17 lethargy 58 31 frequent (33%) Frequent (79-30%) HP:0001254
18 impaired vibratory sensation 58 31 frequent (33%) Frequent (79-30%) HP:0002495
19 speech apraxia 58 31 frequent (33%) Frequent (79-30%) HP:0011098
20 oroticaciduria 58 31 frequent (33%) Frequent (79-30%) HP:0003218
21 tachypnea 58 31 frequent (33%) Frequent (79-30%) HP:0002789
22 generalized hypotonia 58 31 frequent (33%) Frequent (79-30%) HP:0001290
23 confusion 58 31 frequent (33%) Frequent (79-30%) HP:0001289
24 progressive cerebellar ataxia 58 31 frequent (33%) Frequent (79-30%) HP:0002073
25 poor coordination 58 31 frequent (33%) Frequent (79-30%) HP:0002370
26 episodic vomiting 58 31 frequent (33%) Frequent (79-30%) HP:0002572
27 acute encephalopathy 58 31 frequent (33%) Frequent (79-30%) HP:0006846
28 protein avoidance 58 31 frequent (33%) Frequent (79-30%) HP:0002038
29 coma 58 31 occasional (7.5%) Occasional (29-5%) HP:0001259
30 multifocal cerebral white matter abnormalities 58 31 occasional (7.5%) Occasional (29-5%) HP:0007052
31 spastic gait 58 31 occasional (7.5%) Occasional (29-5%) HP:0002064
32 abnormality of the coagulation cascade 58 31 occasional (7.5%) Occasional (29-5%) HP:0003256
33 respiratory alkalosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0001950
34 generalized myoclonic seizure 31 occasional (7.5%) HP:0002123
35 hepatic failure 58 31 very rare (1%) Very rare (<4-1%) HP:0001399
36 chorioretinal atrophy 58 31 very rare (1%) Very rare (<4-1%) HP:0000533
37 chorioretinal hypopigmentation 58 31 very rare (1%) Very rare (<4-1%) HP:0040030
38 decreased liver function 58 31 Frequent (79-30%) HP:0001410
39 global developmental delay 31 HP:0001263
40 seizures 58 Occasional (29-5%)
41 generalized myoclonic seizures 58 Occasional (29-5%)
42 decreased nerve conduction velocity 31 HP:0000762
43 hyperreflexia 58 Very frequent (99-80%)
44 hypopigmentation of the fundus 31 HP:0007894
45 spastic paraparesis 31 HP:0002313
46 acute hepatitis 31 HP:0200119
47 psychomotor retardation 31 HP:0025356
48 morphological abnormality of the pyramidal tract 31 HP:0002062
49 abnormality of citrulline metabolism 58 Very frequent (99-80%)

Symptoms via clinical synopsis from OMIM:

56
Abdomen Liver:
hepatomegaly
acute hepatitis
liver dysfunction

Growth Other:
failure to thrive

Abdomen Gastrointestinal:
episodic vomiting
protein avoidance

Hematology:
coagulopathy due to liver dysfunction

Neurologic Central Nervous System:
seizures
spasticity
hyperreflexia
clonus
lethargy
more
Laboratory Abnormalities:
hyperammonemia
hyperornithinemia
homocitrullinuria

Neurologic Peripheral Nervous System:
decreased vibration sense (rare)

Clinical features from OMIM:

238970

UMLS symptoms related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:


seizures, clonus, lethargy, muscle spasticity, abnormal pyramidal signs, paraparesis, spastic

MGI Mouse Phenotypes related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 mortality/aging MP:0010768 9.65 ALDH18A1 ASL ASS1 CPS1 NAGS OAT
2 renal/urinary system MP:0005367 9.1 ASL OAT OTC SLC25A13 SLC25A15 SLC25A20

Drugs & Therapeutics for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Increasing Ureagenesis in Inborn Errors of Metabolism With N-Carbamylglutamate Withdrawn NCT01341379 Phase 2 N-carbamylglutamate
2 Determination of the Oxygen Dissociation Curve Under the Conditions of an Avalanche Burial With an Air Pocket Active, not recruiting NCT04041531

Search NIH Clinical Center for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Genetic Tests for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Genetic tests related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

# Genetic test Affiliating Genes
1 Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome 29 SLC25A15

Anatomical Context for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

MalaCards organs/tissues related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

