autosomal recessive hypercholesterolemia

Autosomal Recessive Hypercholesterolemia (ARH) is a rare genetic disorder characterized by very high levels of cholesterol in the blood, particularly low-density lipoprotein cholesterol (LDL-C). This condition presents with a clinical phenotype similar to that of classical homozygous familial hypercholesterolemia (FH), but it is caused by mutations in both alleles of the ARH gene.

ARH is a severe disease that can lead to premature atherosclerotic cardiovascular disease (ASCVD) due to the accumulation of cholesterol in the bloodstream. It is estimated to have a prevalence of less than 1:1,000,000, making it an extremely rare disorder.

The symptoms of ARH are similar to those of classical FH and include:

• Markedly elevated levels of LDL-C
• Premature ASCVD
• High risk of cardiovascular events

ARH is caused by homozygosity or compound heterozygosity for disruptive mutations in the ARH gene, which leads to impaired lipid metabolism. This results in the accumulation of cholesterol in the bloodstream, leading to the development of atherosclerosis and increased risk of cardiovascular disease.

It's worth noting that ARH is often misdiagnosed as classical FH due to its similar clinical presentation. However, genetic testing can confirm the diagnosis of ARH by identifying mutations in both alleles of the ARH gene.

References:

• [1] Autosomal recessive hypercholesterolemia (ARH) presents with a clinical phenotype similar to that of classical homozygous familial hypercholesterolemia (FH).
• [2] Autosomal recessive familial hypercholesterolemia (ARH) is a very rare lipid metabolic monogenic disorder characterized by markedly elevated levels of LDL-C.
• [3] Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD).
• [5] Autosomal recessive hypercholesterolemia (ARH) is a rare monogenic disease, with an estimated prevalence of less than 1:1 000 000.
• [6] Autosomal recessive familial hypercholesterolemia (ARH) is a very rare lipid metabolic monogenic disorder characterized by markedly elevated levels of LDL-C.

Autosomal recessive hypercholesterolemia (ARH) is a rare genetic disorder characterized by very high levels of cholesterol in the blood. The symptoms of ARH can vary from person to person, but here are some common signs and symptoms:

• High levels of total cholesterol and LDL cholesterol: Individuals with ARH have extremely high levels of low-density lipoprotein (LDL) cholesterol, which is often referred to as "bad" cholesterol.
• Fatty skin deposits (xanthomas): Xanthomas are yellowish or orange-colored patches that can appear on the hands, elbows, knees, ankles, and around the cornea of the eye. These deposits are made up of excess cholesterol and can be painful.
• Cholesterol deposits in the tendons: In some cases, individuals with ARH may develop xanthomas on their Achilles tendons or other tendons.
• Yellow discoloration around the eyes (xanthelasmata): A white ring or yellowish discoloration may appear around the colored part of the eye due to cholesterol deposits.

It's worth noting that symptoms of ARH can be similar to those of familial hypercholesterolemia, but they tend to be milder and less severe. However, if left untreated, ARH can lead to serious complications such as cardiovascular disease and stroke.

References:

• [1] Familial hypercholesterolemia (FH) ... Signs & Symptoms. Individuals with HoFH have ... Autosomal recessive FH is very rare. Parents ...
• [3] Jan 1, 2020 — Familial hypercholesterolemia is an inherited condition characterized by very high levels of cholesterol in the blood.
• [7] Symptoms of familial hypercholesterolemia · Yellow discoloration around your eyes · A white ring around the colored part of your eye · Cholesterol deposits in the ...
• [8] by Z Petrulioniene · 2019 · Cited by 8 — The earliest clinical sign, noticed at the age of 5 years, was painful and enlarging nodules on Achilles tendons. At the age of 10 years, xanthomas of the ...

Autosomal Recessive Hypercholesterolemia (ARH) is a rare genetic disorder characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C). Confirming a diagnosis of ARH allows for accurate recurrence risk information to be provided to relatives.

Diagnostic tests for ARH typically involve genetic testing, which can detect pathogenic variants in the LDLRAP1 gene. This gene encodes the LDLR adaptor protein 1, and biallelic pathogenic variants in this gene are associated with ARH [1].

