primary hyperoxaluria type 1

Primary Hyperoxaluria Type 1 (PH1) Description

Primary hyperoxaluria type 1 (PH1) is a rare and serious genetic disorder that affects the kidneys, bladder, or urinary tract. It is characterized by an excessive accumulation of oxalate in the body, which can lead to kidney stones, nephrocalcinosis, and ultimately renal failure.

Key Features:

• Rare condition: PH1 affects only 1-3 people per million population.
• Genetic disorder: PH1 is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition.
• Oxalate accumulation: The liver enzyme AGT, which converts glyoxylate to glycine, is deficient or absent in people with PH1. This leads to an excessive buildup of oxalate in the body.
• Kidney stones and damage: The accumulated oxalate can form insoluble calcium oxalate crystals that cause kidney stones, nephrocalcinosis, and ultimately renal failure.

Causes and Risk Factors:

• Genetic mutation: PH1 is caused by mutations in the AGXT gene, which codes for the liver enzyme AGT.
• Inheritance: PH1 is inherited from parents who are carriers of the mutated gene.
• Age of onset: The condition can manifest at any age, but it often becomes apparent during childhood or adolescence.

References:

• [2] Primary hyperoxaluria type 1 (PH1) is a rare disorder that mainly affects the kidneys. It results from buildup of a substance called oxalate, which normally is filtered through the kidneys and excreted in the urine.
• [4] by DS Milliner · 2022 · Cited by 77 — Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver enzyme AGT, which converts glyoxylate to glycine.
• [10] Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate (PLP)-dependent enzyme involved in the metabolism of glyoxylate.
• [12] Primary hyperoxaluria type 1 (PH1) is a rare genetic form of calcium oxalate kidney stone disease. It is caused by a deficiency in the liver-specific enzyme, alanine:glyoxylate aminotransferase (AGT), a pyridoxal-5′-phosphate (PLP)-dependent enzyme involved in the metabolism of glyoxylate.

Primary hyperoxaluria type 1 (PH1) is a rare disorder that mainly affects the kidneys, and its signs and symptoms can vary in severity from person to person.

Common Warning Signs:

• Kidney stones are the most common symptom of PH1, and they often form early in life, typically before age 20 [7][8].
• Recurring kidney stones can be a sign of PH1, especially if they occur frequently or at a young age.
• Other symptoms may include:
  • Flank pain (pain in the side of the body)
  • Dysuria (painful urination)
  • Hematuria (blood in the urine)
  • Urinary tract infections (UTIs)

Age-Related Symptoms:

• Symptoms can develop anytime from infancy to adulthood, with an average age of 5 years old [5].
• Infants and young children may experience kidney stones or other symptoms early on.
• Older children and adults may also experience recurring kidney stones or other symptoms.

Kidney Function Decline:

• The kidneys of many people with PH1 stop working well by early to middle adulthood, but kidney failure can occur even in babies [3].
• Some individuals may never experience kidney failure, while others may have a gradual decline in kidney function over time.

It's essential to note that the severity and progression of symptoms can vary significantly from person to person. If you suspect you or someone else has PH1, consult with a healthcare professional for proper diagnosis and treatment.

Diagnostic Tests for Primary Hyperoxaluria Type 1

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that can be challenging to diagnose. However, several diagnostic tests can help confirm the condition.

• Molecular Genetic Test: A molecular genetic test can detect the AGXT gene mutation responsible for PH1, confirming the diagnosis [1].
• 24-HOUR URINE TEST: This test measures the level of oxalate in the urine and is a critical component of diagnosing PH1. Normal levels are <45 mg (<0.50 mmol) /1.73 m^2 /24 hours [2].
• DNA Testing: DNA testing can identify the gene changes that cause PH1, providing a definitive diagnosis.
• Kidney Biopsy: A kidney biopsy can check for the buildup of oxalate in the kidneys and is often used to confirm the diagnosis.
• Echocardiogram: An echocardiogram can detect oxalate deposits in the heart.
• Eye Exam: An eye exam can identify oxalate deposits in the eyes.
• Bone Marrow Biopsy: A bone marrow biopsy can check for the buildup of oxalate in the bones.

These diagnostic tests are essential for confirming PH1 and developing an effective treatment plan. Early diagnosis is critical, given the progressive nature of PH1 [3].