40
Liver, Brain, Testes, Cerebellum, Skin, Retina

Publications for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Articles related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

(show top 50) (show all 121)
# Title Authors PMID Year
1
Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. 61 56 6 24 54
19242930 2009
2
Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. 54 24 56 6 61
16940241 2006
3
Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. 61 54 56 24 6
10369256 1999
4
Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. 6 56 24 61
11552031 2001
5
Diagnosis of Japanese patients with HHH syndrome by molecular genetic analysis: a common mutation, R179X. 6 56 61 54
11355015 2001
6
The human and mouse SLC25A29 mitochondrial transporters rescue the deficient ornithine metabolism in fibroblasts of patients with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. 61 54 56 24
19287344 2009
7
Phenotypic variability among patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome homozygous for the delF188 mutation in SLC25A15. 61 54 24 56
18978333 2008
8
Cloning and characterization of human ORNT2: a second mitochondrial ornithine transporter that can rescue a defective ORNT1 in patients with the hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a urea cycle disorder. 61 54 56 24
12948741 2003
9
Clinical, biochemical and ultrastructural study on the pathogenesis of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. 56 6 61
3407856 1988
10
Hyperornithinemia, hyperammonemia, and homocitrullinuria. A new disorder of amino acid metabolism associated with myoclonic seizures and mental retardation. 24 56
5782534 1969
11
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome 61 6
22649802 2012
12
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with stroke-like imaging presentation: clinical, biochemical and molecular analysis. 54 24 61
17825324 2008
13
Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome with evidence of mitochondrial dysfunction due to a novel SLC25A15 (ORNT1) gene mutation in a Palestinian family. 24 61 54
14759633 2004
14
Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. 54 61 24
11668643 2001
15
Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. 24 54 61
10805333 2000
16
Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome: presentation as acute liver disease with coagulopathy. 56 61
1469525 1992
17
Neonatal form of the hyperornithinaemia, hyperammonaemia, and homocitrullinuria (HHH) syndrome and prenatal diagnosis. 61 56
1438066 1992
18
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: low creatine excretion and effect of citrulline, arginine, or ornithine supplement. 61 56
3116497 1987
19
Studies on a case of HHH-syndrome (hyperammonemia, hyperornithinemia, homocitrullinuria). 61 56
3960284 1986
20
A new patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria treated early with low protein diet. 56 61
3091924 1986
21
Ornithine loading did not prevent induced hyperammonemia in a patient with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. 61 56
4080446 1985
22
Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea-cycle disorders: On the basis of information from a European multicenter registry. 24 61
30734935 2019
23
Chronic liver involvement in urea cycle disorders. 61 24
31260111 2019
24
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in pregnancy: Considerations for management and review of the literature. 24 61
31240152 2019
25
Hyperornithinemia, Hyperammonemia, and Homocitrullinuria Syndrome Causing Severe Neonatal Hyperammonemia. 61 24
30187369 2019
26
Late onset hyperornithinemia-hyperammonemia-homocitrullinuria syndrome - how web searching by the family solved unexplained unconsciousness: a case report. 61 24
30243302 2018
27
Lactate/pyruvate in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. 24 61
30058227 2018
28
[Clinical diagnosis and treatment of three cases with hyperornithinemia-hyperammonemia-homocitrullinuria syndrome]. 61 24
28592010 2017
29
Milder Form of Urea Cycle Defect Revisited: Report and Review of Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH) Syndrome Diagnosed in a Teenage Girl Presenting with Recurrent Encephalopathy. 24 61
28062886 2016
30
Improving long term outcomes in urea cycle disorders-report from the Urea Cycle Disorders Consortium. 24 61
27215558 2016
31
The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. 24 61
25874378 2015
32
Ocular manifestations in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: a rare association. 61 24
25411929 2015
33
A longitudinal study of urea cycle disorders. 56
25135652 2014
34
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome in adulthood: a rare recognizable condition. 61 24
23247599 2013
35
Creatine metabolism in urea cycle defects. 61 24
22644604 2012
36
Long-term follow-up of four patients affected by HHH syndrome. 61 24
22465082 2012
37
Diagnosis and high incidence of hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome in northern Saskatchewan. 61 24
20574716 2010
38
Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH) presenting with acute fulminant hepatic failure. 61 24
18376250 2008
39
HHH syndrome (hyperornithinaemia, hyperammonaemia, homocitrullinuria), with fulminant hepatitis-like presentation. 24 61
16601889 2006
40
Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, and neuropsychologic examination of six patients. 56
1432421 1992
41
Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. 56
2222247 1990
42
Potential for the prenatal diagnosis of hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. 56
2929667 1989
43
Hyperornithinemia, hyperammonemia, and homocitrullinuria: case report and biochemical study. 56
3670619 1987
44
A new family affected by the syndrome of hyperornithinaemia, hyperammonaemia and homocitrullinuria. 56
3106719 1987
45
Possible pathogenetic mechanism in hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome. 56
3580547 1987
46
The mechanism of hyperammonaemia and hyperornithinaemia in the syndrome of hyperornithinaemia, hyperammonaemia with homocitrullinuria. 56
6422148 1983
47
Studies on the pathway from ornithine to proline in cultured skin fibroblasts with reference to the defect in hyperornithinaemia with hyperammonaemia and homocitrullinuria. 56
6422153 1983
48
Reduced ornithine catabolism in cultured fibroblasts and phytohaemagglutinin-stimulated lymphocytes from a patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria. 56
6120052 1982
49
Hyperornithinemia, hyperammonemia, and homocitrullinuria associated with decreased carbamyl phosphate synthetase I activity. 56
166348 1975
50
Ornithinemia, hyperammonemia, and homocitrullinuria. A disease associated with mental retardation and possibly caused by defective mitochondrial transport. 56
4825593 1974

