Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.1
• Status (Pediatric): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: SLC25A15
• Condition: Ornithine translocase deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• SLC25A15 ⇔ 0009393 (ornithine translocase deficiency): Moderate Actionability

Actionability Rationale

The experts changed the preliminary assertion from limited to moderate given there is a treatment that could be implemented, but acknowledge additional evidence is needed on penetrance and long term outcomes among individuals diagnosed in adulthood.

Final Consensus Scores

Gene Condition Pairs: SLC25A15 ⇔ 0009393 (OMIM:238970)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity due to ornithine translocase deficiency / Surveillance by specialists to guide management, including diet, supplements, nitrogen scavengers, and emergency planning	2	0D	2C	2	6DC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Over 120 individuals with ornithine translocase (ORNT1) deficiency have been reported to date. In the US, the frequency of ORNT1 deficiency is less than 1 in 2,000,000 live births. Using two large longitudinal registries, an incidence for ORNT1 deficiency was calculated at 1% and 3% of all urea cycle disorders (UCDs) in the US and Europe, respectively.
Although ORNT1 deficiency can be considered a very rare condition with a panethnic distribution, it has been more frequently reported in three countries: Canada (French Canadian), Italy, and Japan. [1, 2]

Clinical Features

Most symptoms of ORNT1 deficiency, also known as hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome, are like those seen in all other UCDs. However, ORNT1 deficiency has additional unique clinical features including hyperreflexia and other pyramidal signs that precede spastic paraparesis. Liver dysfunction and coagulopathy are also more commonly observed than in other UCDs. Clinical manifestations are variable but can present as chronic neurocognitive deficits including developmental and speech delay, ataxia, spasticity, learning disabilities, cognitive deficits and/or unexplained seizures. Individuals can also present with acute encephalopathy secondary to hyperammonemic crisis which can manifest as lethargy, decreased appetite, nausea, vomiting, increased respiratory rate and seizures. Chronic liver dysfunction can be seen with or without mild coagulopathy and with or without mild hyperammonemia. Individuals diagnosed in adolescence/adulthood may present with recurrent encephalopathy secondary to hyperammonemia (lethargy, disorientation, episodic confusion, unexplained seizures), intellectual disabilities, recurrent vomiting, chronic behavioral problems, cerebellar signs (dizziness, loss of balance, poor coordination, abnormal gait/posture), and pyramidal track dysfunction (inability to perform fine movements, positive Babinski reflex, muscle weakness, ataxia, hyperreflexia, and spasticity). Hyperammonemia can cause brain damage visualized on MRI including multiple supratentorial stroke-like lesions, demyelination, cortical or subtentorial atrophy, and/or calcifications/lesions of the basal ganglia. Ophthalmological signs are rare, with few individuals showing signs of severe retinal degeneration. [1, 2, 3, 4, 5, 6]

