obsolete mannosidase deficiency disease

Mannosidase Deficiency Disease

Mannosidase deficiency disease, also known as mannosidosis, is a rare genetic disorder characterized by the deficiency of the enzyme mannosidase. This enzyme plays a crucial role in breaking down certain sugars in the body.

• Definition: Mannosidase deficiency disease is an autosomal recessive lysosomal storage disorder caused by mutations affecting the alpha-mannosidase lysosomal enzyme, resulting in its deficiency [7][8].
• Symptoms: The symptoms of mannosidase deficiency disease vary but often include:
  • Intellectual disability
  • Hearing loss
  • Ataxia (loss of coordination)
  • Skeletal abnormalities
  • Coarse facial features
  • Weakened immune system
  • Cerebellar disorders [6][12]
• Progression: The disease is progressive, meaning that the symptoms worsen over time. In some cases, it can lead to severe and life-threatening complications if left untreated [9].
• Prevalence: Mannosidase deficiency disease is a rare condition, affecting approximately 1 in 500,000 live births [1].

It's essential to note that mannosidase deficiency disease is an obsolete term, and the current preferred name for this condition is alpha-mannosidosis.

Overview of Obsolete Mannosidase Deficiency Disease

Obsolete mannosidase deficiency disease, also known as alpha-mannosidosis or beta-mannosidosis, is a rare genetic disorder characterized by a deficiency of the enzyme alpha-D-mannosidase or beta-mannosidase. This enzyme deficiency leads to progressive accumulation of oligosaccharides, resulting in various clinical features.

Clinical Features

• Intellectual Disability: Individuals with obsolete mannosidase deficiency disease often exhibit intellectual disability, ranging from mild to severe [10].
• Hearing Loss: Hearing loss is a common symptom, affecting both children and adults [2], [6], [8].
• Ataxia: Ataxia, or coordination and balance problems, are also characteristic of this disorder [1], [13].
• Skeletal Abnormalities: Skeletal abnormalities, such as dysostosis multiplex, are a hallmark of obsolete mannosidase deficiency disease [2], [12].
• Coarse Facial Features: Coarse facial features, including a prominent forehead and nose, are often observed in individuals with this disorder [13].

Other Symptoms

• Recurrent Respiratory Infections: Recurrent respiratory infections, such as pneumonia and bronchitis, are common due to impaired immune function [10].
• Muscle Weakness: Muscle weakness and wasting can occur, particularly in the lower limbs [7], [14].
• Visual Impairment: Visual impairment, including blindness, has been reported in some cases [4].

Progression of Symptoms

The progression of symptoms varies widely among affected individuals. In some cases, symptoms may appear in infancy or early childhood, while others may not manifest until adulthood [11]. The severity and progression of the disease also vary, with some individuals experiencing a slowly progressive course (mild form) and others experiencing a rapidly progressive and potentially life-threatening course (severe form) [12].

References

[1] Oct 11, 2001 — Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." Muscular hypotonia is also common.

[2] Jun 13, 2024 — The main clinical features in alpha-mannosidosis – intellectual disability, ataxia, coarse face, and dysostosis multiplex – may overlap with those of beta-mannosidosis.

[3] by M Beck · 2013 · Cited by 72 — Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation.

[4] Feb 17, 2023 — Symptoms of alpha

Diagnostic Tests for Alpha-Mannosidosis

Alpha-mannosidosis is a rare genetic disorder caused by the deficiency of the enzyme alpha-mannosidase. Accurate diagnosis is crucial to differentiate it from other lysosomal storage disorders and provide appropriate treatment.

• Enzyme Activity Measurement: The most common diagnostic test for alpha-mannosidosis is measuring the activity of the alpha-mannosidase enzyme in plasma, isolated leukocytes, or cultured cells [1]. This test can confirm the deficiency of the enzyme.
• Genetic Testing: Molecular genetic testing can also confirm the diagnosis by identifying mutations in the MAN2B1 gene [7][11].
• Urine Oligosaccharide Screening: An initial diagnostic workup may include a screening assay for several oligosaccharides in urine, which can be suggestive of alpha-mannosidosis if positive [10].