Variations for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

ClinVar genetic disease variations for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

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# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 SLC25A15 NM_014252.4(SLC25A15):c.408del (p.Met137fs)deletion Pathogenic 851641 13:41379346-41379346 13:40805210-40805210
2 SLC25A15 NM_014252.4(SLC25A15):c.446del (p.Ser149fs)deletion Pathogenic 567983 rs1566123619 13:41379385-41379385 13:40805249-40805249
3 SLC25A15 NC_000013.11:g.(?_40727821)_(40810887_?)deldeletion Pathogenic 583427 13:41301957-41385023 13:40727821-40810887
4 SLC25A15 NM_014252.4(SLC25A15):c.514G>T (p.Gly172Ter)SNV Pathogenic 656435 13:41381491-41381491 13:40807355-40807355
5 SLC25A15 NM_014252.4(SLC25A15):c.521C>A (p.Ser174Ter)SNV Pathogenic 650947 13:41381498-41381498 13:40807362-40807362
6 SLC25A15 NM_014252.4(SLC25A15):c.553_555TTC[3] (p.Phe188del)short repeat Pathogenic 5992 rs202247803 13:41381530-41381532 13:40807394-40807396
7 SLC25A15 NM_014252.4(SLC25A15):c.538G>A (p.Glu180Lys)SNV Pathogenic 5993 rs104894424 13:41381515-41381515 13:40807379-40807379
8 SLC25A15 NM_014252.4(SLC25A15):c.535C>T (p.Arg179Ter)SNV Pathogenic 5994 rs104894429 13:41381512-41381512 13:40807376-40807376
9 SLC25A15 NM_014252.4(SLC25A15):c.79G>A (p.Gly27Arg)SNV Pathogenic 5995 rs104894430 13:41373216-41373216 13:40799080-40799080
10 SLC25A15 NM_014252.4(SLC25A15):c.824G>A (p.Arg275Gln)SNV Pathogenic 5996 rs104894431 13:41383721-41383721 13:40809585-40809585
11 SLC25A15 NM_014252.4(SLC25A15):c.110T>G (p.Met37Arg)SNV Pathogenic 5997 rs121908533 13:41373247-41373247 13:40799111-40799111
12 SLC25A15 NM_014252.4(SLC25A15):c.212T>A (p.Leu71Gln)SNV Pathogenic 5998 rs121908534 13:41373349-41373349 13:40799213-40799213
13 SLC25A15 NM_014252.4(SLC25A15):c.59del (p.Gly20fs)deletion Pathogenic 857237 13:41373195-41373195 13:40799059-40799059
14 SLC25A15 NM_014252.4(SLC25A15):c.95C>G (p.Thr32Arg)SNV Pathogenic 6000 rs121908536 13:41373232-41373232 13:40799096-40799096
15 SLC25A15 NM_014252.4(SLC25A15):c.847C>T (p.Leu283Phe)SNV Pathogenic 38404 rs202247809 13:41383744-41383744 13:40809608-40809608
16 SLC25A15 NM_014252.4(SLC25A15):c.569G>A (p.Gly190Asp)SNV Pathogenic 38400 rs202247804 13:41381546-41381546 13:40807410-40807410
17 SLC25A15 NM_014252.4(SLC25A15):c.658G>A (p.Gly220Arg)SNV Pathogenic 38401 rs202247805 13:41382609-41382609 13:40808473-40808473
18 SLC25A15 NM_014252.4(SLC25A15):c.823C>T (p.Arg275Ter)SNV Likely pathogenic 38403 rs202247807 13:41383720-41383720 13:40809584-40809584
19 SLC25A15 NM_014252.4(SLC25A15):c.564C>G (p.Phe188Leu)SNV Likely pathogenic 38399 13:41381541-41381541 13:40807405-40807405
20 SLC25A15 NM_014252.4(SLC25A15):c.815C>T (p.Thr272Ile)SNV Likely pathogenic 5999 rs121908535 13:41383712-41383712 13:40809576-40809576
21 SLC25A15 NM_014252.4(SLC25A15):c.452+2T>CSNV Likely pathogenic 863850 13:41379393-41379393 13:40805257-40805257
22 SLC25A15 NM_014252.4(SLC25A15):c.147C>G (p.Asp49Glu)SNV Conflicting interpretations of pathogenicity 706683 13:41373284-41373284 13:40799148-40799148
23 SLC25A15 NM_014252.4(SLC25A15):c.388G>A (p.Val130Met)SNV Conflicting interpretations of pathogenicity 619129 rs553432772 13:41379327-41379327 13:40805191-40805191
24 SLC25A15 NM_014252.4(SLC25A15):c.706A>G (p.Arg236Gly)SNV Conflicting interpretations of pathogenicity 432095 rs142236568 13:41382657-41382657 13:40808521-40808521
25 SLC25A15 NM_014252.4(SLC25A15):c.55+6G>CSNV Conflicting interpretations of pathogenicity 509277 rs200219313 13:41367423-41367423 13:40793287-40793287
