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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome(HHHS; HHH)

MedGen UID:
82815
Concept ID:
C0268540
Disease or Syndrome
Synonyms: HHH syndrome; Ornithine translocase deficiency; Ornithine translocase deficiency syndrome
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: HPO
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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
SNOMED CT: HHH - Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (30287008); Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (30287008)
 
Gene (location): SLC25A15 (13q14.11)
OMIM®: 238970
Orphanet: ORPHA415

Disease characteristics

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is characterized by variable clinical presentation and age of onset. Neonatal onset (~12% of affected individuals). Infants are normal for the first 24-48 hours followed by onset of symptoms related to hyperammonemia (poor feeding, vomiting, lethargy, low temperature, rapid breathing). Information on long-term outcome is limited. Infancy, childhood, and adult presentation (~88%). 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 description

From GHR
Ornithine translocase deficiency is an inherited disorder that causes ammonia to 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. An infant with ornithine translocase deficiency may be lacking in energy (lethargic) or refuse to eat, or have poorly controlled breathing or body temperature. Some babies with this disorder may experience seizures or unusual body movements, or go into a coma. Episodes of illness may coincide with the introduction of high-protein formulas or solid foods into the diet.In most affected individuals, signs and symptoms of ornithine translocase deficiency do not appear until later in life. Later-onset forms of ornithine translocase deficiency are usually less severe than the infantile form. Some people with later-onset ornithine translocase deficiency 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 may lead to episodes of vomiting, lack of energy (lethargy), problems with coordination (ataxia), confusion, or blurred vision. Complications of ornithine translocase deficiency may include developmental delay, learning disabilities, and stiffness caused by abnormal tensing of the muscles (spasticity).  http://ghr.nlm.nih.gov/condition/ornithine-translocase-deficiency

Clinical features

Retinal depigmentation
MedGen UID:
101805
Concept ID:
C0151891
Pathologic Function
Decreased amount of pigmentation of the retina.
Chorioretinal atrophy
MedGen UID:
99273
Concept ID:
C0521683
Disease or Syndrome
Atrophy of the choroid and retinal layers of the fundus.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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
A coma is a deep state of unconsciousness. An individual in a coma is alive but unable to move or respond to his or her environment. Coma may occur as a complication of an underlying illness, or as a result of injuries, such as brain injury. A coma rarely lasts more than 2 to 4 weeks. The outcome for coma depends on the cause, severity, and site of the damage. People may come out of a coma with physical, intellectual, and psychological problems. Some people may remain in a coma for years or even decades. For those people, the most common cause of death is infection, such as pneumonia. NIH: National Institute of Neurological Disorders and Stroke.
Epilepsies, Myoclonic
MedGen UID:
4988
Concept ID:
C0014550
Disease or Syndrome
A clinically diverse group of epilepsy syndromes characterized either by myoclonic seizures or by myoclonus in association with other seizure types. Myoclonic epilepsy syndromes are divided into three subtypes based on etiology: familial, cryptogenic, and symptomatic (i.e., occurring secondary to known disease processes such as infections, hypoxic-ischemic injuries, trauma, etc.).
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
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.
Pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Brain atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
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
Decreased 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.
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.
Morphological abnormality of the pyramidal tract
MedGen UID:
866549
Concept ID:
C4020859
Disease or Syndrome
Any structural abnormality of the pyramidal tract, whose chief element, the corticospinal tract, is the only direct connection between the brain and the spinal cord. In addition to the corticospinal tract, the pyramidal system includes the corticobulbar, corticomesencephalic, and corticopontine tracts.
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.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
Abnormal liver function
MedGen UID:
39248
Concept ID:
C0086565
Pathologic Function
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Acute hepatitis
MedGen UID:
82759
Concept ID:
C0267797
Disease or Syndrome
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Protein avoidance
MedGen UID:
326521
Concept ID:
C1839531
Finding
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.
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.
Acute hepatitis
MedGen UID:
82759
Concept ID:
C0267797
Disease or Syndrome
Hyperammonaemia
MedGen UID:
113136
Concept ID:
C0220994
Pathologic Function
Elevated level of AMMONIA in the blood. It is a sign of defective CATABOLISM of AMINO ACIDS or ammonia to UREA.
Ornithine aminotransferase deficiency
MedGen UID:
109343
Concept ID:
C0599035
Disease or Syndrome
Gyrate atrophy of the choroid and retina due to deficiency of ornithine aminotransferase is clinically characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. Characteristic chorioretinal atrophy with progressive constriction of the visual fields leads to blindness at the latest during the sixth decade of life. Patients generally have normal intelligence (summary by Peltola et al., 2002). See 238970 for another hyperornithinemia syndrome.

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.

Recent clinical studies

Etiology

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. PMID: 11552031

Diagnosis

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. [Epub ahead of print] PMID: 25874378Free PMC Article
Kumar K, Agarwal A, Agarwal A, Dhawan A, Chandani N, Raj P
Retin Cases Brief Rep 2015 Spring;9(2):134-7. doi: 10.1097/ICB.0000000000000116. PMID: 25411929
Mhanni AA, Chan A, Collison M, Seifert B, Lehotay DC, Sokoro A, Huynh HQ, Greenberg CR
J Pediatr Gastroenterol Nutr 2008 Mar;46(3):312-5. doi: 10.1097/MPG.0b013e318145a8e5. PMID: 18376250
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. [Epub ahead of print] PMID: 17825324
Zammarchi E, Ciani F, Pasquini E, Buonocore G, Shih VE, Donati MA
J Pediatr 1997 Sep;131(3):440-3. PMID: 9329423

Therapy

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. [Epub ahead of print] PMID: 17825324
Zammarchi E, Ciani F, Pasquini E, Buonocore G, Shih VE, Donati MA
J Pediatr 1997 Sep;131(3):440-3. PMID: 9329423
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. 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

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. [Epub ahead of print] PMID: 25874378Free PMC Article

Clinical prediction guides

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. [Epub ahead of print] 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. [Epub ahead of print] PMID: 25874378Free PMC Article

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