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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome(HHHS)

MedGen UID:
82815
Concept ID:
C0268540
Disease or Syndrome
Synonyms: HHH syndrome; HHHS; Ornithine translocase deficiency; Ornithine translocase deficiency syndrome
SNOMED CT: HHH - Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (30287008); Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (30287008); SLC25A15-gene related hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (30287008); Solute carrier family 25 member 15-gene related hyperornithinemia, hyperammonemia, homocitrullinuria syndrome (30287008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SLC25A15 (13q14.11)
 
Monarch Initiative: MONDO:0009393
OMIM®: 238970
Orphanet: ORPHA415

Disease characteristics

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway. Clinical manifestations and age of onset vary among individuals even in the same family. Neonatal onset (~8% of affected individuals). Manifestations of hyperammonemia usually begin 24-48 hours after feeding begins and can include lethargy, somnolence, refusal to feed, vomiting, tachypnea with respiratory alkalosis, and/or seizures. Infantile, childhood, and adult onset (~92%). Affected individuals may present with: Chronic neurocognitive deficits (including developmental delay, ataxia, spasticity, learning disabilities, cognitive deficits, and/or unexplained seizures); Acute encephalopathy secondary to hyperammonemic crisis precipitated by a variety of factors; and Chronic liver dysfunction (unexplained elevation of liver transaminases with or without mild coagulopathy, with or without mild hyperammonemia and protein intolerance). Neurologic findings and cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia. [from GeneReviews]
Authors:
Jose Camacho  |  Natalia Rioseco-Camacho   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/238970
From MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/ornithine-translocase-deficiency