26 SLC25A15 NM_014252.4(SLC25A15):c.216C>T (p.Ile72=)SNV Conflicting interpretations of pathogenicity 739891 13:41373353-41373353 13:40799217-40799217
27 SLC25A15 NM_014252.4(SLC25A15):c.255C>T (p.Tyr85=)SNV Conflicting interpretations of pathogenicity 742355 13:41373392-41373392 13:40799256-40799256
28 SLC25A15 NM_014252.4(SLC25A15):c.182G>A (p.Arg61His)SNV Conflicting interpretations of pathogenicity 203939 rs34615430 13:41373319-41373319 13:40799183-40799183
29 SLC25A15 NM_014252.4(SLC25A15):c.225C>T (p.Ile75=)SNV Conflicting interpretations of pathogenicity 312176 rs765380976 13:41373362-41373362 13:40799226-40799226
30 SLC25A15 NM_014252.4(SLC25A15):c.565G>A (p.Gly189Ser)SNV Conflicting interpretations of pathogenicity 312181 rs151239794 13:41381542-41381542 13:40807406-40807406
31 SLC25A15 NM_014252.4(SLC25A15):c.345C>T (p.Phe115=)SNV Conflicting interpretations of pathogenicity 312179 rs35434090 13:41379284-41379284 13:40805148-40805148
32 SLC25A15 NM_014252.4(SLC25A15):c.278G>A (p.Arg93Gln)SNV Conflicting interpretations of pathogenicity 312177 rs369201060 13:41373415-41373415 13:40799279-40799279
33 SLC25A15 NM_014252.4(SLC25A15):c.564C>T (p.Phe188=)SNV Conflicting interpretations of pathogenicity 387375 rs141028076 13:41381541-41381541 13:40807405-40807405
34 SLC25A15 NM_014252.4(SLC25A15):c.-101C>GSNV Uncertain significance 312173 rs886050239 13:41363768-41363768 13:40789632-40789632
35 SLC25A15 NM_014252.4(SLC25A15):c.*871T>CSNV Uncertain significance 312195 rs767132355 13:41384674-41384674 13:40810538-40810538
36 SLC25A15 NM_014252.4(SLC25A15):c.*2373T>CSNV Uncertain significance 312218 rs886050249 13:41386176-41386176 13:40812040-40812040
37 SLC25A15 NM_014252.4(SLC25A15):c.*2494G>ASNV Uncertain significance 312219 rs886050250 13:41386297-41386297 13:40812161-40812161
38 SLC25A15 NM_014252.4(SLC25A15):c.343T>G (p.Phe115Val)SNV Uncertain significance 312178 rs886050240 13:41379282-41379282 13:40805146-40805146
39 SLC25A15 NM_014252.4(SLC25A15):c.552T>C (p.Tyr184=)SNV Uncertain significance 312180 rs374352017 13:41381529-41381529 13:40807393-40807393
40 SLC25A15 NM_014252.4(SLC25A15):c.632C>T (p.Pro211Leu)SNV Uncertain significance 312182 rs139034961 13:41382583-41382583 13:40808447-40808447
41 SLC25A15 NM_014252.4(SLC25A15):c.*2071C>TSNV Uncertain significance 312212 rs757326840 13:41385874-41385874 13:40811738-40811738
42 SLC25A15 NM_014252.3(SLC25A15):c.-245C>TSNV Uncertain significance 312171 rs886050237 13:41363624-41363624 13:40789488-40789488
43 SLC25A15 NM_014252.3(SLC25A15):c.-167G>ASNV Uncertain significance 312172 rs886050238 13:41363702-41363702 13:40789566-40789566
44 SLC25A15 NM_014252.4(SLC25A15):c.*1485T>ASNV Uncertain significance 312200 rs886050244 13:41385288-41385288 13:40811152-40811152
45 SLC25A15 NM_014252.4(SLC25A15):c.*1682C>TSNV Uncertain significance 312205 rs557871939 13:41385485-41385485 13:40811349-40811349
46 SLC25A15 NM_014252.3(SLC25A15):c.-273C>GSNV Uncertain significance 312169 rs541415883 13:41363596-41363596 13:40789460-40789460
47 SLC25A15 NM_014252.4(SLC25A15):c.*1345G>CSNV Uncertain significance 312199 rs886050243 13:41385148-41385148 13:40811012-40811012
48 SLC25A15 NM_014252.4(SLC25A15):c.*1721C>TSNV Uncertain significance 312206 rs536553279 13:41385524-41385524 13:40811388-40811388
49 SLC25A15 NM_014252.4(SLC25A15):c.*217G>ASNV Uncertain significance 312186 rs886050241 13:41384020-41384020 13:40809884-40809884
50 SLC25A15 NM_014252.4(SLC25A15):c.*1595G>ASNV Uncertain significance 312202 rs886050245 13:41385398-41385398 13:40811262-40811262