References: [1] Context 2 [2] Context 2 [3] Context 2

Treatment Options for Primary Hyperoxaluria Type 1 (PH1)

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by excessive oxalate production, leading to kidney stones and potential kidney damage. While there is no cure for PH1, various treatment options are available to manage the condition.

Supportive Treatment

• High fluid intake: Drinking plenty of water helps to dilute the concentration of oxalate in the urine, reducing the risk of stone formation [1].
• Crystallization inhibitors: Medications such as pyridoxine (vitamin B6) may be prescribed to help prevent kidney stones by inhibiting crystallization [6].

Specific Drug Treatment

• Lumasiran (Oxlumo): This is a first-in-class RNA interference therapeutic agent that targets glycolate oxidase, reducing hepatic oxalate production. It was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration [5], [7].
• Nedosiran: Another investigational RNAi therapeutic agent targeting hepatic lactate dehydrogenase (LDHa), which has shown promise in reducing oxalate production [3].

Other Considerations

• Early diagnosis and treatment are crucial to prevent long-term complications. Patients with PH1 should work closely with their healthcare providers to develop a personalized treatment plan.
• Regular monitoring of kidney function, urine output, and stone formation is essential to adjust treatment strategies as needed.

References:

[1] Gupta A (2022) Supportive treatment for primary hyperoxaluria type 1 (PH1) focuses on high fluid intake and crystallization inhibitors. [Context #1]

[3] Dejban P (2022) Available evidence supports the efficacy of both Lumasiran (targeting glycolate oxidase) and Nedosiran (targeting hepatic lactate dehydrogenase (LDHa)) to reduce oxalate production. [Context #3]

[5] FDA Approval (2020) Oxlumo (lumasiran) approved for the treatment of primary hyperoxaluria type 1 (PH1). [Context #5]

[6] General Guidelines (2024) Everyone living with PH1 should try pyridoxine (vitamin B6) when they are first diagnosed for at least 3 months to see if it helps. However, it does not always work. [Context #6]

[7] Bacchetta J (2022) Lumasiran was approved for the treatment of PH1 in 2020 by both the European Medicines Agency and the Food and Drug Administration, whilst also being investigated as a potential treatment for other conditions. [Context #7]

Note: The information provided is based on the search results within the context block.

Differential Diagnosis of Primary Hyperoxaluria Type 1 (PH1)

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder that requires a comprehensive differential diagnosis to rule out other conditions. The following are the key considerations for differentiating PH1 from other causes:

• Other monogenic causes of stone diseases: PH1 should be considered in the differential diagnosis of patients with recurrent kidney stones, particularly those with a family history or known mutations in the AGXT gene.
• Calcium oxalate stone disease of unknown cause (idiopathic calcium oxalate nephrolithiasis): PH1 can be distinguished from idiopathic calcium oxalate nephrolithiasis by the presence of systemic symptoms, such as kidney failure and end-stage renal disease (ESRD).
• Hypercalciuria and hypocitraturia: These conditions can also cause recurrent kidney stones, but they are not directly related to PH1.
• Cystinuria: This is another rare genetic disorder that can cause kidney stones, but it is caused by mutations in the SLC3A1 or SLC7A9 genes.

Key Diagnostic Features

To diagnose PH1, clinicians should look for the following features:

• High levels of oxalate in urine: Elevated urinary oxalate levels are a hallmark of PH1.
• Kidney failure and ESRD: PH1 can lead to progressive kidney damage and eventual ESRD if left untreated.
• Recurrent kidney stones: Patients with PH1 often experience recurrent episodes of nephrolithiasis.

Genetic Testing

The definitive diagnosis of PH1 is achieved through molecular genetic testing, which can identify mutations in the AGXT gene. This test is essential for confirming the diagnosis and ruling out other causes of stone disease.

References:

• [3] Clinical characteristics: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder resulting in the overproduction of plasma oxalate.
• [10] The differential diagnosis should include conditions that lead to nephrolithiasis, specifically calcium oxalate stones and excess deposition in tissues leading to nephrocalcinosis.
• [11] Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive metabolic disorder resulting in the overproduction of plasma oxalate.
• [13] PH1 should be strongly considered in the differential in any patient with renal failure of unknown etiology, particularly when there is nephrocalcinosis with reduced renal function or a high occurrence of renal stones.