Clinical features

From HPO
Homocitrullinuria
MedGen UID:
382116
Concept ID:
C2673490
Finding
An increased amount of L-homocitrulline in the urine. L-homocitrulline is an L-lysine derivative that is L-lysine having a carbamoyl group at the N(6)-position. It is found in individuals with urea cycle disorders.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Decreased liver function
MedGen UID:
65430
Concept ID:
C0232744
Finding
Reduced ability of the liver to perform its functions.
Acute hepatitis
MedGen UID:
82759
Concept ID:
C0267797
Disease or Syndrome
Acute hepatic injury resulting from inflammation typically accompanied by increased serum alanine transaminase activity. Etiologies include viral hepatitis, drugs, toxins, and autoimmune disorders.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Protein avoidance
MedGen UID:
326521
Concept ID:
C1839531
Finding
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Spastic diplegia
MedGen UID:
44181
Concept ID:
C0023882
Disease or Syndrome
Spasticity (neuromuscular hypertonia) primarily in the muscles of the legs, hips, and pelvis.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Spastic gait
MedGen UID:
115907
Concept ID:
C0231687
Finding
Spasticity is manifested by increased stretch reflex which is intensified with movement velocity. This results in excessive and inappropriate muscle activation which can contribute to muscle hypertonia. Spastic gait is characterized by manifestations such as muscle hypertonia, stiff knee, and circumduction of the leg.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Dysdiadochokinesis
MedGen UID:
115975
Concept ID:
C0234979
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to perform rapidly alternating movements, such as pronating and supinating his or her hand on the dorsum of the other hand as rapidly as possible.
Scanning speech
MedGen UID:
116113
Concept ID:
C0240952
Mental or Behavioral Dysfunction
An abnormal pattern of speech in which the words are as if measured or scanned; there is a pause after every syllable, and the syllables themselves are pronounced slowly.
Truncal ataxia
MedGen UID:
96535
Concept ID:
C0427190
Sign or Symptom
Truncal ataxia is a sign of ataxia characterized by instability of the trunk. It usually occurs during sitting.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Poor coordination
MedGen UID:
107874
Concept ID:
C0563243
Finding
Impaired vibratory sensation
MedGen UID:
220959
Concept ID:
C1295585
Finding
A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient.
Acute encephalopathy
MedGen UID:
224930
Concept ID:
C1306587
Disease or Syndrome
A life-threatening disorder characterized by delirium, seizures, and neuromuscular changes.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Generalized myoclonic seizure
MedGen UID:
892704
Concept ID:
C4021759
Disease or Syndrome
A generalized myoclonic seizure is a type of generalized motor seizure characterized by bilateral, sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Specific learning disability
MedGen UID:
871302
Concept ID:
C4025790
Mental or Behavioral Dysfunction
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Hyperornithinemia
MedGen UID:
109343
Concept ID:
C0599035
Disease or Syndrome
Gyrate atrophy of the choroid and retina, which is often shortened to gyrate atrophy, is an inherited disorder characterized by progressive vision loss. People with this disorder have an ongoing loss of cells (atrophy) in the retina, which is the specialized light-sensitive tissue that lines the back of the eye, and in a nearby tissue layer called the choroid. During childhood, they begin experiencing nearsightedness (myopia), difficulty seeing in low light (night blindness), and loss of side (peripheral) vision. Over time, their field of vision continues to narrow, resulting in tunnel vision. Many people with gyrate atrophy also develop clouding of the lens of the eyes (cataracts). These progressive vision changes lead to blindness by about the age of 50.\n\nMost people with gyrate atrophy have no symptoms other than vision loss, but some have additional features of the disorder. Occasionally, newborns with gyrate atrophy develop excess ammonia in the blood (hyperammonemia), which may lead to poor feeding, vomiting, seizures, or coma. Neonatal hyperammonemia associated with gyrate atrophy generally responds quickly to treatment and does not recur after the newborn period.\n\nGyrate atrophy usually does not affect intelligence; however, abnormalities may be observed in brain imaging or other neurological testing. In some cases, mild to moderate intellectual disability is associated with gyrate atrophy.\n\nGyrate atrophy may also cause disturbances in the nerves connecting the brain and spinal cord to muscles and sensory cells (peripheral nervous system). In some people with the disorder these abnormalities lead to numbness, tingling, or pain in the hands or feet, while in others they are detectable only by electrical testing of the nerve impulses.\n\nIn some people with gyrate atrophy, a particular type of muscle fibers (type II fibers) break down over time. While this muscle abnormality usually causes no symptoms, it may result in mild weakness.
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.
Hypopigmentation of the fundus
MedGen UID:
101805
Concept ID:
C0151891
Disease or Syndrome
Reduced pigmentation of the fundus, typically generalized. Fundoscopy may reveal a low level pigment in both RPE and choroid with clear visibility of choroidal vessels (pale/albinoid) or low pigment level in the RPE with deep pigment in choroid so that visible choroidal vessels are separated by deeply pigmented zones (tesselated/tigroid).
Chorioretinal atrophy
MedGen UID:
884881
Concept ID:
C4048273
Disease or Syndrome
Atrophy of the choroid and retinal layers of the fundus.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHyperornithinemia-hyperammonemia-homocitrullinuria syndrome
Follow this link to review classifications for Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in Orphanet.

Professional guidelines

PubMed

Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C
J Inherit Metab Dis 2019 Nov;42(6):1192-1230. Epub 2019 May 15 doi: 10.1002/jimd.12100. PMID: 30982989

Recent clinical studies

Etiology

Silfverberg T, Sahlander F, Enlund M, Oscarson M, Hårdstedt M
J Med Case Rep 2018 Sep 23;12(1):274. doi: 10.1186/s13256-018-1794-9. PMID: 30243302Free PMC Article
Salvi S, Santorelli FM, Bertini E, Boldrini R, Meli C, Donati A, Burlina AB, Rizzo C, Di Capua M, Fariello G, Dionisi-Vici C
Neurology 2001 Sep 11;57(5):911-4. doi: 10.1212/wnl.57.5.911. PMID: 11552031
Hommes FA, Roesel RA, Metoki K, Hartlage PL, Dyken PR
Neuropediatrics 1986 Feb;17(1):48-52. doi: 10.1055/s-2008-1052499. PMID: 3960284