UniProtKB/Swiss-Prot genetic disease variations for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome:

73 (show all 14)
# Symbol AA change Variation ID SNP ID
1 SLC25A15 p.Gly27Glu VAR_012757 rs120899402
2 SLC25A15 p.Gly27Arg VAR_012758 rs104894430
3 SLC25A15 p.Pro126Arg VAR_012759
4 SLC25A15 p.Glu180Lys VAR_012760 rs104894424
5 SLC25A15 p.Gly190Asp VAR_012762 rs202247804
6 SLC25A15 p.Arg275Gln VAR_012764 rs104894431
7 SLC25A15 p.Met37Arg VAR_058948 rs121908533
8 SLC25A15 p.Leu71Gln VAR_058950 rs121908534
9 SLC25A15 p.Gly113Cys VAR_058951 rs199894905
10 SLC25A15 p.Phe188Leu VAR_058952 rs141028076
11 SLC25A15 p.Gly216Ser VAR_058953 rs141716760
12 SLC25A15 p.Thr272Ile VAR_058954 rs121908535
13 SLC25A15 p.Met273Lys VAR_058955 rs202247808
14 SLC25A15 p.Leu283Phe VAR_058956 rs202247809

Expression for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Search GEO for disease gene expression data for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome.

Pathways for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Pathways related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
13.8 SLC25A20 SLC25A2 SLC25A15 SLC25A13 OTC OAT
2
Show member pathways
13.42 SLC25A2 SLC25A15 OTC OAT NAGS CPS1
3
Show member pathways
11.96 OTC NAGS CPS1 ASS1 ASL ALDH18A1
4 11.61 OTC OAT CPS1 ASS1 ALDH18A1
5
Show member pathways
11.1 OAT ALDH18A1
6 11.05 CPS1 ASS1 ASL
7
Show member pathways
10.77 OTC NAGS CPS1 ASS1 ASL
8
Show member pathways
10.57 ASS1 ASL
9
Show member pathways
10.55 OTC OAT NAGS CPS1 ASS1 ASL
10
Show member pathways
10.43 OAT ALDH18A1

GO Terms for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

Cellular components related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrion GO:0005739 9.8 SLC25A48 SLC25A38 SLC25A29 SLC25A22 SLC25A20 SLC25A2
2 mitochondrial matrix GO:0005759 9.46 OTC OAT NAGS CPS1
3 mitochondrial inner membrane GO:0005743 9.36 SLC25A48 SLC25A38 SLC25A29 SLC25A22 SLC25A20 SLC25A2

Biological processes related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome according to GeneCards Suite gene sharing:

(show all 25)
# Name GO ID Score Top Affiliating Genes
1 liver development GO:0001889 9.75 OTC CPS1 ASS1
2 ATP transport GO:0015867 9.67 SLC25A48 SLC25A29 SLC25A22 SLC25A13
3 response to zinc ion GO:0010043 9.65 OTC CPS1 ASS1
4 response to amino acid GO:0043200 9.62 CPS1 ASS1
5 response to steroid hormone GO:0048545 9.62 CPS1 ASS1
6 cellular response to glucagon stimulus GO:0071377 9.61 CPS1 ASS1
