Acid Sphingomyelinase Deficiency (ASMD)

 

Meera Minnu Mohan

Lecturer, OBG, Holy Family Institute of Nursing Education, Mumbai.

 

ABSTRACT:

Acid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder that results from a deficiency of the enzyme acid sphingomyelinase, which is required to metabolize lipid called sphingomyelin. Consequently, sphingomyelin and other substances accumulate in various tissues of the body. ASMD is highly variable and the age of onset, specific symptoms and severity of the disorder can vary dramatically from one person to another, sometimes even among members of the same family. The disorder may be best thought of as a spectrum of disease. At the severe end of the spectrum is a fatal neurodegenerative disorder that presents in infancy (Niemann-Pick disease type A). At the mild end of the spectrum, affected individuals have no or only minimal neurological symptoms and survival into adulthood is common (Niemann-Pick disease type B). Intermediate forms of the disorder exist as well. ASMD is caused by mutations in the SMPD1 gene and is inherited in an autosomal recessive manner.

 

 

 

INTRODUCTION:

There are three disorders known as Niemann-Pick disease, types A, B, and C. These disorders were initially grouped together because of similar symptoms, but we now know that they are different diseases. NPD types A and B are due to mutations in the SMPD1 gene, which causes a deficiency of a specific enzyme, acid sphingomyelinase (ASM). NPD type C is due to mutations in one of two different genes and does not involve a deficient enzyme. NPD type C is now considered a separate disorder, distinct from Niemann-Pick disease types A and B. ASMD is also known as acid sphingomyelinase-deficient Niemann-Pick disease. ASMD has traditionally been broken down into two subgroups – neuronopathic (type A) and non-neuronopathic (type B). Neuronopathic refers to disorders that damage neurons.

 

Type A generally causes severe neurodegenerative disease during infancy, while type B is generally not considered to be a neurologic disease¹.

 

Classification:

Niemann-Pick disease (NPD), also called sphingomyelin-cholesterol lipidosis, is a group of autosomal recessive disorders associated with splenomegaly, variable neurologic deficits, and the storage of lipids including sphingomyelin and cholesterol. Niemann-Pick disease originally was defined in terms of its histology as a reticuloendotheliosis. It now is subdivided into two major categories:

 

Niemann-Pick disease type A (NPD-A) and type B (NPD-B) are allelic disorders caused by pathogenic variants in the sphingomyelin phosphodiesterase-1 gene (SMPD1), and characterized by a primary deficiency of acid sphingomyelinase activity. NPD-A is the severe, early-onset form, and NPD-B is the less severe, later-onset form. Some authors have proposed using the term acid sphingomyelinase deficiency to embrace the NPD-A and NPD-B disease spectrum.

Niemann-Pick disease type C is caused by pathogenic variants of the NPC1 and NPC2 genes that result in impaired cellular processing and transport of low-density lipoprotein (LDL) cholesterol and other macromolecules, including glycosphingolipids².

 

Causes:

Acid sphingomyelinase deficiency is caused by a mutation in the sphingomyelin phophodiesterase-1 (SMPD1) gene. The SMPD1 gene encodes an enzyme known as acid sphingomyelinase (ASM). A mutation in this gene leads to deficient levels of functional copies of the ASM enzyme. This enzyme is essential to metabolize certain lipids in the body. Reduced or absent activity of the ASM enzyme results in the abnormal accumulation sphingomyelin in various tissues of the body³.

 

Signs and Symptoms:

ASMD is a highly variable disorder, it is important to note that affected individuals will not have all of the symptoms described below and that every individual case is unique. Some children will develop severe, life-threatening complications early in life, others have mild disease that may go undiagnosed well into adulthood. Parents should talk to their child’s physician and medical team about the specific symptoms and overall prognosis⁴.

 

1) NIEMANN-PICK DISEASE TYPE A:

·       Hepatosplenomegaly, Ascites, Jaundice, Feeding problems, constipation, nausea, vomiting, significant gastrointestinal reflux, irritability, loss of reflexes, frequent vomiting

·       The accumulation of sphingomyelin in the lungs can result in recurrent respiratory infections and difficulty breathing, potentially resulting in life-threatening respiratory failure.

·       A cherry red spot affects the macula, which is the region of the retina that contains light-sensing cells necessary for central vision.

·       Affected infants may experience profound neurologic deterioration and increased muscle tone and stiffness of muscles (spasticity), and the disorder is often fatal by 3 years of age⁴.

 

2) NIEMANN-PICK DISEASE TYPE B:

·       Nystagmus, cerebellar signs includes unsteady manner of walking and clumsiness. Intellectual disability and psychiatric disorders, Abnormalities of the retina, Peripheral Neuropathy.

·       Dyspnea Recurrent pneumonia

·       Hepatosplenomegaly, Thrombocytopenia. Abdominal pain,Cirrhosis and Liver failure.

·       Delayed puberty,osteopenia, dyslipidemia, hypertriglyceridemia

·       Affected individuals may be at risk early coronary artery disease⁴.