Natural History

Disease onset usually ranges from early infancy to childhood and, in rarer cases, adulthood. Approximately 8% of affected individuals have neonatal onset and 70% manifest in infancy and childhood. Onset in adolescence/adulthood (>12 years) accounts for about one third of individuals with ORNT1 deficiency. Aside from the severe neonatal form, there is no evidence of a direct correlation between age of onset, which is variable, and disease severity.
Decompensation is often triggered by metabolic stress such as intercurrent illness, fasting, diarrhea or vomiting, surgery, infection, medication, and any protein loading. Mild encephalopathy may resolve spontaneously without treatment or quickly normalize with treatments that include glucose. Although infrequent, acute or chronic liver failure has been reported as the presenting manifestation in ORNT1 deficiency. Progressive spastic diplegia or quadriplegia starts in childhood. Pyramidal tract findings and intellectual disability, which range from mild to severe, are generally evident by childhood, but pyramidal signs of the lower extremities may develop years after the initial diagnosis. Late onset cases present with hyperammonemia accompanied by lethargy and/or coma and signs of severe liver dysfunction and/or life-threatening episodes of acute liver failure.
Early intervention allows almost normal life span, but the prognosis is highly variable ranging from mild neurological involvement to a severely disabling disease. Despite early metabolic control that prevents hyperammonemia, neurologic and cognitive deterioration can continue. Even in the absence of hyperammonemic episodes, affected individuals may continue to develop neurologic complications such as spasticity or learning disabilities. [1, 2, 4, 5, 6, 7, 8]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs of an individual with newly diagnosed ORNT1 deficiency the following evaluations are recommended:
•Measurement of height, weight, and head circumference
•Assess cerebellar motor function (e.g., ataxia, tremor, nystagmus)
•Assess spasticity
•Refer to neuromuscular clinic to assess gross motor and fine motor skills, ambulation, and need for adaptive devices and physical therapy
•EEG if seizures are suspected
•Baseline MRI/MRS in individuals with significant neurologic impairment
•Developmental assessment to include speech/language evaluation, general cognitive and vocational skills
•Assess for skeletal involvement related to spasticity
•Neuropsychiatric evaluation in individuals over 12 months to screen for behavioral problems including sleep disturbances, ADHD, and anxiety
•Evaluate for evidence of hepatic dysfunction with biochemical profile and ultrasound
•Consultation with a clinical or metabolic geneticist, genetic counselor and/or social worker (Tier 4) [1]

Long-term management aims to maintain stable metabolic control, to reduce chronic complications, and to achieve as close to normal development and growth as possible. A low protein diet and citrulline or arginine supplementation is recommended, which prevents hyperammonemia and liver disease but the impact of these measures on pyramidal dysfunction is unclear. Optimal protein intake must be determined by individual titration in every individual. If protein tolerance is very low, essential amino acids have to be supplemented. Vitamin and trace element supplementation may also be required. A specialist metabolic dietitian should be involved. (Tier 2) [3]

Nitrogen scavengers (sodium benzoate, sodium phenylbutyrate [PBA] or sodium phenylacetate, glycerol phenylbutyrate) are a mainstay of therapy in individuals with a UCD. Individualized dosing is recommended. (Tier 2) [3]

Since secondary creatine deficiency has been reported, creatine supplementation can be used in individuals with low plasma creatine levels. (Tier 2) [9]

Since hyperammonemia responds quickly to treatment, early diagnosis leads to an overall improved long-term outcome regardless of the age of onset. The long-term neurodevelopmental outcome usually (but not always) correlates with the severity and duration of the hyperammonemic insult. (Tier 4) [1]

A cohort of 16 individuals with ORNT1 deficiency, ranging from age 3 months to 16 years at diagnosis, were treated by protein restriction and sodium benzoate. Age at last follow-up ranged from 5 to 40 years. The three oldest individuals never followed any diet and had very poor compliance with treatment. Three individuals received arginine supplementation, but this was stopped after several months because of hyperargininemia. All individuals had normal growth. No individual experienced hyperammonemic coma under treatment, and post-feeding ammonia concentrations were usually normal. Only three (18%) had recurrent episodes of mild hyperammonemia. Usually, liver dysfunction normalized over a few weeks after starting treatment. Seven individuals (44%) experienced recurrent episodes of asymptomatic elevated transaminases lasting up to three months. Mild coagulopathy occurred frequently during these episodes. No individual had any sign of chronic liver disease. During follow-up all individuals presented signs of pyramidal tract involvement with a marked predominance in the lower limbs: hyper-reflexia (15/16), clonus (11/16), tip-toe gait and spasticity (12/14). There were 8/16 (50%) individuals with obvious spastic paraparesis. Four individuals had intellectual disability. However, 13/15 (86%) experienced learning problems, and none completed regular secondary school. Only one adult individual was living completely autonomous and self-sufficient. (Tier 3) [1, 6]

Despite early detection and adequate metabolic control (i.e., absence of hyperammonemia), some individuals continue to worsen neurologically with pyramidal tract involvement and cognitive decline. Maintaining as low a level of plasma ornithine as possible by restricting protein intake could help prevent some of the progressive neurologic complications. In one study of four adults with ORNT1 deficiency (ages 29 to 57) who maintained normal levels of plasma ammonia for 11 to 38 years, all showed serious neurologic outcomes. Three exhibited progressive neurologic and cognitive deterioration. (Tier 3) [1, 2]