Other Diagnostic Methods

• Functional Testing: Oligosaccharide levels have been correlated with functional testing and may serve as biomarkers of disease severity, progression, and response to treatment [2][6].
• Leukocyte or Fibroblast Enzyme Activity: Deficiency in alpha-mannosidase enzyme activity can be measured in leukocytes or fibroblasts, which can confirm the diagnosis [7].

References

[1] A Mehta · 2023 - Diagnosis/testing. Identification of deficient α-Gal A enzyme activity in plasma, isolated leukocytes, and/or cultured cells is the most ...

[2] M Beck · 2013 - Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to ...

[6] M Beck · 2013 - Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to ...

[7] Deficiency in alpha-mannosidase enzyme activity as measured in fibroblasts or leukocytes; Molecular genetic testing confirms mutations in the MAN2B1 gene;

[10] An initial diagnostic workup may include a screening assay for several oligosaccharides in urine, OLIGU / Oligosaccharide Screen, Random, Urine.

[11] Diagnosis/testing. The diagnosis of alpha-mannosidosis is established in a proband by identification of deficiency of lysosomal enzyme acid alpha-mannosidase (typically 5%-10% of normal activity) in leukocytes or other nucleated cells AND/OR by the identification of biallelic pathogenic variants in MAN2B1 by molecular genetic testing.

Enzyme Replacement Therapy (ERT) for Alpha-Mannosidosis

Alpha-mannosidosis, a rare genetic disorder caused by alpha-D-mannosidase deficiency, has been treated with Enzyme Replacement Therapy (ERT). ERT involves administering the missing enzyme to patients to help restore normal cellular activity.

Velmanase Alfa: The First FDA-Approved Treatment

In 2023, the US FDA approved Lamzede (velmanase alfa), the first enzyme replacement therapy for the treatment of non-central nervous system manifestations of alpha-mannosidosis. Velmanase alfa is a recombinant human form of alpha-mannosidase that aims to reduce oligosaccharide levels in patients with alpha-mannosidosis [4][5][6].

Mechanism of Action

Velmanase alfa acts as the missing enzyme, restoring normal cellular activity by breaking down oligosaccharides. This helps alleviate symptoms and slow disease progression.

Clinical Trials and Approval

The approval of velmanase alfa was based on years of clinical trials demonstrating its efficacy in treating non-central nervous system manifestations of alpha-mannosidosis [5][6].

Expanded Access Program

For patients with severe or life-threatening forms of the disease, an Expanded Access program may be available to gain access to investigational medical products, including velmanase alfa.

Note: While ERT has shown promise in treating alpha-mannosidosis, it is essential to consult a healthcare professional for personalized advice and treatment plans.

The differential diagnosis for alpha-mannosidosis, an inherited lysosomal storage disorder, involves considering other conditions that may present with similar symptoms. Some of the key differential diagnoses include:

• Other lysosomal storage diseases: Such as mucopolysaccharidoses, which can also cause skeletal abnormalities, immune deficiency, and intellectual disability.
• Acute viral hepatitis: This condition can cause hepatosplenomegaly (enlargement of the liver and spleen), which may be similar to the symptoms seen in alpha-mannosidosis.
• EBV (Epstein-Barr Virus) infection: EBV can also cause hepatosplenomegaly, as well as other systemic symptoms such as fever and fatigue.
• CMV (Cytomegalovirus) infection: CMV can cause a range of symptoms including hepatosplenomegaly, and may be considered in the differential diagnosis for alpha-mannosidosis.
• Tropical diseases such as malaria: These conditions can also cause hepatosplenomegaly, and may need to be ruled out in patients with suspected alpha-mannosidosis.
• Malignancies such as leukemia or lymphoma: These conditions can also cause hepatosplenomegaly, and may need to be considered in the differential diagnosis for alpha-mannosidosis.

It's worth noting that the diagnosis of alpha-mannosidosis is typically made through a combination of clinical evaluation, laboratory tests (such as measuring acid alpha-mannosidase activity), and genetic testing. [9][10][11]

References: [9] - Context result 9 [10] - Context result 10 [11] - Context result 11