Next-generation sequencing (NGS) is a common technique used to detect single nucleotide and copy number variants in genes associated with familial hypercholesterolemia (FH), including ARH. This test can identify variants in 12 genes, including LDLRAP1 [2][7].

In addition to genetic testing, clinical evaluation and family history are also important factors in diagnosing ARH. A diagnosis of ARH is often suspected when patients present with extremely high levels of LDL-C and xanthomas (fatty deposits under the skin) [15].

It's worth noting that genetic testing for ARH can be complex and should be performed by a qualified healthcare professional or genetic counselor. This test can provide accurate recurrence risk information to relatives, but it also requires careful interpretation of results.

References:

[1] Confirming a diagnosis of autosomal recessive hypercholesterolemia allows accurate diagnosis of this recessive form as well as the provision of accurate recurrence risk information to relatives. [2] This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 12 genes associated with familial hypercholesterolemia (FH) ... [7] This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 12 genes associated with familial hypercholesterolemia (FH) ... [15] Mutations in the LDLRAP1 gene inherited from both parents cause autosomal recessive hypercholesterolemia (ARH), an extremely rare disease.

Autosomal Recessive Hypercholesterolemia (ARH) is a rare genetic disorder characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C). The treatment for ARH typically involves a combination of lifestyle modifications and pharmacological interventions.

Pharmacological Treatment

According to a case study published in [6], the pharmacological treatment of a Sardinian patient affected by Autosomal Recessive Hypercholesterolemia involved the use of lomitapide. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP), which plays a crucial role in the assembly and secretion of VLDL and chylomicrons.

• The combination of lomitapide with conventional LDL-C-lowering medications appears to be a promising approach to treat this condition [1].
• In another study, a patient with ARH was treated with a combination of simvastatin and ezetimibe from the age of 5-10 years. Her lowest achieved LDL-C was 6.3 mmol/L (243.6 mg/dL) [9].

Other Treatment Options

In addition to pharmacological interventions, other treatment options for ARH may include:

• LDL apheresis: This is a procedure that involves the removal of LDL particles from the bloodstream.
• Liver transplantation: In severe cases of ARH, liver transplantation may be considered.

It's worth noting that the treatment of ARH can vary depending on individual factors and the severity of the condition. A healthcare professional should be consulted for personalized advice and guidance.

References:

[1] L D'Erasmo · 2020 · Cited by 40

[6] S Muntoni · 2015 · Cited by 14

Autosomal Recessive Hypercholesterolemia (ARH) is a rare genetic disorder characterized by very high levels of cholesterol in the blood. When diagnosing ARH, it's essential to consider differential diagnoses that can mimic its symptoms.

Differential Diagnoses:

• Familial Hypercholesterolemia (FH): A common inherited disorder caused by mutations in the APOB, LDLR, and PCSK9 genes. Like ARH, FH is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) [12].
• Sitosterolemia: An autosomal recessive hereditary disease that presents with skin and tendon xanthomas from a young age. It's diagnosed based on elevated blood levels of plant sterols, which can be similar to the lipid profile seen in ARH [11].
• Cholestatic liver disease: A condition where the liver is unable to properly remove bile from the body, leading to high cholesterol levels. This diagnosis should be considered when evaluating patients with suspected ARH [5].

Key Considerations:

When differentiating between these conditions, it's crucial to consider the following factors:

• Genetic inheritance pattern: ARH is inherited in an autosomal recessive manner, whereas FH and sitosterolemia are typically autosomal dominant.
• Lipid profile: While all three conditions present with high cholesterol levels, the specific lipid profile can help differentiate between them. For example, sitosterolemia often presents with normal or only mildly elevated LDL-C levels [11].
• Clinical presentation: The presence of skin and tendon xanthomas from a young age is more characteristic of sitosterolemia than ARH.

References:

[5] - Cholestatic liver disease can mimic the lipid profile seen in ARH, making it essential to consider this diagnosis when evaluating patients with suspected ARH. [11] - Sitosterolemia presents with skin and tendon xanthomas from a young age and is diagnosed based on elevated blood levels of plant sterols. [12] - Familial Hypercholesterolemia (FH) shares similarities with ARH in terms of lipid profile, but has distinct genetic and clinical characteristics.