Prompt diagnosis and intervention of acute hyperammonemia is vital for a good outcome. The family should be taught to recognize the symptoms and signs to initiate treatment at earliest possible stage. An emergency regimen for treatment of intercurrent illness is recommended. A management plan should be provided to parents, caregivers, nursery, and school. The treatment of hyperammonemia is based on clinical status, with particular attention to any degree of encephalopathy, and should be started without delay. If the individual is not well or at risk of illness, emergency treatment could be initiated at home followed by hospital admission, if needed. Acute treatment also includes high glucose perfusion (with withdrawal of proteins and lipids) and administration of intravenous nitrogen scavengers to promote waste nitrogen excretion, L-arginine (or L-citrulline), essential nutrients, and essential amino acids. Any infection or constipation (which increases ammonia absorption from the gut), should be treated. Regular monitoring should include blood pH and gases, ammonia, urea and electrolytes, and glucose. If there is any hint of encephalopathy, neurological observations should be done at least hourly. Individual should be transferred to a specialist center without delay. In adults, hemodialysis or continuous renal replacement therapy is the first-line therapy in case of acute hyperammonemia. (Tier 2) [7, 8, 9]

Given the risk of acute metabolic decompensation during surgery and general anesthesia, elective surgery should only be carried out in centers able and prepared to deal with hyperammonemic decompensations. The individual should be well, with normal preoperative ammonia and amino acid concentrations and without even minor intercurrent illness. Postsurgical close monitoring of the clinical status and ammonia is required. (Tier 2) [3]

Successful pregnancies in individuals with UCDs require addressing the special nutritional needs of pregnancy and lactation, avoiding undernutrition of protein. Close monitoring during and early after delivery is essential to recognize hyperammonemia within the first 5 days after delivery. Continuation of treatment with nitrogen scavengers is generally necessary. The use of sodium benzoate is recommended. (Tier 2) [3]

Delivery by cesarean section is recommended to optimize metabolic control. (Tier 4) [1]

Surveillance

Monitoring should include the following:
•Record growth and head circumference; inspect for thin, sparce hair or hair loss, skin rashes, or other signs of protein/vitamin deficiency
•Brain MRI, even in the absence of neurological and/or cognitive impairment, at 2-year intervals (if individuals do not require anesthesia)
•Neurological and neurocognitive assessments should be performed at regular intervals even in individuals with milder presentation
•Liver size and structure should be assessed by ultrasound scan
•Regular dietary assessment, including review of supplementations
•Monitor plasma ammonia and amino acid profile as well as vitamin, mineral, trace elements, carnitine, creatine, ferritin, cholesterol, triglyceride, alpha-fetoprotein, and essential fatty acid levels
•Psychological monitoring and counseling to address health-related quality of life, anxiety, stress, and psychosocial factors. (Tier 2) [3]

Circumstances to Avoid

Excess dietary protein intake, nonprescribed protein supplements such as those used to increase size of skeletal muscle during exercise regimens, prolonged fasting during an illness or weight loss, oral and intravenous steroids, and valproic acid should be avoided. (Tier 4) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 6]

Prevalence of Genetic Variants

No genetic variant prevalence information has been provided for the Adult context.

Penetrance

A summary of clinical findings in 122 individuals with ORNT1 deficiency reported the following:
Lethargy 62% (52/84)
Significant elevation of liver transaminases 52% (44/84)
Coagulopathy 49% (34/69)
Coma 33% (33/101)
Pyramidal signs 75% (71/95)
Intellectual disability 66% (63/91)
Myoclonic seizures 34% (31/91) (Tier 3) [1]

Individuals with ORNT1 deficiency with limited clinical manifestations throughout life have been reported. (Tier 3) [1]

Relative Risk

No information on relative risk was found.