 

Diagnosis:

A diagnosis of ASMD is based on:

·       Identification of characteristic symptoms

·       Detailed patient history

·       Thorough clinical evaluation and a variety of specialized tests⁵.

 

Clinical Testing and Workup:

·       Individuals suspected of ASMD will be tested to determine whether the activity of the enzyme, ASM, is reduced or absent.

·       Peripheral blood leukocytes

·       Cultured skin fibroblast

·       Molecular genetic testing can detect mutations in the SMPD1 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories⁵.

 

Standard Therapies:

The treatment of ASMD may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, hepatologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

·       Psychosocial support for the entire family is essential as well.

·       Genetic counseling may be of benefit for affected individuals and their families.

 

Niemann-Pick type A:

·       Physical and occupational therapy and periodic nutritional assessment may be recommended.

·       Ensuring proper nutritional intake may require the implantation of a feeding (gastronomy) tube. With this procedure, a thin tube is placed into the stomach via a small incision in the abdomen, allowing for direct intake of food and/or medicine.

·       The sleep issues associated with the disorder can be treated with nocturnal sedatives⁵.

 

Niemann-Pick type B:

·       Nutritional support is also encouraged for individuals with type B disease to guide sufficient high quality caloric intake, ensure proper calcium and vitamin D intake because of the risk of osteopenia, and reduce the risk of dyslipidemia in adults.

·       Blood transfusions may be required for individuals who experience prolonged bleeding due to thrombocytopenia.

·       Individuals with lung disease may require supplemental oxygen.

·       Individuals with an enlarged spleen are advised to avoid contact sports to prevent the spleen from rupturing.

·       Adults with hyperlipidemia should be treatment to correct cholesterol levels.

·       Liver transplantation has been reported in some adults with liver failure⁵

 

Resources:

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.

 

NORD Member Organizations⁵:

·       National Niemann-Pick Disease Foundation, Inc.

·       401 Madison Avenue

·       Suite B

·       Fort Atkinson, WI 53538-0049

·       Phone: (920) 563-0930

·       Toll-free: (877) 287-3672

·       Email: nnpdf@nnpdf.org

·       Website: http://www.nnpdf.org

 

Other Organizations⁵:

·       Genetic and Rare Diseases (GARD) Information Center

·       PO Box 8126

·       Gaithersburg, MD 20898-8126

·       Phone: (301) 251-4925

·       Toll-free: (888) 205-2311

·       Website: http://rarediseases.info.nih.gov/GARD/

·       gold, Global Organisation For Lysosomal Diseases

·       3 Albion Rd

·       Chalfont St Giles

·       Buckinghamshire, HP8 4EW United Kingdom

·       Phone: 441494870708

·       Email: enquiries@goldinfo.org

·       Website: http://www.goldinfo.org

·       Hide and Seek Foundation for Lysosomal Disease Research

·       6475 East Pacific Coast Highway Suite 466

·       Long Beach, CA 90803

·       Phone: (877) 621-1122

·       Email: info@hideandseek.org

·       Website: http://www.hideandseek.org

·       Instituto de ErroresInnatos del Metabolismo

·       Pontificia Universidad Javeriana Ed. Jesús Emilio

·       Ramírez (53) Laboratorios 305A - 303

·       Bogota, Colombia

·       Phone: (571) 320-8320

·       Email: abarrera@javeriana.edu.co

·       Website: http://www.javeriana.edu.co/ieim/programas_ieim.htm

·       Metabolic Support UK

·       5 Hilliards Court, Sandpiper Way

·       Chester Business Park

·       Chester, CH4 9QP United Kingdom

·       Phone: 0124420758108452412173

·       Email: contact@metabolicsupportuk.org

·       Website: https://www.metabolicsupportuk.org/

·       NIH/National Institute of Neurological Disorders and Stroke

·       P.O. Box 5801

·       Bethesda, MD 20824

·       Phone: (301) 496-5751

·       Toll-free: (800) 352-9424

·       Website: http://www.ninds.nih.gov/

·       Vaincre Les Maladies Lysosomales

·       2 Ter Avenue

·       Massy, 91300 France

·       Phone: 169754030

·       Email: accueil@vml-asso.org

·       Website: http://www.vml-as

 

REFERENCES:

1.     Irun P, Mallen M, Dominguez C, et al. Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B. Clin Genet. 2013;84:356-361. http://www.ncbi.nlm.nih.gov/pubmed/23252888

2.     https://rarediseases.org/rare-diseases/acid-sphingomyelinase-deficiency/

3.     http://www.uptodate.com/contents/overview-of-niemann-pick-disease

4.     Schuchman EH, Wasserstein MP. Types A and B Niemann-Pick disease. Best Pract Res Clin EndocrinolMetab. 2015;29:237-247. http://www.ncbi.nlm.nih.gov/pubmed/25987176

5.     https://rarediseases.org/rare-diseases/acid-sphingomyelinase-deficiency/

 

 

 

Received on 02.11.2020          Modified on 11.12.2020

Accepted on 05.01.2021      ©A&V Publications All right reserved