7 L-glutamate transmembrane transport GO:0015813 9.61 SLC25A22 SLC25A13
8 midgut development GO:0007494 9.61 OTC CPS1 ASS1
9 response to growth hormone GO:0060416 9.6 CPS1 ASS1
10 glutamate metabolic process GO:0006536 9.59 NAGS ALDH18A1
11 response to amine GO:0014075 9.58 CPS1 ASS1
12 acyl carnitine transmembrane transport GO:1902616 9.58 SLC25A48 SLC25A29 SLC25A20
13 aspartate transmembrane transport GO:0015810 9.57 SLC25A22 SLC25A13
14 L-aspartate transmembrane transport GO:0070778 9.56 SLC25A22 SLC25A13
15 L-proline biosynthetic process GO:0055129 9.55 OAT ALDH18A1
16 cellular amino acid biosynthetic process GO:0008652 9.55 OTC OAT ASS1 ASL ALDH18A1
17 malate-aspartate shuttle GO:0043490 9.54 SLC25A22 SLC25A13
18 acyl carnitine transport GO:0006844 9.52 SLC25A48 SLC25A29
19 cellular response to oleic acid GO:0071400 9.51 CPS1 ASS1
20 citrulline biosynthetic process GO:0019240 9.5 OTC CPS1 ALDH18A1
21 arginine biosynthetic process via ornithine GO:0042450 9.49 OTC ASL
22 anion homeostasis GO:0055081 9.46 OTC CPS1
23 mitochondrial L-ornithine transmembrane transport GO:1990575 9.43 SLC25A29 SLC25A2 SLC25A15
24 arginine biosynthetic process GO:0006526 9.26 OTC NAGS ASS1 ASL
25 urea cycle GO:0000050 9.17 SLC25A2 SLC25A15 OTC NAGS CPS1 ASS1

Molecular functions related to Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 identical protein binding GO:0042802 9.88 SLC25A13 OTC OAT ASS1 ASL ALDH18A1
2 catalytic activity GO:0003824 9.76 OAT CPS1 ASL ALDH18A1
3 transmembrane transporter activity GO:0022857 9.56 SLC25A48 SLC25A29 SLC25A22 SLC25A13
4 amino acid binding GO:0016597 9.43 OTC ASS1
5 L-glutamate transmembrane transporter activity GO:0005313 9.37 SLC25A22 SLC25A13
6 L-aspartate transmembrane transporter activity GO:0015183 9.32 SLC25A22 SLC25A13
7 L-ornithine transmembrane transporter activity GO:0000064 9.16 SLC25A2 SLC25A15
8 acyl carnitine transmembrane transporter activity GO:0015227 9.13 SLC25A48 SLC25A29 SLC25A20
9 ATP transmembrane transporter activity GO:0005347 8.92 SLC25A48 SLC25A29 SLC25A22 SLC25A13

Sources for Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
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56 OMIM
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61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
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72 UMLS via Orphanet
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