Expressivity

Individuals with ORNT1 deficiency present with a variable clinical spectrum, ranging from a chronic mild form with aversion for protein-rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction, to a more severe acute form with intermittent episodes of vomiting, confusion or coma, acute liver failure or hepatitis-like attacks. Cognitive development ranges from normal (34%) to severe impairment (34%), with the majority having normal to mild neurocognitive deficit (59%). Some affected individuals have significant neurologic findings such as spasticity and ataxia without cognitive impairment. Genetic analysis does not have a prognostic value, since even in the same family and with the same variant, the phenotype can be quite variable. (Tier 3) [1, 2]

4. What is the Nature of the Intervention?

Nature of Intervention

Individuals with UCDs require lifelong monitoring by a multidisciplinary team. Long-term treatment of UCDs is challenging for individuals and families because of the poor palatability (particularly of essential amino acids), the volume and frequency of diet and drug administrations. Over-restriction of protein may compromise growth and well-being and can cause metabolic instability. The low protein diet also places individuals with a UCD at risk of Fe, Zn, Cu, Ca, and cobalamin deficiencies. Individuals following a low protein diet may have an increased risk for osteoporosis. Nasogastric tube or gastrostomy feeding may be necessary to ensure sufficient energy and/or protein intake. Nitrogen scavengers may be administered orally as a powder, granules, capsules, tablets, or liquid. There are fewer side effects and fewer safety concerns with sodium benzoate. Sodium PBA causes amenorrhea or menstrual dysfunction in ~25% of females. It can also decrease appetite, cause taste disturbances, result in a disagreeable body odor, and can deplete branch chain amino acids which increases the risk of endogenous protein catabolism. Sodium benzoate and sodium phenylbutyrate can cause mucositis or gastritis and therefore must be taken with meals and abundant fluids. Hypokalemia can occur during long-term treatment with glycerol phenylbutyrate. Metabolic acidosis has been observed with high doses of nitrogen scavengers. [3]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Symptoms of UCDs are nonspecific. Some individuals may show an incomplete biochemical phenotype and a lower degree of hyperammonemia compared with other UCDs. Although the onset of symptoms is in most cases in infancy and childhood, the diagnosis is often delayed. Mild encephalopathy manifesting as disorientation, irritability, and episodic confusion with mild hyperammonemia is difficult to detect as it may resolve spontaneously without treatment or quickly normalize with IV solutions that include glucose. (Tier 3) [1, 2, 3]

Some individuals with ORNT1 deficiency learn to self-restrict their protein intake to avoid the malaise and vomiting that accompanies protein-rich meals. These individuals with the milder form and self-adherence to a low-protein diet can lead a relatively symptom-free life and remain undetected until ammonia overload occurs from catabolic events (i.e., surgery). (Tier 4) [1]

Date of Search: 02.12.2024

Reference List

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2. Martinelli D, Fiermonte G, Häberle J, Boenzi S, Goffredo BM, Travaglini L, Agolini E, Porcelli V, Dionisi-Vici C. CUGC for hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. Eur J Hum Genet. (2020) 28(1476-5438):982-987.

3. 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. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. (2019) 42(1573-2665):1192-1230.

4. Ah Mew N, Simpson KL, Gropman AL, Lanpher BC, Chapman KA, Summar ML. Urea Cycle Disorders Overview. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews((R)). Seattle (WA). (1993) Website: https://www.ncbi.nlm.nih.gov/pubmed/20301396

5. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=415

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. HYPERORNITHINEMIA-HYPERAMMONEMIA-HOMOCITRULLINURIA SYNDROME; HHHS. MIM: 238970: 2020 Mar 11. World Wide Web URL: http://omim.org.

7. BIMDG. HHH Syndrome. British Inherited Metabolic Disease Group. (2017) Website: https://www.bimdg.org.uk/store/guidelines/ER-HHH-LPI-v5_221725_15042017.pdf

8. BIMDG. Adult Emergency Management HHH Syndrome. British Inherited Metabolic Disease Group. (2018) Website: https://www.bimdg.org.uk/store/guidelines/ADULT_HHH_2018_549653_15072018.pdf

9. Haberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. (2012) 7:32.