Diagnosis

Silvera-Ruiz SM, Gemperle C, Peano N, Olivero V, Becerra A, Häberle J, Gruppi A, Larovere LE, Motrich RD
Front Immunol 2022;13:861516. Epub 2022 May 27 doi: 10.3389/fimmu.2022.861516. PMID: 35711415Free PMC Article
Hoshino Y, Kodaira M, Matsuno A, Kaneko T, Fukuyama T, Takano K, Yazaki M, Sekijima Y
Intern Med 2022 Feb 15;61(4):553-557. Epub 2021 Aug 24 doi: 10.2169/internalmedicine.7843-21. PMID: 34433721Free PMC Article
Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C
J Inherit Metab Dis 2019 Nov;42(6):1192-1230. Epub 2019 May 15 doi: 10.1002/jimd.12100. PMID: 30982989
Ono H, Tamada T, Shigematsu Y
Pediatr Int 2018 Aug;60(8):762-764. Epub 2018 Jul 30 doi: 10.1111/ped.13608. PMID: 30058227
Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C
Orphanet J Rare Dis 2015 Mar 11;10:29. doi: 10.1186/s13023-015-0242-9. PMID: 25874378Free PMC Article

Therapy

Ono H, Tamada T, Shigematsu Y
Pediatr Int 2018 Aug;60(8):762-764. Epub 2018 Jul 30 doi: 10.1111/ped.13608. PMID: 30058227
Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK
J Neurol Sci 2008 Jan 15;264(1-2):187-94. Epub 2007 Sep 7 doi: 10.1016/j.jns.2007.08.003. PMID: 17825324
Nakajima M, Ishii S, Mito T, Takeshita K, Takashima S, Takakura H, Inoue I, Saheki T, Akiyoshi H, Ichihara K
Brain Dev 1988;10(3):181-5. doi: 10.1016/s0387-7604(88)80025-1. PMID: 3407856
Gordon BA, Gatfield DP, Haust MD
Clin Invest Med 1987 Jul;10(4):329-36. PMID: 3652557
Dionisi Vici C, Bachmann C, Gambarara M, Colombo JP, Sabetta G
Pediatr Res 1987 Sep;22(3):364-7. doi: 10.1203/00006450-198709000-00025. PMID: 3116497

Prognosis

Silfverberg T, Sahlander F, Enlund M, Oscarson M, Hårdstedt M
J Med Case Rep 2018 Sep 23;12(1):274. doi: 10.1186/s13256-018-1794-9. PMID: 30243302Free PMC Article
Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C
Orphanet J Rare Dis 2015 Mar 11;10:29. doi: 10.1186/s13023-015-0242-9. PMID: 25874378Free PMC Article
Hommes FA, Roesel RA, Metoki K, Hartlage PL, Dyken PR
Neuropediatrics 1986 Feb;17(1):48-52. doi: 10.1055/s-2008-1052499. PMID: 3960284

Clinical prediction guides

Rizkallah D, Daher RT, Haddad L, Karam PE
Metab Brain Dis 2024 Jun;39(5):909-913. Epub 2024 Jun 4 doi: 10.1007/s11011-024-01366-z. PMID: 38833093
Silvera-Ruiz SM, Gemperle C, Peano N, Olivero V, Becerra A, Häberle J, Gruppi A, Larovere LE, Motrich RD
Front Immunol 2022;13:861516. Epub 2022 May 27 doi: 10.3389/fimmu.2022.861516. PMID: 35711415Free PMC Article
Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Zanatta A, Viegas CM, Dutra-Filho CS, Wajner M
Int J Dev Neurosci 2009 Nov;27(7):635-41. Epub 2009 Aug 13 doi: 10.1016/j.ijdevneu.2009.08.004. PMID: 19683047
Gordon BA, Gatfield DP, Haust MD
Clin Invest Med 1987 Jul;10(4):329-36. PMID: 3652557

Recent systematic reviews

Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C
Orphanet J Rare Dis 2015 Mar 11;10:29. doi: 10.1186/s13023-015-0242-9. PMID: 25874378Free PMC Article

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