OVERVIEW

What is HHH syndrome?

HHH syndrome, also known as hyperornithinemia-hyperammonemia-homocitrullinuria syndrome or ornithine translocase deficiency, is a type of autosomal recessive genetic disorder caused by gene mutations. It primarily leads to neurological and liver damage.

Symptoms often appear during infancy or childhood and may include learning difficulties, vomiting, impaired consciousness, seizures, lethargy, and coma. Without timely treatment, it can be fatal.

HHH syndrome has no cure, and treatment focuses on symptom relief, including medication, dietary therapy, hemodialysis, and liver transplantation. The quality of life for severely affected patients is significantly compromised.

Is HHH syndrome common?

It is extremely rare and is listed in China's First Catalog of Rare Diseases. Data shows only slightly over 100 cases have been reported worldwide, with limited research available domestically.

Which age group is most commonly affected by HHH syndrome?

It can occur at any age, but 80% of cases are observed in newborns, infants, and children.

SYMPTOMS

What are the manifestations of HHH syndrome?

This disease primarily causes neurological and liver damage.

• Approximately 12% of patients may exhibit symptoms during the neonatal period. Within the first 1–2 days after birth, there are no obvious symptoms, but subsequently, symptoms such as lethargy, refusal to eat, vomiting, and seizures may appear.

• About 88% of patients experience a later onset, with 40% developing symptoms before the age of 3, 29% during childhood, and 19% in adulthood. The main manifestations include developmental delays, learning disabilities, spasms (commonly known as "cramps"), epilepsy, acute encephalopathy (which may occur with worsening hyperammonemia, presenting as headaches, confusion, etc.), persistently elevated liver enzymes, inability to stop bleeding spontaneously after injury (coagulation dysfunction), and difficulty digesting proteins. In severe cases, liver failure, cerebral edema, or even death may occur.

CAUSES

What is the cause of HHH syndrome?

The primary cause of HHH syndrome is a mutation in the SLC25A15 gene, which encodes the mitochondrial ornithine transporter. This leads to the accumulation of ornithine in the cytoplasm, disrupts the hepatic urea cycle, and results in a series of clinical symptoms.

Is HHH syndrome hereditary? How is it inherited?

Yes, it is an autosomal recessive genetic disorder. The inheritance pattern of this disease is characterized as follows:

• If a patient marries someone with a normal genotype, all their children will be unaffected;

• If a patient marries a normal individual who is a heterozygous carrier, there is a 50% chance their child will inherit the disease;

• If two affected individuals marry, 100% of their children will inherit the disease, with equal probability for both genders.

DIAGNOSIS

How is HHH Syndrome Diagnosed?

When diagnosing HHH syndrome, doctors primarily consider whether the infant or child has a family history of the disease, as well as symptoms such as vomiting, refusal to eat, coma, abnormal liver function, hepatomegaly, and intellectual disabilities. Parents should closely monitor these signs in their child's daily life.

What Tests Are Needed for HHH Syndrome Patients?

• Laboratory Tests: Elevated blood ammonia, ornithine, and urinary homocitrulline levels, along with increased plasma glutamine, urea cycle intermediates, and orotic acid. Some patients may show elevated urinary organic acids and abnormal coagulation function.

• Imaging Tests: Brain abnormalities such as atrophy, white matter changes, subdural hemorrhage, internal capsule lesions, calcification, or diffuse cerebral edema may be observed in CT or MRI scans.

• Neurophysiological Tests: Some patients may have peripheral nerve damage, abnormal evoked potentials in the lower limbs, or abnormal nerve conduction velocity in electromyography.

• Genetic Analysis: Detection of SLC25A15 gene mutations and assessment of mitochondrial C-ornithine transport capacity in skin fibroblasts are key methods for confirming the diagnosis.

Which Diseases Can HHH Syndrome Be Easily Confused With?

HHH syndrome should be differentiated from ornithine aminotransferase deficiency (causing hyperornithinemia), other inherited metabolic disorders affecting the urea cycle, lysinuric protein intolerance (causing homocitrullinuria), as well as hyperinsulinism-hyperammonemia syndrome and pyruvate carboxylase deficiency.

Genetic analysis is crucial for differential diagnosis.

TREATMENT

Which department should HHH syndrome patients visit?

For childhood-onset cases, visit neonatology or pediatrics; for adult-onset cases, visit neurology.

What are the treatment methods for HHH syndrome?

• Correcting hyperammonemia: Intravenous glucose to address hyperammonemia. Severe cases may require hemodialysis for rapid ammonia reduction to protect the brain and liver.

• Promoting ammonia bypass metabolism: Use ammonia scavengers like sodium phenylbutyrate, sodium phenylacetate, and sodium benzoate to facilitate urinary excretion of endogenous ammonia.

• Dietary control: Restrict natural protein intake while providing energy through carbohydrates and fats, ensuring other nutrient supply. Supplement with citrulline or arginine to enhance ammonia excretion.

• Liver transplantation: An effective treatment to improve urea cycle function and quality of life.

Can HHH syndrome be completely cured?

As a genetic disorder, it cannot be fully cured; treatment focuses on symptom management.

Can HHH syndrome cause death?

Yes, timely and effective treatment is crucial.

What is the final outcome for HHH syndrome patients?

The progression and outcome depend on age of onset, disease severity, and treatment timing. Earlier onset correlates with poorer prognosis.

Early liver transplantation can significantly improve quality of life.

DIET & LIFESTYLE

What should patients with HHH syndrome pay attention to in their diet?

Since HHH syndrome is caused by a genetic defect leading to impaired urea cycle function in the liver, dietary protein intake should be restricted. Energy should primarily come from carbohydrates and fats, while ensuring supplementation of other essential amino acids such as citrulline and arginine. Specific dietary adjustments should be discussed with a nutritionist.

What lifestyle precautions should be taken for HHH syndrome?

Maintain a positive mindset and healthy habits, avoid infections and overexertion, and pursue active treatment. For severely ill patients, enhanced care is necessary, including regular repositioning and back patting, as well as providing palliative care when needed.

Does HHH syndrome affect fertility?

HHH syndrome does not cause infertility. However, as it is a genetic disorder, genetic counseling and prenatal diagnosis are essential before conception to ensure healthy reproduction and prevent the disease in newborns.

PREVENTION

Can HHH syndrome be prevented?

HHH syndrome is a genetic disorder. Genetic counseling and prenatal diagnosis can help prevent the birth of potentially affected newborns, achieving the goal of eugenics.

How can patients with HHH syndrome prevent severe complications?

Patients should be closely monitored for disease progression, with early detection and treatment. They should also seek standardized treatment at reputable hospitals.